Obtaining crystalline antibiotic

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to process of crystallisation, obtaining and isolation of novel crystalline form of fusidic acid, to application of said processes in production of pharmaceutical composition or medication, and to application of said form of crystalline fusidic acid in treatment of bacterial infections.

EFFECT: obtaining pharmaceutical composition for treatment of bacterial infections.

11 cl, 10 ex, 1 tbl, 10 dwg

 

The technical field to which the invention relates

The present invention relates to a new crystalline form guideway acid, its acquisition, its containing pharmaceutical compositions and the use of specified crystalline form guideway acid as a drug for the treatment of infectious diseases.

The level of technology

Positieve acid [CAS6990-06-3] [Nature, Vol. 193, no. 4819, p. 987, 1962], which can be isolated from the fermented brothFusidium coccineumis the most active antibiotic component of Positano and is the only Fusiderm used in the clinic for the treatment of infectious diseases. Positieve acid (Fucidin®) is used in the clinic for the treatment of severe staphylococcal infections, in particular infectious diseases of bones and joints, acute and irreversible forms of the disease (The Use of Antibiotics, 5thEd., A. Kucers and N. McK. Bennett (Eds.), Butterworth 1997, pp. 580-587, and references cited herein).

Positieve acid

Although positieve acid is most often used against staphylococci, it is also used against some other gram-positive strains. Clinical value guideway acid also depends upon its effective distribution in various tissues, a low degree of toxicity and the lergicheskie reactions and lack of cross-resistance with other antibiotics, used in the clinic. Positieve acid is widely used in the local treatment of some infections of the skin and eyes caused by staphylococci. It is widely prescribed in combination with common antibiotics, such as penicillins, eritromicina or clindamycin. It is also used as an alternative to vancomycin for the suppression of theClostridium difficile. In comparison with staphylococci and some other gram-positive cocci are often less sensitive to guideway acid. As an example of the types of streptococci usually up to 100 times less sensitive to guideway acid than staphylococci [Kuchers et al.; supra]. Other sensitive bacteria include gram-positive anaerobic cocci, such asPeptococcusandPeptostreptococcus spp.aerobic or anaerobic gram-positive bacteria, such asCorynebacterium diphtheriae,Clostridium tetani,Clostridium difficileandClostridium perfringens. Gram-negative bacteria are resistant, exceptNeisseria spp.andLegionella pneumophila. This tool is highly effective against both intracellular and extracellularM. Leprae.

Solid form, in particular crystalline form, drugs or active pharmaceutical ingredient used in the pharmaceutical composition or drug, important and based on the difference in solubility, with whom oresti dissolution, hygroscopicity, bioavailability and stability between different solid forms. Thus, the existence of different solid forms, in particular polymorphism or pseudopolymorphs, can affect the properties of the medicinal product.

Therefore, special crystalline form, including a solvate and hydrate, it may be preferable to the other form. Further, certain forms may be preferred depending on the specific composition and/or application. For example, the properties of drugs, such as the dissolution rate of the active ingredient, can be changed by a proper choice of a particular crystalline form, or mixtures thereof.

In a special commercial pharmaceutical composition positieve acid is present in the market in the form of a hemihydrate, which is the only form of hemihydrate, which has been described above.

Patent GB 930786 reveals salt guideway acid with organic and inorganic bases, solvate guideway acid, namely benzene MES and methanol MES. This patent further discloses a nonspecific form guideway acid with absorption bands in the IR (KBr) in 1265, 1385, 1695, 1730 and

3450 cm-1and having a specific rotation [a]D22in minute 9 C (1% solution CHCl3that, the floor is resolved by crystallization in methanol MES guideway acid from ether. However, such a shape that differs from the present invention, as is clear from the reflected infrared spectrum in GB 930786, which indicates that this form actually corresponds to the form of the hemihydrate, which is now available in the market.

The solvate and salt guideway acid have also been disclosed in the British patent GB 999794. Patent ES 2208110 reveals two solvent free crystalline form guideway acid also known as Form I and Form II and crystalline hemihydrate, called Form III, which is identical to the hemihydrate present currently on the market, respectively. Crystalline forms have been identified and characterized by IR spectroscopy, differential scanning calorimetry, x-ray and melting points.

Patent WO 96/03128 discloses a tablet form, containing the sodium salt guideway acid, and WO 86/03966 describes the ophthalmic composition of the gel containing the indeterminate form suspended guideway acid.

Disclosure of invention

The present invention unexpectedly provides a new crystalline form guideway acid and the process of obtaining the specified crystalline form guideway acid.

In one aspect this invention relates to crystalline guideway acid, characterized by the nalitch who eat one or more of the following properties (a)-(k), respectively:

a) Fourier-transformed spectrum of the Raman (FT-NIR)exhibiting one or more of the following peaks in intensity at approximately 3008, 2937, 2871, 1725, 1707, 1666, 1651, 1468, 1379, 1348, 1195, 1078, 1032, 972, 917, 792, 745, 696, 612, 569, 547, 527, 463, 175, 120 or 86 (±3 cm-1), respectively;

(b) Fourier-transformed spectrum of the Raman (FT-NIR), essentially similar to the one shown in figure 1;

c) Fourier-transformed infrared (FTIR-ATR) spectrum of the fading full reflectivity of exhibiting one or more of the following peaks fading full reflectivity at approximately 3644, 3489, 2992, 2937, 2871, 1722, 1708, 1442, 1381, 1352, 1283, 1255, 1218, 1204, 1175, 1149, 1109, 1069, 1048, 1028, 962, 941, 917, 851, 828, 791, 750, 690 or 656 (±3 cm-1respectively;

d) Fourier-transformed infrared (FTIR-ATR) spectrum of the fading full reflectivity, essentially similar to the one shown in figure 2;

e) spectrum in the near infrared (FT-NIR)exhibiting one or more of the following absorption peaks at approximately 10414, 8373, 7115, 6846, 6503, 5824, 4996, 4889, 4831, 4680, 4365, 4306 or 4067 (±5 cm-1respectively;

f) spectrum in the near infrared (FT-NIR), essentially similar to the one shown in figure 3;

g) powder x-ray diffraction (XDR)exhibiting one or more of the following the reflection angles 2θ (±0,1) at approximately 7,2, 9,3, 9,9, 12,6, 13,1, 14,3, 14,7, 14,9, 15,4, 16,7, 17,9, 18,1, 18,9, 19,5, 20,8, 21,8, 22,7, 2,5, 24,0, 24,4, 25,3, 26,0, 26,6, 26,8, 28,2, 28,9 or, 29,7, respectively;

h) a powder x-ray diffraction (XDR), essentially similar to that shown in figure 4;

i)13From the NMR spectrum of the solid sample with cross-polarization and rotation of the sample (CP/MAS)exhibiting one or more of the following resonances at approximately 173,9, 169,3, 146,1, 137,0, 133,3, 120,6, 76,2, 71,1, 69,1, 49,7, 49,4, 45,0, 39,9, 38,5, 36,9, 35,8, 34,5, 32,7, 30,9, 29,5, 28,0, 26,5, 20,7, 20,0, 18,0 or 16.9 (±0,5) frequent.·million-1respectively;

j)13From the NMR spectrum of the solid sample with cross-polarization and rotation of the sample (CP/MAS), essentially similar to the one shown in figure 6;

k) one or more of the following experimental results on single-crystal x-ray diffraction analysis: the crystal system = monoclinic, space group = P21, a [A] = 12,2, b [E] = 8,0, c [E] = 13,9, α [°] = 90 β [°] = 94,

γ [°] = 90, chamber volume [E3] = 1360, or Z = 2, respectively.

