Solid forms containing (-)-o-desmethylvenlafaxine and use thereof. RU patent 2477269.

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of desmethylvenlafaxine of formula in form of a hydrochloride salt of a stereomerically pure compound which is suitable for treating, preventing or managing a disease selected from depression, pain, anxiety, incontinence or vasomotor symptoms caused by menopause. The crystalline form contains water in amount of about 4% to about 8% of the total weight of the sample, and molar ratio of the water to the hydrochloride salt is about 1:1, and the crystalline form has X-ray powder diffraction peaks at positions of about 12.7, 14.5, 19.1, 21.4, 23.0, 25.5 and 27.3°2θ, and is characterised by the following corresponding unit cell parameters measured at 150 K: a=6.78 A; b=9.29 A; c=27.65 A; α=90°; β=90°; γ=90°. The crystalline form is characterised by weight loss during thermal gravimetric analysis of about 4% to about 8%, primarily about 5.6% of the total weight of the sample when heated from about 25°C to about 110°C and endothermic effect during differential scanning calorimetry with onset temperature of the effect of about 50°C to about 125°C, primarily about 93°C. The crystalline form is non-hygroscopic at relative humidity from about 5% to about 85% and absolute form.

EFFECT: obtaining a compound which is suitable for treating, preventing or managing a disease selected from depression, pain, anxiety, incontinence or vasomotor symptoms caused by menopause.

20 cl, 58 dwg, 7 tbl, 18 ex

This application claims priority on the basis of the provisional application for patent of the United States 60/902950, registered on February 21, 2007, the contents of which are included in this description as a link in full.

1. THE TECHNICAL FIELD TO WHICH THE INVENTION RELATES

The present invention relates to solid forms containing net (-)-O-, including its salts, to compositions containing solid forms, methods of production of solid forms and the ways of their use for the treatment of various illnesses and/or disorders.

2. THE LEVEL OF TECHNOLOGY

Every pharmaceutical connection has optimal therapeutic concentrations in the blood and lethal concentration. Bioavailability connection determines the dose concentration in the medicinal product, necessary to achieve the right level in the blood. If the medicine may crystallize in the form of two or more crystalline forms, differing in bioavailability, the optimal dose will depend on the crystalline form, is present in a preparation. In the event of such medicines, there is a great distinction between therapeutic and lethal concentrations. Chloramphenicol-3-palmitate (CAPP), for example, is an antibiotic of a wide spectrum of action, which, as is known, it crystallizes at least three polymorphic crystal forms and one amorphous shape. The market sells the most stable form A. The biological activity of the specified and other forms differ in eight times, thus creating the possibility of fatal overdoses connection if accidentally injected connection in the form of B due to changes that occurred during the processing and/or storage. Therefore, the monitoring bodies such as the Administration of food and medicines of the USA, began to establish tight control over the content of polymorphic forms of the active component in the solid dosage forms. In General, for medicines that exist in the polymorphic forms, in case you need to sell the new drug, which is distinct from pure thermodynamically preferable , the Supervisory authority may require to carry out inspections of each party. Thus, it becomes important as medical, and commercial reasons receive and sell pure medicinal product in its most thermodynamically stable polymorphic form, is essentially not containing other kinetically preferable polymorphs.

New solid form pharmaceutical can contribute to the development of drugs to treat diseases. For example, in the pharmaceutical industry know that solid forms salts connection affect, for example, on the solubility, the rate of dissolution, bioavailability, chemical and physical stability, turnover, fragility and the ability to be pressing connection, as well as the safety and efficacy of medicinal products on the basis of such a connection (see, for example, Byrn, S.R., Pfeiffer, R.R., and Stowell, J.G. (1999) Solid-State Chemistry of Drugs, 2 nd ed., SSCI, Inc.: West Lafayette, IN).

Respectively, the identification of solid forms containing salt or free base connection with optimal physical and chemical properties, will contribute to progress in the development of connection in the form of pharmaceutical. Useful physical and chemical properties are reproducible receive, lack of hygroscopicity, water solubility, stability under the action of visible and ultraviolet radiation, low rate of decay in the conditions of high temperature and humidity, low speed isomerization between isomeric forms and safety in case of long-term administration of man. Often you want crystallinity, although in some cases profiles accelerated dissociation can be achieved as a result of obtaining amorphous forms.

O-, having the chemical name 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol, is a metabolite of connection venlafaxine, salt which is currently commercially available under the brand name Effexor®. Effexor®, the ratsemicheskuyu mixture (+) and (-)-enantiomer venlafaxine, is indicated for the treatment of depression. Racemic O- as an example in the form of salt in U.S. patent № 4535186, and and salts are described in the patents of USA № 6673838 and 7001920, respectively. Stereochemically net (-)-O- and its pharmaceutically acceptable salts are described in the patents of USA № 6342533 B1, 6441048 B1 and 6911479 B2.

The authors found that not all solid form, containing the (-)-O-, including its salts, equally applicable, if the value them above the list of properties. Thus, the present invention is directed on satisfaction of needs of improved solid forms containing the (-)-O-, for example, for the production and preparations.

3. THE ESSENCE OF THE INVENTION

The present invention relates to new solid forms, including amorphous and crystalline forms of the form containing the (-)-O- and its salts with practical application to treat, prevent or assist with the conditions and disorders, including, without limitation, affective disorders, such as depression, bipolar or manic disorders, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, weight increase, syndrome Gilles de La Tourette's syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome; disorder consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons, related disorders, and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).

In some versions of the solid forms are crystalline forms, including polymorphs, salts according to the invention. The invention also covers the water and waterless crystalline form to contain the (-)-O- and its salts. Without intending to limit any theory, suggest that such properties as stability during storage, the ability to be compressed, and bulk density solubility or solid forms are useful for the production, preparation and bioavailability (-)-O- and its salts. In some embodiments of the invention refers to the pharmaceutical compositions containing solid forms and methods of their application for treatment, prevention and/or assist with the conditions and disorders, including, without limitation, affective disorders, such as depression, bipolar or manic disorders, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, weight increase, syndrome Gilles de La Tourette syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome, a disorder of consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons, related disorders, and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).

In some versions of the connection and composition according to the invention applied for the treatment, prevention and/or assist with the above States and disorders, while reducing or eliminating adverse effects, including, without limitation, persistent hypertension, headache, asthenia, sweating, nausea, constipation, drowsiness, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred or altered vision and abnormal ejaculation/orgasm or impotence in men.

Solid forms obtained from the (-)-O-, which is described in the patents of USA № 6342533 B1, 6441048 B1 and 6911479 B2, which are incorporated into this description as a link in full. (-)-O- has the following structure (I):

In some embodiments, the present invention relates to crystalline salts (-)-O-. In other embodiments, the present invention relates to crystalline salts (-)-O-. In some versions of crystal salt (-)-O- have unexpected excellent properties, as detailed below. In some embodiments, the present invention relates to salts of hydrochloric acid and (-)-O-. In some embodiments, the present invention relates to salts (-)-O-. In some embodiments, the present invention relates to solvate salts (-)-O-. In some embodiments, the present invention relates to the hydrates salts (-)-O-. In some embodiments, the present invention relates to hydrates salts (-)-O-. In some embodiments, the present invention relates to an amorphous salts (-)-O-. In some embodiments, the present invention relates to an amorphous salts (-)-O-.

In some embodiments, the present invention relates to pharmaceutical compositions containing crystalline form, crystal salt form, salt forms, salt forms, salt hydrate form or amorphous salt form according to the invention and/or pharmaceutically acceptable diluent or media. In some embodiments, the present invention also relates to a method of treatment, prevention and/or assistance in case of one or more of the following conditions or disorders: affective disorders, such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and neurogenic bulimia, obesity, increase of the weight, syndrome Gilles de La Tourette's syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, Smoking cessation, drug addiction, mediated by the nervous system of sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, dementia, memory loss, amnesia/amnestic syndrome; disorders of consciousness, coma, disorders of speech, the syndrome Lennox, autism; with hyperkinetic syndrome, schizophrenia, migraines, obesity and increase of the weight, incontinence, chronic fatigue syndrome, sleep apnea, menopauzhnykh vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons related disorders and mental diseases described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), with such methods include introduction to the subject, for example, a person in need of such treatment, prevention and/or care, therapeutic and/or preventive efficient quantity of the solid form of the invention. The present invention also relates to a method of treatment, prevention or relief of conditions and disorders including, without limitation, affective disorders, such as depression, bipolar or manic disorders, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, weight increase, syndrome Gilles de La Tourette's syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome, a disorder of consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons related disorder and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), including introduction to the subject, such as a person in need of such treatment, prevention or care therapeutic or prophylactic efficient quantity of the solid form of the invention.

In some embodiments, the present invention relates to the methods of production, allocation and/or characteristics of the solid forms according to the invention.

Figure 3 presents powder x-ray sample containing form A most commonly available as hydrochloride salt (-)-O-.

Figure 4 presents the spectrum of infrared radiation for a sample containing form A most commonly available as hydrochloride salt (-)-O-.

Figure 5 presents a range of Raman scattering for the sample containing the shape of A most commonly available as hydrochloride salt (-)-O-.

Figure 6 presents the isotherm of adsorption of moisture for the sample containing the shape of A most commonly available as hydrochloride salt (-)-O-.

Figure 7 presents an asymmetric unit of crystal structure forms A, obtained by x-ray diffraction in single crystal sample containing form A most commonly available as hydrochloride salt (-)-O-.

On Fig.8 presents powder x-ray, modeled on the basis of the data of x-ray diffraction in single crystal obtained for the sample containing the shape of A most commonly available as hydrochloride salt (-)-O-.

Figure 9 presents thermogram thermal gravimetric analysis sample containing form B (most commonly available as hydrochloride salt (-)-O-.

Figure 10 presents thermogram of differential scanning calorimetry sample containing form B (most commonly available as hydrochloride salt (-)-O-.

Figure 11 presents powder x-ray sample containing form B (most commonly available as hydrochloride salt (-)-O-.

On fig.12 presents the spectrum of infrared radiation for a sample containing form B (most commonly available as hydrochloride salt (-)-O-.

On fig.13 presented Raman spectra of a sample containing form B (most commonly available as hydrochloride salt (-)-O-.

On figure 14 presents the isotherm of adsorption of moisture for sample containing form B (most commonly available as hydrochloride salt (-)-O-.

On fig.15 presents thermogram thermal gravimetric analysis of the sample containing the form C is most commonly available as hydrochloride salt (-)-O-.

On fig.16 presents thermogram of differential scanning calorimetry sample containing form C most commonly available as hydrochloride salt (-)-O-.

On fig.17 presents powder x-ray of the sample, containing a form C, the most commonly available as hydrochloride salt (-)-O-.

On fig.18 presents the spectrum of infrared radiation for a sample containing a form C, the most commonly available as hydrochloride salt (-)-O-.

On fig.19 presented Raman spectra of a sample containing a form with most commonly available as hydrochloride salt (-)-O-.

On fig.20 presents isotherm of adsorption of moisture for the sample, containing a form C, the most commonly available as hydrochloride salt (-)-O-.

On fig.21 presents thermogram thermal gravimetric analysis of the sample containing the form D most commonly available as hydrochloride salt (-)-O-.

On fig.22 presents thermogram of differential scanning calorimetry sample containing form D most commonly available as hydrochloride salt (-)-O-.

On fig.23 presents powder x-ray of the sample, containing a form D most commonly available as hydrochloride salt (-)-O-.

On fig.24 presents thermogram thermal gravimetric analysis of a sample containing a form E most commonly available as hydrochloride salt (-)-O-.

On fig.25 presents thermogram of differential scanning calorimetry sample containing form E most commonly available as hydrochloride salt (-)-O-.

On fig.26 presents powder x-ray of the sample, containing a form E most commonly available as hydrochloride salt (-)-O-.

On fig.27 presents the spectrum of infrared radiation for a sample containing a form E most commonly available as hydrochloride salt (-)-O-.

On fig.28 presented Raman spectra of a sample containing a form E most commonly available as hydrochloride salt (-)-O-.

On fig.29 presents isotherm of adsorption of moisture for the sample, containing a form E most commonly available as hydrochloride salt (-)-O-.

On fig.30 presents thermogram thermal gravimetric analysis sample containing a form F most commonly available as hydrochloride salt (-)-O-.

On fig.31 presents thermogram of differential scanning calorimetry sample containing a form F most commonly available as hydrochloride salt (-)-O-.

On fig.32 presents powder x-ray sample containing a form F most commonly available as hydrochloride salt (-)-O-.

On fig.33 presents powder x-ray, modeled on the basis of the data of x-ray diffraction in single crystal obtained for the sample containing the form F most commonly available as hydrochloride salt (-)-O-.

On fig.34 presents the spectrum of infrared radiation for a sample containing a form F most commonly available as hydrochloride salt (-)-O-.

On fig.35 presented Raman spectra of a sample containing a form F most commonly available as hydrochloride salt (-)-O-.

On fig.36 presents isotherm of adsorption moisture for a sample containing a form F most commonly available as hydrochloride salt (-)-O-.

On fig.37 presents asymmetric unit of the crystal structure of the form F obtained by x-ray diffraction in single crystal sample containing a form F most commonly available as hydrochloride salt (-)-O-.

On fig.38 presents thermogram thermal gravimetric analysis of the sample containing the form G most commonly available as hydrochloride salt (-)-O-.

On fig.39 presents thermogram of differential scanning calorimetry sample containing the form G most commonly available as hydrochloride salt (-)-O-.

On fig.40 presents powder x-ray sample containing the form G most commonly available as hydrochloride salt (-)-O-.

On fig.41 presents isotherm of adsorption of moisture for the sample containing the form G most commonly available as hydrochloride salt (-)-O-.

On fig.42 presents thermogram thermal gravimetric analysis of the sample containing the form H most commonly available as hydrochloride salt (-)-O-.

On Fig.43 presents thermogram of differential scanning calorimetry sample containing the form H most commonly available as hydrochloride salt (-)-O-.

On fig.44 presents powder x-ray sample containing the form H most commonly available as hydrochloride salt (-)-O-.

On fig.45 presents thermogram thermal gravimetric analysis sample containing a form I most commonly available as hydrochloride salt (-)-O-.

On fig.46 presents thermogram of differential scanning calorimetry sample containing a form I most commonly available as hydrochloride salt (-)-O-.

On fig.47 presents powder x-ray sample containing a form I most commonly available as hydrochloride salt (-)-O-.

On fig.48 presents powder x-ray sample containing form J most commonly available as hydrochloride salt (-)-O-.

On fig.49 presents powder x-ray of the sample, containing a form K most commonly available as hydrochloride salt (-)-O-.

On fig.50 presents powder x-ray, modeled on the basis of the data of x-ray diffraction in single crystal obtained for the sample containing the form K most commonly available as hydrochloride salt (-)-O-.

On fig.51 presents thermogram thermal gravimetric analysis of the sample containing the form L most commonly available as hydrochloride salt (-)-O-.

On fig.52 presents thermogram of differential scanning calorimetry sample containing the form L most commonly available as hydrochloride salt (-)-O-.

On fig.53 presents powder x-ray sample containing the form L most commonly available as hydrochloride salt (-)-O-.

On fig.54 presents powder x-ray sample containing relating to family 1 most commonly available as hydrochloride salt (-)-O-.

On fig.55 presents thermogram thermal gravimetric analysis sample containing amorphous form most commonly available as hydrochloride salt (-)-O-.

On fig.56 presents thermogram modulated differential scanning calorimetry sample containing amorphous form most commonly available as hydrochloride salt (-)-O-.

On fig.57 presents powder x-ray sample containing amorphous form most commonly available as hydrochloride salt (-)-O-.

On fig.58 presents isotherm of adsorption of moisture for sample containing amorphous form most commonly available as hydrochloride salt (-)-O-.

5. DETAILED DESCRIPTION OF THE INVENTION

5.1 DEFINITIONS

Used in this description of the meaning of the term «(-)-O-» means a compound, which has the chemical name (-)-1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol.

Used in this description of the meaning of the term «pharmaceutically acceptable salt» refers to salts obtained from pharmaceutically acceptable, relatively non-toxic acids, including inorganic acids and organic acids. Suitable acetic acid include, , benzojnuju, , coal, citric, , , , , gluconic, , glutamic, , hloristovodorodnuyu, , , , dairy, , malic, , almond, , , , , , nitric, , Pantothenic, phosphoric, , propionic, , amber, sulphuric acid, tartaric, , including p-, m- and o- acid, and similar (see, for example, Berge et al., J. Pharm. Sci., 66: 1-19 (1977); Stahl and Wermuth, Handbook of Pharmaceutical Salts, Wiley VCH, (2002)). Also included salts other relatively non-toxic compounds that have the properties of acids, including amino acids such as arginine and the like, and other compounds, such as aspirin, ibuprofen, saccharin and the like. Especially it is preferable to hydrochloric, Hydrobromic, and sulphuric acid, and the most preferable is the salt. Acid-additive salts can be obtained from the contact neutral form such compounds with sufficient required acid, either undiluted or in a suitable inert solvent. In the form of solids salt may exist in crystalline and/or amorphous modifications.

Specific salt, described below, include « salt», «salts of hydrochloric acid and HCl-salt» (-)-O- according to the invention. salt, salt hydrochloric acid HCl or Sol is an acid-additive salt, formed with the use of hydrochloric acid.

The term «solid forms» and related terms used in this description, unless otherwise stated, refer to crystalline and amorphous forms of forms containing the (-)-O-, and, in particular, includes crystalline and amorphous forms forms containing salt (-)-O-.

The term «crystal» and related terms used in this description when used to describe a substance, component or product, mean that the substance, component or product is crystalline, which is determined on the basis of x-ray diffraction. See, for example, Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23 rd ed., 1843-1844 (1995).

The term «crystal form» and related terms in the present description belong to different crystal modifications of the substance, including, without limitation, polymorphs, , hydrates, and other molecular complexes, as well as salt, salts, hydrates salts, other molecular complexes of salts and their polymorphs. Crystalline forms of matter can be obtained in several ways, which are known in this area. Such methods include, without limitation, recrystallization step of the melt cooling of the melt recrystallization step of the solvent, recrystallization step in a confined space, such as in nanopores or capillaries, recrystallization step on surfaces or matrices, such as, for example, polymers, recrystallization step in the presence of additives, such as, for example, , , dehydration, quick , quick cooling, slow cooling, the diffusion of vapor phase, sublimation, crushing and grinding with added dropwise solvent.

The terms «polymorphs», «polymorphic forms» and related terms in the present description refer to two or more crystalline forms, which consist of the same molecules, molecules, or ions. Different polymorphs may have different physical properties, such as, for example, the melting temperature, the heat of melting, solubility, dissolution and/or oscillatory spectra, as a result of the arrangement or conformation of molecules or ions in the crystal lattice (see, for example Byrn, S.R., Pfeiffer, R.R., and Stowell, J.G. (1999) Solid-State Chemistry of Drugs, 2 nd ed., SSCI, Inc.: West Lafayette, IN). Differences in physical properties exhibited by affect the pharmaceutical options, such as stability during storage, the ability to be compressed and density (important for the preparation of compositions and production of the product), and the rate of dissolution (important factor in terms of bioavailability). Differences in the stability can be the result of changes of the chemical activity (for example, different oxidation, so that the dosage form is faster in that case when contains one , compared with a form containing other ) or mechanical changes (for example, tablets crumble when stored as kinetically preferable becomes thermodynamically more stable ) or simultaneously changes the chemical activity and mechanical changes (for example, tablets, one more susceptible to fracture at high humidity). Due to differences in solubility/dissolution in an extreme situation some polymorphic transitions can lead to a loss of efficiency or other limiting case to toxicity. In addition, the physical properties of a crystal can be important for processing, for example, one may be more likely to form or may be difficult to filtered and laundering of impurities (i.e., the form and the particle size can be different in different polymorphs).

The term «» and «» used in the present description sense refers to the crystalline form of matter that contains a solvent. The term «hydrate» and «hydrated» refers to , in which water is the solvent. The term «polymorphs solvate» refers to the livelihoods of more than one crystal forms for a particular composition. Similarly, «polymorphs hydrates» refers to the livelihoods of more than one crystal forms for a particular hydrated composition.

The term « » used in the present description sense refers to the crystalline form of matter that can be obtained removal of solvent from .

The term « family» used in the present description sense refers to a series of two or more crystalline forms of substances, which have structural similarities, including approximately similar the interplanar distances in the crystal lattice. (A more detailed account of the lattices can be found in chapters 2 and 3 in the work of the Stout and Jensen, X-Ray Structure Determination: A Practical Guide, MacMillan Co., New York (1968)). Thanks to the structural similarity of representatives family crystalline form is typically have similar but not necessarily identical powder x-rays. In the basis of of the family may be a substance which represented a neutral molecule, salt or molecular complex. A series may consist of solvate, including hydrates, and crystalline forms of matter in the form of solvate. Solvated representatives family crystalline forms usually contain one or more solvents, including water, in the crystal lattice. Solvent or solvents in the crystal lattice can be solvent or solvents for crystallization used in the production of crystalline form. Conventional solvents used for crystallization includes water and all classes of organic and other types of laboratory solvents, including, without limitation, alcohols such as methanol, ethanol, n-propanol, isopropyl, n-butanol, sec-butanol, tert-butanol, hydroxyphenyl, glycerin, and similar; solvents, such as acetone, methyl ethyl ketone, formic acid, acetic acid, ethyl acetate, butyl acetate, N,N-dimethylformamide and the like; hydrocarbons such as pentane, hexane, cyclohexane benzene, toluene, and the like; halogenated solvents, such as dichloromethane, chloroform, carbon tetrachloride, and the like; and laboratory solvents, containing other heteroatoms and/or functional groups such as acetonitrile, tetrahydrofuran, diethyl ether, diisopropyl ether, carbon disulfide, dimethyl sulfoxide, 1,4-dioxane, nitrobenzene, nitromethane, pyridine and the like.

