Solid forms of macrolides

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to solvated and non-solvated crystalline forms of 20,23-dipiperidinyl-5-O-micaminosyl-tylonolide having characteristics specified in the description. The application materials also present methods for preparing such crystalline forms. The invention declares a pharmaceutical composition for treating hemorrhagic septicemia, ruminant respiratory disease and swine respiratory disease, containing 20,23-dipiperidinyl-5-O-micaminosyl-tylonolide in the solid form wherein a therapeutically effective amount of 20,23-dipiperidinyl-5-O-micaminosyl-tylonolide in the composition consists of a substantially pure phase of the crystalline form or at least 50% of 20,23-dipiperidinyl-5-O-micaminosyl-tylonolide in the composition consists of a crystalline form.

EFFECT: use of the therapeutically effective amount of the pharmaceutical composition for preparing the drug for treating hemorrhagic septicemia, ruminant respiratory disease and swine respiratory disease.

13 cl, 23 ex, 22 tbl, 40 dwg

The technical field to which the invention relates

The present invention relates to a solvated and nonsolvated crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize, as well as to methods for obtaining such crystalline forms, to medicines containing such crystalline forms (or received from them), to methods for medicines containing these crystalline forms (or received from them), to methods of treatment using such crystal forms, and kits containing such crystalline forms.

The level of technology

Macrolides, as it has long been known, are effective for the treatment of infectious diseases in humans, livestock, poultry and other animals. Long known macrolides include 16-membered macrolides such as tylosin A:

See, for example, U.S. patent No. 4920103 (pillar. 5, line 12-38). Cm. also U.S. patent No. 4820695 (pillar. 7, lines 1-32) and EP 0103465B1 (page 5, line 3). Over the years there were developed various derivatives of tylosin to improve antibacterial activity and selectivity.

Derivatives of tylosin include, for example:

tylosin B (also known as desmycosin)

tylosin C (that is also known as macrotin) and

tylosin D (also known as elemicin).

Derivatives of tylosin also include, for example, compounds described in U.S. patent No. 6514946 whose structure corresponds to formula (I):

Here:

each R¹and R³represents methyl and R²represents hydrogen; each R¹and R³represents hydrogen and R²represents methyl or each R¹, R²and R³represents hydrogen and

each R⁴and R⁶represents methyl and R⁵represents hydrogen; each R⁴and R⁶represents hydrogen and R⁵represents methyl or each R⁴, R⁵and R⁶represents hydrogen.

Such compounds include, for example, on 20, 23-piperidinyl-5-O-mycaminose-tionale, which has the following structure:

These compounds and, in particular, on 20, 23-piperidinyl-5-O-mycaminose-tionale, as expected, have pharmacokinetic and pharmacodynamic properties for safe and effective treatment, for example, hemorrhagic septicemia, respiratory diseases of ruminants and respiratory diseases of pigs. A discussion regarding the use of these compounds for the treatment of for the of olivani livestock and poultry are included in U.S. patent No. 6514946. This discussion is included as reference in the present patent. Applicants not know of any described stable crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

From the point of view of the importance of macrolides in the treatment of various pathological conditions, there is still a need for cost-effective, high-performance methods for their preparation. There is also a need in the crystalline forms of the macrolide that demonstrate the advantages of, for example, from the point of view of physical stability, chemical stability, packaging, thermodynamic properties, kinetic properties, surface properties, mechanical properties, filtration or chemical purity; or can mainly be used for production of solid forms that exhibit such properties. The following description satisfies these needs.

The invention

The present invention relates to crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Briefly, the present invention is directed, in part, on the first crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form I"). Polymorphic form I, as a rule, can be characterized as a substance with, for example, at least one (and usually more than one) of the following characteristics:

a. the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2935, about 1633, about 1596, about 1712, about 1683, and approximately 781 cm^-1;

b. range of x-ray diffraction on powder containing at least one peak selected from the group consisting of 5,0 (±0,2) and 5.6 (±0,2) degrees of angle 2θ;

c. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2932, about 1711, about 1682, about 1635, about 1599, about 1442, about 1404, about 1182, about 1079, about 1053, about 1008, about 985, approximately 842 and approximately 783 cm^-1;

d. melting point from about 192 to about 195°C or

e. the enthalpy of melting of about 57 j/g

The present invention also is directed, in part, on the second crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form II"). Polymorphic form II, as a rule, can be characterized as a substance with, for example, at least one (and usually more than one) of the following character is a stick:

a. the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2929, about 1625, about 1595, about 1685, and 783 cm^-1;

b. range of x-ray diffraction on powder containing peak at about 6.5 (±0,2) degrees 2θ;

c. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2935, about 1736, about 1668, about 1587, about 1451, about 1165, about 1080, about 1057, about 1042, about 1005, approximately 981, approximately 838 and approximately 755 cm^-1;

d. melting point from about 113 to about 119°C or

e. the enthalpy of fusion of about 15 j/g

The present invention also is directed, in part, on the third crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form III). Polymorphic form III, as a rule, can be characterized as a substance with, for example, at least one (and usually more than one) of the following characteristics:

a. the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of frequency PR is about 2943, about 2917, about 1627, about 1590, about 1733, about 1669, about 1193, approximately 1094 and approximately 981 cm^-1;

b. range of x-ray diffraction on powder containing at least one peak selected from the group consisting of 5,6 (±0,2) and 6.1 (±0,2) degrees of angle 2θ;

c. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2931, about 1732, about 1667, about 1590, about 1453, about 1165, about 1081, about 1057, about 1046, about 1005, approximately 981, approximately 834 and approximately 756 cm^-1;

d. the melting temperature of from about 107 to about 134°C or

e. the enthalpy of melting of about 38 j/g

The present invention also is directed, in part, on the fourth crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form IV). Polymorphic form IV, as a rule, can be characterized as a substance with, for example, at least one (and usually both) of the following characteristics:

a. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 3559, approximately 2933, about 1743, about 1668, note the RNO 1584, about 1448, about 1165, about 1075, about 1060, about 1045, about 1010, about 985, approximately 839 and approximately 757 cm^-1or

b. the melting temperature from about 149 to about 155°C.

The present invention also is directed, in part, on the solvated crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

In some embodiments, the implementation of the solvated crystalline form includes an ethyl acetate ("EtOAc"), ethanol or diethylketone solvated crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize, as well as any other crystalline MES, which is isomorphic to an ethyl acetate, ethanol or diethylketone solvated crystalline form. These crystalline solvate jointly identified in this patent as "crystalline solvate S1".

In some embodiments, the implementation of the solvated crystalline form includes crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize, solvated tert-butylmethylamine ether (or "tBME"), as well as any other crystalline MES, which is isomorphic to solvated tBME crystalline form. These crystalline solvate together are identified in this patent as "crystalline solvate S2".

In some embodiments, is sushestvennee solvated crystalline form includes tertrahydrofuran ring (or "THF") solvated crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize, as well as any other crystalline MES, which is isomorphic to THF solvated crystalline form. These crystalline solvate jointly identified in this patent as "crystalline solvate S3".

In some embodiments, the implementation of the solvated crystalline form includes methylacetate or ethylformate solvated crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize, as well as any other crystalline MES, which is isomorphic to methylacetate or ethylformate solvated crystalline form. These crystalline solvate jointly identified in this patent as "crystalline solvate S4".

The present invention also is directed, in part, to compositions containing on 20, 23-piperidinyl-5-O-mycaminose-tionale. In these embodiments, the implementation of a number (typically at least detective number) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition consists of one of the above solvated or resolutiony crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

The present invention also is directed, in part, to a method of treating diseases, such as hemorrhagic septicemia, respiratory disease of pigs or respirato the Noah disease of ruminants. The method includes:

combining a therapeutically effective amount of the above kristalloterapii composition, at least one carrier with obtaining pharmaceutical compositions and

introduction the pharmaceutical composition to an animal in need of such treatment.

In some such embodiments, the implementation of, for example, a therapeutically effective amount kristalloterapii composition is dissolved in a liquid carrier(s) to obtain the solution, which can, in turn, be used for parenteral or oral administration. In other such embodiments, the implementation of a therapeutically effective amount kristalloterapii composition suspended in a liquid carrier(s) to obtain a suspension, which may, in turn, be used for parenteral or oral administration.

The present invention also is directed, in part, on the application of a therapeutically effective amount of the above kristalloterapii composition to obtain drugs for the treatment of disease (e.g., hemorrhagic septicemia, respiratory diseases of pigs or respiratory disease of ruminants) of the animal.

The present invention also is directed, in part, to a pharmaceutical composition obtained by the method in which with the Association, at least one carrier with a therapeutically effective amount of the above kristalloterapii composition. In some such embodiments, the implementation of, for example, a therapeutically effective amount kristalloterapii composition is dissolved in a liquid carrier(s) to obtain the solution, which can, in turn, be used for parenteral or oral administration. In other such embodiments, the implementation of a therapeutically effective amount kristalloterapii composition is suspended, for example, in a liquid carrier(s) to obtain a suspension, which may, in turn, be used for parenteral or oral administration.

The present invention also is directed, in part, on the set. Set contains:

a therapeutically effective amount of the above kristalloterapii compositions and

instructions for combining kristalloterapii composition, at least one carrier.

The kit may additionally (or alternatively) include additional components, such as one or more carriers, one or more additional pharmaceutical or biological materials and/or one or more diagnostic tools.

Additional aspects and advantages of the present invention will be chevigny the person skilled in the art from reading the present description.

Brief description of drawings

Figure 1 shows an illustrative range of x-ray diffraction on the powder ("PXRD") for the polymorphic forms I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Figure 2 shows an illustrative spectrum of Raman scattering Fourier transform ("FT-Raman") for the polymorphic forms I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Figure 3 shows illustrative results of thermogravimetry coupled with infrared spectroscopy with Fourier transform ("TG-FTIR") for the polymorphic forms I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Figure 4 shows illustrative results of differential scanning calorimetry ("DSC") for the polymorphic forms I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Figure 5 shows illustrative results of the dynamic adsorption of vapors ("DVS") for the polymorphic forms I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

6 shows an illustrative infrared spectrum of frustrated total internal reflection (ATR-IR) (or "profile of the absorption bands") for the polymorphic forms I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

7 shows an illustrative IR spectrum for the suspension in the medical oil containing polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative PXRD spectrum for polim hnoi form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig.9 shows an illustrative spectrum of Raman scattering Fourier transform for the polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Figure 10 shows illustrative results of TG-FTIR for the polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

11 shows illustrative results of DSC for polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize. The continuous line corresponds to the first scan, and the dotted line corresponds to the second scan.