In another aspect this invention relates to the selected crystal guideway acid of the present invention, which, as defined above, has a polymorphic purity of at least 80%, in particular 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

In another aspect this invention relates to the selected crystal guideway acid of the present invention, which, as Opredelenie, has a degree of crystallization of at least 80%, in particular 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

The following aspect of this invention relates to a mixture or composition of the crystalline forms guideway acid, including pseudopolymorphic form guideway acid, where the mixture or composition contains guideway acid according to this invention, as defined above.

In another aspect this invention relates to a mixture or composition containing the crystalline form guideway acid of the present invention, as described above, which further includes a crystalline hemihydrate guideway acid.

In another aspect this invention relates to the use of guideway acid according to this invention for the production of hemihydrate guideway acid.

In another aspect this invention relates to a method for producing a crystalline hemihydrate guideway acid, where the method includes the step of crystallization of the hemihydrate guideway acid in a suitable solvent or solvent mixture.

In another aspect this invention relates to crystalline guideway acid, as defined above, for use in therapy.

In another aspect this invention relates to pharmaceutical compositions containing cu is stallions guideway acid, as described above, together with a pharmaceutically acceptable excipient or filler.

In another aspect this invention relates to a method for treatment, prevention or suppression of infection in a patient, introducing a specified patient an effective amount of crystalline guideway acid, as defined above, and, optionally, simultaneous or sequential introduction of one or more other therapeutically active compounds.

In another aspect this invention relates to the use of crystalline guideway acid, as described above, for the manufacture of a medicinal product for treating, suppressing or preventing infections.

In another aspect this invention relates to the use of crystalline guideway acid as described above for the inhibition of microbial growth.

In another aspect this invention relates to the use of crystalline guideway acid in accordance with the order, as described above, to prevent or prevention of bacterial infections in animal breeding.

In another aspect this invention relates to a method for producing crystalline guideway acid, as described above, providing the stage of dissolution of hemihydrate guideway acid, for example, in a suitable solvent or mixture of such rest is ritala.

In another aspect this invention relates to a method for producing crystalline guideway acid, as described above, involving the steps:

e) dissolving guideway acid in acetonitrile, Acrylonitrile, adiponitrile, benzonitrile, propanenitrile or mixtures of these solvents, optionally with heating;

f) cooling or concentrating the solution obtained in step a);

g) implementation of crystallization of the crystalline guideway acid according to the present invention;

h) the selection of crystalline guideway acid of the present invention.

In another aspect this invention relates to a method for producing crystalline guideway acid, as described above, involving the steps:

(j) mixing guideway acid with the solvent in which the crystalline positieve acid of the present invention, as described above, mainly insoluble or sparingly soluble;

k) the keeping or mixing the mixture obtained in step j), optionally with heating, followed by cooling, to obtain a slurry of crystals, mainly consisting of crystalline guideway acid of the present invention, as described above;

l) the selection of crystalline guideway acid, as described above, of the suspension.

In one the aspect, this invention relates to a method for producing a pharmaceutical composition, providing the phase mixing guideway acid according to any one of the above variants of the invention with pharmaceutically acceptable excipient or filler.

Brief description of drawings

Figure 1 is a graph showing the Raman spectrum (FT-NIR and Raman) crystal guideway acid of the present invention. Y axis shows the intensity of the Raman and X - wave number (cm-1).

Figure 2 is a graph showing the infrared spectrum (FTIR-ATR) crystal guideway acid of the present invention. Y axis shows units of extinction total reflectivity and X - wave number (cm-1).

Figure 3 is a graph showing the near-infrared spectrum (FT-NIR) crystal guideway acid of the present invention. Y axis shows the absorption and the X-axis is the wave number (cm-1).

Figure 4 is a graph showing the powder x-ray diffraction (XDR) crystal guideway acid of the present invention. Y axis shows the absolute intensity and the X axis is the angle 2θ.

The figure 5 presents ORTEP diagram form guideway acid of the present invention.

The figure 6 presents13From the NMR spectrum of the solid sample with cross-polarization and rotation of the sample (CP/MAS) crystal fused the eve acid of the present invention.

Figure 7 is a graph showing the Raman spectrum (FT-NIR and Raman) of the crystalline hemihydrate guideway acid. Y axis shows the intensity of the Raman and X - wave number (cm-1).

Figure 8 is a graph showing the infrared spectrum (FTIR-ATR) of the crystalline hemihydrate guideway acid. Y axis shows units of extinction total reflectivity, and X is the wave number (cm-1).

Figure 9 is a graph showing the near-infrared spectrum (FT-NIR) of the crystalline hemihydrate guideway acid. Y axis shows the absorption and X - wave number (cm-1).

Figure 10 is a graph showing the powder x-ray diffraction (XDR) crystalline hemihydrate guideway acid. Y axis shows the absolute intensity, and the x - axis, the angle 2θ.

Detailed description of the present invention

Crystallization is a well-known technique for the purification of chemical compounds and to obtain the desired crystalline form of chemical compounds. However, it is known that the crystallization of polymorphic forms influenced by a number of effects, and the mechanism of these effects is not known, and the quantitative relationship between the operating parameters and characteristics of crystallization of polymorphic forms are not fully understood.

The process Crist is lisali polymorphic crystals consists of competitive nucleation, growth and transformation from the metastable to the stable form. In order to selectively crystallize polymorphic form, it is necessary that the mechanism of each elementary step in the crystallization process was a clear relationship with the current settings and key controlling factors [Crystal Growth & Design, 2004, Vol. 4, No.6, 1153-1159].

Now suppose that a new crystalline resolutiona and anhydrous form guideway acid of the present invention, as described above, is thermodynamically more stable polymorphic form. Thermodynamically more stable crystalline forms of drugs are usually preferred because they are not transformed into other crystalline forms during the production process or in the final pharmaceutical composition [Topics in Current Chemistry, Vol. 198, 1998, 164-208].

In the comparative six-month standard stability studies, usually conducted for active pharmaceutical ingredients with known forms guideway acid, including present now in the market hemihydrate, form guideway acid according to the present invention has shown itself as the most stable form.

Table 1
A stability test (after 6 months x is anemia at 40°C) for various forms of guideway acid.
Crystalline formTest HPLC* (% from the beginning)Total impurities (%)
Positieve acid according to the present invention99,20,1
The hemihydrate guideway acid87,78,7
Form I guideway acid from
ES 2208110
of 98.21,0
Form II guideway acid from
ES 2208110
88,25,2
*column: LiChrospher 100 RP-18 5 μm, 125×4 mm; mobile phase: MeCIM: MeOH: 0,05 M H3PO4(60:10:30), flow rate: 1.2 ml/min, wavelength of detection: 235 nm. The temperature of the column: 25°C. Scope of application: 10 μl.

Untreated guideway acid, such as technical guideway acid, can be obtained by methods well known in the literature, through fermentation. Methods of cooking guideway acid and its isolation and purification have been described previously, for example, in patent ES 2204331 or ES 2208110, in U.S. patent 3072531, GB 930786, in the patent Denmark 99802, W. O. Godtfredsen et al. in Tetrahedron 1962, Vol. 18, pp. 1029-1048 or in Process Biocheistry, December 1969, or in Biotechnology of Industrial Antibiotics, EJ. Vandamme Ed., Marcel Dekker, Inc., New York & Basel 1984, pp. 427-449, and references cited here, which are all incorporated herein by reference.

Crystalline hemihydrate guideway acid can be obtained by dissolving the raw or untreated guideway acid in ethanol to obtain a solution, particular solution of 20-30% (wt./about.) guideway acid, after which a thorough mixing of the specified solution with water in a ratio of from 0.9 to 1.1 in parallel and controlled flow of both fluids in the container at 23-28°C so that the formed crystalline particles.