The term «amorphous», «amorphous form» and related terms used in this description, means that the considered material, substance, component or product is crystalline, which is determined on the basis of x-rays. Amorphous forms of matter can be obtained in several ways, which are known in this area. Such methods include, without limitation, heating, cooling of the melt, the rapid cooling of the melt evaporation the solvent, the rapid evaporation of the solvent, , sublimation, grinding, krioizmelchenie and drying freezing.

Ways characteristics of the crystalline forms and amorphous forms include, without limitation, thermal gravimetric analysis (TGA), differential scanning (DSK), powder x-ray (XRPD), x-ray single crystals, oscillatory spectroscopy, such as infrared (IR) spectroscopy and spectroscopy of Raman scattering, solid state NMR, optical microscopy, high-temperature optical microscopy, scanning electron microscopy (SEM), e-crystallography and quantitative analysis, particle size analysis (PSA), analysis square surface, solubility studies and research dissolution.

Used in this description of sense, and unless otherwise noted, the terms «about» and «about» when used in connection with doses, number or mass percentage of ingredients composition or the dosage form, the mean dose, number or mass percentage, which, as understandable to specialists in the field, provide pharmacological effect is equivalent to the action, received from the use of a particular dose, quantity or weight percent. In particular, the terms «about» and «about» when used in this context, refers to the dose, the number or mass percentage in the range of 15%, 10%, 5%, 4%, in the range of 3%, 2%, 1% or 0,5% from a particular dose, quantity or weight percent.

Used in this description of sense, and unless otherwise noted, the term « pure» means a composition that contains one stereoisomer connection and essentially contains no other stereoisomers this connection. For example, net composition connection having one chiral center, essentially will not contain the opposite enantiomer connection. net composition connection having two chiral center on the merits will not contain other diastereoisomers connection. In some versions of net connection contains more than 80 percents of one stereoisomer connections and less than about 20 percents other stereoisomers of compound, more than about 90 percents of one stereoisomer connections and less than about 10 percents other stereoisomers of compound, more than 95 percents of one stereoisomer connections and less than approximately 5 mass percent other stereoisomers of compound, more than approximately 97 percents one stereoisomer connections and less than approximately 3 mass% other stereoisomers or more than about 99 percents one stereoisomer connections and less than approximately 1 mass percentage of other stereoisomers of compound.

Used in this description of sense, and unless otherwise noted, the term «enantiomerically pure» means clean composition connection having one chiral center.

Used in this description of sense to describe the connection of the term «substance not containing his (+)-stereoisomer» means that the connection consists of a much larger proportion of (-)-stereoisomer than of its optical antipode (i.e. (+)-stereoisomer). In some cases, according to the invention of the term «essentially does not contain his (+)-stereoisomer» means that the connection is, at least, about 90% of the mass. from his (-)-stereoisomer and about 10% of the mass. or less of their (+)-stereoisomers. In some cases, according to the invention of the term «essentially does not contain his (+)-stereoisomer» means that the connection is, at least, approximately 95% of the mass. from his (-)-stereoisomer and about 5% of the mass. or less of their (+)-stereoisomers. In some embodiments, the term «essentially does not contain his (+)-stereoisomer» means that the connection is, at least, approximately 99% of the mass. from his (-)-stereoisomer and about 1% or less of their (+) stereoisomer. In some embodiments, the term «essentially does not contain his (+)-stereoisomer» means that the connection consists of approximately 100% of the mass. from his (-)-stereoisomers. The above percentages based on the total number of the United stereoisomers of compound. All the terms on the merits of optically pure (-)-O-», «optically pure (-)-O-» and «(-)isomer O-» refers to the (-)-O-, which essentially does not contain his (+)-stereoisomers. All the terms on the merits of optically pure (-)-O-», «optically pure (-)-O-» and «(-)isomer O-» refers to the (-)-O-, which essentially does not contain his (+)-stereoisomers.

Used in this description of the sense of the crystalline or amorphous form, which is «clean», i.e. essentially contains no other crystalline or amorphous form, contains less than about 10% of the mass. one or more other crystalline or amorphous forms of less than about 5% by mass. one or more other crystalline or amorphous forms, less than approximately 3% of the mass. one or more other crystalline or amorphous forms, or less than approximately 1% of the mass. one or more other crystalline or amorphous forms.

Used in this description of sense, and unless otherwise noted, composition, which essentially contains no» connection means that the composition contains less than about 20% of the mass., less than about 10% of the mass., less than about 5% by mass., less than approximately 3% of the mass. or less than approximately 1% of the mass. the connection.

Used in this description of sense, and unless otherwise noted, the terms «treat», «the process of treatment» and «treatment» refers to the elimination or the weakening of the disease or disorder or one or more of the symptoms associated with the disease or disorder. In some versions of the terms refer to minimize the spread of or worsening of the disease or a disorder resulting from the introduction of one or more preventive or therapeutic drugs to a patient with this disease or disorder. In some versions of the terms refer to the introduction of the connection, proposed in the invention together or without other optional active funds after the onset of symptoms of a particular disease.

Used in this description of sense, and unless otherwise noted, the terms «prevent», «preventing» and «prevention» refers to prevent, recurrence or spread of a disease or a disorder or one or more of their symptoms. In some versions of the terms refer to treatment using the connection or the introduction of a connection, proposed in the present invention, whether with or without other additional active connection before symptoms appear, especially in patients at risk of the disease or disorder specified in this description. The terms cover the suppression or symptom reduction of specific diseases. In particular, in some versions patients with the disease in the family history are candidates for the application of preventive schemes. In addition, patients who have a history of recurrent symptoms are also potential candidates for prevention. In this sense, the term «prevention» may be used interchangeably with the term «preventive treatment».

Used in this description of sense, and unless otherwise noted, the terms «assistance», «assistance» and «disease management» refers to prevent or slow progression, distribution or worsening of the disease or disorder or one or more of its symptoms. Often useful effects that the patient receives preventive and/or therapeutic agent, does not lead to cures for diseases or disorders. In this context, the term «assistance» covers the treatment of a patient who has had the disease, in order to try to prevent or minimize the recurrence of the disease.

Used in this description of the meaning of the term «affective disorder includes depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar or manic state and the like. The terms «attention deficit disorder» (ADD) and attention deficit hyperactivity disorder» (ADDH) disorder or attention deficit/hyperactivity disorder (AD/HD) is used in the present description in accordance with the adopted values that are listed in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association (1997) (DSM-IV(TM).

Used in this description of the meaning of the term «method of treatment of depression» means the weakening of the symptoms of depression, which, without limitation, include changes in mood, feeling of deep sadness, despair, decrease the speed of thinking, lack of concentration, pessimistic mood, agitation and self-deprecation. Can also be physical changes, including insomnia, anorexia, weight loss, decreased energy and sexual function, and abnormal hormonal circadian rhythms.

Used in this description of the meaning of the term «a method of treatment, prevention or assist with obesity or increase of the mass» means the mass reduction or prevention or getting rid of excess weight, regain weight or obesity; all these symptoms are generally the result of overeating.

Used in this description of the meaning of the term «a method of treatment, prevention or relief disorders, inhibition of reuptake neurons» means to prevent or get rid of the symptoms of pathological conditions associated with abnormal levels of monoamines in the neurons; such symptoms are reduced by inhibiting the reuptake neurons. Monoamines, reuptake which inhibited compounds or compositions according to the present invention, include, without limitation, norepinephrine (or norepinephrine), serotonin and dopamine. Disorders, which are treated by inhibiting the reuptake neurons, include, without limitation, Parkinson's disease and epilepsy.

Used in this description of the meaning of the term «a method of treatment, prevention or assist with Parkinson's disease» means to prevent or get rid of the symptoms of Parkinson's disease, which include, without limitation, slow progressing impaired ability to purposeful movement, tremor, , rigidity and posture problems in humans.

The terms «obsessive-compulsive-impulsive disorder, substance abuse, «premenstrual syndrome», «anxiety», «eating disorders» and «migraine» used in the present description in accordance with their adopted in the field values. See, for example DSM-IV (TM). The terms «a method of treatment, prevention or relief», «a method of treatment», «way to prevent» and the «way of helping» when used in connection with such disorders means weakening, prevention or elimination of symptoms and/or effects associated with these disorders. Without intending to be limited and on any theory, they believed the treatment, prevention or assistance in some of these disorders may be associated with the activity of the active ingredient(s) as inhibitors takeover serotonin.

Used in this the description of the meaning of the term «a method of treatment, prevention or assist with incontinence» means to prevent or get rid of the symptoms of incontinence, including involuntary discharge of the faeces or urine, and drip selection or leakage or feces or urine, which may be attributed to one or more cases, including, without limitation, pathology, changing the control of the sphincter, loss of cognitive function, bladder, and/or involuntary relaxation urethra, muscle weakness associated with bladder, or neurologic disorders.

Used in this description of sense, and unless otherwise noted, «therapeutically effective amount» connection is the number sufficient to ensure therapeutic value in treating or assisting an illness or disorder, or to slow or minimize one or more of the symptoms associated with the disease or disorder. Therapeutically effective amount of coupling means the quantity of a therapeutic agent, separately or in combination with other therapeutic agents, that provides therapeutic benefit in the treatment or assistance in case of illness or disorder. The term «therapeutically effective amount» may cover a number, which improves the General therapy, reduces or eliminates the symptoms or cause of the disease or disorder or enhances therapeutic effectiveness of the other therapeutic means.

Used in this description of sense, and unless otherwise noted, «preventative effective number of connections is the number sufficient to prevent disease or a disorder or prevent its recurrence. Oseltamivir effective number of connections means the quantity of a therapeutic agent, separately or in conjunction with other tools, which provides prevention benefit in case of prevention of the disease. The term «preventative effective number» may cover a number, which improves the overall prevention or enhances the prophylactic effectiveness of the different preventive measure.

It is implied that the term «composition» used in the present description sense covers product containing specific ingredients (and in specific amounts, if specified), and also a product that is directly or indirectly the result of a combination of specific ingredients in specific quantities. Under the «pharmaceutically acceptable» imply that thinner, or media must be compatible with the other ingredients of the drug and not be dangerous for the recipient.

The term «therapeutic and/or preventive effective number» refers to the amount of the solid form, which will cause the biological or medical reply tissue, systems, animal or human, which is seeking a researcher, a veterinarian, doctor or other health worker, or which is sufficient to prevent the development or weakening to some extent one or more symptoms of the disease being treated.

The term «entity», in the present description defined as a term that includes animals such as mammals, including, without limitation, primates (e.g. humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and similar. In a particular subject is man.

In some versions of the compounds according to the present invention can also contain isotope atoms in not found in the nature of ratios of one or more atoms. For example, a connection can be labeled with radioactive and/or non-radioactive isotopes, such as, for example, deuterium ( 2 H), tritium ( 3h), iodine-125 ( 125 I), sulphur-35 ( 35 S), carbon-13 ( 13 C) or carbon-14 ( 14 C). Radioactively labelled compounds applicable as therapeutic tools, such as anticancer therapeutics, reagents for research, for example, reagents for analysis binding, and diagnostic tools, for example, tools for visualization in vivo . You should assume that everything isotopic connection options according to the present invention, or radioactive or non-radioactive, included in the scope of the present invention.

5.2 OPTIONS for carrying out the INVENTION

In some embodiments, the present invention relates to solid forms containing net (-)-O- and its salts, including their solvated and hydrated form, and the amorphous form, and to compositions containing solid form alone or in combination with other active ingredients, to methods of their application to treat, prevent, and/or assist with the conditions and disorders, including, without limitation, affective disorders such as depression, bipolar or manic disorders, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, weight increase, syndrome Gilles de La Tourette's syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome, a disorder of consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons, related disorders, and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Without intent to be bound to any particular theory, suggest that stability during storage, the ability to resist compression, density or properties solubility of solid forms are useful for the production, preparation of compositions and bioavailability according to the present invention.

In one embodiment, the condition or disorder is affective disorder. In other variant of a condition or disorder is a depression. In other variant of a condition or disorder is an anxiety disorder. In other variant of a condition or disorder is a disorder of brain function. In other variant of a condition or disorder is a fibromyalgia. In other variant of a condition or disorder is a pain. In other variant of a condition or disorder is a neuropathic pain.

In some versions of the solid forms according to the invention, are forms which are characterized by physical properties, for example, stability, solubility and dissolution rate, suitable for clinical and therapeutic dosage forms. Some solid forms according to the invention, based on physical properties, for example, the morphology of the crystals, the ability to be compressed and hardness, suitable for the production of solid dosage forms. Such properties can be defined using methods such as the x-ray diffraction, electron microscopy, infrared spectroscopy and thermal analysis, which are described in this publication and are known in this area.

5.2.1 Salt net (-)-O-

In one embodiment, the present invention relates to a specific pharmaceutically acceptable salts (-)-O- applicable to treat, prevent or assist with the conditions and disorders, including, without limitation, affective disorders, such as depression, bipolar or manic disorders, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, weight increase, syndrome Gilles de La Tourette's syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome, a disorder of consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons, related disorders, and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM - IV).

In some embodiments, the present invention relates to salts net (-)-O-. As shown above, (-)-O- is one of General formula (I):

In salts (-)-O- acid is an acid formula HCl.

Preferred salt hydrochloric acid and (-)-O- is salt, represented by formula (II):

Each salt according to the invention may be obtained from the drug net (-)-O- or additive salts (-)-O-. (-)-O- can be synthesized or obtained by any method known experts in this field. In the preferred options (-)-O- receive according to the methods set forth in the examples below, in patents of USA № 6342533 B1, 6441048 B1 and 6911479 B2, which are incorporated into this description as a link in full.

In some versions of (-)-O- obtained in any way, may be subject to contact with a suitable acid, either undiluted or in a suitable solvent to get salt according to the invention. For example, (-)-O- may be subject to contact with hydrochloric acid to get salt according to the invention.

In some versions of the additive salts (-)-O- gathered in any manner known in this area may be subject to contact with a suitable acid, either undiluted or in a suitable solvent to get salt according to the invention. For example, salt acid and (-)-O- may be subject to contact with hydrochloric acid to get salt according to the invention.

As shown below, some forms containing salt (-)-O- are excellent properties of stability, solubility and hygroscopicity compared with other forms containing the (-)-O-.

5.2.2 Solid forms containing net (-)-O- and its salts

In one embodiment, the present invention relates to form A crystalline form most commonly available as hydrochloride salt (-)-O- ( salt (-)-1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol). In particular, form A is a crystalline form salt (-)-O-. In some versions of the sample crystalline form of A most commonly available as hydrochloride salt (-)-O- has a water content in the range from about 4% to about 8% of the total mass of the sample. In some versions of the form has A water content of approximately 6% of the total mass of the sample, that is approximately one molar equivalent of water per mole (-)-O-. In some embodiments, the study of using titration according to the Karl Fischer method according to the methods described in this publication, form A has a water content of approximately 5.7% of the mass. In the following variants form A has thermal gravimetric analysis, similar to a thermogram, shown in figure 1. In particular, studies using thermal gravimetric analysis according to the methods described in this publication, form And is characterized by weight loss, corresponding to about 5.6% of the total mass of the sample, which occurs approximately between 25 and 110 C. In some versions of the form And has differential scanning calorimetry, such thermogram, shown in figure 2. In some ways, in the case of research with the help of differential scanning calorimetry according to the methods described in this publication form And is characterized by an endothermic effect with the temperature effect beginning at about 93 C. In some versions of the form And in the form of a crystalline form of the most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in figure 3, obtained using Cu K-radiation. In some versions of the crystal shape And the most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in Fig.8, which was designed for Cu K-radiation using the data of x-ray analysis of the monocrystal obtained for the form A. In some cases, specific crystalline form A according to the invention, are the main peaks of the powder x-ray about 12,7, 14,5, 19,1, 21,4, 23,0, 25,5, 27,3 °2 in case of use of Cu K-radiation. In some embodiments, the crystalline form And according to the invention has the main peaks of the powder x-ray in the first, second, third, fourth, fifth, sixth or seventh position on the powder x-ray about 12,7, 14,5, 19,1, 21,4, 23,0, 25,5, 27,3 °2 in case of use of Cu K-radiation. In some embodiments, the crystalline form And according to the invention is characterized by a water content of approximately 5.7% of the total mass of the sample and is the main peaks of the powder x-ray in the first, second, third, fourth, fifth, sixth or seventh position on the powder x-ray about 12,7, 14,5, 19,1, 21,4, 23,0, 25,5, 27,3 °2 in case of use of Cu K-radiation. In some embodiments of the invention, the form And has the spectrum of infrared radiation, similar to the spectrum shown in figure 4. In some embodiments of the invention, the shape And has a range of Raman scattering of light, similar to the spectrum shown in figure 5. In some ways, in the case of research about 150 K according to the mode, which allows to determine the parameters of elementary cell, for example, x-ray diffraction by crystals, form And has the following model parameters elementary lattice: a=6,78 & A; b=9,29& c=27,65 & A; a=90 C; & beta=90 C; g=90 C; V=1741,39 & 3 . In some versions of the form And crystallizes in the space group P2 1 2 1 2 1 .

Not limited to a particular theory, found that the crystalline form most commonly available as hydrochloride salt (-)-O- has excellent properties of hygroscopicity. For example, not limited to a particular theory, the study of dynamic sorption from the vapor phase according to the methods described in this publication, the form has A weight gain of less than <1% increase in the relative humidity of a sample from 5% to 90%. In addition, weight gain form as A function of the relative humidity is reversible, so that, for example, a sample loses approximately 1% of the mass while reducing the relative humidity of 90% to 5%. In some versions of the crystal form of A described in this publication has isotherm of adsorption of moisture, such isotherm, shown in figure 6.

In addition, not limited to a particular theory, found that the crystal form of A most commonly available as hydrochloride salt (-)-O- also has excellent stability properties.

Form A is most commonly available as hydrochloride salt (-)-O- can be obtained in any way of obtaining the shape of A well-known specialists in this field, on the basis of the information given in this description, the instruction. In some cases, A shape can be obtained by crystallisation most commonly available as hydrochloride salt (-)-O- of systems of solvents containing one or more solvents such as, without limitation, water, acetone, acetonitrile, ethanol, isopropanol, methanol, methyl ethyl ketone, methyl tert-butyl ether, heptane, , toluene and their mixtures. In some cases, A shape can be obtained as a result of the transition process between the crystal forms from another crystalline or amorphous form most commonly available as hydrochloride salt (-)-O-, for example, as a result of indirect solvent and/or indirect water process of transition between forms.

In another embodiment, the present invention relates to the form B, the crystalline form of salt (-)-O-, which contains a solvent tetrahydrofuran (THF) in the crystal lattice. In some versions of the THF is present in the approximate ratio of 0.25 molar equivalents THF mole most commonly available as hydrochloride salt (-)-O-. In units of mass is equal to the content of the THF, constituting approximately 6% of the total mass of a sample form B. In some versions of the content of the THF in the form of B is in the range from about 4% to about 8% of the total mass of a sample form B. In some versions of the form B has thermal gravimetric analysis similar to thermogram, shown in figure 9. In some variations in the study of thermal gravimetric analysis according to the methods described in this publication, form B is characterized by weight loss, corresponding to approximately 5.7% of the total mass of the sample, which occurs approximately 25 to 180 C. In some embodiments, the crystalline form B has differential scanning calorimetry, such thermogram, shown in figure 10. In some variations in the study of differential scanning calorimetry according to the methods described in this publication, form B is characterized by an endothermic effect with temperatures begin the effect approximately 176°C and other endothermic effect with temperatures begin the effect approximately 199 C. In some versions of form B is characterized by additional endothermic effect with the temperature peak approximately 160 degrees C. In some versions of crystal form B most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in figure 11, when using Cu-K-radiation. In some versions of crystalline form B according to the invention, are the main peaks of powder x-rays about 13,1, 14,7, 18,8, 21,1, 24,2, 26,3, 29,4 °2 when using Cu K-radiation. In some versions of crystal form B according to the invention has the main peaks of the powder x-ray in the first, second, third, fourth, fifth, sixth or seventh position on the powder x-ray about 13,1, 14,7, 18,8, 21,1, 24,2, 26,3, 29,4 °2 in case of use of Cu K-radiation. In some versions of crystal form B according to the invention, contains content THF, constituting approximately 6% of the total mass of the sample, and the main peaks of the powder x-ray in the first, second, third, fourth, fifth, sixth or seventh position on the powder x-ray about 13,1, 14,7, 18,8, 21,1, 24,2, 26,3, 29,4 °2 in case of use of Cu K-radiation. In some versions of the form B has the spectrum of infrared radiation, similar to the spectrum shown in fig.12. In some versions of crystal form B according to the invention has Raman spectra of a similar range to that shown in fig.13. In some embodiments of the invention, the form B has isotherm dynamic sorption from the vapor phase, such isotherm, shown in figure 14. In some variations in the study of dynamic sorption from the vapor phase according to the methods described in this publication, form B has a weight gain of about 25%, increasing the relative humidity from 5% to 95%, with the subsequent loss of mass of approximately 26% at a lower relative humidity 95% to 5%.