Fig shows illustrative results for DVS polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative range of ATR-IR for polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative IR spectrum for the suspension in the medical oil containing polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative PXRD spectrum for polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative spectrum of Raman scattering Fourier transform for the polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG for the polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

IG shows illustrative results of DSC for polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize. The continuous line corresponds to the first scan, and the dotted line corresponds to the second scan.

Fig shows illustrative results for DVS polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative range of ATR-IR for polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative IR spectrum for the suspension in the medical oil containing polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative PXRD spectrum for polymorphic form IV on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of DSC for polymorphic form IV on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative range of ATR-IR for polymorphic form IV on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative IR spectrum for the suspension in the medical oil containing polymorphic form IV on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative PXRD spectrum for sample an ethyl acetate crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionale.

Fig shows an illustrative spectrum of Raman scattering Fourier transform for the sample an ethyl acetate crystalline SOLV is that on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG-FTIR to sample an ethyl acetate crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG-FTIR for sample ethanol crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG-FTIR for sample diethylketone crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative PXRD spectrum for sample tBME crystalline MES S2 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative spectrum of Raman scattering Fourier transform for the sample tBME crystalline MES S2 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG-FTIR for sample tBME crystalline MES S2 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative PXRD spectrum for a sample of crystalline THF MES S3 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative spectrum of Raman scattering Fourier transform for the sample crystalline THF MES S3 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG-FTIR for sample THF Cree is of a metallic MES S3 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative PXRD spectrum for sample methylacetate crystalline MES S4 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows an illustrative spectrum of Raman scattering Fourier transform for the sample methylacetate crystalline MES S4 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG-FTIR for sample methylacetate crystalline MES S4 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Fig shows illustrative results of TG-FTIR for sample ethylformate crystalline MES S4 on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

A detailed description of the preferred embodiments

The present detailed description of the preferred embodiments is intended only to inform other specialists in this field with the present invention, its principles, and its practical applications so that other experts in this field could adapt and apply the invention in its numerous forms, as they can best be adapted to the requirements of a particular use. The present detailed description and specific examples, while and show preferred embodiments of N. the present invention, are intended only for illustration purposes. The present invention is therefore not limited to the preferred versions of the implementation described in the present description, and can be modified in various ways.

A. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Chemical and physical properties of macrolides and, in particular, on 20, 23-piperidinyl-5-O-mycaminose-tionalize are often important for their industrial development. These properties include, for example: (1) physical stability; (2) chemical stability; (3) properties that are important in packaging, such as molar volume, density and hygroscopicity; (4) thermodynamic properties such as melting point, vapor pressure and solubility; (5) the kinetic properties such as dissolution rate and stability (including stability in environmental conditions, especially with respect to humidity and storage conditions); (6) surface properties such as surface area, wettability, surface tension and form; (7) mechanical properties such as hardness, tensile strength, compatibility, ease of manipulation, fluidity and mixing; (8) properties for filtering and (9) chemical purity. These properties can be influenced, for example, to the processing and storage of the pharmaceutical is a mini-compositions containing on 20, 23-piperidinyl-5-O-mycaminose-tionale. Although Applicants believe that all solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize described in this patent, are therapeutically effective, solid forms, which provide improvement in one or more of the above properties relative to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize are generally desirable because there is a solid form that can be used as intermediate compounds in the methods of obtaining the desired solid form.

In accordance with the present invention receive several crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. These crystalline forms, generally have one or more of the above-described advantages of chemical and/or physical properties relative to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize and/or are suitable for use as intermediates in obtaining one or more other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. A particular crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize that are found include the following:

(1) the first waterless and resolutionyou crystalline form on 20, 23-dipiperidino the Il-5-O-mycaminose-tionalize, possessing unique properties relative to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form I");

(2) the second waterless and resolutionyou crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize possessing unique properties relative to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form II");

(3) the third and anhydrous resolutionyou crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize possessing unique properties relative to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form III");

(4) fourth anhydrous and resolutionyou crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize possessing unique properties relative to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "Polymorphic form IV");

(5) is isomorphic to an ethyl acetate, ethanol and diethylketone solvated crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize (collectively identified in this patent as "crystalline solvate S1");

(6) the solvated cristalli the mini-form on 20, 23-piperidinyl-5-O-mycaminose-tionalize in tert-butylmethylether ether (identified in this patent as "crystalline MES S2");

(7) tertrahydrofuran ring solvated crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize (identified in this patent as "crystalline MES S3") and

(8) is isomorphic to methylacetate and ethylformate solvated crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize (together identified in this patent as "crystalline solvate S4").

In some embodiments, the implementation of the present invention is directed to polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Illustrative methods of obtaining polymorphic forms I include, for example, those shown in examples 3 (part F) and 12-16.

Based on the observations of the applicants, it is assumed that the polymorphic form I, as a rule, has more stability at ambient temperature, other than the above solid form on 20, 23-piperidinyl-5-O-mycaminose-tionalize, in particular, in the absence of solvent. In many cases implementation is desirable to use a solid form, such as polymorphic form I, which usually does not require special handling or storage conditions and eliminates the need for frequent replacements in inventories. For example, the choice of a solid form that is physically stable during the production process (for example during grinding to obtain a material with reduced particle size and increased surface area) can eliminate the need for special processing conditions and rising costs, usually associated with such special conditions. Similarly, the choice of a solid form that is physically stable in a wide range of storage conditions (in particular, given the various possible storage conditions, which may occur during the period of use of the product on 20, 23-piperidinyl-5-O-mycaminose-tionalize), can help in resolving polymorphic or other degradation of changes in on 20, 23-piperidinyl-5-O-mycaminose-tionalize, which can lead to loss of product or deteriorating the efficiency. Thus, the choice of a solid shape having a higher physical stability, gives a significant advantage over less stable solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Polymorphic form I also tend less water absorption than other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize, for example, when environmental conditions (e.g., 25°C). It is additionally assumed that the polymorphic form I shows a preferred property with a value when packaging, thermodynamic properties, kinetic properties, surface properties, mechanical properties, fluid properties and chemical purity with respect to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form I can be identified using various analytical techniques. In some embodiments, the implementation of polymorphic form I is defined as a substance having at least one (and usually two, three, four or all five) of the following characteristics:

a. the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2935, about 1633, about 1596, about 1712, about 1683, and approximately 781 cm^-1;

b. range of x-ray diffraction on powder containing at least one peak selected from the group consisting of 5,0 (±0,2) and 5.6 (±0,2) degrees of angle 2θ;

c. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2932, about 1711, about 1682, about 1635, about 1599, about 1442, about 1404, about 1182, about 1079, about 1053, about 1008, about 985, approximately 842 and approximately 783 cm^-1.

d. melting point from about 192 to about 195°C or

e. the enthalpy of melting of about 57 j/g

In some embodiments, the implementation of polymorphic form I is defined as a substance with a spectrum of Raman scattering Fourier transform that contains p is the experience of absorption at the frequency 2935 cm ^-1. In other embodiments, the implementation of polymorphic form I is defined as a substance with a spectrum of Raman scattering Fourier transform containing the absorption band about the frequency of 1633 cm^-1.

In some embodiments, the implementation of polymorphic form I is defined as a substance with a range of x-ray diffraction on powder containing peak at 5,0 (±0,2) degrees 2θ.

In some embodiments, the implementation of polymorphic form I is defined as a substance having an infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 1711, about 1682, about 1635, about 1599, about 1404, about 1182, and approximately 783 cm^-1. In some such embodiments, the implementation for example, the polymorphic form I is defined as a substance having an infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 1711 and about 1682 cm^-1. In other such embodiments, the implementation of polymorphic form I is defined as a substance having an infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected the C group, consisting of a frequency of about 1635, about 1404, and approximately 1182 cm^-1.

In some embodiments, the implementation of polymorphic form I is defined as a substance having at least one (and usually two or all three) of the following characteristics:

a. range of x-ray diffraction on the powder essentially, as shown in figure 1,

b. range violated Raman scattering Fourier transform essentially, as shown in figure 2, or

c. the infrared spectrum of frustrated total internal reflection on the merits, as shown in Fig.6.

Some embodiments of the present invention is directed to compositions containing on 20, 23-piperidinyl-5-O-mycaminose-tionale, where at least detective number on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition is a polymorphic form I. In some such embodiments, the implementation of, for example, at least about 50% or at least about 75%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or at least about 99.9 percent) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition are polymorphic form I. In other such embodiments, the implementation of a therapeutically effective amount on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the comp the flies is a polymorphic form I. In other such embodiments, the implementation on 20, 23-piperidinyl-5-O-mycaminose-tionale in the composition is essentially phase-pure crystalline form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

In other embodiments, implementation of the present invention is directed to polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Methods of obtaining polymorphic form II include, for example, the method shown in example 4. As for polymorphic form I polymorph, the form II has a tendency to less water absorption than other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize, for example, when environmental conditions. It is assumed that the polymorphic form II shows a preferential physical stability, chemical stability, properties that are important in packaging, thermodynamic properties, kinetic properties, surface properties, mechanical properties, fluid properties and chemical purity with respect to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Polymorphic form II is also suitable for use as intermediate compounds for various other solid forms. Table 1 provides examples of such methods.

Polymorphic form II can be identified using various analytical techniques. In some embodiments, the implementation of polymorphic form II is defined as a substance having at least one (and usually two, three, four or all five) of the following features : the tick:

a. the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2929, about 1625, about 1595, about 1685, and 783 cm^-1;

b. range of x-ray diffraction on powder containing peak at about 6.5 (±0,2) degrees 2θ;

c. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2935, about 1736, about 1668, about 1587, about 1451, about 1165, about 1080, about 1057, about 1042, about 1005, approximately 981, approximately 838 and approximately 755 cm^-1;

d. melting point from about 113 to about 119°C or

e. the enthalpy of fusion of about 15 j/g

In some embodiments, the implementation of polymorphic form II is defined as a substance with a spectrum of Raman scattering Fourier transform containing the absorption band about the frequency 2929 cm^-1. In other embodiments, the implementation of polymorphic form II is defined as a substance with a spectrum of Raman scattering Fourier transform containing the absorption band about the frequency 1685 cm^-1.

In some embodiments, the implementation of polymorphic form II is defined as a substance with a range of d is the fraction of x-ray radiation on the powder, containing peak at about 6.5 (±0,2) degrees 2θ.

In some embodiments, the implementation of polymorphic form II is defined as a substance having at least one (and usually two or all three) of the following characteristics:

a. range of x-ray diffraction on the powder essentially as shown in Fig,

b. the spectrum of Raman scattering Fourier transform is essentially as shown in Fig.9, or

c. the infrared spectrum of frustrated total internal reflection on the merits, as shown in Fig.