Time precipitation and nucleoli can be varied by titration of the concentration of insoluble substances, the flow rate of the solution and InterStorage water, and the temperature of the solvent and antibacterial. After the full transfer of the mixture can be left in the idle state, optionally with stirring, for example, to complete the crystallization process or to assist the growth of large crystals at the expense of small in order to achieve the preferred distribution of crystal size (re-dissolution). It is preferable to filter the solution guideway acid before mixing with water, because it removes all debris and unwanted seed cu is the growth as self-priming. Preferably the solution and antibacterial transferred in the same proportions relative to each other, which means that the solution and antibacterial mostly mixed in a constant ratio. The speed at which crystallization occurs, does not depend on the feed rate. Preferably, the transfer solution, and water was continuous and mostly linear. Particles of crystalline hemihydrate guideway acid can be distinguished by simple methods, for example by filtration or by centrifugation, preferably by filtration. The use of seed for crystallization of the mixture may be required to obtain the desired crystals of the hemihydrate. This may be due to the fact that crystallization under the above conditions occurs as a spontaneous nucleation kinetically preferred crystalline form. However, the application of seed to obtain crystals of the hemihydrate may, depending on production conditions, to be used to improve the physical properties of the crystals of the hemihydrate, in particular the size of the crystals.

Crystal guideway acid of the present invention, as described above, can be obtained by dissolving guideway acid, in particular of hemihydrate guideway acid, as described above, or the fully, to obtain the solution, or part of, to obtain a slurry or suspension, optionally with heating, in a suitable solvent, for example, to the boiling point of the employed solvent. When using MES or hydrate process is a process desolvatation, in which the solvent is removed or hydrated water. Suitable solvent includes a solvent which, for example, can resolutionat specified hemihydrate guideway acid or other original shape guideway acid, and in which the crystalline positieve acid of the present invention, as described above, mainly insoluble or sparingly soluble. The suspension or solution can then be heated or kept at an elevated temperature after dissolution process depending on the applied solvent. This can ensure that, for example, upon receipt of a suspension transformation in anhydrous form guideway acid of the present invention may be completed sooner. Depending on the solvent and temperature of the crystalline positieve acid of the present invention may precipitate from solution or, after a certain period of time, suspended crystals are mainly to consist of forms guideway acid according to the present invention is Generally transformation or desolate respectively may fail after 3-4 hours in mixtures of alcohols and water, in particular methanol or ethanol and water, at 50°C, or after 2-3 hours in the same mixtures at 60°C or 70°C. Cooling or evaporation of solvent can be used to facilitate precipitation or to enhance product yield, which can be selected, for example, by filtering.

Moreover, crystalline guideway acid according to the present invention can be obtained by crystallization from a suitable solvent, in particular a solvent selected from the list consisting of acetonitrile, Acrylonitrile, benzonitrile and propanenitrile, or mixtures of these solvents, where positieve acid dissolved, usually by heating, in particular, to the boiling point of these solvents, and where crystalline positieve acid of the present invention crystallizes, usually after cooling the solution, for example, to room temperature, for example up to 5-30°C, for example 0-15°C 20-25°C, or after concentrating the solution, for example, by evaporation of the solvent. Because guideway acid usually mostly dissolved before the crystallization process, any solid form guideway acid can be used as source material, including but not limited to, all polymorphic forms, solvate, or mixtures thereof, described in this application is whether the links quoted here.

Next, the crystalline guideway acid according to the present invention can be obtained by mixing guideway acid, including any polymorphic form, or mixtures thereof with a solvent in which the crystalline positieve acid of the present invention, as described above, is predominantly insoluble or sparingly soluble, such as water, ethanol, a mixture of methanol and water, acetonitrile, ethyl formate or a mixture of these solvents.

The mixture can be either a solution or suspension, depending on the solubility of the original solid form, preferably with stirring, can form thermodynamically more stable crystalline form of the present invention, which can be isolated from the suspension by, for example, filtration. The time required for complete transformation, can vary depending on temperature, the original solid form, such as crystal shape, solvent, etc. To enhance the crystalline transformation can be heated suspension, in particular, the boiling point of the solvent, followed by cooling, for example, to room temperature, for example, up to 5-30°C, for example, 0-15°C, e.g., 20-25°C, to increase the amount of precipitated in the sediment guideway acid of the present invention, which is possible to filter.

Instead of heating and cooling to achieve crystallization by concentration of the diluted solution to any value above the concentration at which crystallization occurs.

A mixture of one or more crystalline forms of the same pharmaceutically active ingredient can be applied successfully to achieve the specific nature of the release composition due to differences in solubilities and dissolution profiles of different crystalline forms. Therefore, physicochemical properties, such as bioavailability of the composition can be modified by suitable mixing of different crystalline forms to create compositions with optimized properties, in particular compositions with delayed release.

Options exercise

In a more private aspect of this invention relates to mixtures of crystalline forms guideway acid containing crystalline guideway acid of the present invention, as described above, where the mixture of crystalline forms guideway acid contains crystalline guideway acid exhibiting one or more of the following characteristics t) or (u):

t) infrared (FT-IR) spectrum (KBr) has one or more significant bands at approximately 973, 1253, 1377, 1721 or 3559 (±3 cm-1respectively; or

u) on Eskova x-ray diffraction (XDR) with one or more characteristic peaks of intensity, more than 20% relative to the highest peak appearing at 2θ values (±0,1) approx 2,1, 6,8, 9,4, 10,4, 11,8, 12,8, 13,7, 14,2, 15,8, 17,3, 18,5 or 22.9, respectively.

In another more private aspect the present invention relates to mixtures of crystalline forms guideway acid containing crystalline guideway acid of the present invention, as described above, where the mixture of crystalline forms guideway acid contains crystalline guideway acid exhibiting one or more of the following characteristics v or w):

v) infrared (FT-IR) spectrum (KBr) has one or more significant bands at approximately 976, 1255, 1377, 1679, 1721 (±3 cm-1respectively; or

w) powder x-ray diffraction (XDR) with one or more characteristic peaks of intensity greater than 20% relative to the highest peak appearing at 2θ values (±0,1) about 8.8, 11,5, 13,6, 14,4 or 17.4, respectively.

Any mixture of crystalline forms guideway acid containing crystalline guideway acid of the present invention described herein may further comprise other components or ingredients, including noncrystalline guideway acid or derivative guideway acid.

Crystal positieve acid is characterized by the manifestation of one or more SV is ist t) or (u), v or w), respectively, or crystalline hemihydrate guideway acid can be obtained in accordance with methods disclosed in patent ES 2208110, which is included in this description by reference.

In another more private aspect the present invention relates to mixtures of crystalline forms guideway acid, which contains 70-99,99 (mol.%), for example 90-99,9 (mol.%), in particular, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99,5, 99,6, 99,7, 99,8 or 99.9 mol.%), crystalline hemihydrate guideway acid and optionally containing from 0.01 to 30 mol.%), for example, 0.1 to 10 mol.%), in particular, 0,1, 0,2, 0,3, 0,4, 0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29 or 30 (mol.%), crystal guideway acid of the present invention, as described above.

In another more private aspect the present invention relates to a polymorphic form guideway acid, which is characterized by the presence of the reflection angle (2θ) at approximately 22,7 (±0,1) exceeding 30% with respect to the highest peak intensity in x-ray powder diffraction (XDR), the absence of the reflection angles (2θ) in the powder x-ray diffraction (XDR) in the range of 10.2 to 12.0 (±0,1) with excess of 5% relative to the highest peak intensity, and/or which is characterized by the absence of the peak intensity at 1743 (±1 cm-1 ), exceeding by 10% relative to the highest peak of the Fourier transform spectrum of the Raman (FT-NIR).