Form B, most commonly available as hydrochloride salt (-)-O- can be obtained in any way for the form B, known experts in this field, on the basis of the instructions in this description. In some versions of the form B can be obtained by crystallization from solutions most commonly available as hydrochloride salt (-)-O- in THF.

In another embodiment, the present invention relates to the form C, the crystalline form of salt (-)-O- that contains one or more solvents - ethyl acetate, ethyl ester and water in the crystal lattice. In particular variant of ethyl acetate is present in the approximate ratio of 0.2 molar equivalent of ethyl mole most commonly available as hydrochloride salt (-)-O-. In units of mass is equal to the content of ethyl acetate approximately 6% of the total mass of a sample form C. In particular variant ethyl ester is present in the approximate ratio of 0.2 molar equivalent of ethyl ether mole most commonly available as hydrochloride salt (-)-O-. In units of mass is equal to the content of ethyl ether approximately 5% of the total mass of a sample form C. In particular variant of the total content of ethyl acetate, ethyl ester and water is in the range from about 3% to about 8% of the total mass of a sample form C. In some versions of the form C has thermal gravimetric analysis, similar to a thermogram shown in fig.15. In some variations in the study of thermal gravimetric analysis according to the methods described in this publication, form C is characterized by weight loss, corresponding to approximately 5.1% of the total mass of the sample, which comes from about 25 to about 110 C. In some versions of crystal form C has differential scanning calorimetry, similar to a thermogram shown in fig.16. In some variations in the study of differential scanning calorimetry according to the methods described in this publication, form C is characterized by an endothermic effect with temperatures begin the effect of approximately 84 degrees C, other endothermic effect with the temperature peak approximately 136 C and other endothermic effect with temperatures begin the effect approximately 167 C. In some embodiments, the crystalline form C most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.17 obtained from the use of Cu K-radiation. Specific crystalline form C according to the invention, are the main peaks of the powder x-ray about 5,8, 11,7, 14,7, 18,8, 21,0, 21,2 °2 in the case of the use of alpha radiation. In some versions of crystal form C according to the invention has the main peaks of the powder x-ray in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 5,8, 11,7, 14,7, 18,8, 21,0, 21,2 °2 in case of use of Cu K-radiation. In some versions of crystal form C according to the invention has a total content of ethyl acetate, ethyl ester and water, taking about 3% to about 8% of the total mass of the sample, and the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 5,8, 11,7, 14,7, 18,8, 21,0, 21,2 °2 in case of use of Cu K-radiation. In some versions of crystal form C has the spectrum of infrared radiation, similar to the spectrum shown in fig.18. In some versions of crystal form C according to the invention has a range of Raman scattering of light, similar to the spectrum shown in fig.19. In some embodiments of the invention, the form C has isotherm dynamic sorption from the vapor phase, similar to shown in fig.20. In some variations in the study of dynamic sorption from the vapor phase according to the methods described in this publication, form C has a weight gain of approximately 27% when the relative humidity 5% to 95%, with the subsequent loss of mass by about 27% at a lower relative humidity 95% to 5%.

Form C most commonly available as hydrochloride salt (-)-O- can be obtained in any way for the form C, known to specialists in the field, on the basis of the instructions in this description. In some versions of the form C can be obtained by crystallization from solutions most commonly available as hydrochloride salt (-)-O- in ethyl acetate, ethyl ether, water, mixture of two or more of these solvents, or so forth.

Form D most commonly available as hydrochloride salt (-)-O- can be obtained in any way receipt of form D, well-known specialists in this field, on the basis of the instructions in this description. In some versions of the form D may be obtained by crystallization from solutions most commonly available as hydrochloride salt (-)-O- of the IPA.

In one embodiment, the present invention relates to a form E, the crystalline form of salt (-)-O-, which contains methyl tert-butyl ether (MTBE) and/or water in the crystal lattice. In one embodiment, a sample of crystalline form E most commonly available as hydrochloride salt (-)-O- has a total content of MTBE and water in the range from about 4% to about 10% of the total mass of the sample. In some versions of crystal form E is the content of MTBE approximately 6% of the total mass of the sample, which is equal to approximately 0.2 molar equivalents MTBE mole (-)-O-. In some versions of the form E has thermal gravimetric analysis, similar to a thermogram shown in fig.24. In some variations in the study of thermal gravimetric analysis according to the methods described in this publication, form E is characterized by weight loss of about 5.9% from the total mass of the sample, which occurs in the range from about 25 to about 180 C. In some versions of the form E has differential scanning calorimetry, similar to a thermogram shown in fig.25. In some variations in the study of differential scanning calorimetry according to the methods described in this publication, form E is characterized by an endothermic effect with the temperature effect beginning at about 93°C followed by an endothermic effect with temperatures begin the effect approximately 167 C. In some versions of the crystal form of E most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.26 obtained from the use of Cu K-radiation. Specific crystalline form E according to the invention, are the main peaks of the powder x-ray about 5,8, 11,9, 13,0, 14,4, 18,5, 20,9 °2 in case of use of Cu K-radiation. In some versions of the crystal form of E according to the invention has the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 5,8, 11,9, 13,0, 14,4, 18,5, 20,9 °2 in case of use of Cu K-radiation. In some versions of the crystal form of E according to the invention has the solvent content in the range from about 4% to about 10% of the total mass of the sample and the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 5,8, 11,9, 13,0, 14,4, 18,5, 20,9 °2 using Cu K-radiation. In some versions of the crystal form of E according to the invention has the spectrum of infrared radiation, similar to the spectrum shown in fig.27. In some versions of the crystal form of E according to the invention has a range of Raman scattering of light, similar to the spectrum shown in fig.28. In some embodiments of the invention, the form E has isotherm dynamic sorption from the vapor phase, similar to shown in fig.29. In some variations in the study of dynamic sorption from the vapor phase according to the methods described in this publication, form E has a net gain in weight of about 4.7% when the relative humidity 5% to 95%, with the subsequent loss of mass by an estimated 5.8% at a lower relative humidity 95% to 5%.

E form most commonly available as hydrochloride salt (-)-O- can be obtained in any way for the form E, well known to specialists in the field, on the basis of the instructions in this description. In some versions of the form E can be obtained by dissolving the solid form containing salt (-)-O-, solvent or solvent mixtures containing, for example, methanol and water, with the subsequent crystallization conducted with the addition of , such as methyl tert-butyl ether.

In one embodiment, the present invention relates to a form F, hydrated crystalline form salt (-)-O-. In one embodiment, the invention sample crystalline form F most commonly available as hydrochloride salt (-)-O- has a water content in the range from about 4% to about 8% of the total mass of the sample. In some versions of the crystal form of F has a water content of approximately 6% of the total mass of the sample, which is approximately one molar equivalent of water per mole (-)-O-. In some embodiments of the invention, the form F has thermal gravimetric analysis, similar to a thermogram shown in fig.30. In some variations in the study of thermal gravimetric analysis according to the methods described in this publication, form F is characterized by weight loss, corresponding to approximately 5.8% of the total mass of the sample, which occurs in the range from about 25 to about 125 C C. In some embodiments of the invention, the form F has differential scanning calorimetry, similar to a thermogram shown in fig.31. In some variations in the study of differential scanning calorimetry according to the methods described in this publication, form F is characterized by an endothermic effect with the temperature effect beginning at about 89 C. In some embodiments, the crystalline form F most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.32. In some versions of crystal form F most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.33, which is designed for Cu K-radiation using the data of x-ray analysis of the monocrystal, obtained in the case of forms F. Specific crystalline form F according to the invention, are the main peaks of the powder x-ray about 14,4, 16,0, 17,4, 19,0, 25,5, 26,8 °2 in case of use of Cu K-radiation. In some versions of crystal form F according to the invention has the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 14,4, 16,0, 17,4, 19,0, 25,5, 26,8 °2 when using Cu K-radiation. In some versions of crystal form F according to the invention has a water content of approximately 6% of the total mass of the sample and the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 14,4, 16,0, 17,4, 19,0, 25,5, 26,8 °2 when using Cu K-radiation. In some versions of crystal form F according to the invention has the spectrum of infrared radiation, similar to the spectrum shown in fig.34. In some versions of crystal form F according to the invention has a range of Raman scattering of light, similar to the spectrum shown in fig.35. In some embodiments of the invention, the form F has isotherm dynamic sorption from the vapor phase, similar to shown in fig.36. In some variations in the study of dynamic sorption from the vapor phase according to the methods described in this publication, form F is characterized by the growth of the mass of approximately 32% when the relative humidity 5% to 95%, with the subsequent loss of mass by approximately 33% at a lower relative humidity 95% to 5%. In some ways, in the case of the analysis of about 173 K according to the mode, which lets you to determine the unit cell parameters, such as diffraction of x-rays in a single crystal form F has the following unit cell parameters: a=9,29 & A; b=PC 6.82& c=13,91 & A; a=90 C; & beta=92,58 degrees; g=90 C; V=879,95 & 3 . In some versions of the form F crystallizes in the space group P2 1 .

Form F most commonly available as hydrochloride salt (-)-O- can be obtained in any way for the form F, known experts in this field, on the basis of the instructions in this description. In some versions of the form F can be obtained by dissolving the solid form containing salt (-)-O-, in the mixture of solvents containing, for example, methanol and water, with the subsequent crystallization pursued by adding , such as methyl tert-butyl ether.

In one embodiment, the present invention relates to a form of G, the crystalline form of salt (-)-O-. In one embodiment, a sample of crystalline form G most commonly available as hydrochloride salt (-)-O- has a water content in the range from 0% to 6% of the total mass of the sample. In some versions of the crystal form of G has a water content of approximately 3% of the total mass of the sample, which is equal to approximately 0.5-molar equivalent of water per mole (-)-O-. In some versions of the form G has thermal gravimetric analysis, similar to a thermogram shown in fig.38. In some variations in the study of thermal gravimetric analysis according to the methods described in this publication, form G is characterized by weight loss, corresponding to approximately 3.0% of the total mass of the sample, which occurs in the range from approximately 25 to approximately 125 C. In some versions of the form G has differential scanning calorimetry, similar to a thermogram shown in fig.39. In some variations in the study of differential scanning calorimetry according to the methods described in this publication, form G is characterized by an endothermic effect with temperatures begin the effect approximately 91 C. In some embodiments, the crystalline form G most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.40 obtained using Cu K-radiation. Specific crystalline form G according to the invention have characteristic peaks of powder x-ray about 12,6, 15,1, 16,7, 18,8, 21,0, 25,3 °2 in case of use of Cu K-radiation. In some versions of the crystal form of G according to the invention has the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,6, 15,1, 16,7, 18,8, 21,0, 25,3 °2 using Cu K-radiation. In some versions of the crystal form of G according to the invention has a water content of approximately 0 to 6% of the total mass of the sample and the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,6, 15,1, 16,7, 18,8, 21,0, 25,3 °2 using Cu K-radiation. In some embodiments of the invention form G has isotherm dynamic sorption from the vapor phase is similar to shown in fig.41. In some variations in the study of dynamic sorption from the vapor phase according to the methods described in this publication, form G is characterized by the growth of the mass of about 3% when the relative humidity from 5% to 90%. In some variations in the study of dynamic sorption from the vapor phase according to the methods described in this publication, form G is characterized by the growth of the mass of approximately 23% when the relative humidity 5% to 95% and the loss of mass by approximately 22% while the relative humidity of 95% to 5%.

Form G most commonly available as hydrochloride salt (-)-O- can be obtained in any way for the form G, known experts in this field, on the basis of the instructions in this description. In some versions of the form G is produced as a result of drying of crystalline form A according to the present invention described above and in the examples below, above the appropriate agent for drying, such as, for example, P 2 O 5 .

In another embodiment, the present invention relates to the form I, the crystalline form of salt (-)-O-, which contains a solvent isopropanol in the crystal lattice. In particular variant isopropanol is present in the form I in the approximate ratio of 0.2 molar equivalent of isopropanol mole most commonly available as hydrochloride salt (-)-O-. In units of mass is equal to the content of isopropanol approximately 4% of the total mass of a sample form I. In some versions of isopropanol content in the form of I is running from approximately 2% to about 6% of the total mass of a sample form I. In some versions of the form I has thermal gravimetric analysis, similar to a thermogram shown in fig.45. In some variations in the study of thermal gravimetric analysis according to the methods described in this publication, form I is characterized by weight loss, corresponding to about 4.2% of the total mass of the sample, which occurs in the range from about 25 to about 180°C. In some versions of crystal form I has differential scanning calorimetry, similar to a thermogram shown in fig.46. In some variations in the study of differential scanning calorimetry according to the methods described in this publication, form I is characterized by an endothermic effect with the temperature peak approximately 178 degrees C. In some versions of the form I is characterized by additional endothermic effect with the temperature peak approximately 158 degrees C. In some versions of crystal form I most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.47, which is obtained using Cu K-radiation. Specific crystalline form I according to the invention, are the main peaks of the powder x-ray about 13,0, 14,6, 18,7, 21,0, 23,5, 26,2 °2 in case of use of Cu K-radiation. In some versions of crystal form I according to the invention has the main peaks of the powder x-ray in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 13,0, 14,6, 18,7, 21,0, 23,5, 26,2 °2 in case of use of Cu K-radiation. In some versions of crystal form I according to the invention has isopropanol content of about 4% of the total mass of the sample and the main peaks of the powder x-ray in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 13,0, 14,6, 18,7, 21,0, 23,5, 26,2 °2 in case of use of Cu K-radiation.

Form I most commonly available as hydrochloride salt (-)-O- can be obtained any way to get the forms I, well-known specialists in this field, on the basis of the instructions in this description. In some versions of the form I can be obtained by sedimentation from the solution most commonly available as hydrochloride salt (-)-O- in isopropanol with subsequent filtering. In some versions of the form I can be obtained quick solution most commonly available as hydrochloride salt (-)-O- in isopropanol.

In another embodiment, the present invention relates to the form J, the crystalline form of salt (-)-O-, which contains a solvent acetonitrile in the crystal lattice. In particular variant acetonitrile is present in the form of J in the approximate ratio of 0.2 molar equivalent of an mol most commonly available as hydrochloride salt (-)-O-. In units of mass is equal to the content of acetonitrile approximately 3% of the total mass of a sample form J. In some versions of the content of acetonitrile in the form J ranges from about 1% to about 5% of the total mass of a sample form J. In some embodiments, the crystalline form J is most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.48 obtained using Cu K-radiation. Specific crystalline form J according to the invention, are the main peaks of the powder x-ray about 12,2, 14,7, 16,9, 18,8, 21,0, 23,7 °2 in case of use of Cu K-radiation. In some versions of crystal form J according to the invention has the main peaks of the powder x-ray in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,2, 14,7, 16,9, 18,8, 21,0, 23,7 °2 in case of use of Cu K-radiation. In some versions of crystal form J according to the invention, contains content acetonitrile approximately 3% of the total mass of the sample and the main peaks of the powder x-ray in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,2, 14,7, 16,9, 18,8, 21,0, 23,7 °2 in case of use of Cu K-radiation.

In another embodiment, the present invention relates to the form K, the crystalline form of salt (-)-O-, which contains ethanol solvent in the crystal lattice. In some versions of the ethanol content in the form of K is less than approximately 13% of the total mass of the sample of the form K, which is less than about one molar equivalent of ethanol per mole most commonly available as hydrochloride salt (-)-O-. In some versions of the crystal form of K most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.49. In some versions of the crystal form of K most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.50, which is designed for Cu K-radiation according to the methods described in this publication, using the data of x-ray structural analysis of single-crystal obtained for the form K. Specific crystalline form K according to the invention, are the main peaks of the powder x-ray about 12,1, 13,1, 14,6, 18,7, 21,0, 21,2 °2 in case of use of Cu K-radiation. In some versions of the crystal form of K according to the invention has the main peaks of the powder x-ray in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,1, 13,1, 14,6, 18,7, 21,0, 21,2 °2 in case of use of Cu K-radiation. In some versions of the crystal form of K according to the invention has the ethanol content less than approximately 13% of the total mass of the sample and the main peaks of the powder x-ray in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,1, 13,1, 14,6, 18,7, 21,0, 21,2 °2 in case of use of Cu K-radiation. In some cases, when analyzing approximately 173 K according to the mode, which lets you to determine the unit cell parameters, for example in the study of x-ray diffraction on monocrystal, the form K has the following unit cell parameters: a=30,06 & A; b=7,74& c=21,21 & A; a=90 C; & beta=134,50 degrees; g=90 C; V=3517,7 & 3 . In some versions of the form K crystallizes in the space group C2.

Form K most commonly available as hydrochloride salt (-)-O- can be obtained in any way for the form K, well-known specialists in this field, on the basis of the instructions in this description. In some versions of the form K may be obtained by crystallization from solution most commonly available as hydrochloride salt (-)-O- in the system solvents ethanol/acetone.

In another embodiment, the present invention relates to a form of L, the crystalline form of salt (-)-O-, which contains a solvent 2- in the crystal lattice. In particular option 2- is present in the form of L in the approximate ratio from 0.1 to 0.3 molar equivalent of 2- mole most commonly available as hydrochloride salt (-)-O-. In units of mass is equal to the contents of the 2- approximately 3% to 8% of the total mass of sample forms of L. In some versions of contents 2- in the form of L is from about 1% to about 10% of the total mass of sample forms of L. In some versions of the form L is thermal gravimetric analysis, similar to a thermogram shown in fig.51. In some variations in the study of thermal gravimetric analysis according to the methods described in this publication form L is characterized by weight loss, corresponding to approximately 2% of the total mass of the sample, which occurs in the range from about 25 to about 125 C and weight loss of about 7% of the total mass of the sample, which occurs in the range from about 25 to about 180 C. In some versions of the crystal form of L has differential scanning calorimetry, similar to a thermogram shown in fig.52. In some variations in the study of differential scanning calorimetry according to the methods described in this publication form L is characterized by an endothermic effect with temperatures begin the effect approximately 166 C. In some versions of the crystal form of L most commonly available as hydrochloride salt (-)-O- has a powder x-ray, similar to that shown in fig.53 obtained from the use of Cu K-radiation. Specific crystalline form L according to the invention, are the main peaks of the powder x-ray about 12,0, 13,0, 14,5, 18,8, 21,0, 23,4 °2 in case of use of Cu K-radiation. In some versions of the crystal form of L according to the invention has the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,0, 13,0, 14,5, 18,8, 21,0, 23,4 °2 in case of use of Cu K-radiation. In some versions of the crystal form of L according to the invention has contents 2- from about 1% to about 10% of the total mass of the sample and the main peaks of powder x-rays in the first, second, third, fourth, fifth or sixth position on the powder x-ray about 12,0, 13,0, 14,5, 18,8, 21,0, 23,4 °2 in case of use of Cu K-radiation.

In another embodiment, the present invention relates to crystalline forms containing salt (-)-O-, who are representatives of family crystalline forms. Representatives of specific family crystalline forms have some structural similarity with other representatives of the family on the basis of grounds such as, for example, the interplanar distances in the crystal lattice. Structural similarity between representatives of specific family leads to the appearance of some of the General characteristics of these crystalline forms, for example, representatives of family crystalline forms containing salt hydrochloric acid and (-)-O- have similar powder x-rays. Each representative of this family crystalline forms contains one or more types of organic solvents and/or water in the crystal lattice, or alternatively can be a . Preferred solvents for inclusion in the crystal lattice of a representative of a family crystalline forms containing salt hydrochloric acid and (-)-O- are routine laboratory organic solvents and water. In other variants the invention refers to the representatives of family crystalline forms containing salt hydrochloric acid and (-)-O-, representing a . is formed when the crystal lattice of one or more types of solvents and/or water; as a result of crystalline form as solvate not have a significant amount of solvent or water in the crystal lattice. Removing solvents may include drying, heating and/or the methods based on the application of vacuum, as well as other methods known to specialists in the field.

In one embodiment, the invention relates to the crystalline forms containing salt (-)-O- relating to family 1. In some embodiments of the invention representatives families 1 selected from the group consisting of the B shape, form C, form H, I, form J, forms K and forms of L. In some embodiments of the invention representative families 1 crystalline forms of the characteristic peaks of powder x-ray about 5,8, 13,0, 14,6, 18,7, 21,1, 26,3 °2 in case of use of Cu K-radiation. In some embodiments of the invention representative families 1 crystalline forms containing salt hydrochloric acid and (-)-O- has one, two, three, four, five or six of characteristic peaks in powder x-ray in the provisions of the approximately 5.8, KZT13.0, 14,6, 18,7, 21,1 and 26.3 °2 in case of use of Cu K-radiation. Solvents for inclusion in the crystal lattice representative families 1 crystalline forms containing salt hydrochloric acid and (-)-O- include, without limitation, tetrahydrofuran, ethyl acetate, ethyl ether, acetone, isopropanol, acetonitrile, ethanol, water, and combinations thereof. Some embodiments of the invention belong to the representative families 1 crystalline forms containing salt hydrochloric acid and (-)-O-, which is a crystalline form as . In some versions of relating to family 1, can be obtained by removing any of the above solvents of crystal lattice of any and/or hydrated representative of the crystalline forms family 1. In some versions of solvents (ethyl acetate, diethyl ether and/or water are removed from the crystal lattice of the form C (crystal form of HCl-salt (-)-O- described in this publication) by using heat to get , being the representative of family 1. In some versions of , who is representative of the families 1, has a picture of a XRPD, similar to that shown on fig.54 obtained using Cu K-radiation.