Some embodiments of the present invention is directed to compositions containing on 20, 23-piperidinyl-5-O-mycaminose-tionale, where at least detective number on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition is a polymorphic form II. In some such embodiments, the implementation of, for example, at least about 50% or at least about 75%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or at least about 99.9 percent) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition are polymorphic form II. In other such embodiments, the implementation of a therapeutically effective amount on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition is a polymorphic forms of the II. In other such embodiments, the implementation on 20, 23-piperidinyl-5-O-mycaminose-tionale in the composition is essentially phase-pure form II crystal on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

In other embodiments, implementation of the present invention is directed to polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Illustrative methods of obtaining polymorphic form III include, for example, those shown in examples 7, 10 and 11. It is assumed that the polymorphic form III exhibits a higher stability in comparison to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. It is also assumed that the polymorphic form III shows the pre-emptive properties that are important in packaging, thermodynamic properties, kinetic properties, surface properties, mechanical properties, fluid properties and chemical purity with respect to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Polymorphic form III is also suitable for use, for example, to obtain polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize. This can be achieved, for example, by dissolving crystals of polymorphic form III in a solvent tBME/heptane and solvent removal. See, for example, example 15.

Poly is ohna form III can be identified using various analytical techniques. In some embodiments, the implementation of polymorphic form III is defined as a substance having at least one (and usually two, three, four or all five) of the following characteristics:

a. the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2943, about 2917, about 1627, about 1590, about 1733, about 1669, about 1193, approximately 1094 and approximately 981 cm^-1;

b. range of x-ray diffraction on powder containing at least one peak selected from the group consisting of 5,6 (±0,2) and 6.1 (±0,2) degrees of angle 2θ;

c. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2931, about 1732, about 1667, about 1590, about 1453, about 1165, about 1081, about 1057, about 1046, about 1005, approximately 981, approximately 834 and approximately 756 cm^-1;

d. the melting temperature of from about 107 to about 134°C or

e. the enthalpy of melting of about 38 j/g

In some embodiments, the implementation of polymorphic form III is defined as a substance with a spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group, ostoja frequency of about 2943, about 2917, about 1590, about 1733, about 1669, about 1193, approximately 1094 and approximately 981 cm^-1. In some such embodiments, the implementation of, for example, polymorphic form III is defined as a substance with a spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2943, about 2917, about 1590, about 1733, about 1094 and approximately 981 cm^-1.

In some embodiments, the implementation of polymorphic form III is defined as a substance with a range of x-ray diffraction on powder containing peak at 6,1 (±0,2) degrees 2θ.

In some embodiments, the implementation of polymorphic form III is defined as a substance having at least one (and usually two or all three) of the following characteristics:

a. range of x-ray diffraction on the powder essentially as shown in Fig,

b. the spectrum of Raman scattering Fourier transform is essentially as shown in Fig, or

c. the infrared spectrum of frustrated total internal reflection on the merits, as shown in Fig.

Some embodiments of the present invention is directed to compositions containing on 20, 23-piperidinyl-5-O-mycaminose-tionale, where at least detective number on 20, 23-piperidinyl-5-O-MIC is minusil-tionalize in the composition is a polymorphic form III. In some such embodiments, the implementation of, for example, at least about 50% or at least about 75%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or at least about 99.9 percent) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition are polymorphic form III. In other such embodiments, the implementation of a therapeutically effective amount on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition is a polymorphic form III. In other such embodiments, the implementation on 20, 23-piperidinyl-5-O-mycaminose-tionale in the composition is essentially phase-pure crystalline form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

In other embodiments, implementation of the present invention is directed to polymorphic form IV on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Methods of obtaining polymorphic form IV include, for example, the method shown in example 23. It is assumed that the polymorphic form IV shows the predominant physical stability, chemical stability, properties that are important in packaging, thermodynamic properties, kinetic properties, surface properties, mechanical properties, fluid properties and chemical purity with respect to the other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Polymorphic form IV can be identified using various analytical techniques. In some embodiments, the implementation of polymorphic form IV is defined as a substance having at least one (and usually both) of the following characteristics:

a. the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 3559, approximately 2933, about 1743, about 1668, about 1584, about 1448, about 1165, about 1075, about 1060, about 1045, about 1010, about 985, approximately 839 and approximately 757 cm^-1; or

b. the melting temperature from about 149 to about 155°C.

In some embodiments, the implementation of polymorphic form IV is defined as a substance having an infrared spectrum of frustrated total internal reflection, which has an absorption band at 1743 cm^-1. In other embodiments, the implementation of polymorphic form IV is defined as a substance having an infrared spectrum of frustrated total internal reflection, containing the absorption band at 3559 cm^-1.

In other embodiments, the implementation of polymorphic form IV is defined as a substance having at least one (and usually both) of the following characteristics:

a. range of x-ray diffraction on the powder essentially as shown in Fig, or

. the infrared spectrum of frustrated total internal reflection on the merits, as shown in Fig.

Some embodiments of the present invention is directed to compositions containing on 20, 23-piperidinyl-5-O-mycaminose-tionale where at least detective number on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition is a polymorphic form IV. In some such embodiments, the implementation of, for example, at least about 50% or at least about 75%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or at least about 99.9 percent) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition are polymorphic form IV. In other such embodiments, the implementation of a therapeutically effective amount on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition is a polymorphic form IV. In other such embodiments, the implementation on 20, 23-piperidinyl-5-O-mycaminose-tionale in the composition is essentially phase-pure form IV crystal on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

In other embodiments, implementation of the crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize includes solvated crystalline form. In some variations the tah implementation of the solvated crystalline forms, particular interest, are those which can be converted into more desirable solid form. In other embodiments, implementation pharmaceutically acceptable solvated crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize directly used in pharmaceutical compositions. It is assumed, for example, that some crystalline solvate tend to demonstrate a preferential physical stability, chemical stability, properties that are important in packaging, thermodynamic properties, kinetic properties, surface properties, mechanical properties, fluid properties and chemical purity with respect to other solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. It is also expected that the solvated crystalline forms may jointly offer a range of different speeds of dissolution, for example, in solid dosage forms. When they are directly used in pharmaceutical compositions, solvated crystalline form preferably essentially eliminate solvents which are not pharmaceutically acceptable.

In some embodiments, the implementation of the crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize on the includes crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize. Illustrative methods of obtaining an ethyl acetate crystalline MES S1 include, for example, those shown in examples 3 (part E), 6, 8 and 9. Methods of obtaining ethanol crystalline MES S1 include, for example, the method shown in example 17. And the ways to get diethylketone crystalline MES S1 include, for example, the method shown in example 18. An ethyl acetate crystalline MES S1 is suitable for use, for example, as intermediate compounds for other solid forms. Table 2 provides examples of such methods.

In some embodiments, the implementation of the crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize includes crystalline MES S2 on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Methods of obtaining crystalline MES S2 include, for example, the method shown in example 19. It is assumed that the crystalline MES S2 (that is solvated tBME crystalline form) may be particularly suitable for use in pharmaceutical compositions. This crystalline MES demonstrates stability, for example, at 60°C at 1 mbar (absolute.) within 1 day.

In some embodiments, the implementation of the crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize includes crystalline MES S3 on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Methods of obtaining crystalline MES S3 include, for example, str is about, shown in example 20.

In some embodiments, the implementation of the crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize includes crystalline MES S4 on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Methods of obtaining methylacetate crystalline MES S4 include, for example, the method shown in example 21. And the ways to get ethylformate crystalline MES S4 include, for example, the method shown in example 22.

Some embodiments of the present invention is directed to compositions containing on 20, 23-piperidinyl-5-O-mycaminose-tionale, where at least detective number on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition represents one of the above-mentioned forms of crystalline solvate. In some embodiments, implement, for example, at least about 50% or at least about 75%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or at least about 99.9 percent) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition represent a form of crystalline MES. In some such embodiments, the implementation of at least about 50% or at least about 75%, at least about 85%, at least about 90%, at the ore, about 95%, at least about 99% or at least about 99.9 percent) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition represent an ethyl acetate crystalline MES S1. In other embodiments, the implementation of a therapeutically effective amount on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition is in one of the above forms of crystalline solvate. In other embodiments, the implementation on 20, 23-piperidinyl-5-O-mycaminose-tionale in the composition is essentially phase-pure, as one of the above, the shape of the crystalline MES. In some such embodiments, the implementation of, for example, on 20, 23-piperidinyl-5-O-mycaminose-tionale in the composition is essentially phase-pure an ethyl acetate crystalline MES S1.

In other embodiments, implementation of the present invention is directed to a combination of two or more solid form selected from the group consisting of polymorphic form I polymorph, the form II polymorph form III polymorph of form IV and solvated crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Such combinations may be suitable for use, for example, when producing solid pharmaceutical compositions having a variety of profiles dissolution, including songs with controlling the th release. In one embodiment, the implementation contains a combination of polymorphic form I, at least, in detektiruya amount, with the remainder on 20, 23-piperidinyl-5-O-mycaminose-tionalize represents one or more solid forms selected from the group consisting of polymorphic form II polymorph form III polymorph of form IV and solvated crystalline forms. In another embodiment, the combination includes a polymorphic form II, at least in detektiruya amount, with the remainder on 20, 23-piperidinyl-5-O-mycaminose-tionalize represents one or more solid forms selected from the group consisting of polymorphic form I, polymorphic form III polymorph of form IV and solvated crystalline forms. In another embodiment, the combination includes a polymorphic form III, at least in detektiruya amount, with the remainder on 20, 23-piperidinyl-5-O-mycaminose-tionalize represents one or more solid forms selected from the group consisting of polymorphic form I polymorph, the form II polymorph of form IV and solvated crystalline forms. In another embodiment, the combination includes a polymorphic form IV, at least in detektiruya amount, with the remainder on 20, 23-piperidinyl-5-O-mycaminose the l-tionalize represents one or more solid forms, selected from the group consisting of polymorphic form I polymorph, the form II polymorph form III and solvated crystalline forms.

Depending on the intended use of the solid form on 20, 23-piperidinyl-5-O-mycaminose-tionalize technological considerations can contribute to the competitive selection of solid forms or specific combinations of such solid forms. Ease of access to solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize (or solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize with minimal phase purity)typically varies from one solid form to another.

Characterization of solid dosage forms

Methods

Samples of solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize who receive in accordance with the present invention is characterized by using several different techniques. These techniques include the following :

Range of x-ray diffraction on the powder ("PXRD") for all samples, but not for the polymorphic form IV obtained using x-ray diffractometer Bruker D8 Advance using radiation Cu Kα (wavelength to calculate the value of d: λ=1,5418 Å); the capacity of the tube 35 kV/45 mA; detector VANTECl and a 2θ step size of 0.017°, the time for one step 105±5 seconds and the scan range of 2θ 2°-50°. Use the holders of a sample of single crystals is alicebraga silicon, having a diameter of 12 mm and a depth of 0.1 mm PXRD Spectrum for polymorphic form IV obtained using x-ray diffractometer Siemens D5000 using software Diffract Plus, a 2θ step size of 0.04°, one time step of 2 seconds, the scan range of 2θ of 5.0°-80,0, crack discrepancies when installed V20, protivovrashchatelnyj gap when installed V20, slit detector no rotation, the generator voltage of 40 kV, a current generator 30 mA, scintillation counter high sensitivity and x-ray tube at Cu.