Crystal positieve acid of the present invention is useful for treatment, prevention or attenuation of infections in a patient, including a mammal, particularly humans. Animals that can be treated with compound for this invention include, in particular domestic animals, such as horses, cows, pigs, sheep, poultry, fish, cats, dogs and zoo animals. Crystal positieve acid of the present invention may be particularly useful in the treatment of bacterial infections such as skin infections or secondary skin infections or infections of the eyes. Crystal positieve acid of the present invention may also be useful in the treatment of simple abscesses, purulent wounds, boils or cellulites. Crystal positieve acid of the present invention may be particularly useful in the treatment, for example for local treatment, contagious, superficial skin infections, in particular nebulizer impetigo (or contagious impetigo) or bullous impetigo. Therefore, the present invention provides a method of treatment, prevention or suppression of bacterial infectious diseases, providing for the introduction to patient effective the number of crystalline guideway acid, optionally together with another therapeutically active compound. Examples of these therapeutically active compounds include antibiotics, such as β-lactam, for example, penicillins (phenoxymethylpenicillin penicillin, dicloxacillin, amoxicillin, pivampicillin, Flucloxacillin, piperacillin and mecillinam), cephalosporins (cephalexin, cephalothin, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidone (linezolid), rifamycin, metronidazole and positieve acid. Other compounds that can successfully be combined with the connection according to the invention, especially for the local treatment include, for example, corticosteroids, such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide. Crystal positieve acid and other compounds can be either brought together or sequentially.

Crystal positieve acid really izobreteny is also applicable for the prevention and prophylaxis of bacterial infections in animals, and, therefore, applicable at the time of breeding of domestic animals, such as mammals, such as horses, cows, pigs, sheep, poultry, fish, cats, dogs and zoo animals.

For use in the treatment of crystalline positieve acid of the present invention is represented generally in the form of pharmaceutical compositions. Thus, the invention relates to pharmaceutical compositions containing crystalline guideway acid described herein, optionally together with other therapeutically active compounds together with pharmaceutically acceptable excipient or filler. Excipient must be "acceptable" in the sense of being compatible with other ingredients of the composition and is not harmful to the recipient. For convenience, the active ingredient is 0.05 to 99.9% by weight of the composition. Compositions include, for example, those in a form suitable for oral (including slow or delayed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intra-articular and intravenous), transdermal, intraocular, local, nasal or buccal administration. The composition may for convenience be presented in a standard dosage form and may be prepared by any method well known in the area of the tee pharmacy, for example, as described in Remington, The Science and Practice of Pharmacy, 20thed., 2000. All methods include the step of bringing the active ingredient into interaction with the media, which is formed of one or more additional ingredients. Typically, the compositions get through the monotonous and closely linked bringing the active ingredient into interaction with a liquid carrier or a well-powdered solid carrier or both, and then, if necessary, shaping the product into the desired composition. The compositions of the present invention is applicable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or lozenges, each containing a particular amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid, in particular ethanol or glycerol; or in the form of emulsions of the type oil-in-water" or "water in oil". Such oils can be edible oils, such in particular as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable softening or suspendresume substances for water suspensions include synthetic and natural gums, such as tragacanth, alginate, Arabian, dextranase, sodium carboxymethylcellulose, gelatin, methylcellulose is, the hypromellose, hydroxypropylcellulose, carbomer and polivinilpirrolidon. The active ingredients can also be entered in the form of a bolus, medicinal porridge or pasta. A tablet may be made by compression or otlivanija active ingredient optionally with one or more additional substances. Molded tablets may be made by molding in a suitable machine the active(s) ingredient(s) in free flowing form such as powder or granules, optionally mixed with a binder, such as, in particular, as lactose, glucose, starch, gelatin, Arabic gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hypromellose, polyethylene glycol, paraffin and the like; a lubricant such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like; loosening agent, such as starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium glycolate, crosspovidone or similar, or dispersing agent, such as Polysorbate 80. Molded tablets may be made by casting, in an appropriate apparatus, a mixture of powdered active ingredient and a suitable carrier moistened with what's inert liquid diluent. Compositions for rectal injection can be in the form of suppositories, in which the substances of the present invention is mixed with low-melting water-soluble or water-insoluble solids, such as coconut oil, hydrogenated vegetable oil, polyethylene glycol or ethers of fatty acids and glycols, while elixirs can be obtained using myristoleate.

Compositions suitable for parenteral administration, usually contain sterile oil or aqueous preparation of the active ingredients, which are preferably isotonic with the blood of the recipient, for example, isotonic saline, isotonic glucose solution or a buffer solution. The composition can be conveniently sterilized by, for example, by filtration through a filter traps bacteria, added to the composition sterilizing agents, irradiation of the composition or heating the composition. Liposomal compositions, as described, for example, in Encyclopedia of Pharmaceutical Technology, vol.9, 1994, also suitable for parenteral administration. Alternatively, the crystalline hemihydrate guideway acid may be present as a sterile solid preparation, such as freeze-dried powder, which is easily dissolved in sterile solvent immediately before use. Transdermal is oppozitsii can be in the form of gypsum or plaster. Compositions suitable for intraocular injection may be in the form of a sterile aqueous preparations of the active ingredients, which may be in the form of microcrystals, for example in the form of an aqueous microcrystalline suspension. Liposomal compositions or biorstwami polymer systems, for example, as disclosed in Encyclopedia of Pharmaceutical Technology, vol.2, 1989, can also be used to represent the active ingredient for intraocular injection. Compositions suitable for local or intraocular injection, include liquid or semi-liquid preparations such as liniments, lotions, gels, wraps, emulsions of the type oil-in-water" or "water in oil", such as creams, ointments or pastes; or solutions or suspensions, in particular drops. Compositions suitable for nasal or buccal introduction, include powders, volatile and aerosol composition, such as aerosols and fine composition. Such compositions are disclosed in more detail, for example, in Modern Pharmaceutics, 2nd ed., G. S. Banker and CT. Rhodes (Eds.), pages 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3th ed., G. S. Banker and CT. Rhodes (Eds.), pages 618-619 and 718-721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology vol. 10, 3 Swarbrick and J. C. Boylan (Eds), pp. 191-221, Marcel Dekker, New York. In addition to the above substances, the composition of the crystalline hemihydrate guideway acid can include one or more additional ingredients, such as Abbeville, buffers, flavoring agents, dyes, surfactants, thickeners, preservatives, such as methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

Parenteral compositions are especially useful in the treatment of conditions in which the desired fast response to treatment. During continuous treatment of patients suffering from infectious diseases, tablets or capsules can be a suitable form of a pharmaceutical preparation effective long-term effect achieved with oral medications, in particular, in the form of tablets with delayed release. As suggested above, the composition may contain other therapeutic active ingredients that can be entered correctly together with the compounds of this invention in the treatment of infectious diseases, for example, appropriate antibiotics, in particular, of such antibiotics, which can enhance the activity and/or prevent development of resistance. Corticosteroids also can successfully be included in compositions of the present invention. In particular, the other active ingredient may include β-lactams, including penicillins (phenoxymethylpenicillin penicillin, dicloxacillin, amoxicillin, pivampicillin, Flucloxacillin, piperacillin and mecillinam), cephalosporins (ceph is Leksin, cefalotin, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidone (linezolid), rifamycin, metronidazole and positieve acid. Other compounds that can successfully be combined with the compound of the invention, especially for the local treatment include, for example, corticosteroids, such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

Such other therapeutically active compound can be in the same container or in different containers, designed for simultaneous or sequential introduction of these therapeutically active compounds.