In another embodiment, the invention relates to the crystalline forms containing salt (-)-O- relating to family of 2. In some embodiments of the invention representatives family 2 selected from the group consisting of forms E and forms of L. In some embodiments of the invention crystal form, which is representative of the family 2, the characteristic peaks of powder x-ray approximately of 11.9, KZT13.0, 14.4V, 18,5 and 20.9 °2 in case of use of Cu K-radiation. In other variants of realization of the invention crystal form most commonly available as hydrochloride salt (-)-O-, which is representative of the family 2 has one, two, three, four or five of characteristic peaks in powder x-ray in the provisions about 11,9, KZT13.0, 14.4V, 18,5, and 20.9 °2 in case of use of Cu K-radiation. Solvents for inclusion in the crystal lattice representative family 2 crystalline forms containing salt hydrochloric acid and (-)-O- include, without limitation, methyl tert-butyl ether, 2-, water, and combinations thereof. Some embodiments of the invention include crystalline form solvate, who are representatives of family 2. In some versions of crystalline form as solvate, who are representatives of family 2, are formed in the and/or dehydration of crystalline form, which is representative of the family 2.

In some embodiments, the present invention relates to an amorphous forms containing the (-)-O- and its salts, especially to treat, prevent or assist with the conditions and disorders, including, without limitation, affective disorders, such as depression, bipolar and manic disorder, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, weight increase, syndrome Gilles de La Tourette's syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome, a disorder of consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons, related disorders, and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Amorphous forms according to the invention may be obtained according to the method of obtaining the (-)-O- described in this publication. Specific options include amorphous form, contains either a free base or salt (-)-O-. In some versions of the amorphous form of the invention are amorphous forms containing pharmaceutically acceptable salt (-)-O-.

Amorphous form most commonly available as hydrochloride salt (-)-O- can be obtained in any way, well-known specialists in this field to obtain an amorphous form, on the basis of the instructions in this description. The specific options for carrying out the invention crystalline form most commonly available as hydrochloride salt (-)-O- dissolved in a solvent or solvent, such solvents as acetonitrile, isopropanol, ethyl acetate, ethanol, methanol, or the like, which are then evaporated, receiving amorphous form of the invention. In some versions of the solid form, containing HCl-salt (-)-O-, dissolved in a suitable solvent or solvents, for example in water, then subjected to drying freezing out, getting amorphous form of the invention. In some embodiments, hydrate, or waterless crystalline form HCl-salt (-)-O-, such as, for example, form A, heated to a temperature above its temperature dehydration, or melting, receiving amorphous form of the invention.

In some embodiments of the invention, the offers of the mixture, including physical mixture and/or solid solutions of solid forms containing the (-)-O- or its salts. In some of the options offered a mixture of solid forms containing salt (-)-O-. In some of the options offered mixtures containing amorphous shape HCl-salt (-)-O- with one or more crystalline forms HCl-salt (-)-O-. In some of the options offered a mixture containing two or more, three or more, four, five, or six, or more solid forms HCl-salt (-)-O- containing approximately 0,1%, 0,5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99,5% or 99.9% amorphous forms HCl-salt (-)-O-. In some of the options offered a mixture containing two or more, three or more, four, five or six or more crystalline forms HCl-salt (-)-O-, for example, a mixture containing form A and form F HCl-salt (-)-O-. In some of the options offered a mixture containing two or more, three or more, four, five or six or more crystalline forms HCl-salt (-)-O- containing approximately 0,1%, 0,5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99,5% or 99.9% of the same shape, for example, form A HCl-salt (-)-O-. In some of the options offered solid solution of crystalline forms HCl-salt (-)-O-, when analyzing mixtures reveal the characteristic structural characteristics (for example, lattice parameters, position of peaks XRPD and/or one or more solvents for the crystallization of two or more, three, four, or more, five or six or more crystalline forms, who are representatives of a particular family crystalline forms, for example, family 1.

5.2.3. Composition

The present invention relates to pharmaceutical compositions to treat, prevent or assist with the conditions and disorders, including, without limitation, affective disorders, such as depression, bipolar or manic disorders, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, the increase in mass, syndrome Gilles de La Tourette's syndrome Shay-, Alzheimer's disease, Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome, a disorder of consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms, such as hot flashes, disorders, inhibition capture monoamine neurons, related disorders, and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Songs include one or more of crystalline forms and/or amorphous forms according to the present invention, and a pharmaceutically acceptable diluent or media. In some cases, pharmaceutical composition according to the invention, contains pure crystalline or amorphous form of salt (-)-O-. For example, pharmaceutical composition according to the invention may contain a clean form A, monohydrate salt of hydrochloric acid and (-)-O-.

Pharmaceutical compositions for the introduction of the crystalline or amorphous forms according to the present invention, for convenience, can be represented in the standard dosage form and can be obtained by any method known in the field of pharmacy. All methods include the stage of receipt of the Association of the active ingredient with the medium, which consists of one or more auxiliary ingredients. In General, pharmaceutical compositions receive as a result of creation of uniform and homogeneous mixture of active ingredients with liquid carrier or solid carrier or both specified carriers, and then, if necessary, by molding product with obtaining of the required preparation. The pharmaceutical composition of the crystalline or amorphous form included in the quantity sufficient to produce a desired effect in the case of the process, condition or disease, exposed to treatment, prevention or control.

You can use any suitable way of introduction to the patient receives the treatment and/or prophylaxis effective dose of the active ingredient according to the present invention. For example, the present invention includes the standard formulations suitable for oral administration, the introduction of a mucous membrane (e.g. nasal, , vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous bolus injections, intramuscular or intraarterial) or transdermal the introduction of the patient. Examples dosage forms include, without limitation, pills, tablets capsules; capsules, such as gelatin or soft elastic gelatinous capsules; wafers; lozenges; cakes; dispersion; suppositories; ointment; poultices (lotion); pasta; powders; dressings; creams; plasters; solutions; stickers; aerosols (e.g., nasal spray or inhaler); gels, liquid dosage forms, suitable for oral administration, or entry through the mucous membrane of the patient, including suspension (for example, aqueous or non-aqueous liquid suspensions, emulsii type «oil-in-water or liquid emulsion type «water-in-oil»)solutions and elixirs; liquid standard formulations suitable for parenteral administration to the patient; and sterile solids (e.g. crystalline or amorphous solids that may be affected for production of liquid dosage forms, suitable for parenteral administration to the patient.

In the practical implementation of the active ingredient can be combined in the form of a uniform mixture with pharmaceutical carrier according to the usual methods of preparation of pharmaceutical compounds. The media can have a broad variety of forms depending on the form of the preparation required for the introduction. In the case of preparation of compositions standard for oral dosage form you can use any regular pharmaceutical environment as media such as water, glycols, oils, alcohols, , preservatives, dyes and the like in the case of oral liquid products (such as suspensions, solutions and elixirs) or aerosols; or you can use devices such as starches, sugar, microcrystalline cellulose, thinners, means moving substances, connecting substances and agents, in the case of solid oral drugs, preferably without the use of lactose. For example, a suitable media include powders, capsules and tablets, solid oral drugs are preferable in comparison with liquid drugs.

Composition, form and type of dosage forms according to the invention can normally vary depending on their application. For example, dosed form used for urgent treatment of the disease, can contain large amounts of one or more active ingredients it contains, what dosage form used for the chronic treatment of this condition. Similarly, parenteral dosage form may contain smaller amounts of one or more active ingredients it contains than oral dosage form used to treat the same disease. These and other ways, depending on which specific dosage forms, proposed in the present invention will vary, can easily identify experts in the field. See, for example, Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton PA (1990).

5.2.3.1. Oral dosage forms

Pharmaceutical compositions of the invention which are suitable for oral administration may be represented in the form of discrete dosage forms, such as, without limitation, tablets, chewable tablets in the form of capsules, capsule, and liquid (for example, flavored syrups). Such dosage forms contain pre-defined number of active ingredients and can be obtained ways pharmacy, well-known experts in the given area. In General, see Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton PA (1990).

Pharmaceutical compositions and dosage forms according to the invention can be used funds or sliding substances. For production of pharmaceutical compositions or dosage forms according to the present invention, in addition to therapeutic medicinal ingredients, may be required or supplements, including, without limitation, thinners, linking tools, sliding substances products, dyes, , sweeteners, and similar or their mixture. As a result of inclusion in the composition of these and other additives can be obtained in a variety of dosage forms (e.g. tablets, capsules, tablets in the form of capsules, pastilles, and the like). Such forms include, for example, hard capsules, tablets, capsules, coated with sugar tablets, tablets with coating to slow the action, repeatedly pressed tablets, tablets prolonged action, pills to obtain a solution, effervescent tablets, bukkalnye and sublingual tablets, lozenges, and the like.

Thus, the standard dosage forms or metered-dose drug pharmaceutical composition according to the present invention, such as , tablet or capsule, can be formed by the unification of the required quantity of each of the active ingredients with one or more pharmaceutically compatible or acceptable , which are described below, in farmatsevticeski compatible quantities to get a standard drug required amount of each active ingredient. Dosage form or metered-dose drug can be obtained ways, well-known in this field.

Tablets are often the preferred dosage form due to the benefits to the patient (for example, the accuracy of batching, compactness and portability, the softness of taste and simplicity of administration)and the producer (e.g., simplicity and cost-effectiveness of receipt, stability, and ease of packaging, transportation and distribution). Tablets are solid pharmaceutical dosage forms, containing therapeutic drugs with suitable or without additives.

Tablets are usually receive casting, pressing or by conventional methods molding tablets. Accordingly, the pressed tablets are usually receive ways large-scale production, while the cast tablets often receive using operations on a small scale. For example, there are three General ways to obtain tablets: (1) the method damp a granulating; (2) a way to dry a granulating and (3) direct pressing. These methods are well known to specialists in the field. See, for example, Remington's Pharmaceutical Sciences, 16 th and 18 th eds., Mack Publishing Co., Easton, Pa. (1980 and 1990). See also U.S. Pharmacopeia XXI, U.S. Pharmacopeial Convention, Inc., Rockville, Md. (1985).

A variety of drugs in pill form may be obtained according to the present invention. Such drugs include tablets dosage forms, such as coated with sugar tablets, film coated tablets, tablets with coating, repeatedly pressed tablets, tablets prolonged action and the like. Covered with sugar pills (SCT) are extruded tablets have a coating of sugar. Such coatings can be painted and useful for the creation of coverings of medicinal substances that have an unpleasant taste or smell and for the protection of substances that are sensitive to oxidation. Coated film tablets (FCT) are extruded tablets, which are covered with a thin layer or film from a water-soluble material. You can use a variety of polymeric compounds with the ability of a layer formation properties. Film coating gives the same General features as a sugar coating, while providing the added advantage of a substantial decrease in the period of time necessary for the implementation of the coating. Tablets with coating also suitable for use in the present invention. Tablets with coating (ECT) are extruded tablets, coated with substances that are resistant to dissolution in gastric juice, but destroyed in the gut. Enteric coated can be used for tablets containing medicinal substances, which are inactivated or destroyed in the stomach, tablets, which irritate the mucous membrane, or as a means to achieve long-term release of the medicinal product.

Repeatedly pressed tablets (MCT) are extruded pills obtained using more than one cycle of pressing, such as layered tablets or coated tablets, received pressing. Layered tablets obtained by pressing additional granulated weight of tablets on previously pressed granulated mass. The operation can be repeated to obtain multilayered tablets, consisting of two, three or more layers. Usually for reception layered tablets requires special presses for tablets. See, for example, US patent # 5213738 included in this description as a link in full.

Covered by pressing tablets are another form repeatedly pressed pellets. Such pills, also known as tablets, coated by dry method, receiving, downloading the previously pressed tablets in machine and exposing pressing another layer of granulated material from the pre-laminated tablets. These pills have all the advantages of CT, i.e. the possibility for application of notches, monograms, the rate of decay etc. while maintaining the signs covered with sugar pills in relation to the masking of taste of medicinal substance in the core of the pills. Covered by pressing pills may also be used for separation of incompatible medicinal substances. In addition, they can be used to obtain cover core tablets. Both types of tablets (i.e. layered tablets tablets, coated pressing) can be used, for example, when you create a dosage forms long-acting according to the present invention.

Pharmaceutical compositions or standard dosage forms according to the present invention, in the form of tablets prolonged action may constitute pressed tablets, prepared for the liberation of medicinal substances in a way to ensure the availability of medicinal product during a certain period of time. There are several types of tablets, which include tablets delayed action, in which the liberation of medicinal substances is prevented during a certain time interval after the introduction or until there are certain physiological conditions. Can be obtained pills repetitive action that periodically release the full dose of medicinal substances in liquid gastrointestinal tract. Can also be obtained pills delayed the release, which continuously release additional portions located in them medicinal substances in liquid gastrointestinal tract.

To get drugs or therapeutic ingredients according to the present invention, with or without excipients in the form of solid dosage forms (tablets) with the use of pressure, using existing equipment, it is necessary that substance, or in the crystalline or amorphous form, had a range of physical properties. Such properties may include, for example, the ability to free turnover, in the form of powder ability to stick together during consolidation and the ability to easily be extracted from the equipment. Because many of the substances does not possess such properties or possess only some properties have been developed the methods of preparation and receipt of pills to give these required properties of the substance, that need to be pressed into tablets or similar dosage forms.

As indicated, except for medicines or therapeutic ingredients tablets and similar dosage forms can contain a number of substances called or supplements. Such additives are classified in accordance with the role which they play in the preparation dosage forms, such as a tablet, a tablet in the form of capsules, capsule, or the like. One group of additives include, without limitation, linking tools, thinners (fillers), funds, sliding substances and surfactants. In one embodiment, the thinner linking tool, tool and moving tool are not one and the same substance.

Connecting means reasonable for use in metered drugs, obtained according to the present invention, include, without limitation, corn starch, potato starch or other starch, gelatin, natural and synthetic gums, such as the Arabian gum, sodium alginate, alginic acid, other alginates, powdery gum, guar gum, cellulose and its derivatives (for example, , cellulose acetate, calcium-, sodium carboxymethylcellulose), polivinilpirrolidon (povidone), methylcellulose, starch, (such as # 2208, 2906, 2910), cellulose or their mixture. Suitable forms of microcrystalline cellulose may include, for example, a substance sold as AVICEL PH-101, AVICEL PH-103 and AVICEL PH-105 (available FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa., U.S.A.).

Napolniteli, or thinners used to produce powder mass (for example, in tablet or capsule) in order to obtain an acceptable size pills, capsules or other required dosage forms. Usually therapeutic ingredients are dosed in a convenient form suitable size thanks to include a diluent. As in the case of binding of funds may occur linking of medicinal products (tools) with filler and affect the bioavailability. Therefore, you must use a sufficient amount of filler to achieve the desired dilution without adverse effects on liberation of medicinal ingredients from the dosage form containing filler. Furthermore, use the filler, which is physically and chemically compatible with therapeutic ingredient(s) dosage forms. The amount of filler used varies depending on the type of drug and a way of introduction and can easily be determined by experts in the field. Examples of fillers include, without limitation, lactose, glucose, sucrose, fructose, talc, a carbonate of calcium (for example, granules, or powder), pulp powder pulp, , kaolin, mannitol, acid, sorbitol, starch, starch or of a mixture.

tools are used to cause the disintegration of dosage forms (e.g. tablets) when exposed to water environment. Too many funds will result in tablets, which can be destroyed in a bottle due to the effects of atmospheric moisture. Too small number may be insufficient to a disintegration and can therefore change the speed and degree of liberation of medicinal product (means) or of the active ingredient(s) from the dosage form. Thus, to obtain dosage forms according to the present invention, you should use a sufficient amount of funds, which are not too large to adversely modify the release of ingredients of the medicinal product. The amount of funds varies depending on the type of drug and a way of introduction and can easily be determined by a specialist in this field. Examples tools include, without limitation, an agar-agar, alginic acid, calcium carbonate, cellulose, sodium , crospovidone, sodium, sodium starch, potato starch or tapioca starch, other starches, starch, clay, other , other cellulose, gum, or their mixture.

In the case where you want dosed form that quickly dissolved at introduction to the subject, for example, in the stomach of the subject, you can use tool such as, without limitation, sodium croskar or sodium starch glycolate. The term « tool» used in this sense means the description of tool that leads to the rapid disintegration of the medicinal product, or an active ingredient in the stomach after oral administration. Use tools may contribute to the rapid absorption of a drug or active ingredient(s)that may result in a more rapid onset of action.

As indicated, moving substance use in order to increase the flow of powder mixture for tabletirovanija at machine and prevent sticking tablets to the mold after pressing tablets. A very small number of moving matter will not get satisfactory pills, but too much can result in tablets with waterproof hydrophobic coating, which can be formed because the sliding substances are usually hydrophobic substances, for example, stearic acid, magnesium stearate, calcium stearate, and the like. In addition, waterproof hydrophobic coating can inhibit the dispersion of the tablets and suspension of ingredient(s) of the medicinal product. Therefore, you should use a sufficient amount of sliding substances which will ensure the free release of the pressed tablets from the mold without education waterproof hydrophobic coating, which has the undesirable effect of interfering with the desired disperse and/or dissolution of ingredient(s) of the medicinal product.

Examples of suitable sliding substances for the application of the present invention include, without limitation, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, etiloleat, ethyl laurate, agar or mixture of them. Additional sliding substances include, for example, silica gel (AEROSIL 200, production W.R. Grace Co. of Baltimore Md.), aerosol synthetic silicon dioxide (sold Deaussa Co. of Piano, Tex.), CAB-O-SIL ( product silicon dioxide, selling Cabot Co. of Boston, Mass.) or their mixture.

Surfactants are used in dosage forms for the improvement of wetting and/or strengthening of dissolution, and such substances are particularly useful in the case of pharmaceutical compositions or dosage forms containing poorly soluble or insoluble medicinal product(a) or active ingredients. Examples of surface-active substances include, without limitation, esters and fatty acids, such as ether, commercially available under the name twins (for example, the twin 20 and tween 80), polyethylene glycols, stearaty , polyvinyl alcohol, polivinilpirrolidon, block-copolymers of poly()/poly(), such as (for example, commercially available as PLURONIC), and block copolymers obtained as a result of successive addition of propylene oxide and ethylene oxide to , such as (for example, commercially available as TETRONIC (BASF)), acid, lecithin, sodium salt of complex dialkyl ethers acids, such as aerosol OT, sodium lauryl sulfate, sulfonates polyesters or alcohols, such as Triton X-200 or , p-() (for example, Olin-10G or surfactant 10-G (Olin Chemicals or their mixture. Other pharmaceutically acceptable surfactants are well known in this area and described in detail in the Handbook of Pharmaceutical Excipients, 4 th ed., Pharmaceutical Press, London, UK and American Pharmaceutical Association, Washington, DC (2003).

Other classes of additives for use in pharmaceutical compositions or dosage forms according to the present invention, include, without limitation, the means to prevent the monitor or prevent sticking, antimicrobial preservatives, remedies for coatings, paints, , and fragrances, plasticizers, tools that enhance viscosity, sweeteners, buffer funds, hygroscopic substances and the like.

Examples of products preventing the monitor, include, without limitation, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or their mixture.

Examples of antimicrobial preservatives include, without limitation, the solution of chloride benzalconia chloride , an acid benzojnuju, benzyl alcohol, butylparaben, chloride , , cresol, acid, , methylparaben, hydroxyphenyl, phenylethyl alcohol, , , potassium sorbate, , sodium benzoate, sodium, sodium propionate, acid, , thymol, or their mixture.

Examples of dyes for use in the present invention include, without limitation, pharmaceutically acceptable dyes and varnishes, caramel, red iron oxide, yellow ferric oxide or a mixture of them. Examples of defoliants include, without limitation, calcium chloride, sulfate, calcium, silica or a mixture of them.

that can be used include, without limitation, Arabian gum, gum, almond oil, anethol, anise oil, benzaldehyde, cumin, caraway oil, oil, cardamom seeds, complex infusion cardamom, cherry juice, cinnamon and cinnamon oil, clove oil, what, cilantro oil, , liquid extract , ethyl acetate, ethylvanillin, eucalyptus oil, oil, , pure extract of licorice, liquid extract of licorice, lavender oil, lemon oil, menthol, methyl salicylate, glutamate monosodium, Muscat oil, orange flower, orange water, orange oil, sweet infusion orange crusts, complex tincture, orange, peppermint, peppermint oil, alcohol infusion of mint, pine oil, rose oil, concentrated rose water, curly mint, mint oil curly, thymol, infusion balm, vanilla, infusion of vanilla and vanillin or their mixture.

Examples of sweeteners include, without limitation, aspartame, , mannitol, saccharin, saccharin calcium, sodium saccharin, Acesulfame potassium, (Splenda brand®), sorbitol, sorbitol solution or mixture thereof.

Examples of plasticizers for the application of the present invention include, without limitation, castor oil, monoglycerides, , glycerin, mono - and monoglycerides, polyethylene glycol, propylene glycol and triacetin or their mixture. Appropriate means of increasing viscosity, include, without limitation, Arabian gum powder, agar, acid, monostearate aluminium, bentonite, bentonite suspension, carbomer 934, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethylcellulose 12, carrageenan, cellulose, cellulose, gelatin, guar gum, hydroxyethyl cellulose, , (no. 2208; 2906; 2910), magnesium aluminum silicate, methylcellulose, pectin, polyvinyl alcohol, povidone, silica, colloidal silicon dioxide, sodium alginate, and gum or their mixture.