Raman spectrum with the Fourier transform ("FT-Raman") obtained using the spectrometer Bruker RFS100 FT-Raman with Nd:YAG laser using a wavelength of 1064 nm excitation, the laser power of 100 mW, Ge detector, 64 scans, range 50-3500 cm^-1, resolution 2 cm^-1and the aluminum sample holder.

Thermogravimetric measurements in combination with infrared spectroscopy with Fourier transform ("TG-FTIR"), make use of a microbalance Netzsch TG 209 together with the spectrometer Bruker Vector 22 FT-IR using an aluminum crucible (with microscopic hole or open), atmospheric N₂, heating rate 10°C/min and the temperature range of 25-250°C.

Thermogravimetric measurement (TG) is performed using a thermogravimetric analyzer Perkin Elmer TGS 2 using aluminum crucible (open), almost the ry N ₂, heating rate 10°C/min and the temperature range of 25-500°C.

Measurements of differential scanning calorimetry ("DSC") is conducted for the polymorphic forms I, II and III using a differential scanning calorimeter (Perkin Elmer DSC 7 with the Golden crucible; heating rate 10°C/min. These measurements are carried out in sealed trays for samples close in the atmosphere of inert gas (i.e. in the absence of oxygen) after removal of any residual solvent and moisture. Perform one scan with polymorphic form I. This scanning is carried out from -50°C to about 210°C. Two scanning is carried out for polymorphic forms II and III, the first scan is carried out from -50°C to 150°C, and the second scan is carried out from -50°C to 200°C. the DSC Measurements for the polymorphic form IV obtained using a Mettler DSC 822e using aluminum crucible, air as a protective gas, heating rate 10 K/min, range of heating from 30 to 200°C and sample size 5 mg. Applicants think DSC is particularly prone to variation, and for this reason it should be used with caution.

Measurement of dynamic adsorption of vapors ("DVS") was produced using the analyzer water vapor sorption Projekt Messtechnik SPS11-100n. The sample is placed in an aluminum crucible on a microbalance and allow balanced at 25°C and at 50% relative to the humidity before starting the next preset programs humidity at 25°C: relative humidity 50-95-0-50% and scan with 5% relative humidity per hour and with periods of equilibration at constant humidity at extreme values.

Infrared spectra ("IR") is obtained using the spectrometer FT-IR Excalibur from Portmann Instruments AG (now Varian). Use two techniques. The first method represents the infrared spectroscopy of frustrated total internal reflection (ATR). To obtain a spectrum using ATR sample at the tip of the spatula is placed on the site for sample cell ATR (rotational torque of 120 N·cm) and detect the infrared spectra from 3600 to 700 cm^-1. The second method uses the sample suspended in the medical oil (i.e. suspension in medical oil). To obtain a spectrum with the use of such a sample at the tip of a spatula carefully ground in a mortar together with two or three drops of medical oil to obtain a homogeneous paste. Pasta, in turn, distribute the record of NaCl and pressed together with a second plate of NaCl to obtain a thin homogeneous film. For these samples the infrared spectra recorded from 3600 to 600 cm^-1.

Finally, the applicants have made various observations regarding shapes and sizes of solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize and lead these observations below. Applicants note, however, that this information should be used with caution, because there may be other shapes and/or sizes to istoricheskikh forms depending on the procedures, used for production of solid forms.

Polymorphic form I

The following discussion provides a variety of observed characteristics of polymorphic form I.

i. The appearance of polymorphic form I

Polymorphic form I, as a rule, is in the form of small particles.

ii. Range of x-ray diffraction on the powder for the polymorphic form I

The observed PXRD spectrum for polymorphic form I is shown in figure 1, and the corresponding data is shown forth in the following table 3:

Characteristic features of the spectra include the initial peaks at 2θ=5,0° and 5.6°.

For some samples PXRD spectrum shows the pollution to some extent on 20, 23 amorphous-piperidinyl-5-O-mycaminose-chronoliths. It is assumed, however, that this amorphous material is essentially not present in the sample corresponding to the above PXRD spectrum.

iii. The spectrum of Raman scattering Fourier transform for the polymorphic form I

The observed spectrum of Raman scattering Fourier transform for the polymorphic form I is shown in figure 2, and the corresponding data is shown forth in the following table 4:

Characteristic features of the spectra include intense peaks at 2935 cm^-1, 1633 cm^-1and 1596 cm^-1and smaller peaks at 1712 cm^-1, 168 cm ^-1and 781 cm^-1.

iv. Tg for polymorphic form I

Figure 3 shows the results of the analysis of TG-FTIR polymorphic form I. the weight Loss of 0.6% is observed in the temperature range from 60 to 180°C. the Applicants suggest that this is due to water loss. Because of the small number of applicants, in addition, suggest that this loss of water occurs most likely due to adsorbed on the surface of the water than is associated with the existence of hydrate.

v. Differential scanning calorimetry for the polymorphic form I

Figure 4 shows the results of DSC analysis for polymorphic form I. Has a sharp melting peak at 195°C with enthalpy of fusion ΔH_fus57 j/, As will be shown below, both of these parameters is greater than the melting temperature and enthalpy of melting for the polymorphic form II and form III. Figure 4 stage T_gbarely visible. It is assumed that this confirms that the crystalline sample more than 90%.

Samples of the polymorphic form I independently analyzed to determine the melting temperature. Samples having a purity of about 98% (wt./wt.), demonstrate the melting point of 192 to 195°C.

vi. Dynamic adsorption of vapors for polymorphic form I

Figure 5 shows the results of the analysis DVS polymorphic form I. This analysis is carried out at 25°C. the Observed maximum water absorption of less than 1 (wt.) at 95% relative humidity.

vii. The IR spectrum of polymorphic form I

Fig.6 shows the spectrum of the ATR-IR for the polymorphic forms I and 7 results in the IR spectrum of polymorphic form I in suspension in the medical oil. The relevant data is shown forth in the following table 5:

Characteristic features of the spectra, in particular, the ATR spectra include intensive absorption bands at 2932 cm^-1, 1711 cm^-1, 1682 cm^-1, 1599 cm^-1, 1442 cm^-1, 1182 cm^-1, 1079 cm^-1, 1053 cm^-1, 1008 cm^-1, 985 cm^-1, 842 cm^-1and 783 cm^-1. The absorption band at 1711 cm^-1and 1682 cm^-1evidently, are completely unique to this polymorphic forms. The absorption band at 1635 cm^-1, 1404 cm^-1and 1182 cm^-1also, apparently, are completely unique to this polymorphic form.

Polymorphic form II

The following discussion provides a variety of observed characteristics of polymorphic form II.

i. The appearance of polymorphic form II

Polymorphic form II is usually in the form of prismatic crystals up to several hundreds of microns.

ii. Range of x-ray diffraction on the powder for the polymorphic form II

The observed PXRD spectrum for polymorphic form II is shown in Fig, and the corresponding data are shown in the following next t the blitz 6:

Characteristic features of the spectra include the initial and the most intense peak at 2θ=about 6.5°.

iii. The spectrum of Raman scattering Fourier transform for the polymorphic form II

The observed spectrum of Raman scattering Fourier transform for the polymorphic form II is shown in Fig.9, and the corresponding data is shown forth in the following table 7:

Characteristic features of the spectra include intense peaks at 2929 cm^-1, 1625 cm^-1and 1595 cm^-1and smaller, but sharp peaks at 1685 cm^-1and 783 cm^-1.

iv. Tg for the polymorphic form II

Figure 10 shows the results of the analysis of TG-FTIR polymorphic form II. Weight loss is observed at 0.7 percent, mainly in the temperature range from 50 to 100°C. the Applicants suggest that this is due to water loss. Decomposition starts at temperatures greater than 220°C.

v. Differential scanning calorimetry for the polymorphic form II

11 shows the results of DSC analysis of polymorphic form II. First scan (continuous line) shows a peak melting at 113°C with enthalpy of fusion ΔH_fus=15 j/, the Second scan (dotted line) shows the glass transition temperature (T_g") for 96.1°C. Recrystallization does not occur.

Samples of the floor is isomorphous form II independently analyzed to determine the melting temperature. Samples having a purity of about 96% (wt./wt.), demonstrate a melting point of 113 to 119°C.

vi. Dynamic adsorption of vapors for polymorphic form II

Fig shows the results of the analysis DVS polymorphic form II. This analysis is carried out at 25°C. the Observed maximum water absorption of about 2% (wt.) at a relative humidity of 95%.

vii. The IR spectrum of polymorphic form II

Fig shows the spectrum of the ATR-IR for polymorphic form II, and Fig leads the IR spectrum for the polymorphic form II in suspension in the medical oil. The relevant data is shown forth in the following table 8:

Characteristic features of the spectra, in particular, the spectrum of the ATR include intense absorption band at 2935 cm^-1, 1736 cm^-1, 1668 cm^-1, 1587 cm^-1, 1451 cm^-1, 1165 cm^-1, 1080 cm^-1, 1057 cm^-1, 1042 cm^-1, 1005 cm^-1, 981 cm^-1, 838 cm^-1and 755 cm^-1.

Polymorphic form III

The following discussion provides a variety of observed characteristics of polymorphic form III.

i. The appearance of polymorphic form III

Polymorphic form III is usually in the form of fine needles.

ii. Range of x-ray diffraction on the powder for the polymorphic form III

The observed PXRD spectrum for polymorphic form III is shown in Fig, and according to the corresponding data is shown forth in the following table 9:

Characteristic features of the spectra include the most intense peak at 2θ=6,1°, which is accompanied by a smaller peak at 2θ=5,6°. See that the relative intensity of these two peaks varies from boot to boot, as well as the relative intensity of other peaks in the spectrum. Such changes are not something unusual for PXRD. Often they arise from orientation effects, in particular, in the context of anisotropic (i.e., needle-like and plate) crystals. These changes, however, generally do not affect the identification of polymorphic forms, as it usually depends more on the position of the peak than to the intensity.

iii. The spectrum of Raman scattering Fourier transform for the polymorphic form III

The observed spectrum of Raman scattering Fourier transform for the polymorphic form III is shown in Fig, and the corresponding data is shown forth in the following table 10:

Characteristic features of the spectra include intense peaks at 2943 cm^-1, 2917 cm^-1, 1627 cm^-1and 1590 cm^-1and smaller peaks at 1733 cm^-1, 1669 cm^-1, 1193 cm^-1, 1094 cm^-1and 981 cm^-1.

iv. Tg for polymorphic form III

Analysis of the TG-FTIR one is about sample shows the mass loss from 1.7% to 220°C, with most of the loss occurs between 50 and 120°C. it is Assumed that these weight loss associated with water or acetonitrile in the sample (the sensitivity of the IR detector to the acetonitrile is low).