The treatment of infectious diseases often involve the definition, stable or refracture specified disease treatment, before, actually, begins treatment. As an example, the patient can take samples containing infectious organism, such as blood or urine, after hahoopoker cultivated and subjected to treatment to determine whether this microorganism on this treatment. Accordingly, the present invention also provides a method for identifying compounds effective against microorganisms, introducing a crystalline guideway acid of the present invention, as described above, optionally together with other therapeutically active ingredients, microorganisms, and determine whether this compound or mixture of compounds toxic effect on the organism.

The compositions of the present invention is not limited to pharmaceutical, but can not be applied in a therapeutic context to control the growth of microorganisms. For example, compositions or compounds of the present invention can be useful as additives that inhibit the growth of microorganisms, for example, in the processes of fermentation. As an example, the selectivity of antimicrobial substances makes them suitable to stimulate the reproduction of specific microorganisms at the expense of others in multi-view culture.

In a more private aspect of this invention relates to pharmaceutical compositions containing crystalline guideway acid of the present invention, as described above, together with a pharmaceutically acceptable excipient or carrier, also containing other those who piticescu active connection selected from the group consisting of penicillins (phenoxymethylpenicillin penicillin, dicloxacillin, amoxicillin, pivampicillin, Flucloxacillin, piperacillin and mecillinam), cephalosporins (cephalexin, cephalothin, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole and guideway acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

In a more private aspect of this invention relates to a method for treatment, prevention or suppression of infection in a patient, introducing a specified patient an effective amount of crystalline guideway acid of the present invention, as described above, and optionally additionally containing simultaneous or sequential introduction of one or more therapeutically active compounds, where the specified other therapeutically AK the active compound selected from the group consisting of antibiotics and corticosteroids.

In a more private aspect of this invention relates to a method for treatment, prevention or suppression of infections in the patient, for example, bacterial infection, introducing a specified patient an effective amount of crystalline guideway acid of the present invention, as described above, and optionally additionally containing simultaneous or sequential introduction of one or more therapeutically active compounds, where the specified another therapeutically active compound selected from the group consisting of penicillins (phenoxymethylpenicillin penicillin, dicloxacillin, amoxicillin, pivampicillin, Flucloxacillin, piperacillin and mecillinam), cephalosporins (cephalexin, cephalothin, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, Metron is desola and guideway acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

In a more private aspect of this invention relates to the use of crystalline guideway acid of the present invention, as described above, for preparing a medicinal product for the treatment, inhibition or prevention of infections, such as bacterial infection, where the specified drug also contain other therapeutically active compound in the same or different containers, designed for simultaneous or sequential introduction of these therapeutically active compounds.

In a more private aspect of this invention relates to the use of crystalline guideway acid of the present invention, as described above, for preparing a medicinal product for the treatment, inhibition or prevention of infections, such as bacterial infection, where the specified drug also contain other therapeutically active compound in the same or different containers, designed for simultaneous or sequential introduction of these therapeutically active compounds, where the specified another therapeutically active compound selected from the group consisting of penicillins (phenoxymethylpenicillin penicillin, dicloxacillin, amoxicillin, pivampicillin is, Flucloxacillin, piperacillin and mecillinam), cephalosporins (cephalexin, cephalothin, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole and guideway acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

Positieve acid according to the present invention can have a successful preservation in comparison with the known polymorphic forms. Manufacturing packaging raw guideway acids can thus be transformed into a crystalline form of the present invention to limit degradation during storage. Then, for example, shortly before production in the present preferred pharmaceutical compositions that include the hemihydrate guideway acid, more stable anhydrous and solvent free form guideway acid according to the present invention can b the th successfully transformed before being on the market in the present form of the hemihydrate. The methods disclosed in this application for transformation or synthesis guideway acid of the present invention, including the methods described in the examples can use any polymorphic form guideway acid as the starting material.

In a more private aspect of this invention relates to a method for producing crystalline guideway acid of the present invention, as described above, involving the steps:

a) dissolution or suspension of the hemihydrate guideway acid in a solvent which can dissolve the specified hemihydrate guideway acid, and in which the crystalline positieve acid according to the present invention mainly insoluble or sparingly soluble, such as miscible with water, an organic solvent, optionally with heating, to obtain a suspension or solution;

b) optionally heating the specified suspension or solution, or maintaining a specified suspension or solution at an elevated temperature after heating in step (a);

c) optionally cooling or concentrating the specified suspension or solution;

d) isolation of the crystalline guideway acid of the present invention.

In yet another embodiment, the solvent used in the method of obtaining crystalline guideway KIS is the notes of the present invention in step a) above, is an alkyl ester of formic acid, in particular ethyl formate,1-C4alcohol, such as ethanol, With1-C4the alkyl acetate, acetonitrile, acetone or mixtures thereof, or mixtures of these solvents with water, most preferably a mixture of ethanol and water, for example, 50:50 (vol./about.) or a mixture of methanol and water, for example, 50:50 (vol./vol.).

In yet another embodiment, the solvent used in the method of obtaining crystalline guideway acid of the present invention in step a) above is heated to approximately 50°C. during the dissolution of hemihydrate guideway acid.

In yet another embodiment, the suspension or solution is maintained at approximately 50°C for 3-4 hours on the stage (b) above prior to cooling and allocation of crystalline guideway acid.

In yet another embodiment, the suspension or solution is cooled to about 0-10°C. in step c) above prior to extraction of crystalline guideway acid.

In yet another embodiment, the hemihydrate guideway acid completely dissolved by heating in step a) above to obtain a clear solution; not necessarily withstand the specified suspension or solution at an elevated temperature after heating in step (a); followed by cooling in step c) above is about the precipitation of crystalline guideway acid of the present invention, as explained above.

In a more private aspect of this invention relates to a method for producing crystalline guideway acid of the present invention, as described above, involving the steps:

(e) the dissolution or suspension of the hemihydrate guideway acid in acetonitrile, Acrylonitrile, adiponitrile, benzonitrile, propanenitrile or mixtures of these solvents when heated;

f) cooling the solution obtained in (e);

g) ensure that the crystallization of the crystallized guideway acid according to the present invention;

h) isolation of the crystalline guideway acid of the present invention, as described above.

In a more private aspect of this invention relates to a method for producing crystalline guideway acid of the present invention, as described above, involving the steps:

(j) mixing guideway acid with water, ethanol, a mixture of methanol and water, acetonitrile, ethyl formate or a mixture of these solvents;

(k) mixing the mixture obtained in step j), optionally while heating, followed by cooling to obtain a suspension, in which the suspended crystals consisting mainly of crystalline guideway acid of the present invention, as described above;

l) isolation of the crystalline suspension fusili the howling acid of the present invention, as explained above.

Definition

The term "polymorphic purity" includes purity, correlated with other polymorphic and pseudopolymorphic forms of crystals.

The term "C1-C4the alcohol includes methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tertbutanol and 2-butanol.

The term "C1-C4alkyl acetate includes ethyl acetate tributyltin, isopropylacetate, n-propyl, 2-butyl acetate, 1-butyl acetate, methyl acetate.

The term "ethanol" in the context of the present invention includes, but is not limited to, all commercially available brands of ethanol, for example anhydrous ethanol or ethanol, obtained from the azeotrope distilled ethanol with water, usually containing 4-5% water, commonly called alcohol.

The term "polymorphic form" includes all solid forms, such as amorphous solid or crystalline forms, including a solvate with stoichiometric and non-stoichiometric amounts of a solvent and hydrates with stoichiometric and non-stoichiometric quantities of water.