Funds for the buffer that can be used in the present invention, include, without limitation, magnesium hydroxide, aluminum hydroxide, and the like, or their mixture. Examples of hygroscopic funds include, without limitation, glycerin, other hygroscopic substances or their mixtures.

Dosage forms according to the present invention may additionally include one or more of the following means: (1) the slow dissolution, such as paraffin; (2) accelerators suction, such as Quaternary ammonium compounds; (3) humidifiers, such as, for example, cetyl alcohol and ; (4) absorbents, such as kaolin and bentonite clay; (5) antioxidants, such as water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, successfully used sodium, sodium, sodium sulfite, and the like), soluble in oils antioxidants (for example, ascorbyl palmitate, (BHA), factories for bottled butylated hydroxytoluene (BHT), lecithin, , alpha-tocopherol, and the like); and (6) the funds chelating metals, such as citric acid ethylenediaminetetraacetic acid (EDTA), sorbitol, wine acid, phosphoric acid and the such.

Dosage forms according to the present invention, such as a tablet or tablet in the form of capsules, not necessarily a covering. Inert funds to cover usually contain inert film-forming tool, dispersed in a suitable solvent, and additionally may contain other pharmaceutically acceptable adjuvants such as dyes and plasticizers. Suitable inert funds to cover and methods of coverage are well known in this field, including, without limitation, water and non-aqueous techniques covering films or microencapsulation. Examples coating or covering funds include, without limitation, gelatin, pharmaceutical glaze, shellac, sucrose, and titanium dioxide, Carnauba wax, microcrystalline wax, cellulose, such as methylcellulose, , carboxymethylcellulose, phthalate-acetate cellulose, hydroxypropyl methylcellulose (such as # 2208, 2906, 2910), hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate (for example, no 200731, 220824), hydroxyethyl cellulose, , , which may not necessarily be cross sewed, and sodium-carboxymethylcellulose; vinyl, such as polivinilpirrolidon, ; glycols, such as polyethylene glycols; acrylics, such as copolymer ester of methacrylic acid copolymer -methyl; and other carbohydrate polymers such as maltodextrins and , or their mixture. The amount covers the tools and media (aqueous or anhydrous) varies depending on the type of drug and a way of introduction and can easily be determined by experts in the field.

Coating of film-forming polymer may not be applied on the pill or (e.g., tablet, having the shape of capsules) according to the present invention, using one of several types of equipment, such as a normal drageeing boiler, pneumatically suspended column Accelacota, High-Cola or Worster. Such equipment is usually contains exhaust system to remove dust and solvent vapours or water in order to ensure fast drying. Spray guns or other suitable spray equipment can be entered in the drageeing boiler to provide the type of spraying, suitable for fast and homogeneous covering layer tablets. Usually with a hot or cold air drying serves on the layer tablets continuously or alternately with the spraying cycle to accelerate the drying of the solution put in the form of film coverings.

Solution for coatings can be sprayed using a system of positive pneumatic supply or peristaltic pumps in continuous or intermittent cycle spray - drying. The specific type of spraying is chosen depending on the efficiency of the drageeing boiler. In most cases the substance coating sprayed until the tablets are not covered uniformly until the required thickness and until you reach the desired type of pill. You can apply various types of coatings, such as enteric coatings, coatings that provide slow release or settlement of rapidly dissolving type for quick action of tablets. Preferably cover the rapidly dissolving type is used to provide a more rapid release of active ingredients that leads to a more rapid onset of action. Thickness of film-forming polymer caused by, for example, the pill may vary). However preferably thickness mimics the appearance caused by the feeling of tactile sensations and sensation in the mouth) and the function of gelatinous capsules. In the case where you want a more rapid or slow release of therapeutic means (funds), a specialist in this field can easily determine the type of film thickness and, if such is necessary to use, on the basis of characteristics such as the required levels of active ingredient in the blood, the rate of release, the solubility of the active ingredient and the required effectiveness of dosage forms.

A number of suitable film-forming funds for use as a coating final dosage forms such as tablets, includes, for example, methylcellulose, (PHARMACOAT 606 6 cps), polivinilpirrolidon (povidone), (ETHOCEL 10 cps), various derivative methacrylate acids and esters of methacrylic acid, phthalate-cellulose acetate or their mixture.

Way of obtaining and or supplements included in a dosage form (such as a tablet or tablet in the form of capsules), choose so, to give the drug in pill form required physical properties, while simple production (e.g. rapid pressing of tablets). After production dosage form should preferably possess a number of characteristics, for example, in the case of pills such signs include appearance, strength, ability to disintegration and uniformity, which are affected as a way of receiving and additives present in a preparation, in the form of tablets.

In addition, it should be noted that the tablets or other dosage forms of pharmaceutical compositions of the invention should keep your source size, shape, weight and color in normal conditions of handling and storage throughout their shelf life. Thus, for example, the large amount of powder or solid particles on the bottom of the container, cracks or scratches on the outer surface of tablets or the emergence of crystals on the surface of tablets or on the vessel walls are evidence of physical instability tablets without coating. Consequently, it is necessary to carry out impact moderate, uniform and repeatable shaking and rotation tablets to ensure that the tablets have sufficient physical stability. Strength tablets can determine commercially available testers strength. In addition, the availability of the active ingredients in vitro, should not change significantly over time.

Tablets and other dosage forms of pharmaceutical compositions according to the present invention, such as pills, capsules, pills, granules not necessarily have a notch or can be obtained coatings and shells, such as enteric coating and other coatings, well-known in the field of preparation of pharmaceuticals.

In one variant requires the use of sliding substances in the pharmaceutical composition and dosage forms according to the invention, which include ARB, which is poorly soluble or insoluble in water.

5.2.3.2. Parenteral dosage forms

Suitable fillers that can be used for receiving parenteral dosage forms according to the invention, are well known to specialists in the field. Examples include, without limitation, water for injection USP; water fillers such as, without limitation, sodium chloride for injection, ringer solution for injection, dextrose injection, dextrose and sodium chloride for injection and ringer solution for injection; miscible with water fillers such as, without limitation, ethyl alcohol, polyethylene glycol and ; and not water napolniteli, such as, without limitation, corn oil, cottonseed oil, peanut oil, sesame oil, etiloleat, and benzyl benzoate.

Compounds that increase the solubility of one or more active ingredients that are described in this publication (i.e. the compounds according to the present invention can also be included in the parenteral dosage form of the invention.

5.2.3.3. Transdermal, local and dosage forms

Transdermal, local and dosage forms according to the invention, includes, without limitation, eye solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms, famous specialists in this field. See, for example, Remington's Pharmaceutical Sciences, 16 th and 18 th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4 th ed., Lea and Febiger, Philadelphia (1985). Transdermal dosage forms include patches «tank types» or «matrix type, which can cause the skin and wear during a particular period of time, to ensure the penetration of the required quantity of active ingredients.

Suitable (for example, media and thinners) and other substances that can be used to obtain transdermal, local and dosage forms, which are included in the present invention, well-known to specialists in the field of pharmacy and depend on the specific cloth, the pharmaceutical composition or dosage form will be applied.

Depending on the specific tissue that needs to be treated, can be used more components before, with, or after treatment with active ingredients according to the invention. For example, can be used penetration enhancers, contributing to the delivery of active ingredients into the fabric.

pH pharmaceutical composition, or dosage forms, or fabric, which is used pharmaceutical composition or dosage form, you can also adjust to improve the delivery of one or more active ingredients. Similarly, you can adjust the polarity of the solvent carrier, its ionic force or to improve delivery. Compounds such as stearaty, can also be added to pharmaceutical compositions or dosed forms, preferably to change the hydrophilicity or lipophilicity of one or more active ingredients in order to improve delivery. In this respect, stearaty can serve as a lipid media for the drug as an emulsifier or a surfactant, and as a means of reinforcing delivery or strengthening penetration. You can use different crystalline or amorphous form of active ingredients to further adjust the properties of the resulting composition.

5.2.3.4. Composition with increased stability

The applicability of specific also may depend on the specific active ingredients in dose form. For example, the decomposition of certain active ingredients may be accelerated by some , such as lactose, or if exposed to water. The active ingredients, which contain the primary or secondary amines, are particularly sensitive to such accelerated decomposition. The present invention covers pharmaceutical composition and dosage forms that contain little or no, lactose and other mono - or disaccharides. Used in this description of the meaning of the term «lactose» means, that if it is not enough to significantly increase the speed of the collapse of the active ingredient.

Do not contain lactose composition according to the invention may contain , which are well known in this area and are listed, for example, in the U.S. Pharmacopoeia (USP) 25-NF20 (2002). In General, do not contain lactose songs contain active ingredients, binder tool/filler and moving substance in farmatsevticeski compatible and pharmaceutically acceptable quantities. Preferred not contain lactose dosage forms contain active ingredients cellulose, pregelatinized starch and magnesium stearate.

In addition, the present invention covers waterless pharmaceutical compositions and dosage forms that contain active ingredients as the water may contribute to the decomposition of certain compounds. For example, the addition of water (for example, 5%) is widely spread in the field of pharmacy as a way of modelling the long-term storage to determine such characteristics as the expiration date or the stability of drugs over time. See, for example, Carstensen, Drug Stability: Principles and Practice, 2nd ed., Marcel Dekker, New York, NY, pp. 379-80 (1995). In fact, water and heating to accelerate the decomposition of certain compounds. Thus, the impact of water on the drug may be important, as with the problem of moisture and/or humidity are usually encountered during production, processing, packaging, storage, transport and use of drugs.

Waterless pharmaceutical compositions and dosage forms according to the invention can be obtained using the waterless or containing little moisture ingredients and conditions of low moisture or humidity is low. Pharmaceutical compositions and dosage forms that contain lactose and at least one active ingredient that contains the primary or secondary amine, preferably are waterless, if it is assumed significant contact with moisture and/or wet conditions during production, packaging, and/or storage.

Waterless pharmaceutical composition should receive and store to retain its waterless nature. Accordingly, waterless composition preferably Packed with the use of materials known to prevent the effects of water, so that they can be included in appropriate meet certain standards sets. Examples of suitable packages include, without limitation, hermetically sealed container foil, plastics, standard capacity (e.g. bottles), blister packs, and contour packaging.

The invention also refers to the pharmaceutical compositions and dosed forms that contain one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds, which in the present description is called the «stabilizers»include, without limitation, antioxidants such as ascorbic acid, pH buffers or salt buffers.

Like the number and types of the excipients, quantity and specific types of active ingredients in dose form may vary depending on factors such as, without limitation, the path through which they are introduced to patients.

5.2.3.5. Dosage forms slow release

Active ingredients according to the invention can be introduced in a manner ensuring controlled release, or with the help of delivery devices, which are well known to specialists in the field. Examples include, without limitation, methods and devices described in the patents of USA № 3845770, 3916899, 3536809, and 3598123 4008719, 5674533, 5059595, 5591767, 5120548, 5073543, 5639476, 5354556 and 5733566, each of which is included in this description as a link. Such dosage forms can be used to ensure a slow or a controlled release of one or more active ingredients using, for example, , L-100, wax, magnesium stearate, methylcellulose K4M CR, Surelease, Kollidon SR, other polymeric matrixes, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or a combination thereof to meet the required profile of the release in various ratios. Suitable controlled release of drugs known to specialists in the field, including products described in this publication can be easily chosen to apply in the case of compounds according to the present invention. Thus, the patent covers standard formulations suitable for oral administration, such as, without limitation, tablets, capsules, gel capsules and tablets in the form of capsules, which are adapted for controlled release.

The overall purpose of the creation of all pharmaceutical products with controlled-release is to improve therapy drugs compared with the treatment, which is achievable using uncontrolled analogues. Ideally, application of optimal created controlled release of the drug for treatment is characterized by the use of a minimum quantity of the medicinal product for the treatment or control of the state for a minimum period of time. Advantages of drugs with controlled release include long-term activity of medicinal products, a reduction in the frequency of dosing and better adherence by patients. Furthermore, the drugs with controlled-release you can use to affect the start time or other characteristics, such as the levels of the medicinal product in the blood, and thus can affect the appearance of side effects (e.g., adverse).

Most of the drugs controlled release form to first release such quantity of the medicinal product (active ingredient), which quickly gives the desired therapeutic effect, and gradually and continuously emit different amounts of medicinal means to sustain this level of therapeutic or preventive action over a long period of time. To maintain a constant level of the medicinal product in the organism, the drug should be released from the dosage form, with a speed that will replace the quantity of a drug that is metabolized and excreted from the body. Controlled release of the active ingredient can be promoted to various conditions, including, without limitation, pH, temperature, enzymes, water or other physiological conditions or connections. Some embodiments of the invention relates to the slow release of drugs containing (-)-O-, including its salts. In some versions of the drug slow release containing the (-)-O-, including its salts, has the advantage, for example, a slow dissolution profile (-)-O-, including its salts and derivatives. In some versions of the product contains ingredients that are described in the paragraphs «Preparation of premix» and the «end product», which are listed in the «Examples»section, below.

5.2.3.6. Sets

In some cases, the active ingredients according to the invention, preferably not to the patient at the same time or one and the same way of introduction. Therefore, the present invention covers the sets that when using the attending physician can facilitate the introduction of appropriate amounts of active ingredients patient.

A typical set according to the invention, contains the standard dosage form of the compounds according to the invention, or a pharmaceutically acceptable salt, prodrug, , hydrate, chlorate or stereoisomer connection and standard dosage form another tool that can be used in conjunction with the compounds of the invention. Sets according to the invention, in addition, may contain devices that are used for the introduction of active ingredients. Examples of such devices include, without limitation, syringes, droppers, patches, inhalers.

Sets according to the invention, may additionally contain a pharmaceutically acceptable excipients, which can be used for introduction of one or more active ingredients. For example, if the active ingredient is presented in solid form, which should be for parenteral administration set can contain a sealed container with a suitable filler, in which the active ingredient can be dissolved with formation not containing particles of sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable fillers include, without limitation, water for injection USP; water fillers such as, without limitation, sodium chloride for injection, ringer solution for injection, dextrose injection, dextrose and sodium chloride for injection and ringer solution for injection; miscible with water fillers such as, without limitation, ethyl alcohol, polyethylene glycol and ; and not water napolniteli, such as, without limitation, corn oil, cottonseed oil, peanut oil, sesame oil, etiloleat, and benzyl benzoate.

The invention of advanced described with reference to the following examples. Specialists in this area is clear that many of the modifications, both in terms of materials, and the approach can be implemented in practice, not departing from the essence, and not going beyond the present invention.

Pharmaceutical composition and method according to the present invention may additionally contain other therapeutically active compounds specified in this description that is usually used to treat, prevent or assist with the above pathological conditions.

5.2.4. Methods of application

In some cases, the use of optically pure or on the merits of optically pure (-)-O- or salts to treat, prevent, and/or assist with the conditions described in this publication results in a more accurate associated with a dose of determination of efficiency, fewer adverse effects, and accordingly higher therapeutic index compared with venlafaxine.

In some embodiments, the present invention relates to methods of treatment, prevention or assist with one or more diseases, disorders or conditions with the help of introduction of therapeutic and/or preventive dose solid form, containing the (-)-O- described in this publication, for example, crystalline forms, containing salt (-)-O-, entity, such as a person in need of such treatment, prevention and/or care, the disease, disorder or condition include, without restrictions, affective disorders, such as depression, bipolar or manic disorders, attention deficit disorder, attention deficit hyperactivity disorder, anxiety disorder, panic disorder type, social anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive-compulsive disorder, anorexia and : bulimia, obesity, weight increase, syndrome Gilles de La Tourette's syndrome Shay- Alzheimer's disease Parkinson's disease, epilepsy, , Smoking cessation, drug addiction, mediated by the nervous system sexual dysfunction, pain, including chronic and neuropathic pain, disorders of brain function, senile dementia, memory loss, amnesia/Korsakoff syndrome, a disorder of consciousness, coma, speech disorders, the syndrome Lennox, autism, giperkineticeski syndrome, schizophrenia, headache, incontinence, chronic fatigue syndrome, sleep apnea, vasomotor symptoms such as hot flashes, disorders, inhibition capture monoamine neurons related disorders, and mental illness described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).

The value of preventive or therapeutic dose (-)-O- (also called «active ingredient») in acute or chronic treatment of disease will vary depending on the severity of the condition being treated, and a way of introduction. Dose and in some versions of the frequency of dose will vary depending on the age, body weight, sensitivity and medical history of the individual patient. In some embodiments of the invention range recommended daily dose in the case of States described in this publication is in the range of about 10 mg to about 1000 mg per day. In some embodiments, the recommended daily dose administered as a single dose once a day, for example in the morning. In some embodiments, the recommended daily dose administered as fractional doses, taken during a day with food. In some versions of the range of doses is approximately 50 mg up to approximately 500 mg / day. In some versions of the range of doses is approximately 75 mg to approximately 300 mg / day. In some versions of the range of doses is approximately 50 mg to approximately 200 mg / day. In some versions of the range of doses is from about 25 mg to about 250 mg / day. When helping a patient treatment should begin with a low dose, possibly from some 50 mg to about 75 mg, and if necessary increase to about 250 mg of 325 mg per day or as a single dose or fractional doses, depending on the overall sensitivity of the patient. If the dose is increased, then it is preferable to this exercise at intervals of about 75 mg, separated by at least a period of 4 days.

So as elimination of (-)-O- of blood flow depends on the functioning of the kidneys and liver, the recommended reduction in the total daily dose by at least 50% in patients with moderate violation of the liver, and reduced by 25% for patients in the case of small-to-moderate violations of the kidneys. For patients who undergo hemodialysis, it is recommended to decrease the total daily dose of 5% and termination of the dose until the completion of the dialysis procedure. As reported some adverse reactions in patients receiving venlafaxine simultaneously or immediately after receiving monoamine oxidase inhibitor, it is recommended not to enter (-)-O- patients receiving currently such inhibitors. In General, the simultaneous introduction of connections according to the invention with other drugs, especially with other takeover serotonin inhibitors, should be made with caution. See, for example, von Moltke, et al. Biol. Psychiat., 41: 377-380 (1997); and Sinclair, J. et al. Rev. Contemp. Pharmacother., 9: 333-344 (1998).

Various terms «the specified amount, sufficient to facilitate affective disorder», «specified the amount, sufficient for the weakening of the depression,» «the specified amount, sufficient for the weakening of attention deficit disorder», «specified the amount, sufficient for the weakening of obsessive-compulsive disorder,» «the specified amount, sufficient for preventing or reducing substance abuse,» «the specified amount, sufficient to prevent or relieve premenstrual syndrome,» «the specified amount, sufficient to prevent or relieve anxiety», «specified the amount, sufficient for preventing or reducing eating disorders,» «the specified amount, sufficient to prevent or relieve migraine», «specified the amount, sufficient for the weakening of Parkinson's disease», «specified the amount, sufficient for the weakening of the epilepsy,» «the specified amount, sufficient for the weakening of obesity or increase of the weight, quantity, sufficient for achieving weight loss,» «the specified amount, sufficient to achieve weight reduction in humans», «the specified number of, sufficient for the relief of pain,» «the specified amount, sufficient for the weakening of dementia,» «the specified amount, sufficient to facilitate these disorders, inhibition of reuptake neurons,» «the specified amount sufficient to weaken disorders of the function of the brain,» «the specified amount, sufficient for the relief of mental illness, where these disorders are selected from the group consisting of senile dementia, dementia type of Alzheimer's, memory loss, amnesia/amnestic syndrome, a violation of consciousness, coma, reducing attention, disorders of speech, Parkinson's disease, the syndrome Lennox, autism; with hyperkinetic syndrome, schizophrenia and vascular diseases of the brain, such as ischemic stroke, bleeding in the brain, arteriosclerosis of the brain, thrombosis of the veins of the brain, head injuries, mental diseases, including diseases that are described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), and the like, «this amount sufficient to treat, prevent or assist with incontinence»where the specified incontinence includes, without restrictions, incontinence, stress incontinence, urinary incontinence, urinary incontinence during exercise, emergency, reflexive, passive, incontinence and urinary incontinence due to the overflow of bladder, are in the range described above dose quantities schemes and frequency of dose. Similarly, a number sufficient to loosen each of the above disorders, but insufficient to cause adverse effects associated with venlafaxine, also included in the range described above dose quantities schemes and frequency of dose.

The invention further defined with reference to the following examples. Specialists in this field will be clear that in practice can be implemented numerous modifications, both in terms of materials and methods for moving away from the goal and interest tasks of the present invention.

6. EXAMPLES

6.1 MATERIALS AND METHODS

Reagents and solvents used below may be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis., USA). Standard chemical analysis was carried out using NMR, MS and HPLC. Significant peaks NMR grouped by chemical shift and marked in accordance with their complexity (with, singlet; e, doublet; t, triplet; kV, Quartet; m, multiplet; ., uširennyj singlet) and the number of protons. Mass spectroscopy presents the relative mass of the initial ion, M. Data HPLC presented as a percentage of purity.

X-ray powder data (XRPD) received one of the following two methods. In some versions of the tests XRPD carried out using diffractometer Inel XRG-3000, equipped CPS detector (curved position sensitive) with an area of 2 120 degrees. Real-time data collected using Cu-K-radiation starting approximately 2,5 °2 with a resolution of 0.03 °2. Voltage and current tubes installed at 40 kV and 30 mA, respectively. Installing slit meet 130 and 160 microns at a distance of 5 mm Samples were prepared for analysis, packaging them in a thin-walled glass capillaries. Each capillary established on the head of a goniometer, which is mechanized, to be able to rotate capillary accumulation of data. Samples were analyzed for five or ten minutes. Calibration of the instrument was carried out using for comparison silicon standard.