Fig shows the results of TG analysis of polymorphic form III. The mass loss is less than 0.05% is observed up to 200°C. the Decomposition starts at temperatures greater than 270°C.

v. Differential scanning calorimetry for the polymorphic form III

Fig shows the results of DSC analysis of polymorphic form III. First scan (continuous line) shows a peak melting at 134°C with enthalpy of fusion ΔH_fus=38 j/g During cooling, the material solidifies in the amorphous state. The second scan (dotted line) shows T_g96°C, recrystallization and the new melting at 195°C.

Samples of polymorphic form III independently analyzed to determine the melting temperature. Samples having a purity of about 99%, demonstrating the melting temperature from 122 to 126°C.

vi. Dynamic adsorption of vapors for polymorphic form III

Fig shows the results of the analysis DVS polymorphic form III. This analysis is carried out at 25°C. the water Absorption of about 6% is observed at a relative humidity of between 70 and 85%.

vii. The IR spectrum of polymorphic form III

Fig shows the spectrum of the ATR-IR for polymorphic form II, and Fig leads the IR spectrum for the polymorphic form III in suspension in the medical oil. The relevant data is shown forth in the following table 11:

Characteristic features of the spectra, in particular, the spectrum of the ATR include intensive absorption bands at 2931 cm^-1, 1732 cm^-1, 1667 cm^-1, 1590 cm^-1, 1453 cm^-1, 1165 cm^-1, 1081 cm^-1, 1057 cm^-1, 1046 cm^-1, 1005 cm^-1, 981 cm^-1, 834 cm^-1and 756 cm^-1.

Polymorphic form IV

The following discussion provides a variety of observed characteristics of polymorphic form IV.

i. Range of x-ray diffraction on the powder for the polymorphic form IV

The observed PXRD spectrum for polymorphic form IV is shown in Fig, and the corresponding data are shown in the following next table 12:

ii. Differential scanning calorimetry for the polymorphic form IV

Fig shows the results of DSC analysis of polymorphic form IV. The curve shows a peak at 155°C, which, as expected, corresponds to the polymorphic form IV. The curve also shows a peak at 191°C, which, as expected, corresponds to the polymorphic form I. it is Assumed that the sample contains both polymorphic form I and form IV or that polymorphic form IV is converted to polymorph the Orme I during heating.

Samples of the polymorphic form IV independently analyzed to determine the melting temperature. The samples, which is net of approximately 90.0% of (wt./wt.), demonstrate the melting point of from 149 to 152°C.

iv. The IR spectrum of polymorphic form IV

Fig shows the spectrum of the ATR-IR for polymorphic form IV, and Fig leads the IR spectrum for the polymorphic form IV in suspension in the medical oil. The relevant data are shown in the following next table 13:

Characteristic features of the spectra, in particular, the spectrum of the ATR include intense absorption band at 2933 cm^-1, 1743 cm^-1, 1668 cm^-1, 1584 cm^-1, 1448 cm^-1, 1165 cm^-1, 1075 cm^-1, 1060 cm^-1, 1045 cm^-1, 1010 cm^-1, 985 cm^-1, 839 cm^-1and 757 cm^-1. The absorption band at 3559 cm^-1it is quite unique for this polymorphic form.

Crystalline MES S1

The following discussion provides a variety of observed characteristics of the crystalline MES S1. Although data PXRD and FT-Raman below correspond to an ethyl acetate crystalline MES S1, this data can also be used for characterization diethylketone and crystalline ethanol solvate of, because they are isomorphic with an ethyl acetate crystalline with what Iwata.

i. The appearance of an ethyl acetate crystalline MES S1

An ethyl acetate crystalline MES S1 is, as a rule, in the form of fine needles or crystals of a larger size with a tendency to collapse on the fiber.

ii. Range of x-ray diffraction on the powder to an ethyl acetate crystalline MES S1

The observed PXRD spectrum for an ethyl acetate crystalline MES S1 shown in Fig, and the corresponding data are shown in the following next table 14:

Characteristic features of the spectra include the initial peaks at 2θ=5,6° and 6.1°.

iii. The spectrum of Raman scattering Fourier transform to an ethyl acetate crystalline MES S1

The observed spectrum of Raman scattering Fourier transform to an ethyl acetate crystalline MES S1 shown in Fig, and the corresponding data are shown in the following next table 15:

Characteristic features of the spectra include intense peaks at 2936 cm^-1, 1625-1627 cm^-1and 1586 cm^-1and smaller, but sharp peaks at 1745 cm^-1, 1669 cm^-1and 978 cm^-1.

iv. Tg for crystalline solvate S1

Fig, 29 and 30 show the results of TG-FTIR to an ethyl acetate, ethanol and diethylketone crystal with whom Lipatov S1, respectively. These results confirm the existence of a crystalline solvate of approximately one molecule of the solvent molecule on 20, 23-piperidinyl-5-O-mycaminose-tionale, assuming mostly clean on 20, 23-piperidinyl-5-O-mycaminose-tionale. An ethyl acetate crystalline MES S1 shows a weight loss of approximately 4.1 per cent, obtained from extraction of ethyl acetate. This corresponds to a molar ratio of ethyl acetate to on 20, 23-piperidinyl-5-O-mycaminose-tionality of 0.36. Ethanol crystalline MES S1 shows a weight loss of approximately 6.6% up to 200°C, obtained from extraction of ethanol (crystalline MES S1 may also contain small amounts of water that can be allocated). This corresponds to a molar ratio of ethanol to on 20, 23-piperidinyl-5-O-mycaminose-tionality of 1.1. And diethylketone crystalline MES S1 shows the mass loss of 10%, obtained from a selection of diethylketone. This corresponds to a molar ratio of diethylketone to on 20, 23-piperidinyl-5-O-mycaminose-tionality of 1.0. These results are given in table 16:

For each of the crystalline solvate weight loss begins in the range from 40 to 50°C. This indicates a relatively low stability and is consistent with the observation that an ethyl acetate crystalline MES can be easily converted, for example, polymorphic form III by vacuum drying at ambient temperature. See, for example, example 7. The results for an ethyl acetate crystalline MES show that the solvent molecule can be replaced with water, and are consistent with the results of the DVS for the polymorphic form III.

Crystalline MES S2

The following discussion provides a variety of observed characteristics of the crystalline MES S2.

i. Appearance tBME crystalline MES S2

tBME crystalline MES S2 is, as a rule is, in the form of ill-defined crystals and shows no tendency to decay into fibers compared with an ethyl acetate crystals of the crystalline MES S1.

ii. Solubility tBME crystalline MES S2 in tBME

Solubility tBME crystalline MES tBME S2 is in the range of between 40 and 50 mg/ml, Respectively, solubility, at least one order of magnitude less than the solubility of polymorph form II in tBME.

iii. Range of x-ray diffraction on the powder for tBME crystalline MES S2

The observed PXRD spectrum for tBME crystalline MES S2 shown in Fig, and the corresponding data are shown in the following next table 17:

Characteristic features of the spectra include several peaks with similar intensities at 2θ=6,1°, 10,0°, 10,3°, 17,0°, 18,6° and 20.1°.

iv. The spectrum of Raman scattering Fourier transform for tBME crystalline MES S2

The observed spectrum of Raman scattering Fourier transform for tBME crystalline MES S2 shown in Fig, and the corresponding data are shown in the following next table 18:

Characteristic features of the spectra include intense peaks at 2928 cm^-1, 1623 cm^-1and 1587 cm^-1and smaller, but sharp peaks at 1674 cm^-1, 1244 cm^-1, 1190 cm^-1, 780 cm^-1and 728 cm^-1.

v. Tg for tBME crystalline MES S2

Fig shows the results of TG-FTIR for sample tBME crystalline MES S2. Weight loss at around 8.7-10% occur due to the release of tBME. This mass loss corresponds to 0.8-0.9 molecules tBME molecule on 20, 23-piperidinyl-5-O-mycaminose-tionalize, assuming mostly clean on 20, 23-piperidinyl-5-O-mycaminose-tionale. Almost all weight loss occurs above 90°C, with a sharp step, when the temperature rises to more than 100°C. Thus, a large part of the weight loss occurs at temperatures greater than the boiling point of tBME. tBME crystalline MES, apparently, is more stable than an ethyl acetate crystalline MES S1. Stability is confirmed through experiments with desolately, where there is no loss of solvent during drying in vacuum, both at ambient temperature and at 70°C.

Crystalline MES S3

The following discussion provides a variety of observed characteristics of the crystalline MES S3.

i. The appearance of crystalline THF MES S3

THF crystalline MES S3 is, as a rule, in the form of irregular lumps and shows no tendency to collapse on the fiber compared to the crystalline salt is the atom S1.

ii. Range of x-ray diffraction on the powder for THF crystalline MES S3

The observed PXRD spectrum for crystalline THF MES S3 shown in Fig, and the corresponding data are shown in the following next table 19:

Characteristic features of the spectra include several peaks with similar intensities at 2θ=6,2°, 10,1°, 10,5°, 13,6°, 16,7°, 17,2°, 18,8° and 20.5°.

iii. The spectrum of Raman scattering Fourier transform to crystalline THF MES S3

The observed spectrum of Raman scattering Fourier transform to crystalline THF MES S3 shown in Fig, and the corresponding data are shown in the following next table 20:

Characteristic features of the spectra include intense peaks at 2928 cm^-1, 1622 cm^-1and 1586 cm^-1and smaller, but sharp peaks at 1673 cm^-1, 1244 cm^-1, 1191 cm^-1and 782 cm^-1.

iv. Tg for THF crystalline MES S3

Fig shows the results of TG-FTIR for THF crystalline MES S3. Most weight loss occurs at temperatures greater than the boiling point of THF. Specifically, less than 10% weight loss occurs in the range of 60 to 100°C, while approximately 80% of the losses occur in the range of 110 to 180°C. P the results show a loss of approximately 8.1%, occurring at temperatures greater than 100°C, followed by the release of THF. This corresponds to about 0.8 THF molecules per molecule on 20, 23-piperidinyl-5-O-mycaminose-tionalize, assuming mostly clean on 20, 23-piperidinyl-5-O-mycaminose-tionale.