The term "crystalline form" includes crystalline polymorphic forms of all degrees of christallizovanne.

Experimental data

Analytical methods

Powder x-ray diffraction: diffraction pattern was obtained in the range of 3-30 degrees 2 theta in the apparatus of the STADI-P from STOE & CIE GmbH. [Diffractometer: transmission; monochromator: curved germanium (111); wavelength: 1,540598 Cu; detector: linear PSD; scan mode: transmission/moving PSD/fixed omega; scan type: 2 theta-omega]. FTIR spectroscopy (Fourier transform of the fading of the total reflectivity in the infrared spectrum): spectrum were obtained using the FTIR apparatus equipped with GoldenGate ATR module from SPECAC.

FT-IR can be obtained on KBr pellets on the device NICOLET Avatar 360 FT-IR.

Spectroscopy the Raman spectrum was obtained with the apparatus of the FTNIR-Raman, RFS 100/S from Bruker.

NIR reflection spectroscopy: the spectrum was obtained using the fiber optic probe connected to the FTIR apparatus, Equinox 55, Bruker.

13With CP/MAS (cross-polarization/rotation under magic angle) solid state nuclear magnetic resonance (NMR) spectrum (microecology sample) was obtained on Varian Unity INOVA NMR spectrometer at a magnetic field strength? 7.04 baby mortality T with frequency 75,42 MHz to13C. Used home-made 5 mm probe CP/MAS TLT (Transmission Line Tuning) sample using rotation frequency of 5.0 kHz.13Since the spectrum was obtained using standard cross-polarization pulse sequence, using a contact time of 1.2 MS, relaxation delay of 4 s, the exposure time is 10 μs, the width range 50 kHz at room temperature. The removal of the proton carried out using field separation with the Loy 110 kHz. 5 mm Si3N4the rotor has a sample volume of 110 μl and contained 103 mg of the substance. The total exposure time was 21.5 hours

The spectrum was processed with zero (32K real points), exponential multiplication and extension lines at 30 Hz. The spectrum was correlated with external TMS.

Chemical shifts are given in ppm relative to external comparison with TMS.

Given in this application error varies for spectroscopic indicators, including those listed in the claims, may be more or less depending on factors well known to a qualified specialist in the field of spectroscopy, and may, for example, depend on the preparation of the drug, in particular on the distribution of particle sizes, or crystalline form is part of the composition, the composition of the composition, as well as from the instrumental fluctuations, and other factors. Spacing errors ±5 includes, but is not limited to variations on±5, ±4, ±3, ±2, ±1, ±0,5, ±0,4, ±0,3, ±0,2 and ±0.1; spacing errors ±3 includes, but is not limited to variations on±3, ±2, ±1, ±0,5, ±0,4, ±0,3, ±0,2 and ±0.1; spacing errors ±1 includes, but is not limited to variations±0,9, ±0,8, ±0,7, ±0,6, ±0,5, ±0,4, ±0,3, ±0,2 and ±0.1; spacing errors ±0,2 includes, but is not limited to variations±0,2, ±0,15, ±0,1, ±0,09, ±0,08, ±0,07, ±0,06, ±0,05, ±0,04, ±0,03, ±0,02 and ±0,01.

X-ray analysis of a single crystal: the data for one crystal obtained on a Siemens SMART CCD Platform (experimental details and detailed results see below).

Refinement of F^2^ against reflections. The weighted R-factor WR and the degree of agreement S are based on F^2^, conventional R-factors based on F, where F was set to zero for negative F^2^. The threshold expression of F^2^>Sigma (F^2^) is used only for calculating R-factors (gt) etc. and is not treated to the choice of reflections for refinement. R-factors based on F^2^are statistically about twice more than those based on F, and R-factors based on all data will be even more.

All esd (except the esd in the dihedral angle between the two l. planes) measured with full covariant matrix. Esd cell is taken into account separately for esd measurement of distances, angles and torsion angles; correlations between esd parameters cuvettes were used only where they are defined by crystal symmetry. An approximate (isotropic) treatment esd ditch was used to measure esd using l. plane.

The present invention includes embodiments of which one or more of the steps in the procedure are omitted, one or more additional stages added, and/or the order of the steps is changed or converted. All the examples described here, should be understood as not limiting.

It should be understood that the invention is not limited to the specific described variants of implementation, which, of course, may vary. Also it should be understood that the terminology used here only for the purpose of describing particular embodiments and is not meant as limitations. In the context of the present invention, each realized value can be represented in the upper or lower limit of the range, which includes any other value. Where provided, the interval of values, it should be understood that each intervening value before the decimal part of the unit from the lower limit unless the context clearly indicates to the contrary, between the upper and lower limits of this interval, or any other specified or an intermediate value in the specified interval implied by the invention. The upper and lower limits of these smaller intervals can independently enter into smaller intervals and included in the invention, subject to any special excluded limit in the specified interval. Where specified interval on which includes one or both of the limit, intervals that exclude one or both of those included limits are also included in the invention. Unless stated otherwise, all technical and scientific terms used herein have the same meaning as is generally accepted by a skilled person in the art to which this invention relates. Although any methods and materials similar or equivalent to those described herein can also be applied in the practical implementation or testing of the present invention described preferred here by reference to disclose and describe the methods and/or materials in the attached claims, the singular number shall include references in the plural if the context does not strictly indicate the opposite. The patents and publications discussed here are provided only in relation to disclosure before the date of filing of this application. Nothing here should not be interpreted as acceptance of the fact that the present invention cannot be dated earlier of these patents or publications through the establishment of priority of an earlier filed application. Moreover, given the date of publication may differ from the actual publication dates which may need independent confirmation. As will be obvious by qualified professionals in this field of technology when the messaging application is Sri disclosure, each individual variant implementation, is described and illustrated here, has discrete components and features which can be easily divided or combined with any other properties for multiple variants of implementation, not deviating from the essence and scope of the present invention. The figures presented here are not necessarily shown to scale, some of the components and features have been exaggerated for clarity.

Examples

Example 1

The hemihydrate guideway acid

17,86 kg crude guideway acid obtained by fermentation, dissolved in a mixture of 69.3 l of ethanol (96%) and 2.52 liters of acetone to obtain 85,5 l of the first solution. The first solution and 93.4 l of water was added in parallel for 17-19 minutes at room temperature in a container with stirring. After mixing this solution with understorage water instantly observed crystallization. The mixture was stirred and then was filtered crystalline hemihydrate guideway acid, washed with a mixture of water and ethanol (3:1,vol/about.) and water. Microecology drug (jet mill) crystals showed endodermally peak in DSC (20°C/min) at 186°C with the temperature of 183°C. the Crystals were dried in vacuum at 50°C for approximately 15-18 hours to obtain crystalline Geiger is the characterized by expression of one or more of the following properties (l)-s), respectively:

l) the Fourier-transformed spectrum of the Raman (FT-NIR)exhibiting one or more of the following peaks in intensity at approximately 2934, 2730, 1743, 1666, 1458, 1442, 1382, 1353, 1325, 1280, 1251, 1212, 1148, 1091, 999, 969, 952, 918, 879, 819, 756, 703, 689, 579, 551, 533, 419, 392, 345, 203 or 85 (±3 cm-1respectively;

m) Fourier-transformed spectrum of the Raman (FT-NIR), essentially similar to the one shown in figure 7;