Analyses TGA carried out using thermogravimetric analyzer TA Instruments 2950. Each sample was placed in aluminium Cup for the sample and put it in a microwave for TGA. Conditions of conducting conventional thermal gravimetric analysis included the achievement of a balance furnace at 25 C followed by warming in the atmosphere of nitrogen at the rate of 10 C/min to a final temperature to 350 degrees C. In the specified way modifications carried out in cases of non-standard analysis, for example, excluded trim before heating, used heating with different speeds and heating up to the temperature below 350 degrees C. Nickel and alumel (Alumel TM ) were used as calibration standards.

High-temperature microscopy is performed using the heating table Linkam (model FTIR 600), mounted on a microscope Leica LP DM. The specimens were examined using the lens c 20-fold increase and the plate with lambda crossed polarizers. The samples were placed on a coverslip and then another coverslip placed on the sample. Each sample was observed visually as they heat the table. Image recorded using a color digital camera SPOT Insight TM , using a computer program, SPOT v. 3.5.8. Heating table was calibrated using standard melting points USP.

Analyses of TG-SG carried TGA-analyzer TA Instruments 2050, the United IR Fourier-spectrophotometer Magna 560® (Thermo Nicolet), equipped with a source of infrared radiation in a medium/long-distance field Ever-Glo, of potassium bromide (KBr) and detector on the basis of deuterated (DTGS). Device for TGA worked at presence of a stream of helium at 90 and 10 cm3 /min in the case of blowing and trims, respectively. Each sample was placed in a platinum crucible for the sample was placed in a microwave for TGA, carefully weighed with the help of the device and the furnace was heated from 20 C up to 200 or 250 C with a speed of 20 C/min Device for TGA included first, then immediately included Fourier transform infrared device. Each spectrum IR was a superposition of 32 scans collected with a spectral resolution of 4 cm-1 . Background scanning was carried out before the beginning of the experiment. Calibration wavelength carried out using polystyrene. As calibration standards for TGA used Nickel and alumel (Alumel TM ). Volatile substances identified on the basis of the search in the library of spectra TGA high resolution for vapor Nicolet.

Data on sorption/desorption moisture received on sorption analyzer pair VTI SGA-100. Data on sorption and desorption received at the relative humidity (RH) in the range 5% to 95% with 10%of the time by intervals of RH in the conditions of purging with nitrogen. For some of the samples of the round of sorption added stage during the 90% RH. The samples prior to analysis not dried. Criteria for achieving equilibrium conditions for the analysis were available in less than 0,0100% weight. changes within 5 minutes at the maximum time to reach the equilibrium 3 hours, if the criteria for changing mass has not been satisfied. Data is not corrected taking into account the initial moisture content of the samples. NaCl and PVP used as calibration standards.

IR-spectra were FTIR-spectrophotometer Magna-IR 860® (Thermo Nicolet), equipped with a source of infrared radiation in a medium/long-distance field Ever-Glo, of potassium bromide (KBr) with extended range and detector on the basis of deuterated (DTGS). Accessory attenuated total reflection (ATR) (Thunderdome TM , ThermoSpectra-Tech) with a crystal of germanium (Ge) was used for data storage. Each range represented a superposition of 256 accumulated scans with a spectral resolution of 4 cm-1 . Baseline data collection was performed using the air. Log 1/R (R = reflectance) spectrum were obtained on the basis of the ratio of these two sets of data. Calibration wavelength carried out using polystyrene.

In some experiments Raman spectra with Fourier transform was measured on an additional module Raman scattering, United with FTIR-spectrophotometer Magna 860® (Thermo Nicolet). In the specified module used wavelength 1064 nm excitation and detector on the basis of gallium arsenide and indium (InGaAs). Laser Nd:YVO 4 capacity of approximately 0.7 W used for irradiation of the sample. Samples were prepared for analysis, placing a substance in a glass tube or capillaries, which is then placed in a holder or a capillary tube covered with gold in the supporting device. Total accumulated 256 scans sample spectral resolution 4 cm-1 using on -. Calibration wavelength carried out using sulfur and cyclohexane.

analysis Karl Fischer (KF) for determination of water was carried out using the Karl Fischer titrator Mettler Toledo DL39. Approximately 14-32 mg of the sample was placed in a vessel for titration by Karl-Fischer containing Hydranal - Coulomat AD and stirred for 60 seconds to ensure its full dissolution. Then the sample was titrated by the working electrode, which electrochemical oxidation forms iodine: 2 I - →I 2 +2e. Carried out three repetitions to ensure the reproducibility of the data.

6.2. EXAMPLE 1: SYNTHESIS

Used three different synthesis method for obtaining the compounds according to the present invention. The first method involves the allocation of (-)-venlafaxine followed by selective . The second method involves dividing a racemic mixture (+or -)- O- on optically pure components. The third method involves the synthesis of (+or -)- O-benzyl-O-, separation of the obtained optically pure components and of these components.

6.2.1. Synthesis and separation of venlafaxine

6.2.1.1. 1-[Cyano-(4-methoxyphenyl)methyl]cyclohexanol

Solution 4- (53,5 g, 0,36 mol) 400 ml THF cooled to -78°C with subsequent slow addition of 2.0 M solution lithium (200 ml, 0,40 mol) in THF, keeping the temperature of the reaction below -65 degrees C. the Reaction mixture was stirred at -78°C for 30 minutes. Cyclohexanone (39.5 g, 0,40 mol) was added at such a speed as to the reaction temperature did not rise above -65 degrees C. After adding the reaction mixture was stirred at -78°C during 2 hours, the mixture was poured into a 1 l saturated aqueous solution NH 4 Cl containing ice. The mixture was stirred for 15 minutes and extracted (4 x 200 ml). Joint layer ethyl acetate washed with water (3 x 100 ml), a saturated solution of salt (1 x 100 ml) and dried (Na 2 SO 4 ). Ethyl acetate is evaporated in a vacuum, receiving a colorless solid, which is rubbed in hexane. Residue was filtered, washed with hexane and dried in a vacuum, receiving a colorless solid (72,0 g, exit 80,7%).

1 H (CDCl 3 ); 7.30 and 6,90 (kV, 4H), 3,80 (c, 3H), to 3.75 (c, 1H), 1,55 (m, 10H); 13 C (CDCl 3 ): 159,8, 130,8, 123,8, 120,0, 114,1, 72,9, 55,5, 49,5, 34,9, 25,3, 21,6.

6.2.1.2. 1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol

3-liter three-neck flask, equipped with a mechanical stirrer and a thermocouple downloaded 1-[cyano(4-methoxyphenyl)methyl] (40,0 g, 0,16 mol) and 1 l of methanol. To received to the solution of the added chloride cobalt (42,4 g, 0,32 mol) and the reaction mixture was stirred to obtain a clear dark blue solution. Small batches added sodium borohydride (62,0 g, 1,63 mol), keeping the temperature of the reaction mixture is below 35 C. once added sodium borohydride formed a dark black cake along with the vigorous emitting gas. When you are finished adding the suspension was stirred at room temperature for 2 hours. Study TLC showed the complete disappearance of the initial substance. The reaction mixture was cooled in a mixture of ice/water and slowly added to 1 l of 3N HCl. The temperature of the reaction mixture is kept below 25 C. the Reaction mixture was stirred for 30 minutes after addition. Even a slight amount of black sludge. Methanol were deleted in vacuum with the subsequent extraction of the water layer (3 x 300 ml). The water layer is cooled in a mixture of ice/water and (pH-paper) slow addition of concentrated NH 4 OH (600 ml). The temperature of the reaction mixture is kept below 25 C. the Reaction mixture is extracted (4 x 200 ml). Joint layer washed with water (3 x 100 ml), a saturated solution of salt (1 x 100 ml) and dried (Na 2 SO 4 ). Ethyl acetate is evaporated in a vacuum, receiving a yellow gum (34,0 g, exit 83,6%).

1 H (CDCl 3 ): 7.20 and 6,85 (kV, 4H), 3,80 (c, 3H), 3,20 m 2H), 2,70 (t, 3H), 2,35 (., 3H), of 1.40 (m, 10H); 13 C (CDCl 3 ): 158,4, 132,6, 130,6, 113,7, 73,7, 56,7, 55,3, 42,4, 37,3, 34,5, 26,0, 21,9.

6.2.1.3. (Yo)-venlafaxine

1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (33,0 g, 0,13 mol) was dissolved in 88% formic acid (66,0 g 55 ml, 1,43 mol) and water (330 ml) followed by the addition of 37% water solution of formaldehyde (44.4 g, 41 ml, 1,48 mol). The resulting solution was boiled under reflux for 20 hours, cooled to room temperature and was concentrated up to 150 ml, adjusted to a pH of 2.0 using 3N HCl and extracted (approximately 6 x 50 ml) until the removal of the pink impurities. The water layer is cooled in a mixture of ice/water and slow addition of 50% NaOH. The water layer is extracted (3 x 75 ml). Joint layer washed with water (3 x 25 ml), a saturated solution of salt (1 x 25 ml) and dried (Na 2 SO 4 ). Ethyl acetate is evaporated in a vacuum, receiving a yellow gum, which slowly turned into a pale yellow solid (34,0 g, exit 92,6%).

1 H (CDCl 3 ): 7,05 and 6.80 (kV, 4H), 3,80 (c, 3H), 3,30 (t, 1H), 2,95 (DD, 1H), 2,35 (c 6H), 2,30 (DD, 1H), 1,30 (m, 10H); 13 C (CDCl 3 ): 158,4, 132,9, 130,3, 113,5, 74,4, 61,4, 55,3, 51,8, 45,6, 38,2, 31,3, 26,2, 21,8, 21,5. MS (277, M+).

6.2.1.4. salt venlafaxine

Hydrochloride venlafaxine received from the free base of venlafaxine addition of hydrochloric acid in a suitable solvent or according to the U.S. patent № 4535186.

A mixture of 2,50 kg hydrochloride, 1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol, 16.8 kg of ethyl 14,0 kg 1N NaOH (water) was stirred for 15 minutes. Mixing stopped and the bottom layer removed. The organic layer, double-washed 3.5 kg of water. Added 2.4 kg methanol and 1.78 kg di-p--D-tartaric acid 7.9 kg of ethyl acetate. Mixture was stirred by working at reflux (about 65 degrees C) for 15 minutes and cooled up to 55 degrees C. The solution made the seed 43 grams of salt Hemi-D-di-p- acid and (R)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol to 0.750 kg of ethyl acetate. Suspension kept at 55 C for 15 minutes, cooled to 30 C for 110 minutes. The mixture is then cooled to 0 C for 1 hour and filtered. The filter cake washed twice with a mixture of 0.23 kg methanol and 2.3 kg of ethyl acetate and dried in a vacuum at 40-50°C, receiving 1,53 kg of salt (R)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol and Hemi-D-di-p- acid (99,1% ee).

1 H NMR (DMSO-D6 ): 0,80-1,6 m, 10H), 2,35 (c, 9H), 2,86 (m, 1H), 2,98 (m, 1H), 3,33 m, 1H), 3.72 points c, 3H), 5,62 (c, 2H), 6,81 (d, 2H, J=8,5 Hz), 7,12 (d, 2H, J=8,5 Hz), 7,31 (d, 4H, J=8.3 Hz), the 7.85 (d, 4H, J=8.3 Hz).

6.2.1.5. (-)-Venlafaxine

50 ml of cold 2H NaOH was added to the di-p--D- salt (R)-(-)-venlafaxine (5.3, 8.0 mmol) and the water layer is extracted (3 x 100 ml). Joint layer washed with cold 2H NaOH solution (1 x 25 ml) and water until rinse waters became neutral. layer was dried (Na 2 SO 4 ), ethyl acetate evaporated, getting the (-)-venlafaxine as a colourless solid substances (2.2 g, quantitative output), e.e. (HPLC): >99,95. Data of 1H, 13C and MS, as in the case of (+or -)- venlafaxine.

6.2.2. Synthesis and separation (-)-O-

6.2.2.1. (Yo)-O-

Solution (3.0 g, 16,1 mmol) in 20 ml of THF cooled to-10oC with the subsequent slow addition of 1,6M TGF solution of n-BuLi (12,7 ml, 20,2 mmol) at a rate such that the temperature of the reaction mixture does not exceed low as 0 C. the Reaction mixture was stirred at 0 degrees C for 30 minutes. Slowly 0C solution was added (+or -)- venlafaxine (1.0 g, 3.6 mmol) in 10 ml of THF. The reaction mixture was stirred at 0 degrees C for 15 minutes and we are allowed to warm to room temperature and stirred for 1 hour. Then pulverized reflux during the night. The reaction mixture was cooled to room temperature and slowly poured in 30 ml of cold 3n HCl solution, keeping the temperature below 15°C. After stirring for 10 minutes water layer is extracted (3 x 30 ml). The water layer is adjusted to a pH of 6.8 and 6.9 slow addition of solid NaHCO 3 . Then it was saturated by the addition of NaCl and extracted (6 x 30 ml). Joint layer was dried (Na 2 SO 4 ), ethyl acetate evaporated in a vacuum, receiving a colorless solid. Solid ground in a cold ethyl acetate, filtered, washed with cold , receiving a colorless solid (0,700 g, exit 73,8%).

1 H (DMSO-D6 ): 9,30 (., 1H); 7,10 and 6.80 (kV, 4H), 5,60 (., 1H), 3,15 (DD, 1H), 2,88 (t, 1H), 2,50 (DD, 1H), 2,30 (c 6H), 1,35 (m, 10H); 13 C (DMSO-d 6 ): 155,5, 131,7, 130,1, 114,4, 72,6, 60,4, 51,6, 45,3, 37,2, 32,4, 25,7, 21,2. MS: (264, M+1).

6.2.2.2. (-)-O-

(-)-O- received from the (-)-venlafaxine, following the method described above. (-)-O-: colourless solid, [α] D =-35,2 (c=0,25, EtOH), cleanliness % (HPLC): >99% e.e. (HPLC): >99%. Data of 1H, 13C and MS are the same as in the case of (+or -)- O-.

6.2.2.3. (-)-O- directly from venlafaxine-DTTA

(-)-O- can also be obtained directly from the Hemi-DTTA salt (-)-venlafaxine using the method described below.

6.2.2.4. (-)-Venlafaxine

A mixture of 1.95 kg of salt (R)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol and Hemi-D-di-p- acid, a 12.03 kg MTBE and 5.85 kg 1M NaOH solution (water) was stirred for 15 minutes, Stirring is stopped and the bottom layer removed. The organic layer, double-washed 5,46 kg of water. The organic layer was concentrated up to 5 HP Added 3.90 kg tetrahydrofuran, anhydrous and a mixture of distilled to a volume of 4.5 l, getting the (-)-venlafaxine in the form of a solution in THF.

Solution lithium received the addition of 6.2 kg n-, 1,6M (15% of the mass), to the mixture of 22.9 kg of tetrahydrofuran and 2.2 kg . A solution of (-)-venlafaxine in THF added to lithium. Mixture was stirred at 50 C and kept until the completion of the reaction (about 24 hours). The mixture is cooled to 22 degrees C, added 11,95 kg deionized water and 3,94 kg 6N HCl. The mixture was stirred for 15 minutes, stirring stopped and the upper organic phase is removed and discarded. The water layer is twice washed 7,98 kg methylene chloride. The pH value of the aqueous layer brought to 9.5 using concentrated ammonium hydroxide. Added 19.4 kg 2-. The mixture was heated to 65 C and the aqueous phase is removed. Organic phase washed at 65 C 8 kg of water and the organic phase was concentrated up to 4,5 HP Added to 14.3 kg of ethyl mixture was stirred at 45-55°C for 30 minutes. Mixture was stirred at 0 degrees C for 30 minutes. Suspension and the filter cake washed twice 2.8 kg of ethyl acetate. Solid dried in a vacuum (>28 inch Hg (9482 kPa)) at 40-50°C, receiving 0,903 kg (R)-O--1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol (99,3% ee).

80,4 g (R)-O--1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol downloaded in a round-bottom flask volume of 1 l, equipped with the top with a mechanical stirrer. Added 326,0 g methanol and 80.3 per g of 15% of the mass./the masses. aqueous solution of hydrochloric acid. The solution is stirred at 20 deg C for 15 minutes and add to 1,797 g heated (40 C) methyl tert-butyl ether (MTBE). Mixture was stirred at 40 C for 20 minutes and cooled up to 20 degrees C. Mixture was stirred at 20 deg C for one hour and as a seed contributed 1.6 g hydrochloride monohydrate (R)-O--1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol in the form of a suspension in 21 ml MTBE. The contents of the flask volume of 5 l stirred at 20 C 2 hours before formation of a suspension. In 5-quart flask added 1.6 l MTBE and mixed at 20 deg C for 2 hours. The mixture was filtered on the funnel with an average size of pores to differentiate their product, and the filter cake washed twice MTBE (2 x 241,0 g). The filter cake squeezing dry, using a vacuum over with an average size of pores within 1 hour, getting 86,3 g monohydrate hydrochloride (R)-O--1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol.

1 H NMR (DMSO-D6 ): 0,80-1,70 (10H, m), 2,60 (3H, C), 2,64 (3H, C), 3,00 (1H, DD, J=9,3, 3,7 Hz), of 3.46 (1H, .), 3,63 (1H, .), 4,52 (1H, s), 6,75 (2H, d, J=8.3 Hz), 7,11 (2H, d, J=8.3 Hz), 9,43 (1H, .), 9,50 (1H, s).

6.2.3. Department of (-)-O-

(-)-O- received by the division (+or -)- O-.

1.0 g (+or -)- O-, and 0.89 g (24 mmol) (R)-1-phenyl-1-cyclohexyl-1- acid, 7.9 g ethanol and 1.05 g water loaded into a flask with a volume of 25 ml of Mixture was stirred at 75C for 30 minutes and cooled to room temperature. The resulting solid is collected by filtration and washed ethanol. Solid dried, receiving 790 mg salt (R)-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol and (R)-1-phenyl-1-cyclohexyl-1- acid (rate of 99.42% ee). 1 H NMR (CDCl 3 ): 4.

6.2.3.1. salt (-)-O-

Salt (R)-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol and (R)-1-phenyl-1-cyclohexyl-1- acid (2.0 g, 4 mmol) was dissolved in methanol (5,4 ml) and 15% (mass./the masses.) HCl in water (1.05 g). Methanol/solution of hydrochloric acid added with stirring to methyl tert-butyl ether (MTBE) (32 ml) at 35-40 Celsius C. After the addition of methanol/solution of hydrochloric acid mixture was stirred at 35-40 C for 60 minutes and cooled to room temperature. The mixture is made seed monohydrate (-)-O- and mixed at 20 deg C for 3 hours. The solid is collected by filtration and washed MTBE (20 ml). Solid dried, receiving 730 mg hydrochloride, 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol. Solid analyzed (5,49% water, impurities <0,05%, DSK 101,38).

1 H NMR (DMSO-D6 ): 0,80-1,70 (10H, m), 2,60 (3H, c), 2,64 (3H, c), 3,00 (1H, DD, J=9,3, 3,7 Hz), of 3.46 (1H, .), 3,63 (1H, .), 4,52 (1H, c), of 6.75 (2H, d, J=8.3 Hz), 7,11 (2H, d, J=8.3 Hz), 9,43 (1H, .), 9,50 (1H, c).

(R)-1-Phenyl-1-cyclohexyl-1- acid obtained according to the method described in the publication Tetrahedron: Asymmetry 14 (2003) 3593, which is included in this description as a link.

6.2.4. Synthesis and separation O-benzyl-O-

(-)-O- received by synthesizing and sharing (+or -)- O-.

6.2.4.1. (Yo)-O-benzyl-O-

In some versions use the way described below. 150 g of 2-(4-benzyloxy)phenyl-N,N-dimethylacetamide, 945 (1062 ml) THF loaded into a reactor with a shirt with 5 HP Added 550 ml chloride (2,0M in tetrahydrofuran) and the mixture was stirred for 1 hour. The reactor added 115 g cyclohexanone and stirred for 1 hour. The reactor added 360 g RedAl (bis(2-) sodium - 65% of the mass./the masses. in toluene) and stirred for 16 hours. After completion of the reaction mixture was added in 2005 to 22% of the mass./the masses. aqueous solution of citric acid. 420 g (600 ml) heptane loaded into a reactor and stirred for 15 minutes. Mixing stopped and the top layer is removed. Added 250 g 50% NaOH to bring the pH value to 9-10, with the subsequent hashing. The reactor added 1114 g (1500 ml) of MTBE. The mixture was heated up to 45±5 C, to dissolve solid substances. Mixing stopped and the bottom layer removed. The organic layer, double-washed 750 g of water at 45 C. 750 ml MTBE removed by distillation and added 750 ml of methanol. Approximately 750 ml of a mixture of MTBE/methanol removed by distillation and added 300 g of methanol and 300 grams of water. The suspension was cooled to 0 C and stirred for 30 minutes. Suspension and solid is washed 375 g mix (4:1 methanol:water). Solid dried, receiving 161 g 1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol.