Crystalline MES S4

The following discussion provides a variety of observed characteristics of the crystalline MES S4. Although data PXRD and FT-Raman below correspond methylacetate crystalline MES S4, these data generally are also applicable for characterization ethylformate crystalline MES, since it is isomorphic with methylacetate crystalline MES.

i. Appearance methylacetate crystalline MES S4

Methylacetate crystalline MES S4 contains a number of well-formed prismatic crystals. The crystals do not exhibit the tendency to disintegration of the fibers compared to the crystalline MES S1.

ii. Range of x-ray diffraction on the powder for methylacetate crystalline MES S4

The observed PXRD spectrum for methylacetate crystalline MES S4 shown in Fig, and the corresponding data are shown in the following next table 21:

Characteristic features of the spectra include the number of peaks with similar intensities at 2θ=6,3°, 10,1° 10,5°, 14,8°, 16,8°, 17,4°, 18,9° and 20.9°.

iii. The spectrum of Raman scattering Fourier transform for methylacetate crystalline MES S4

The observed spectrum of Raman scattering Fourier transform for methylacetate crystalline MES S4 shown in Fig, and the corresponding data are shown in the following next table 22:

Characteristic features of the spectra include intense peaks at 2949 cm^-1, 2934 cm^-1, 1619-1621 cm^-1and 1581-1584 cm^-1and smaller, but sharp peaks at 1671 cm^-1, 1243 cm^-1, 1191 cm^-1, 981 cm^-1and 782 cm^-1.

iv. Tg for crystalline solvate S4

Fig and 40 show the results of TG-FTIR for methylacetate and ethylformate crystalline solvate S4, respectively. These results confirm the existence of a crystalline solvate. For methylacetate crystalline MES are weight loss about 8.4% due to excretion of acetate. And for ethylformate crystalline MES has a mass loss of about 7.7 percent. Based on the results of monitoring to make assessments that methylacetate crystalline MES is about 0.9 molecules of acetate per molecule on 20, 23-piperidinyl-5-O-mycaminose-tionalize and ethylformate crystalline MES is from p is IMEMO 0.6 to about 0.8 molecules of ethylformate per molecule on 20, 23-piperidinyl-5-O-mycaminose-tionalize. Both of these estimates assume mostly clean on 20, 23-piperidinyl-5-O-mycaminose-tionale. Less than 10% weight loss occurs in the range from 70 to 110°C for methylacetate crystalline MES and from 60 to 90°C for ethylformate crystalline MES. For both crystalline solvate desolately happens quickly. Desolately ends directly at 160°C for methylacetate crystalline MES and at 130°C for ethylformate crystalline MES.

B. Receiving medicines and methods of treatment using macrolides

Different crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize described above can be used, for example, for the treatment of hemorrhagic septicemia in animals, particularly livestock and poultry. In some embodiments, the implementation of the crystalline form(s) of the macrolide is used to treat cattle with respiratory disease in ruminants (BRD)associated withMannheimia haemolytica, Pasteurella multocidaandHistophilus somni. In other embodiments, implementation of the crystalline form(s) of the macrolide use for treatment of domestic pigs with respiratory disease of pigs associated withActinobacillus pleuropneumoniae, Pasteurella multocidaandBordetella bronchiseptica.

Typically, a therapeutically effective quantity is the amount of the macrolide is administered to the recipient animal. As used in this patent, the term "therapeutically effective amount" is an amount that is sufficient to prevent, reduce the risk of, slowing the onset of, alleviate, mitigate or eliminate the target infection by the pathogen(s). Typically, therapeutically effective amount is defined as the amount needed to achieve a concentration effective to control the target pathogen(s) at the site of infection (or when they are used to prevent, reduce the risk or delay the onset of infection, in a place prone to infection). The concentration at the site of infection (or in a place subject to infection) is preferably at least level MIC₉₀(minimum inhibitory concentration, i.e. the concentration that inhibits growth in 90% of the target pathogens) of the macrolide for the target pathogen. This amount can be administered to an animal to the recipient in two or more separate doses, although, preferably, it is introduced in one dose. To the extent in which the macrolide is introduced together with another active ingredient(s), the term "therapeutically effective amount" refers to the total quantities of the macrolide and the other active ingredient(s), which together are sufficient to prevent the tion, reducing the risk of, slowing the onset of, alleviate, mitigate or eliminate infection of the target pathogen(s).

Factors affecting the preferred dosage regimen include the type (e.g., species and breed), age, weight, sex, diet, activity and condition of the animal recipient; the severity of the pathological condition; the device used for injection of the composition, and the type of administration; pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular input of the composition; the presence of additional active ingredient(s) in the composition; and then, if you enter the composition as part of the combined drugs and/or vaccines. Thus, the actual dosage may vary for a particular animal patients and therefore may deviate from the typical dosages above. Determination of selection of such doses is generally within the knowledge of experts in the field using conventional means.

As a rule, macrolide may be administered to an animal once, although it is assumed that instead, it may be injected several times.

For cattle the total number of input of the macrolide is usually from about 0.1 to about 40 mg / kg of m is ssy body, and more often from about 1 to about 10 mg per kg of body weight. For example, in some embodiments, the implementation of a number entered in cattle is approximately 4 mg per kg of body weight. Although macrolide may be administered to cattle at any age, in some embodiments, the macrolide is introduced cattle in age from approximately 1 month to approximately 1.5 years of age or from about 6 months to about 1 year. In some embodiments, the macrolide is entered nursing calves entering the enclosure (often at the age of about 6 months). In other embodiments, the implementation of cattle represents calves aged from about 2 to about 12 weeks, and macrolide introduced for prophylaxis at a dose of from about 1 to about 10 mg per kg of body weight or to treat an existing infection at a dose of from about 2 to about 20 mg per kg of body weight.

For pigs the total number of input of the macrolide is usually from about 0.1 to about 50 mg per kg of body weight, and often from about 1 to about 10 mg per kg of body weight. For example, in some embodiments, the implementation of a number of introduced pigs, approximately 4 mg per kg of body weight. In other embodiments, the implementation of a number of introduced pigs, approximately 5 mg per kg of body weight. Although macrolide may be pigs at any age, in some embodiments, the macrolide is introduced farm pigs on a diet of final fattening period.

The method of administration can vary depending on the animal, but in the case of large mammals, such as cattle, pigs and horses, it preferably is administered orally or parenterally. Parenteral administration includes, for example, subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, submucosal injection and infusion. In some embodiments, the implementation of animal-recipients, for example, are cattle, and the composition of the macrolide subcutaneously, for example, in the neck. In other embodiments, implementation animals-recipients, for example, is a domestic pigs, and the composition of the macrolide is injected intramuscularly.

Form(s) of the crystal of the macrolide can be used to obtain pharmaceutical compositions (or drugs). It is assumed that such a composition can completely contain one or more of these crystalline forms of the macrolide. Usually, however, the composition also contains other ingredients.

Other ingredients in the composition may include, for example, other active ingredients. An alternative (or in addition) such other ingredients may include the step one or more pharmaceutically acceptable carriers, binders and/or auxiliary substances (referred to together as the "holders"). The choice of media will depend on various factors such as route of administration; the device used for injection of the composition; pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular composition; the presence of additional active ingredient(s) in the composition, and is entered whether the composition as part of a combined drug and/or vaccine.

Solid compositions of the macrolide may contain, for example, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; and the like.

Liquid compositions of the macrolide may contain, for example, water, isotonic physiological saline, ringer's solution, ethyl alcohol, and/or may be a solution of phosphate buffer. Such compositions can also contain oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, and/or polyhydric alcohols such as glycerin, propylene glycol, sorbitol, mannitol, polyethylene glycol and poly(utiling the Col-2-propylene glycol-2-polyethylene glycol). Also, for example, it may be desirable that in some cases, the composition contains one or more preservatives. The presence of a preservative may, for example, to give the advantage to the compositions or solvents that can be stored for extended periods of time, e.g. days, weeks, months, or years. When you choose the appropriate preservative, consider factors include, for example, its antimicrobial activity; the pH range at which it is desired antimicrobial activity; the minimum concentration at which it is desired antimicrobial activity; its solubility and other physical characteristics (for example, a possible foaming); its suitability for parenteral use; the possibility of its interaction with the active ingredient(s) (for example, its influence on the solubility of the active ingredient); its possible interaction with the inactive ingredients (for example, its influence on the stability of the solvent); and any government regulations that may be applied, when the composition or the solvent is produced, sold or used. Possible preservatives include, for example, parabens, propylene glycol, benzylaniline, phenylethanol, chlorocresol, metacresol, ethanol, Phenoxyethanol and benzyl alcohol.</>

Additional discussion regarding pharmaceutically acceptable carriers that may be suitable for the composition of the macrolide can be found, for example, in Gennaro, Remington: The Science and Practice of Pharmacy" (20th Edition, 2000) (included in the present patent application by reference). For illustration, other suitable carriers may include, for example, coloring agents; flavoring agents and thickening agents, such as providenciasantiago and/or hypromellose.

Usually macrolide is at least about 0.5 wt.% pharmaceutical compositions. For example, in some embodiments, the implementation for use on pigs respective concentrations of the macrolide for parenteral administration can be, for example, from about 5 to about 500 mg/ml, from about 10 to about 100 mg/ml or from about 20 to about 60 mg/ml (e.g., about 40 mg/ml). As an illustration, in some embodiments, the implementation for use in ruminants respective concentrations of the macrolide for parenteral administration can be, for example, from about 5 mg/ml to about 2.0 g/ml, from about 10 mg/ml to about 1.0 g/ml, 50 to about 500 mg/ml, or from about 100 to about 300 mg/ml (e.g., 180 mg/ml).

It should be noted that the concentration of macros is Yes can vary depending on dosage forms. When, for example, macrolide requires parenteral administration, the concentration of the macrolide is preferably sufficient to create the desired therapeutically effective amount of a macrolide in an amount that is acceptable for parenteral administration. The maximum acceptable amount may vary depending on, for example, from the device used to introduce a type of parenteral administration, the size of the recipient animal and subjective desires of the user.

In some embodiments, the implementation of the pharmaceutical composition contains a liquid composition is formed using a method comprising dissolving crystalline forms (forms) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the carrier(s). In other embodiments, implementation of the composition comprises a suspension formed using a method including the suspension of crystalline forms (forms) on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the carrier(s).

Additional discussion regarding the use on 20, 23-piperidinyl-5-O-mycaminose-tionalize and its derivatives for the treatment of diseases of livestock and poultry can be found, for example, in U.S. patent No. 6514946. As indicated earlier, this discussion is included in this patent by reference.

The present invention is also directed to kits, which are rightname, for example, for use in implementing the methods of treatment described above. In some embodiments, the implementation of the set contains a therapeutically effective amount of at least one of the above described crystalline forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize (for example, a therapeutically effective amount of polymorphic form I), and instructions for combining the crystalline form, at least one carrier, such as, for example, instructions for dissolution or suspension of crystalline form in liquid media. The kit may additionally (or alternatively) include additional components, such as, for example, one or more devices (e.g., a syringe for injection of a composition containing a crystalline form (form) on 20, 23-piperidinyl-5-O-mycaminose-tionalize (or derived from it), one or more additional pharmaceutical or biological materials, one or more carriers and/or one or more diagnostic tools.