n) Fourier-transformed infrared (FTIR-ATR) spectrum of the fading full reflectivity, showing one or more peaks in the extinction of the total reflectivity at approximately 3435, 2927, 2868, 1748, 1685, 1443, 1380, 1228, 1183, 1148, 1134, 1106, 1074, 1055, 1030, 975, 934, 876, 855 or 819 (±3 cm-1respectively, the most specific lines of which are: 3435 (broad, m), 1748 (sharp s), 1685 (acute vs), 1228 (acute vs), 975 (sharp, m) (±3 cm-1);

o) IR-spectrometric extinction full reflectivity with the Fourier-transformation is essentially similar to that shown in figure 8;

p) spectrum in the near infrared (FT-NIR)exhibiting one or more of the following absorption peaks at approximately 10358, 8351, 7078, 6801, 6373, 5829, 5710, 5094, 4681, 4347, 4271, 4172 or 4063 (±5 cm-1respectively;

q) spectrum in the near infrared (FT-NIR), essentially similar to the one shown in figure 9;

r) powder the new x-ray diffraction (XDR), manifesting one or more of the following the reflection angles (2θ±0,1) at approximately 5,7, 5,9, 6,7, 7,1, 7,8, 8,0, 8,7, 9,1, 9,6, 11,5, 12,1, 12,8, 13,1, 13,4, 13,7, 14,3, 15,5, 16,0, 16,1, 16,4, 16,5, 17,0, 17,5, 17,9, 18,2, 18,7, 19,1, 19,4, 20,1, 20,9, 21,3, 21,9, 22,3, 22,5, 23,0, 23,5, 24,2, 25,1, 25,8, 26,6 or 27.5, respectively; or

s) powder x-ray diffraction (XDR), essentially similar to that shown in figure 10.

Example 2

The hemihydrate guideway acid

1.64 g guideway acid, 313 ml of ethanol, 380 ml of water and 162 mg of acetone were mixed and saturated solution was filtered through a filter. 178 g guideway acid dissolved in 693 ml of ethanol and 25 ml of acetone, and the solution was filtered through a filter. The first solution was poured into 5 l vessel and stirred at 180 rpm in a water bath at 30°C. For seed solution was added 0.45 g of hemihydrate guideway acid, having the characteristics as described in example 1. The second solution, and water (934 ml) was added to the vessel 7-8 ml/min in parallel, bringing the total time to add up to 90 minutes. When you are finished adding crystalline suspension was stirred for further 30 minutes. The crystals were filtered off, and the crystals were dried at 30°C for 18 hours under vacuum to obtain a crystalline hemihydrate guideway acid as described in example 1, showing one or more of the following properties x)-y), respectively:

x) infrared is (FT-IR) spectrum (KBr), with significant bands at approximately 1229, 1377, 1686 or 1748 (±3 cm-1respectively; or

I) a powder x-ray diffraction (XDR) with the characteristic peaks of intensity greater than 20% relative to the highest peak appearing at 2θ values (±0,1) approximately 7,0, 13,7 or 16,0 respectively.

Example 3

Crystal positieve acid

The hemihydrate guideway acid (0.5 g) from example 1 or 2 was added to acetonitrile (10 ml). The suspension was heated until a clear solution is formed, guideway acid was led by cooling to 20-25°C, collected by filtration and drying in vacuum, the Crystalline positieve acid had NMR, Raman, IR and XDR characteristics, as shown in figures 1-6, the Spectrum of the Raman (FT-NIR-Raman): 3008, 2937, 2871, 1725, 1707, 1666, 1651, 1468, 1379, 1348, 1195, 1078, 1032, 972, 917, 792, 745, 696, 612, 569, 547, 527, 463, 175, 120, 86 (cm-1); Fourier-transformed total reflectivity in the infrared spectrum (FTIR-ATR) peaks in the extinction of the total reflectivity of the: 3644, 3489, 2992, 2937, 2871, 1722, 1708, 1442, 1381, 1352, 1283, 1255, 1218, 1204, 1175, 1149, 1109, 1069, 1048, 1028, 962, 941, 917, 851, 828, 791, 750, 690, 656 (cm-1); absorption peaks in the near-infrared (FT-NIR) spectrum: 10414, 8373, 7115, 6846, 6503, 5824, 4996, 4889, 4831, 4680, 4365, 4306, 4067 (cm-1); the reflection angles (2θ) x-ray diffraction pattern (XDR): 7,22, 9,27, 9,88, 12,61, 13,05, 14,29, 14,70, 14,94, 15,39, 16,67, 17,87, 18,11, 18,51, 18,87, 19,1, 20,75, 21,83, 22,70, 23,51, 23,98, 24,37, 24,80, 25,29, 25,97, 26,60, 26,84, 27,71, 28,20, 28,89, 29,65;13With CP/MAS solid state NMR resonances at 173,9, 169,3, 146,1, 137,0, 133,3, 120,6, 76,2, 71,1, 69,1, 49,7, 49,4, 45,0, 39,9, 38,5, 36,9, 35,8, 34,5, 32,7, 30,9, 29,5, 28,0, 26,5, 20,7, 20,0, 18,0 or 16.9 frequent.·million-1.

Example 4

Crystal positieve acid

The hemihydrate guideway acid (1.0 g) of examples 1 or 2 was added to ethyl formate (10 ml). This suspension was heated to obtain a clear solution. Guideway acid was led by cooling to 20-25°C, collected by filtration and dried using vacuum. The substance was analyzed by NIR, XRD and RAMAN, and it had the same characteristics as described in example 3. Crystal positieve acid showed endodermally peak in DSC (20°C/min) at 191°C with the temperature of 184°C. FTIR-ATR spectrum exhibits one or more of the following characteristics peaks of extinction total reflectivity at approximately 3644 (sharp, m), 3489 (m), 1722 (vs), 1708 (vs), 1381 (m), 1255 (s), 1204 (m), 962 (m) (cm-1).

Example 5

Crystal positieve acid

The hemihydrate guideway acid (1.0 kg), as described in example 1, suspended in a mixture of ethanol (3.0 l) and purified water (3.0 l). The resulting suspension was heated to 50°C and was stirred for 3-4 hours. The suspension was cooled in an ice bath to 0-10°C., filtered and dried, using HAC is the mind. Selected crystal guideway acid were analyzed by NIR, XRD and RAMAN, and it had the same characteristics as described in example 3.

Example 6

Crystal positieve acid

The hemihydrate guideway acid (1.0 kg), as described in example 1, suspended in ethyl formate (8.0 l) and heated to 50°C. the resulting suspension was stirred for 1-2 hours, cooled in an ice bath to 0-10°C., filtered and dried using vacuum. Selected crystal guideway acid were analyzed by NIR, XRD and RAMAN, and it had the same characteristics as described in example 3.

Example 7

Crystal positieve acid

The hemihydrate guideway acid (10 g)as described in example 1, suspended in 50 ml of a mixture of ethanol:water (1:1) and heated to 70°C. the resulting suspension was stirred for 2-3 h, cooled in an ice bath to 0-10°C., filtered and dried using vacuum. Selected crystal guideway acid were analyzed by NIR, XRD and RAMAN, and it had the same characteristics as described in example 3.

Example 8

Crystal positieve acid

The hemihydrate guideway acid (10 g)as described in example 1, suspended in 50 ml of a mixture methanol:water (1:1) and heated to 60°C. the resulting suspension was stirred for 2-3 h, cooled to ledeno the bath to 0-10°C, filtered and dried using vacuum. Selected crystal guideway acid were analyzed by NIR, XRD and RAMAN, and it had the same characteristics as described in example 3.

Example 9

The hemihydrate guideway acid

You can apply the same procedure as in example 1, except that the first solution makes the original crystalline form guideway acids of examples 7 or 8 instead of the crude guideway acid.

Example 10

The hemihydrate guideway acid

You can apply the same procedure as in example 2, except that crystalline guideway acid from examples 3, 4, 5, or 6 is used to obtain the initial solution.