In some versions use the way described below. In the reactor volume of 200 gallons (757 liters) to load 22,98 kg 2-(4-benzyloxy)phenyl-N,N- and 145,1 kg THF. While stirring the temperature brought to 5 degrees C-10 C. In the reactor loaded 82,9 kg of chloride , 2,0M in THF, maintaining the temperature from 5 degrees C to 35 C. Supply lines were washed 2,78 kg THF. The content was stirred for 61 minutes at 10 degrees C to 20 C. In the reactor added 9,31 kg cyclohexanone maintaining the temperature from 5 degrees C to 35 C. Line washed 2,77 kg THF. Temperature is brought up to 15 C-25 C and the contents stirred for 17 minutes in the specified temperature range, after this reaction was completed. The reactor was loaded 55,8 kg bis(2-) sodium (65% of the mass. in toluene), keeping the temperature at 15 C-35 C. the Content was stirred for 10 hours remained <3% of the original substance). The reaction mixture was added to to 334.1 kg 22% solution of citric acid, cooled to 0 C-2 degrees C. The reaction mixture was added THF (22,9 kg) and n-heptane (63.3 per kg). The mixture was stirred for 15 minutes, stirring stopped and gave the opportunity for the phases separated. The top layer was removed and loaded into the reactor 45.4 kg 50% of sodium hydroxide. The reactor was loaded 169,9 kg MTBE and the temperature is brought up to 40-50°C. Content stirred for 14 minutes and agitation stopped, allowing phases separated for 15 minutes. The water layer is removed and added to 115 liters of purified water USP. Temperature is brought up to 40 C-50 C. the Content was stirred for 15 minutes and agitation stopped, giving the opportunity to the phases of the split within 13 minutes. The bottom water layer were removed. The reactor was loaded 115 liters of purified water USP and brought up to a temperature 40 C-50 C. the Content was stirred for 15 minutes and agitation stopped, allowing phases separated. The bottom water layer were removed. The solution was subjected to distillation in vacuum to a final volume of 188 HP loaded Into the reactor to 115.2 kg methanol solution and subjected to distillation in vacuum to a final volume 131 HP loaded Into the reactor 46,0 kg methanol and 57 liters of purified water USP. Temperature brought to 0 C). The suspension was stirred for 41 minutes at temperature from -5 degrees C to 5 degrees C and the mixture was filtered. The filter cake washed 46,2 kg methanol and 11.6 kg of purified water USP (cooled to a temperature from -5 degrees C to 5 degrees C). The wet sediment filter (30,66 kg) dried at 40-50°C, receiving 24,47 kg 1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol.

6.2.4.2. Hemi-D-DTTA salt (-)-O-benzyl-O-

In some versions use the way described below. 160 g 1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol, 100 g D di-p- acid, 1.6 l of acetone, 150 g of water was added to the 5-liter reactor and heated to 50 degrees C. the Mixture was stirred at 50 C for 15 minutes and cooled to 0 C). the Mixture was stirred at 0 degrees C during 120 minutes and filtered. The filter cake washed 600 ml of acetone and dried in a vacuum at 40-50°C, receiving 114.3 g salt (R)-1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol and di-n--D-tartaric acid.

In some versions use the way described below. The reactor was loaded 60,64 kg 1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol, 42,01 kg D-di-p- acid, 512,7 kg of acetone and 61 liters of purified water USP. Temperature is brought up to 50 degrees C-55 C and the contents are mixed in specified temperature range for 16 minutes. The mixture was cooled to 36 degrees C and mixed at 36 degrees C for 35 minutes. The mixture is cooled to a temperature of 2 degrees C to 2 degrees C for 105 minutes and stirred for 122 minutes. The mixture was filtered and the filter cake washed twice with acetone (122,0 kg and 121.8 kg), cooled to a temperature from -5 degrees C to 5 degrees C. the Wet sediment filter (47,06 kg) dried at 40-50°C, receiving 41,50 kg of salt (R)-1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol and di-n--D-tartaric acid.

6.2.4.3. (-)-O-Benzyl-O-

In some versions use the way described below. In the flask 5 l downloaded 190 g of salt (R)-1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol and D-di-p- acid, 703 g MTBE and 870 g 1N NaOH. Mixture was stirred at 45 deg C, the water layer is removed and the organic layer is washed with water (475 g x 2). Layer MTBE subjected to distillation up to 450 ml, added 703 g methanol mixture and again subjected to distillation up to 450 ml Suspension of diluted 450 g of water and the mixture is cooled to 0 C). The mixture was filtered and washed 435 ml methanol/water, getting after drying 112 g (R)-1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol.

1 H NMR (DMSO-D6 ): 0,8-1,6 (10H, m), 2,12 (6H, c), 2,41 (1H, DD, J=6,9, 12,3 Hz), 2,77 (1H, t, J=6,9 Hz), 2,94 (1H, DD, J=7,9, 12,3 Hz), 5,05 (2H, c), 5,23 (1H, c), 6,89 (2H, d, J=Hz 8,7), 7,11 (2H, d, J=8,7 Hz), the 7.3-7.5 (a 5H, m).

In some versions use the way described below. 19.5 g (R)-1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol, 400 mg 10% palladium-on-angle, 58 ml of methanol, a 4.5 ml 37% of the mass. water solution of hydrochloric acid and 6.8 g water loaded into a vessel for hydrogenation. The mixture was interaction with hydrogen at a pressure of 50 psi (0.35 MPa) for 3 days. The resulting mixture was filtered and the catalyst is washed 14 ml of methanol. Joint filtrate and mother solution was added to 434 ml MTBE at 40 degrees C. The mixture was cooled to 20 C, and as a seed made monohydrate hydrochloride (-)-O-. The mixture was stirred for 1 h at 20 C and added 290 ml MTBE. The mixture was stirred for 2 hours, filtered and washed with MTBE (2 x 70 ml), getting after drying 14.4 g monohydrate hydrochloride, 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol.

1 H NMR (DMSO-D6 ): 0,80-1,70 (10H, m), 2,60 (3H, c), 2,64 (3H, c), 3,00 (1H, DD, J=9,3, 3,7 Hz), of 3.46 (1H, .), 3,63 (1H, .), 4,52 (1H, c), of 6.75 (2H, d, J=8.3 Hz), 7,11 (2H, d, J=8.3 Hz), 9,43 (1H, .), 9,50 (1H, c).

Analysis of a rigid body confirmed that the obtained material was a crystalline form A.

In some versions use the way described below. 1,0 kg (R)-1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol, 20 g 10% palladium-on-coal, up 1.76 kg ethanol and 550 g 20% of the mass. hydrochloric acid loaded into a vessel for hydrogenation. The mixture was interaction with hydrogen until was not spent all the original substance. The resulting mixture was filtered and the catalyst is washed 380 g of ethanol. Joint filtrate and mother solution was added to 4,96 kg MTBE at 40 degrees C. the Mixture was cooled to 20 C, and as a seed added 20 g monohydrate hydrochloride, 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol. The mixture was stirred for 2 hours at 40 C and added 6,06 kg MtBE within 8 hours. The mixture was stirred for 2 hours and cooled to 0 C). Suspension, washed 1.67 kg mixture of MTBE, ethanol (5,4:1) and $ 1.66 kg MTBE, getting after drying 1.1 kg monohydrate hydrochloride, 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol. Confirm that the resulting product is a form of A.

In some versions use the way described below. The reactor was loaded 31,80 kg (R)-1-(2-(dimethylamino)-1-(4-)ethyl)cyclohexanol. Suspension 0,636 kg of palladium-on-coal 3,96 kg ethanol (5% denatured methanol). The atmosphere of the reactor it was drained and replaced with nitrogen three times to remove the air. The reactor was loaded 56,1 kg ethanol, then to 17.4 kg to 20% of the mass. HCl solution. Temperature is brought up to 20-25°C. Solids were completely dissolved after 35 minutes when nitrogen through a solution for degassing. The reaction mixture is subjected to pressure hydrogen 45-55 psi (demonstrated to be 0.314-0,384 MPa), gas were produced and then again subjected to pressure hydrogen 45-55 psi (demonstrated to be 0.314-0,384 MPa). Mixture was stirred at 20-30°C until the completion of the reaction. Hydrogen produced in a reactor 3 times created nitrogen pressure 50-60 pounds per square inch (0,349-0,419 MPa). The reaction mixture was filtered through 3 micron filter and reactor/filter washed 12.0 kg ethanol. United filtrate/washing water added to 157,0 kg MTBE at 40 C-45 C. as A seed added salt (-)-O- (635 g) and the mixture was stirred for 2 hours and 4 minutes at 35 C-45 C. Added 191,9 kg MTBE within 8 hours, keeping the temperature at 35 C-45 C. Mixture was stirred at 35 C-45 deg C for 2 hours and 3 minutes and then the mixture is cooled to a temperature from -5 degrees C to +5 C for 2 hours and 3 minutes. The suspension was stirred at temperature from -5 degrees C to +5 C for 37 minutes and filtered. The filter cake washed mixture of MTBE (43.6 kg) and ethanol (8.2 kg), then 100% MTBE (52,3 kg). The wet sediment filter (26,25 kg) dried at a temperature of no higher than 25 C, receiving 25,42 kg hydrochloride monohydrate (R)-1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol.

In the examples presented some typical ways of synthesis of (-)-O-. Alternative ways of synthesis of (-)-O- will be known to the specialists in this field.

6.3. EXAMPLE 2: TO DETERMINE THE EFFICACY AND SPECIFICITY

In the literature describes several techniques that can be applied to determine the efficiency and specificity of the compounds according to the present invention. See, for example, Haskins, J. T. et al. Euro. J. Pharmacol. 115: 139-146 (1985). In some versions of the methods that have been found are especially applicable, are described in publications Muth, E.A. et al. Biochem. Pharmacol. 35: 4493-4497 (1986) and Muth, E.A. et al. Drug Develop. Res. 23: 191-199 (1991), which are incorporated into this description as a link.

6.3.1. Binding with the receptor

Definition of binding to the receptor of the compounds according to the present invention, preferably carry out the ways described Muth et al., and using protocols that have been summarized in patents of USA № 6342533 B1, 6441048 B1 and 6911479 B2.

Used tissue homogenates preferably receive from the whole brain, except for the cerebellum (the binding of histamine-1 and opiate), cortex (linking α 1-adrenergic receptor, capture monoamine); and striatum (receptor binding of dopamine-2 and receptor).

6.3.2. Research capture in

These studies can be performed using the modified technique of Wood, M.D., and Wyllie, M.G.J. Neurochem. 37: 795-797 (1981)described in Muth et al. Biochem. Pharmacol. 35: 4493-4497 (1986). Briefly, sediment P2 received fresh brain tissue of rats as a result of centrifugation in the gradient of the density of sucrose using the vertical rotor. For research capture all components dissolved in the next buffer: 135 mm NaCl, 5 mm KCl, 1.2 mm MgCl 2 , 2.5 mm CaCl2 , 10 mm glucose, 1 mm ascorbic acid, 20 mm Tris, pH of 7.4, is carbonated O 2 for 30 minutes before using. Different concentrations of the test of a medicinal product pre-incubated with 0.1 microns [ 3 H]dopamine or 0.1 microns [ 3 H]norepinephrine (130000 CPM/tube) and 0.1 microns [ 14 C]of serotonin (7500 CPM/tube) 0.9 ml of buffer for 5 minutes at 37 deg C. One-tenth milliliters drug synaptosomes structures were added to each tube and incubated for another 4 minutes at 37 deg C. Then the reaction was stopped by the addition of 2.5 ml of buffer, then the mixture was filtered in a vacuum, using the filters of cellulose acetate (pore size 0,45 microns). Then filters believed in the scintillation counter and results were expressed as pmol capture/mg protein/min. Values IC 50 for inhibition capture calculated on the basis of linear regression log [percentage of Na + -dependent capture] against log [concentration of the test of a medicinal product].

6.3.3. Reversible induced hypothermia rezerpinom

Reversible induced rezerpinom hypothermia in male mice CF-1 (20-25 g, Charles River) can be obtained by using a modification of method Askew, B. Life Sci. 1: 725-730 (1963). The tested compounds, suspended or dissolved in a 0,25% tween 80® in water, then administered intraperitoneally, using multiple levels of doses, male mice (8/dose level), of which 18 hours before the processed 45.0 mg/kg rezerpina subcutaneously. The control group receiving a filler, examined simultaneously with the groups who received the drug. Test the connection, filler and reserpine injected in the amount of 0.01 ml/year Reserpine , adding a small amount (approximately 4 drops) concentrated acetic acid and then brought to the desired volume by adding distilled water. Rectal temperature recorded thermistor sensor Yellow Springs Instruments at a depth of 2 cm Measurements were carried out for 18 hours after preprocessing rezerpinom and intervals within 3 hours after administration of either the test connection or filler.

Data on rectal temperatures for all time periods subjected analysis for multiple measurements with subsequent comparison with use of criterion of with the benchmark values to determine the minimum effective dose (MED) for induced rezerpinom hypothermia.

6.3.4. Induction reduced the pineal noradrenergic sensitivity in rats

As suitable rats used male rats Sprague-Dawley (250-300 g, Charles River), which must be kept under continuous coverage for all experiments in order to reduce the daily fluctuations of the density of beta-adrenergic receptors in the pineal gland and maintain resistant super-sensitive response to the noradrenergic agonists (Moyer, J.A. et al. Soc. Neurosci. Abstract 10: 261 (1984)). After 2 days of continuous exposure to light rats were injected twice a day or saline, or the connection (10 mg/kg, intraperitoneal) for 5 days (only 9 injection). Another group of rats received injections of physiological solution twice a day for 4 days followed a single injection of the tested compounds (10 mg/kg, intraperitoneally) on the 5th day. One hour after the last injection test connection or physiological solution, the animals were injected or 0,1% ascorbic acid (controls)or isoproterenol (2 mmol/kg intraperitoneally 0.1% ascorbic acid). Rats beheaded, after about 2.5 minutes, i.e. the period of time, after which, as shown by preliminary experiments induced increasing levels of cyclic AMP is the maximum (Moyer, J.A. et al. Mol. Pharmacol. 19: 187-193 (1981)). gland was removed and froze, placing dry ice for 30 seconds to minimize any increase in the concentration camp after decapitation.

Before radioimmunoassay camp gland placed in 1 ml of chilled on ice 2,5% acid and treated with ultrasound within about 15 seconds. Then treated with ultrasound material was centrifuged at 49000g for 15 minutes at 4 OC C and then received liquid seized neutralise the excess of the CaCO 3 and was centrifuged at 12000g for 10 minutes at 4 C. Zamf content to offset the extract was possible to measure the standard radioimmunoassay using 125 I-labeled antigen and (New England Nuclear Corp., Boston, Mass.; Steiner, A.L. et al. J. Biol. Chem. 247: 1106-1113 (1972)). All unknown samples should be analysed in two replays and compare with the standard solutions camp, cooked 2.5% solution acid, which was offset CaCO 3 . Results were expressed as pmol camp/ gland and statistical analyses performed using analysis of variance, and the subsequent evaluation based on the criteria of student-Newman-.

6.3.5. Electrophysiology of individual neurons

Frequency of impulses of individual neurons blue spots locus coeruleus (LC) or the kernel of a seam (DR) of rats were measured using single-channel glass , as described earlier in LC. Haskins, J.T. et al. Eur. J. Pharmacol. 115: 139-146 (1985). Using coordinates described in the Konig, J.F.R., and Klippel, R.A. The rat brain: A stereotaxic atlas of the forebrain and lower parts of the brain stem Baltimore: Williams and Wilkins (1963), the tips of the electrodes lowered with the help of hydraulic from point to 1.00 mm above coeruleus (AP at 2.00 mm line and by 1.03 mm lateral of the middle line). Drugs injected intravenously through a cannula in the lateral tail vein. Each rat is necessary to examine only one cell to avoid residual effects of the drug.

6.4. EXAMPLE 3: ORAL

Pharmaceutical compositions according to the present invention can be introduced in different ways, including oral.

6.4.1. Dosage forms in the form of firm gelatinous capsules

Ingredients suitable forms of pharmaceutical compositions according to the present invention, in the form of capsules can be found in the patents of USA № 6342533 B1, 6441048 B1 and 6911479 B2.

The active ingredient (optically pure (-)-O- or pharmaceutically acceptable salt) sift and mix with the listed . Mixture fill consists of two parts, hard gelatin capsules suitable size, using suitable equipment and methods, well-known in the field. Cm. Remington's Pharmaceutical Sciences, 16th or 18th edition, which are incorporated into this description as a link in full. Other dose can be prepared in the result of change of the pledged mass and, if necessary, the resizing of the capsule to a suitable size. Can be created by any of the above described stable preparations in the form of hard gelatin capsules.

6.4.2. Dosage forms in the form of compressed tablets

Ingredients forms of pharmaceutical compositions of the invention in the form of compressed tablets can be found in patents of USA № 6342533 B1, 6441048 B1 and 6911479 B2.

The active ingredient through a suitable sieve and mix with to form a homogeneous mixture. Sift the dry mixture and mix with magnesium. Then, the resulting powder blend is pressed into tablets desired shape and size. Tablets with other efficiency can be obtained as a result of changes in the ratio of the active ingredient and (s) or modifying a lot of pills.

6.4.3. Sample preparation in the form of capsules

(mg/capsule)

(mg/capsule)

Monohydrate hydrochloride (-)-O-

Microcrystalline cellulose (Avicel PH102)

Lactose anhydrous

sodium starch (Primojel)

Magnesium stearate

Total weight

6.4.4. Slow release of the drug

Investigated several slow release of drugs. Found that adding more Methocel K4M CR reduced the rate of dissolution. Tablets produced using drugs, as described below.

Granulirovanie preliminary mixture

Ingredients

Composition of the premix

SEP-227162-01

Avicel pH 102

Surelease (15% of the mass./the masses.)

Final preparations

Ingredients

Composition of the A (mg)

The composition of B (mg)

Composition C (mg)

687.00 is

687.00 is

687.00 is

Methocel K4M CR

Magnesium stearate

Weight the tablets

6.5. EXAMPLE 4: CRYSTALLIZATION AND CHARACTERISTIC FORM A MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.5.1. Crystallization

(-)-O- form A HCl-salt (-)-O-. Free base (-)-O- received according to example 1. Form A HCl-salt (-)-O- received from the form B HCl-salt (-)-O- described below, according to the following method: 3,09 g sample most commonly available as hydrochloride salt (-)-O- (form B) placed in a Cup for crystallization size 70 x 50 mm and kept at 40 C/75%RH within 3 days. The sample was then dried in a vacuum at a temperature of the environment within 2 days.

The crystals form A HCl-salt (-)-O- suitable for single crystal x-ray diffraction, received manner on the basis of the system solvent/ of systems of solvents water/2-. Single crystal x-ray diffraction data received using diffractometers Nonius Kappa CCD with Mo K-radiation (l = 0,71073 & A). The precise value of the mosaic received with the use of DENZO/SCALEPACK (Otwinowski and Minor, Methods Enzymol. 276: 307 (1997)). The space group was determined using the program XPREP (Bruker AXS Inc., Madison, Wisconsin, USA, (2002)). Integration of data was performed using DENZO-SMN (Otwinowski and Minor, Methods Enzymol. 276: 307 (1997)Used the empirical absorption correction, derived using SCALEPACK (Otwinowski and Minor, Methods Enzymol. 276: 307 (1997)). The structure is solved by direct methods using SIR2004 (Burla et al., J. Appl. Cryst., 36: 1103 (2003)) and clarify conducted on a LINUX PC using SHELX97 (Sheldrick, University of Göttingen, Germany, (1997)). The absolute configuration of the molecule (-)-O- installed using the information about the model structure of different crystalline forms (forms F described below)obtained using the same source substance (-)-O-. Details of data collection and structural parameters are shown in table I.

ORTEP-image asymmetric unit model of the structure of the crystal crystalline form of A HCl-salt (-)-O- is shown in Fig.7 (ORTEP-3 for Windows v. 1,05. Farrugia, J. Appl. Cryst, 30: 565 (1997)). Asymmetric unit, shown on the drawing contains one cation (-)-O-, one chloride anion and one molecule of water.

Data on the structure of the crystal and data collection settings to form A HCl-salt (-)-O-

C 16 H 28 ClNO 3

Formulas weight

Space group

P2 1 2 1 2 1 (№ 19)

Dimensions of the unit cell

a=6,7797(2) & A; a=90°, b=9,2896(4& & beta=90°, c=27,6496(15& g=90°

1741,39(13)A 3

d calc. g·cm-3

Crystal dimensions, mm

of 0.46 x 0,13 x 0,04

Temperature, K

Radiation wave length, & A)

Mo K a (0,71073)

Monochromator

Linear coefficient of absorption, mm -1

Used amendment on the absorption of

Empirical and

Transmission factors: min, max

0,916, 0,992

Diffractometer

Nonius Kappa CCD

h, k, l - region

-8-7-11-11-33-34

Region 2, deg

4,38-52,21

Mosaicism, deg

Used programs

weighing 1/[a 2 (F o 2 )+(0,0000P) 2 +1,9052P], where P=(F o 2 +2F c 2 )/3

The number of reflections

The number of independent reflections

The amount of reflection, used in clarifying

Limit cut-off used in calculations of R-factors

F o 2 >2,0(F o 2 )

The number of reflections with I>2,0 Sigma(I)

The number of variables

The biggest changes/estimated standard deviation in the long cycle of clarification

R w F o 2 )

Accuracy of fitting

Definition of absolute patterns

Option Vlek (0,1(2))

Calculated powder x-ray, modeled for Cu-radiation using PowderCell 2,3 (Kraus and Nolze, Federal Institute for Materials Research and Testing, Berlin, Germany, (1999)) on the basis of data about coordinates atoms, space group, and the parameters of elementary cell, obtained on the basis of data on structure of the crystal form A; see Fig.8. Experimental powder x-ray of A shape is consistent with the picture, modelled on the basis of the data of x-ray single crystal diffraction. Small shifts in the provisions of XRPD-peaks occurred as a result of small changes in parameters of elementary cell of the difference in temperature: calculated powder x-ray on the basis of the data of a single crystal, received at 150 K, whereas the experimental pattern of diffraction of a powder receive at ambient temperature. Data collection at low temperature is usually used for analysis of a monocrystal to improve the quality of the data received.