Examples

The following examples are only illustrations of embodiments of the present invention and do not limit the rest of this description in any way.

Example 1

Getting on 20, 23-piperidinyl-5-O-mycaminose-tionalize of tylosin A

Part A. Reductive amination. The connection 23-O-mucinosis-20-piperidinyl-5-O-mycaminose-tionalize (2).

Toluene (19,2 kg), tylosin A (1) (3,68 kg; ≥80% tylosin A; ≥95% tylosin A, B, C and D), piperidine (0,40 kg) and formic acid (0,55 kg) loaded into the reactor. The mixture is heated to 70-80°C under stirring. Then stirring is continued at this temperature for a further 1-2 hours. The formation of compound 20-piperidinyl-tylosin (2) is followed by means of HPLC. After completion of the reaction (≤2% tylosin A (1)) the mixture of products is cooled to ambient temperature.

Part B. Acid hydrolysis of microsilica Deputy. The connection 23-O-mucinosis-20-piperidinyl-5-O-mycaminose-tionalize (3).

HBr (48% HBr, diluted to 24%) are added to a mixture of products of part A with stirring and maintain the mixture at less than 40°C. Subsequently, the phases in the mixture of products separated using a 20-minute period of phase separation. During this phase separation, the mixture of products is at 20-25°C. HPLC lower phase is used to confirm completion of the reaction (≤2% of compound 20-piperidinyl-tylosin (2)).

Part C. Acid hydrolysis of macinazione Deputy. The 23-hydroxyl-20-piperidinyl-5-O-mycaminose-tionalize(4).

Twenty-four percent HBr (18,4 l) is added at ambient temperature to the aqueous phase obtained from part B, and then heated to 54±3°C within about 1 hour under stirring. Stirring is continued at this temperature for more than 2-4 hours, while the reaction is followed using HPLC. After completion of the reaction (≤2% of compound 23-O-mucinosis-20-piperidinyl-5-O-mycaminose-tionalize (3)) the mixture is cooled to ambient temperature using cooled to -10°C casing. After cooling, the mixture is extracted with dichloromethane three times (9,8 kg each time). Water the product is cooled to 4-8°C and then slowly added 6N NaOH (33.6 kg) to bring the pH to ≥10. The resulting mixture was extracted with dichloromethane three times (32,6 kg 29.3 kg and 24.5 kg) at ambient temperature. The combined organic phases are loaded in a separate reactor. Add sodium sulfate (2.9 kg; Na₂SO₄) and filtered.

Then add dichloromethane (4.9 kg) and remove it by distillation. The resulting crude product is dissolved and recrystallized twice tert-butyllithium ether (6.1 kg each time) at ambient temperature. Subsequently, the product can be distinguished in the Nutsch filter, washed twice tert-butylmethylamine ether (1.0 kg each time) and dried in zentraler the Oh drying in vacuum overnight at 40°C. The final product analyzed using HPLC.

Part D. Iodination. The production of activated compounds (5).

Triphenylphosphine (0.9 kg) and pyridine (0.3 kg; does not contain water) dissolved in dichloromethane (11.7 kg) at ambient temperature. Then add iodine (0.8 kg). Then the resulting mixture was stirred to dissolve all of the iodine. The mixture is then cooled to 13°C. the Cooled mixture was added the product from part C in dichloromethane (11.7 kg) under stirring at 15±3°C. the Reaction is followed by HPLC and determined that it should be completed in 2-2,5 hours (≤2% of compound 23-hydroxyl-20-piperidinyl-5-O-mycaminose-tionalize).

Part E. Amination. Getting on 20, 23-piperidinyl-5-O-mycaminose-tionalize (6).

Potassium carbonate (1.8 kg), acetonitrile (16.7 kg) and piperidine (1.1 kg) are added to a product part D. Then the resulting mixture was heated to 78°C and distillation of the dichloromethane. The solvent is then replaced by acetonitrile, the mixture is stirred for 2-2 .5 hours under reflux, and then cooled to ambient temperature. Subsequently, the remainder of the potassium carbonate is filtered off, the filter cake washed with acetonitrile (2.8 kg) and the solvent is distilled off in vacuum at the temperature of the casing 50°C. the resulting residue is dissolved in ethyl acetate (15.8 kg) and mix is with 0,5N HCl (35,6 kg). The phases are separated at ambient temperature and the lower aqueous phase is extracted three times with ethyl acetate (use each time 15.8 kg). The resulting aqueous phase is brought to pH 11 by adding 6N NaOH (6.4 kg) and extracted three times with dichloromethane (18.7 kg each time) at ambient temperature. The joint of the lower organic phase is re-loaded into the reactor with sodium sulfate (5.3 kg). The mixture is then filtered to obtain a precipitate, which, in turn, washed with dichloromethane (4.9 kg) and dried in vacuum at the temperature of the casing 50°C with the formation of the product of the macrolide. This product, in turn, is mixed with acetonitrile (21,7 l) and recrystallized. The obtained crystals emit on a Nutsch filter, washed twice with cold acetonitrile (3.5 l each time) and dried in vacuum at 40°C during the night with obtaining the product of the macrolide (5). The composition of the product is confirmed using HPLC.

Example 2

Alternative amination. Getting on 20, 23-piperidinyl-5-O-mycaminose-tionalize (2)

Potassium carbonate (0,94 kg), xylene (5 l) and piperidine (0,55 kg) is added to 1.0 kg of the activated compound (1)obtained in accordance with the procedure of part D. Then the resulting mixture was heated to 95-105°C for 15 hours. Extraction involves the dissolution of K₂CO₃

Example 3

Obtaining polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Part A. Reductive amination. The connection 23-O-mucinosis-20-piperidinyl-5-O-mycaminose-tionalize (2).

Trainfest (1) and dichloromethane (1.3 l per kg of trainfossato) is loaded into the reactor. The resulting mixture is stirred to obtain a clear solution. Then piperidine (1.2 EQ., in relation to trainfossato), formic acid (4.5 equiv., in relation to trainfossato) and toluene (6.7 l per kg of trainfossato) sequentially loaded into the reactor. The resulting mixture was heated to 76°C under stirring. Then stirring is continued at this temperature for 2.5 hours. Then download additional piperidine (0.1 equiv., in relation to trainfossato) and the resulting mixture was stirred at 76°C for an additional hour. The mixture of products is cooled to 50°C.

Part B. Acid hydrolysis of microsilica Deputy. The floor is a group of 23-hydroxyl-20-piperidinyl-5-O-mycaminose-tionalize (4).

An aqueous solution of HBr (23,3 EQ., in relation to trainfossato used in part (A) is added to a mixture of products of part A at 50°C. the resulting mixture was stirred at 56°C for 5 hours. HPLC is used to monitor the reaction.

After obtaining the desired conversion product mix is cooled. The aqueous phase is extracted twice with dichloromethane at 25-30°C. Then the aqueous phase is cooled to 0°C and the pH adjusted to 10-10,5 using NaOH at ≤5°C. Subsequently, the aqueous phase is extracted twice with dichloromethane at 20°C. the Obtained combined organic phases are extracted twice aqueous solution of NaHCO₃. Then dichloromethane is removed from the combined organic phase by distillation and replaced with isopropyl alcohol. Subsequently, add heptane at 45°C to initiate deposition. The mixture is then stirred at 0°C. Subsequently, the crystalline product produce by filtration. Selected crystals washed with heptane and isopropyl alcohol, dried, and analyzed using HPLC.

The above procedure gives 0,23 kg of product per kilogram of trainfossato used in part A. This product may contain isopropyl alcohol. To remove isopropyl alcohol product can be dissolved in toluene and dichloromethane, followed by distillation.

Frequent Is C. Iodination. The production of activated compounds (5).

Triphenylphosphine (0,41 kg per kg of the product of part B) is dissolved in dichloromethane (12 l per kg of triphenylphosphine, ≤100 ppm H₂O) at 25°C. Then add pyridine (0.3 kg per kg of triphenylphosphine). Next, add iodine (0.9 kg per kg of triphenylphosphine) 5 portions at 25°C. the resulting mixture was stirred for 40 minutes at 25°C, and then cooled to -6°C. the mixture is Then added to the product from part B in 50 minutes under stirring at -6°C. Subsequently, stirring is continued for 7 hours, while maintaining the mixture at -5°C. the Reaction is followed by means of HPLC (if sufficient conversion is not reached, the mixture may be mixed at -5°C for an additional amount of time, for example, 1.5 hours).

When they reach the desired conversion, the mixture of products was washed with aqueous solution of Na₂SO₃at -5°C. Then the dichloromethane is removed from the organic phase by distillation and replaced by tetrahydrofuran.

Part D. Amination. Getting on 20, 23-piperidinyl-5-O-mycaminose-tionalize (6).

To the product from part C added piperidine (0,55 kg per kg of the product from part (B), and then potassium carbonate (0,94 kg per kg of product from part B). The resulting mixture was heated to 55°C, and then maintain this pace is the atur for 3 hours under stirring. Subsequently, the mixture is heated to 72°C for 1 hour and then stirred at this temperature for 6 hours. The product analyzed using HPLC.

After obtaining the desired conversion product mix is cooled to 20°C and add toluene. The resulting mixture was washed twice with water and the organic phase is extracted twice with an aqueous solution of HCl with obtaining the aqueous phase with pH ≤3. This mixture is cooled to 0-5°C.

Part E. Obtaining an ethyl acetate crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize.

The acidic aqueous solution of the product obtained in accordance with part D, unite with ethyl acetate (6.7 l per kg of product from part B) at 3°C. the pH of the resulting emulsion was adjusted to 10.5-11,0 at 3°C with caustic soda. The phases are separated at 3°C. the Organic phase is washed once with water. After phase separation the organic phase is concentrated by distillation to obtain an ethyl acetate solution. Crystallization begins at the entry of the seed. The resulting product is filtered off with obtaining an ethyl acetate precipitate the crystalline MES on the filter. The filter cake is washed with heptane at 0°C. This gives approximately 0,78 kg wet wet crystalline MES per kg of used product from part B.

Part F. Obtaining polymorphic form I on 20, 23-d is piperidinyl-5-O-mycaminose-tionalize.

The washed wet precipitate of the crystalline MES obtained in accordance with part E, together with heptane (6.1 l per kg of wet sediment). The resulting suspension is heated to 72°C and make seed. Subsequently, the suspension is stirred at 72°C, then at 20°C. Then the suspension was filtered and the resulting solids washed with heptane and dried. This gives approximately 0.53 kg of crystals of form I per kg of used product from part B (or 0.68 kg of crystals of form I in kg used crude wet product of the crystalline MES from part E).