1. Crystal positieve acid characterized by the presence of the reflection angle (2θ) at approximately 22,7 (±0,1) exceeding 30% with respect to the highest peak intensity in x-ray powder diffraction (XDR) and the absence of the reflection angles (2θ) in the range of 10.2 to 12.0 (±0,1) with excess of 5% relative to the highest peak intensity.

2. Crystal positieve acid according to claim 1, further characterized by Fourier-transformed infrared (FTIR-ATR) spectrum of the extinction of the total reflectivity, showing peaks in the extinction of the total reflectivity at approximately 3644 is/or 3489 (±3 cm -1).

3. Crystal positieve acid according to claim 1 or 2, further characterized by the spectrum in the near infrared (FT-NIR), showing absorption peaks at approximately 10414 and/or 7155 (±5 cm-1).

4. Crystal positieve acid according to claim 1 or 2, further characterized by Fourier-transformed (FT-NIR) Raman spectrum exhibiting peaks in intensity at approximately 1725, 1707, 1666, 1651 (±3 cm-1), and the absence of a peak intensity at 1743 (±3 cm-1exceeding 10% relative to the highest peak intensity.

5. Crystal positieve acid according to claim 1 or 2, further characterized by solid-phase13From the NMR spectrum with cross-polarization and rotation of the sample under magic angle (CP/MAS)exhibiting one or more of the following resonances at approximately 173,9, 137,0 or 120,6 (±0,5) h·mn-1respectively.

6. Crystal positieve acid, characterized by one or more of the following characteristics (a)-(k), respectively:
a) Fourier-transformed spectrum of the Raman (FT-NIR), showing the following intensity peaks at approximately 3008, 2937, 2871, 1725, 1707, 1666, 1651, 1468, 1078, 1032, 547, 463, 175 and 120 (±3 cm-1), respectively;
(b) Fourier-transformed spectrum of the Raman (FT-NIR), which is shown in figure 1;
c) Fourier-transformed intracr sny (FTIR-ATR) spectrum of the fading full reflectivity, manifesting these peaks fading full reflectivity at approximately 3644, 3489, 1722, 1708, 1149, 962 and 828 (±3 cm-1), respectively;
d) Fourier-transformed infrared (FTIR-ATR) spectrum of the fading full reflectivity, which is shown in figure 2;
e) spectrum in the near infrared (FT-NIR), showing the following absorption peaks at approximately 10414, 7115, 6503, 4996 and 4680 (±5 cm-1), respectively;
f) spectrum in the near infrared (FT-NIR), which is shown in figure 3;
g) powder x-ray diffraction (XDR), showing the following the reflection angles 2θ (±0,1) at approximately 12,6, 13,1, 14,7, 14,9, 18,1, and 22,7, respectively;
h) a powder x-ray diffraction (XDR), which is shown in figure 4;
i)13C NMR spectrum with cross-polarization and rotation of the sample under magic angle (CP/MAS), showing the following resonances at approximately 173,9, 169,3, 146,1, 137,0, 133,3, 120,6, 76,2, 71,1, 69,1, 49,7, 49,4, 45,0, 39,9, 38,5, 36,9, 35,8, 34,5, 32,7, 30,9, 29,5, 28,0, 26,5, 20,7, 20,0, 18,0 and 16.9 (±0,5) h·mn-1, respectively;
j)13C NMR spectrum with cross-polarization and rotation of the sample under magic angle (CP/MAS), which is shown in Fig.6;
k) the following experimental results on single-crystal x-ray diffraction analysis: the crystal system=monoclinic and space group =P21.

7. Crystal fusedav the I acid according to claim 1 or 2, additionally characterized by the manifestation of one or more of the following characteristics (a)-(k), respectively:
a) Fourier-transformed spectrum of the Raman (FT-NIR)exhibiting one or more of the following peaks in intensity at approximately 3008, 2937, 2871, 1725, 1707, 1666, 1651, 1468, 1379, 1348, 1195, 1078, 1032, 972, 917, 792, 745, 696, 612, 569, 547, 527, 463, 175, 120 or 86 (±3 cm-1), respectively;
(b) Fourier-transformed spectrum of the Raman (FT-NIR), which is shown in figure 1;
c) Fourier-transformed infrared (FTIR-ATR) spectrum of the fading full reflectivity of exhibiting one or more of the following peaks fading full reflectivity at approximately 3644, 3489, 2992, 2937, 2871, 1722, 1708, 1442, 1381, 1352, 1283, 1255, 1218, 1204, 1175, 1149, 1109, 1069, 1048, 1028, 962, 941, 917, 851, 828, 791, 750, 690 or 656 (±3 cm-1), respectively;
d) Fourier-transformed infrared (FTIR-ATR) spectrum of the fading full reflectivity, which is shown in figure 2;
e) spectrum in the near infrared (FT-NIR)exhibiting one or more of the following absorption peaks at approximately 10414, 8373, 7115, 6846, 6503, 5824, 4996, 4889, 4831, 4680, 4365, 4306 or 4067 (±5 cm-1), respectively;
f) spectrum in the near infrared (FT-NIR), which is shown in figure 3;
g) powder x-ray diffraction (XDR)exhibiting one or more of the following the reflection angles 2θ (±0,1) at approximately 7,2, 9,3, 9,9, 12,6, 13,1, 14,3, 14,7, 14,9, 15,4, 16,7, 17,9 18,1, 18,9, 19,5, 20,8, 21,8, 22,7, 23,5, 24,0, 24,4, 25,3, 26,0, 26,6, 26,8, 28,2, 28,9 or, 29,7, respectively;
h) a powder x-ray diffraction (XDR), which is shown in figure 4;
i)13C NMR spectrum with cross-polarization and rotation of the sample under magic angle exhibiting one or more of the following resonances at approximately 173,9, 169,3, 146,1, 137,0, 133,3, 120,6, 76.2, 71,1, 69,1, 49,7, 49,4, 45,0, 39,9, 38,5, 36,9, 35,8, 34,5, 32,7, 30,9, 29,5, 28,0, 26,5, 20,7, 20,0, 18,0 or 16.9 (±0,5) h·mn-1, respectively;
j)13C NMR spectrum with cross-polarization and rotation of the sample, which is shown in Fig.6;
k) one or more of the following experimental results on single-crystal x-ray diffraction analysis:
the crystal system=monoclinic, space group =P21, [A]=12,2, b [A]=8,0, [A]=13,9, α [°]=90 β [°]=94, γ [°]=90, chamber volume [And3]=1360, or Z=2, respectively.

8. Crystal positieve acid according to claim 1 or 6 for use in the treatment, inhibition or prevention of bacterial infections.

9. Pharmaceutical composition having antibacterial activity, containing crystalline guideway acid according to any one of claims 1 to 7, together with a pharmaceutically acceptable excipient or filler.

10. The pharmaceutical composition according to claim 9, further containing one therapeutically active compound selected from the group consisting of antibiot the Cove and corticosteroids.

11. The use of crystalline guideway acid according to any one of claims 1 to 7 for the manufacture of a medicinal product for the treatment, inhibition or prevention of bacterial infections.



 

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FIELD: chemistry.

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22 cl, 7 tbl, 41 ex

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FIELD: medicine.

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71 cl, 4 dwg, 2 ex, 1 tbl

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71 cl, 4 dwg, 2 ex, 1 tbl

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27 cl, 7 tbl, 2 dwg

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3 tbl

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3 tbl, 4 ex

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7 cl, 2 tbl, 1 ex

FIELD: medicine.

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7 cl, 4 tbl, 15 dwg, 15 ex

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