6.6. EXAMPLE 5: CRYSTALLIZATION AND CHARACTERISTIC FORM B MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.6.1.

(-)-O- form B HCl-salt (-)-O-. (-)-O- received according to example 1. 5,07 g HCl-salt (-)-O- was dissolved in 400 ml of tetrahydrofuran at 40 degrees C. the Solution was cooled to 25 degrees C and added to 10.6 ml 2,0M HCl in diethyl ether. The mixture was cooled to 0 C and filtered. The filter cake washed 20 ml THF and dried in vacuum at a temperature of environment, receiving 6,09 g form B hydrochloride, 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol.

6.6.2. Characteristic

Crystalline form B HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the parameters of analysis described above.

6.7 EXAMPLE 6: CRYSTALLIZATION AND CHARACTERISTIC FORM C most commonly available as hydrochloride SALT (-)-O-

6.7.1. Crystallization

Crystalline form C HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the parameters of analysis described above.

6.8. EXAMPLE 7: CRYSTALLIZATION AND CHARACTERISTIC FORM D MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.8.1. Crystallization

(-)-O- form D HCl-salt (-)-O-. (-)-O- received according to example 1. Form A (42,8 mg) HCl-salt (-)-O- obtained as described in example 4, weighed and placed in a bottle and added 0.5 ml IPA. The sample treated with ultrasound, and he became very viscous. Solids allocated vacuum filtration and the sample was dried in the air in a fume hood. After drying within days sample stored in the environment, in the course of four days, at the specified point implemented XRPD-analysis.

6.8.2. Characteristic

Crystalline form D HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry and thermal gravimetric analysis, according to the parameters of analysis described above.

6.9. EXAMPLE 8: CRYSTALLIZATION AND CHARACTERISTIC FORM E MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.9.1. Crystallization

(-)-O- form E HCl-salt (-)-O-. (-)-O- received according to example 1. 0.35 ml 37% of the mass. aqueous solution of hydrochloric acid was added to 5.0 g (-)-O- in 25 ml of methanol. The resulting solution is stirred at 25 C for 20 minutes. While stirring the solution was added methanol/hydrochloric acid to 300 ml of methyl tert-butyl ether under 25 C. After adding a solution of methanol/hydrochloric acid mixture was stirred at 25 C for 2 hours and then the solid is collected by filtration and washed with 20 ml of MTBE. Solid dried in air at ambient temperature, gaining 5.4 form E hydrochloride, 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl)cyclohexanol.

6.9.2. Characteristic

Crystalline form E HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the parameters of analysis described above.

6.10. EXAMPLE 9: CRYSTALLIZATION AND CHARACTERISTIC FORM F HCl-SALT (-)-O-

6.10.1. Crystallization

It forms A HCl-salt (-)-O- (19,47 mg) were introduced into the vial and added to 3 ml ethyl acetate. After ultrasonic remained solid substances. The sample is placed on a hot plate, set at 75 C and mixed using a magnetic stirrer, set at 350 rpm After about 2.5 hours mixing at 75C sample was filtered using a syringe, heated bottle of 1 drachma (3,696 ml). (Before filtering, the filter, the syringe and vial was heated on a hot plate with the sample). The sample covered with lid, put on the surface of the table and we are allowed to cool down to ambient temperature. The sample was subjected to vacuum filtered and analyzed as a form of F.

6.10.2. Characteristic

Crystalline form F HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the parameters of analysis described above.

6.10.2.1. Single crystal x-ray diffraction data form F

The crystals form F HCl-salt (-)-O- suitable for single crystal x-ray diffraction, received way, based on vapor diffusion. Three milliliters 2- added to 7.71 mg form A, obtained as described above. Not all solids dissolved. The sample was filtered into the vial with the volume of 1 drachma (3,696 ml). The vial is placed in 20-ml vial for scintillation measurements, contains toluene. Then a larger bottle covered with lid and provided an opportunity to counterbalance the sample. Isolated single crystals form F and defined structure.

Single crystal x-ray analysis was performed using the diffractometer Bruker D8 APEX II CCD with Cu K-radiation (l=1,54178Å) in a sealed tube. Data collection, indexing, and primary refinement of the cells was carried out, using a computer program APEX II (Bruker AXS Inc., Madison, WI, USA, (2005)). Integration of personnel and the final clarification of the cells was carried out, using a computer program SAINT (v. 6,45A, Bruker AXS Inc., Madison, WI, USA (2003)). Spatial group was defined using the XPREP (SHELXTL v. 6,12, Bruker AXS Inc., Madison, WI, USA). Empirical absorption correction applied using SADABS (Blessing, Acta Cryst., A51:33 (1995)). The structure is solved by direct methods using SHELXS-97 (Sheldrick, University of Göttingen, Germany, (1997)). Clarification was performed on PC using SHELXTL (v. 6,12, Bruker AXS Inc., Madison, WI, USA). The absolute configuration of the molecule (-)-O- established on the basis of factor calculation (Flack and Bernardinelli, Acta Cryst., A55: 908 (1999), and J. Appl. Cryst, 33: 1143 (2000)). More detailed information on the collection of data and parameters of the structure is shown in table 2.

ORTEP-image asymmetric unit model of the structure of the crystal crystalline form F HCl-salt (-)-O- shown in fig.37 (ORTEP-3 for Windows v. 1,05. Farrugia, J. Appl. Cryst., 30: 565 (1997)). Asymmetric unit, shown on the drawing contains one cation (-)-O-, one chloride anion and one molecule of water of hydration.

Data on the structure of the crystal and data collection options for the form F HCl-salt (-)-O-

Empirical formula

C 16 H 28 ClNO 3

Formulas weight

Temperature

Wavelength

1,54178Å

Crystal system

Monoclinic

Space group

Dimensions of the unit cell

a=9,2881(2) & A; a=90°, b=6,8185(2)& & beta=92,580(1)deg c=13,9085(3& g=90°

879,95(4)A 3

Density (calculated)

1,200 mg/m 3

Absorption coefficient

1,996 mm -1

The size of the crystal

0,43 x 0,25 x 0.18 mm (3

The scope of data collection on theta

8.07-a 65,77°

Field indexing

-10<=h<=10, -6<=k<=6, -16<=l<=15

The number of reflections

The number of independent reflections

1722 [R(int)=0,0131]

Weight to theta = 65,77°

Amendment on the absorption of

On the basis of semiempirical equivalents

Maximum and minimum transmittance

0,7152 and 0,4807

Way to Refine

least squares F 2

Data/limits/parameters

1722/1/194

Accuracy of fitting F 2

End-R-factors [I>Sigma 2(I)]

R1=0,0265, wR2=0,0714

R-factors on all data)

R1=0,0268, wR2=0,0716

The parameter structure of the absolute

0,034(13)

The highest diffraction peak and failure

0,129 and -0,185 e,A -3

Calculated powder the x-ray, modeled for Cu-radiation using PowderCell 2,3 (Kraus and Nolze, Federal Institute for Materials Research and Testing, Berlin, Germany, (1999)) and data on the coordinates of atoms, space group, and the parameters of elementary cell, obtained on the basis of data on structure of the crystal shape F; see fig.33. Experimental powder x-ray of the form F is consistent with the picture, modelled on the basis of the data of x-ray single crystal diffraction. Differences in intensities may be associated with the preferred orientation. Under the preferred orientation understand the propensity of crystals, especially sticks or needles, be not randomly. Preferred orientation affects the intensity of the peaks in the powder x-ray. Small shifts in the positions of the peaks can be associated with different temperatures experiments: the experimental pattern powder diffraction received at ambient temperature, while the data for the monocrystal have received 173 K. Some samples of the form F, which allocated in the form of physical mixtures with form A, detect peaks, characterizing the shape of A picture XRPD, which are not in the calculated picture XRPD forms F.

6.11. EXAMPLE 10: CRYSTALLIZATION AND CHARACTERISTIC FORM G MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.11.1. Crystallization

(-)-O- form G HCl-salt (-)-O-. (-)-O- received according to example 1. Crystalline form A (-)-O- (31,50 mg)obtained in example 4, placed in a bottle for scintillation volume of 20 ml, which is without a cover was placed in a cell with a P 2 O 5 at ambient temperature. Three days chamber containing the sample was placed in the oven at 70 degrees C. Analysis of ten days after placing the sample in the microwave, showed that the sample is in the shape of G.

6.11.2. Characteristic

Crystalline form G HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry, thermal gravimetric analysis and sorption moisture, according to the parameters of analysis described above.

6.12. EXAMPLE 11: CRYSTALLIZATION AND CHARACTERISTIC FORM H, THE MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.12.1. Crystallization

Crystalline form H HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry and thermal gravimetric analysis, according to the parameters of analysis described above.

6.13. EXAMPLE 12: CRYSTALLIZATION AND CHARACTERISTIC FORM I MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.13.1. Crystallization

(-)-O- as a form I-HCl-salt (-)-O-. (-)-O- received according to example 1. Form I besieged from isopropanol. One sample is obtained by dissolving 46,01 mg form A HCl-salt (-)-O- in 0.5 ml of isopropanol, through processing by ultrasound. Sample received in vial with the volume of 1 drachma (3,696 ml). Precipitation was observed in about 10-15 minutes. Solids allocated vacuum filtration. The second sample obtained using the method described for the first sample, except that dissolved 25,86 mg form A HCl-salt (-)-O-. This is precipitation with in the case of the second sample was observed in about ten minutes. After the synthesis of solid substances were isolated and described as a crystalline form I HCl-salt (-)-O-.

6.13.2. Characteristic

Crystalline form I HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry and thermal gravimetric analysis, according to the parameters of analysis described above.

6.14. EXAMPLE 13: CRYSTALLIZATION AND CHARACTERISTIC FORM J MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.14.1. Crystallization

(-)-O- form J HCl-salt (-)-O-. (-)-O- received according to example 1. Form J HCl-salt (-)-O- received form A acetonitrile for about a day on a hot plate set at 55 degrees C. the Form of A HCl-salt (-)-O- (43,66 mg) was weighed and placed into a vial with the volume of 1 drachma (3,696 ml) and add 0.5 ml of acetonitrile. After ultrasonic remained solid substances. The sample is mixed on a hot plate, using a magnetic stirrer, installed at 300 revs/min. a day solvent was removed. Thus obtained solids described as a crystalline form J HCl-salt (-)-O-.

6.14.2. Characteristic

Crystalline form J HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray and NMR-spectroscopy, according to the parameters of analysis described above. Approximately 0.2 mol acetonitrile mole HCl-salt (-)-O- present in the sample form J as was defined using NMR spectroscopy.

6.15. EXAMPLE 14: CRYSTALLIZATION AND CHARACTERISTICS OF THE FORM K MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.15.1. Crystallization

(-)-O- as a form K-HCl-salt (-)-O-. (-)-O- received according to example 1. Form K HCl-salt (-)-O- received in experiment, based on the diffusion of vapor phase, conducted with the use of ethanol as a solvent and acetone as . Sample received the addition of 0.3 ml of ethanol to 22,20 mg form A HCl-salt (-)-O-. The sample was dissolved and filtered into the vial with the volume of 1 drachma (3,696 ml). The bottle was placed into the vial for scintillation volume of 20 ml, containing acetone. Then a larger bottle covered with lid and the sample was given the opportunity to reach a balance. In such an experiment was isolated single crystals. Thus obtained crystals described as a crystalline form K HCl-salt (-)-O - .

6.15.2. Characteristic

Crystalline form K HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray and x-ray diffraction (single crystals, according to the parameters of analysis described above.

6.15.2.1. Single crystal x-ray diffraction data of the form K

The full content of asymmetric unit of the crystal structure of the form K includes two cation (-)-O-, two chloride anion and one partially occupied by highly molecule of ethanol. As a molecule of ethanol is not fully occupied, the form K is called partial .

Data on the structure of the crystal and data collection options for the form K HCl-salt (-)-O-

Empirical formula

C l6 H 26 ClNO 2 ·0,14(C 2 H 6 O)

Formulas weight

Temperature

Wavelength

1,54178Å

Crystal system

Monoclinic

Space group

Dimensions of the unit cell

a=30,056(3) & A; a=90°, b=7,7375(8& & beta=134,502(4)OC, c=21,208(4& g=90°,

3517,7(8)A 3

Density (calculated)

1,157 mg/m 3

Absorption coefficient

1,944 mm -1

The size of the crystal

0,53 x 0,08 x 0.06 mm 3

The scope of data collection on theta

7,37-44,67°,

Field indexing

-27<=h<=25, -7<=k<=7, -19<=l<=19

The number of reflections

The number of independent reflections

2063 [R(int) = 0,0413]

Weight to theta = 44,67°

Amendment on the absorption of

On the basis of semiempirical equivalents

Maximum and minimum transmittance

0,8923 and 0,4256

Way to Refine

Fully-matrix least-squares F 2

Data/limits/parameters

2063/2/378

Accuracy of fitting F 2

End-R-factors [I>Sigma 2(I)]

R1=0,0518, wR2=0,1391

R-factors on all data)

R1=0,0800, wR2=0,1571

The parameter structure of the absolute

The highest diffraction peak and failure

0,464 and -0,545 e,A -3

Calculated powder x-ray, modeled for Cu-radiation using PowderCell 2,3 (Kraus and Nolze, Federal Institute for Materials Research and Testing, Berlin, Germany, (1999)) and data on the coordinates of atoms, space group, and the parameters of elementary cell, obtained on the basis of data on structure of the monocrystal of the form K; see fig.50. Experimental powder x-ray of the form K is consistent with the picture, modelled on the basis of the data of x-ray single crystal diffraction. Differences in intensities may be the result of preferred orientation. Small shifts in the positions of the peaks can be associated with different temperatures experiments: the experimental pattern powder diffraction received at ambient temperature, while the data for the monocrystal have received 173 K.

6.16. EX 15: CRYSTALLIZATION AND CHARACTERISTIC FORM L MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.16.1. Crystallization

(-)-O- form L HCl-salt (-)-O-. (-)-O- received according to example 1. Form of L received from long-located at an ambient temperature of suspension 2-. The sample is obtained by adding 20 ml 2- to 38,75 mg form A HCl-salt (-)-O-. For the experiment we used a bottle to measure scintillation volume of 20 ml and slowly added 2-. After adding the solvent attended solids, and the sample covered with lid and put on a rotating stand at ambient temperature. After 97 days of rotation on a stand sample form L was removed, was subjected to vacuum filtration and conduct analyses. Thus obtained solids described as a crystalline form L HCl-salt (-)-O-.

6.16.2. Characteristic

Crystalline form L HCl-salt (-)-O- obtained according to the above described method, characterized by such methods as powder x-ray, differential scanning calorimetry, thermal gravimetric analysis and NMR-spectroscopy, according to the parameters of analysis described above. Approximately 0.13-0.14 in mol 2- mole HCl-salt (-)-O- present in the sample form L, as determined using NMR spectroscopy.

6.17. EXAMPLE 16: OBTAINING AND CHARACTERIZATION OF THE FORM MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O- AS

6.17.1 to. Receive

Form C HCl-salt (-)-O- received as described above. Form C was heated to 100 C in a kiln for TGA according to the above described method and watched the mass loss component of 5.4%. The substance is removed from the furnace; the analysis confirmed that the substance represented the .

6.17.2. Characteristic

were analyzed using powder x-rays. Position of peaks in powder x-ray were similar to the peaks XRPD of the original matter, form C. The obtained data together with data on the weight loss derived using TGA, showed that the solvent creates a void in the crystal lattice of the form C, while maintaining the structural features of the form C in the form of .

6.18. EXAMPLE 17: OBTAINING AND CHARACTERIZATION OF AMORPHOUS FORMS MOST COMMONLY AVAILABLE AS HYDROCHLORIDE SALT (-)-O-

6.18.1. Receive

The product is characterized by powder x-rays and modulated differential scanning calorimetry. Data XRPD confirmed that the substance was amorphous. On the basis of data modulated differential scanning calorimetry the glass transition temperature of amorphous forms HCl-salt (-)-O- was approximately 24 degrees C.

6.19. EX 18: COMPOSITION OF THE DRUG THEOPHYLLINES CONTAINING SALT (-)-O-

(-)-O-·HCl and Avicel mixed inside vertical granulator. The mixture slowly added Pharmacoat 606. Then wet a lot of dried in the tray dryer by 45 deg C for 2 hours and then semi-dry mixture is passed through the mill Fitzmill using sieve size 0109 at 2000 rpm Particles again returned to the kiln. Dry granules through a sieve №14 and retained on the sieve №14 material passed through Fitzmill. The ground particles mixed with smaller sifted particles. Composition the drug is given in table 4. Using such a premix, received final drug summarily presented in table 5.

drug

Ingredient

Number (mg)

Active pharmaceutical ingredient: form A (-)-O-·HCl

Avicel 105

Pharmacoat 606 (8% solution)

The final drug

Ingredient

Composition

Magnesium stearate

Methocel K4M CR

In another variation, the active pharmaceutical ingredient and Avicel added into the granulator with great effort to shift and mixed within a short period of time. Was added dropwise suspension Surelease in the implementation process with a large shear. Wet product granulation removed from the granulator with great effort to shift, dried in the dryer with fluidized bed, mixed with Methocel and magnesium and extruded in a suitable car.

drug

Ingredient

Number (mg)

Active pharmaceutical ingredient: form A (-)-O-·HCl

Avicel pH 102

Suspension Surelase 20% mass./the masses. (dry weight/weight suspension)

Matrix tablets

Tablet 50 mg

Ingredient

Number (mg)

Magnesium stearate

Methocel K15M CR

Tablet 100 mg

Ingredient

Number (mg)

Magnesium stearate

Methocel K15M CR

Tablet 150 mg

Ingredient

Number (mg)

Magnesium stearate

Methocel K15M CR

All publications and patents, cited in the present description is included in this publication as a link, just as if specially and separately would be stated that each separate publication or patent application is included as a link. Although the above invention was described in details using illustrations and examples for clarity, the specialists in this field in the light of the above in the present description of the instructions easy to understand, that can be implemented some changes or modifications not departing from the essence, and not going beyond the accompanying volume of claims.

1. Crystal form of salt pure compound of formula (I):

which contains water, and the water is present in the amount of approximately 4% to about 8% of the total mass of the sample, and molar ratio of water to the most commonly available as hydrochloride salt is around one to one, and the crystalline form has peaks of powder x-rays in the provisions about 12,7, 14,5, 19,1, 21,4, 23,0, 25,5 and 27.3°2, and is characterized by the following relevant parameters of elementary cell, measured about 150K: a=6,78 & A; b=9,29& C=27,65 & A; a=90 C; & beta=90 C; γ=90 degrees.

2. Crystal form according to claim 1, which is characterized by the loss of mass in the case of thermal analysis from about 4% to about 8% of the total mass of the sample when heated from about 25 degrees to about 110 degrees C.

3. Crystal form according to claim 2, where weight loss is about 5.6%.

4. Crystal form according to claim 1, which is characterized by an endothermic effect by differential scanning calorimetry with temperatures begin the effect from about 50 to about 125 C C.

5. Crystal form according to claim 4, where the onset of effect is approximately 93°N

6. Crystal form according to claim 1, which is at a relative humidity of approximately 5% to approximately 85%.

7. The crystalline form of claim 1-6, which is the purest form.

8. Pharmaceutical composition, suitable for treatment, prevention or management of the disease, selected from depression, pain, anxiety, incontinence or vasomotor symptoms caused by menopause, containing crystalline form on any one of claims 1 to 7 and pharmaceutically acceptable diluent or media, where the number of crystalline form most commonly available as hydrochloride salt pure compound of formula (I) pharmaceutical compositions is about 10 mg to about 1000 mg

9. Method of treatment, prevention or management of the disease, selected from depression, pain, anxiety, incontinence or vasomotor symptoms caused by menopause, which includes an introduction to the patient in need of such treatment or prevention of disease, therapeutic or prophylactic effective number of pharmaceutical compositions on item 8.

10. The method of claim 9, in which the disease is depressed.

11. The method of claim 9, in which the disease is pain.

12. The method according to claim 11, in which pain is a chronic pain.

13. The method of claim 9, in which the disease is anxiety.

14. The method according to item 13, in which anxiety is an obsessive-compulsive disorder.

15. The method of claim 9, in which the disease is a incontinence.

16. The method according to item 15, which incontinence is a incontinence, urinary incontinence due to the overflow of the bladder, passive incontinence, reflex incontinence, stress urinary incontinence, urgent incontinence, or caused by the physical stress urinary incontinence.

17. The method of claim 9, in which the disease is vasomotor symptom caused by menopause.

18. The method according to paragraph 17, which vasomotor symptom caused by menopause, represents the tides.

19. The method of claim 9, in which the number of crystalline form most commonly available as hydrochloride salt pure compound of formula (I) is not enough to cause adverse effects associated with the introduction of racemic venlafaxine.

20. The method of claim 9, in which the number of crystalline form most commonly available as hydrochloride salt pure compound of formula (I) in the pharmaceutical composition ranges from about 50 mg up to approximately 500 mg or from approximately 75 mg to approximately 300 mg of