Example 4

Obtaining polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Part A. the production of activated connections.

23-Hydroxyl-20-piperidinyl-5-O-mycaminose-tionale (50 g) receive, in accordance with the method described in example 1, parts A-C, except that the acid used in the reaction, acid hydrolysis (that is, parts B and C), represents HCl instead of HBr. 23-hydroxyl-20-piperidinyl-5-O-mycaminose-tionale at 13°C load stir in the reactor containing dichloromethane (250 ml at 13°C). The resulting mixture is stirred for about 5 minutes at 13°C. in Parallel dichloromethane (250 ml) at ambient temperature) load in a separate reactor and begin mixing. Then charged to the reactor triphenyl spin (24,6 g at ambient temperature), and then pyridine (7.8 ml) at ambient temperature)and then iodine (to 22.83 g at ambient temperature). Subsequently, the mixture is stirred for 2 minutes at ambient temperature and then combined with a mixture of dichloromethane containing 23-hydroxyl-20-piperidinyl-5-O-mycaminose-tionale, at 13°C using a dropping funnel. The resulting mixture was stirred for 130 minutes at 13°C with the formation of the activated product.

Part B.Obtaining polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

Potassium carbonate (51,81 g), then acetonitrile (600 ml) and then piperidine (37.1 ml) is added to an activated product of part A at 13°C. Then the resulting mixture was heated to 78°C for 90 minutes, and then stirred at this temperature (reflux) for 130 additional minutes. The mixture is then cooled to 15-25°C for 60 minutes and the stirring stopped. Subsequently, the remainder of the potassium carbonate is filtered off, the filter cake washed with acetonitrile (100 ml) and the solvent is distilled off in vacuum at 50°C for 60 minutes. The resulting residue is dissolved in ethyl acetate (500 ml) and mixed with 0,5h. HCl (1000 ml). After stirring for 5 minutes, the stirring is stopped and the phases are separated. The lower aqueous phase is extracted three times with ethyl acetate (each time using 500 m is). Begin mixing the resulting aqueous phase and the temperature is reduced to 5-8°C. Then the pH was adjusted to pH 11 by adding 6N NaOH (150 ml). The mixture is then installed pH extracted three times with dichloromethane (400 ml each time) at ambient temperature. The joint of the lower organic phase is re-loaded into the reactor with sodium sulfate (150 g) at ambient temperature. The resulting mixture is stirred for 15 minutes and then filtered from the precipitate, which, in turn, washed with dichloromethane (100 ml). The solvent is removed by distillation and the product is dried in vacuum at 50°C for 60 minutes. It gives of 57.5 g of a crude product of the macrolide.

The crude product is crystallized from acetonitrile (90 ml) at 50°C. To prevent the formation of oil seed crystal on 20, 23-piperidinyl-5-O-mycaminose-tionalize add at ambient temperature (seed crystals receive in advance by dissolving 3 g of crude on 20, 23-piperidinyl-5-O-mycaminose-tionalize in 12 ml of acetonitrile and collected by filtration the crystals that are formed after 24 hours at ambient temperature). The product precipitates as a whitish solid product for 5 hours at ambient temperature and during the night (15 h) at 5°C. the Solid product is separated by means of the filtration and washed twice with cold acetonitrile (2×25 ml). The remaining solid product is dried under reduced pressure (8 mbar) at 40°C overnight to obtain 18.2 g on 20, 23-piperidinyl-5-O-mycaminose-tionalize (content: 90% (wt./wt.), as determined by HPLC). The product (15 g) optionally purified by recrystallization in acetonitrile. This gives 10.7 g of product (purity according to HPLC at 254 nm: 100%; content: 94% (wt./wt.), as determined by HPLC).

Example 5

Recrystallization of polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize in acetonitrile

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (80 mg)obtained in accordance with example 4, is dissolved in acetonitrile (2 ml). The resulting solution is filtered and the acetonitrile allow to evaporate at ambient temperature with the formation of crystals. The spectrum of Raman scattering Fourier transform of the crystalline product is essentially identical to the spectrum of the crystalline product of example 4.

Example 6

Obtaining an ethyl acetate crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (312 mg)obtained in accordance with example 4, dissolved in ethyl acetate (0.5 ml). A few minutes after complete dissolution of the formation of new crystals and in a few minutes they fill solution. Add additional ethyl acetate (1 ml) and the crystals are filtered and dried at ambient temperature and atmospheric pressure.

Example 7

Obtaining polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize get by drying in vacuum at ambient temperature for 20 hours, an ethyl acetate crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize (50 mg) are obtained in accordance with example 6.

Example 8

Obtaining an ethyl acetate crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (146,1 mg)obtained in accordance with example 4, dissolved in ethyl acetate (0.5 ml) with stirring. After the beginning of crystallization add heptane (5 ml), while stirring is continued. The obtained solid product is filtered off after 3 days. All these stages is carried out at ambient temperature. The obtained crystals are in the form of very fine needles. The spectrum of Raman scattering Fourier transform for crystals coincides with the spectrum of Raman scattering Fourier transform for crystals from example 6.

Example 9

Getting etelaat is aqueous crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (99,6 mg)obtained in accordance with example 4, dissolved in ethyl acetate (2 ml). The resulting solution is filtered and the solvent allow to evaporate. After evaporation of almost all the solvent remains amorphous residue. Again, add ethyl acetate and allow it to evaporate. A few seed crystals obtained in example 6 add in various stages of evaporation. It gives crystals in the form of needles. The spectrum of Raman scattering Fourier transform for these crystals coincides with FT-Raman for crystals from example 6.

Example 10

Obtaining polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize get by drying in a vacuum ranging from about 40 to about 70°C for 3 days, an ethyl acetate crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize receive in accordance with example 9. The spectrum of Raman scattering Fourier transform for these crystals coincides with the spectrum of Raman scattering Fourier transform for crystals from example 7.

Example 11

Obtaining polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-dipiperidino is l-5-O-mycaminose-tionalize (150,5 mg), obtained in accordance with example 4, and acetonitrile (1 ml) are combined and exposed to Cycling the temperature between 20 and 40°C with intervals of 1 hour for each stage of heating/cooling and the temperature record. This Cycling is stopped after 5 days. The obtained crystals (in the form of fine needles) is filtered off and allow to dry at ambient temperature. Range PXRD for these crystals coincides with the PXRD spectrum for crystals in example 7.

Example 12

Obtaining polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (170,5 mg)obtained in accordance with example 4 was stirred at ambient temperature for 4 days with the solvent (1 ml)consisting of heptane and tert-butyl methyl ether ("tBME") in respect of heptane/tBME 95:5 (volume/volume). Subsequently, the obtained crystals are filtered, washed with additional solvent heptane/tBME (95:5 vol/vol) and dried in vacuum.

Example 13

Obtaining polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (USD 147.4 mg)obtained in accordance with example 4, dissolved in tBME (0.5 ml) with stirring to form prozracnosti. Then add heptane, which leads to a small deposition. Then, the crystals emit after 3 days. All these stages is carried out at ambient temperature. The spectrum of Raman scattering Fourier transform to the obtained crystals coincides with the spectrum of Raman scattering Fourier transform for crystals in example 12.

Example 14

Obtaining polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (164,5 mg)obtained in accordance with example 4 was stirred with heptane (1 ml) at ambient temperature for 4 days. The obtained solid product is filtered, washed with heptane and dried in vacuum. The washed and dried product (90 mg) and crystals of polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize (98 mg) is suspended in heptane and stirred. The temperature of the support at 25°C for 10 days, with the exception of short-term random temperature increase to 60°C in the fifth night. The spectrum of Raman scattering Fourier transform to the obtained crystals coincides with the spectrum of Raman scattering Fourier transform for crystals of example 12.

Example 15

Obtaining polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Crystal is a polymorphic form III on 20, 23-piperidinyl-5-O-mycaminose-tionalize (171,8 mg) is suspended in solvent (1 ml) of heptane and tBME with respect heptane/tBME 95:5 (volume/volume). The resulting solution was stirred for 9 days. The solid product is filtered and washed with heptane (1 ml). All these stages is carried out at ambient temperature. The spectrum of Raman scattering Fourier transform to the obtained crystals coincides with the spectrum of Raman scattering Fourier transform for crystals of example 12.

Example 16

Obtaining polymorphic form I on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Crystals of polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (173,4 mg) is suspended in solvent (1 ml) of heptane and tBME with respect heptane/tBME 95:5 (volume/volume). The resulting solution was stirred for 9 days. The solid product is filtered and washed with heptane (1 ml). All these stages is carried out at ambient temperature. The spectrum of Raman scattering Fourier transform for crystals on day 5 and at the end of the 9 day coincides with the spectrum of Raman scattering Fourier transform for crystals of example 12.

Example 17

Obtaining ethanol crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (150 mg)obtained in accordance with example 4, is dissolved in ethanol (1 ml). After filtering to allow ethanol to evaporate p and the ambient temperature. A solid product, which is again dissolved in ethanol (1 ml). After filtering to allow ethanol to evaporate at ambient temperature. Range PXRD and Raman scattering Fourier transform to the obtained crystals coincides with the corresponding spectrum for the crystalline product of example 6.

Example 18

Getting diethylketone crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (to 206.6 mg)obtained in accordance with example 4, dissolved in diethylketone (0.5 ml), and then allow her to settle in for the night. The next morning, get crystals using filtering. Range PXRD for the obtained crystals coincides with the PXRD spectrum for the crystalline product of example 6.

Example 19

Getting tBME crystalline MES S2 on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (304 mg)obtained in accordance with example 4, is dissolved in tert-butylmethylether ether (0.5 ml). During the night on the bottom of the tank forming large crystals. When soskrebaya the entire volume of the solution is filled with crystals within 15 minutes. Add additional tert-butyl methyl ether (1 ml). Then the crystal is filtered and dried at ambient temperature.

Although this procedure was successfully repeated to obtain the crystalline MES S2, additional loading of the crystals MES S2 are formed by dissolving an additional amount of polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize in tert-butylmethylether ether, the seed crystals MES S2 of the first loading and removal of tert-butyl methyl ether. In one experiment, the crystalline MES S2 receive by dissolving polymorph form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (245,7 mg) in a simple tert-butyllithium ether (0.5 ml) and slow evaporating part of the solvent at ambient temperature. After the termination of the formation of crystals add additional simple tert-butyl methyl ether, and then seed crystals of MES S2 from the first boot. Then allow the solvent to evaporate completely. The spectrum of Raman scattering Fourier transform for these crystals is approximately identical to the spectrum of Raman scattering Fourier transform for crystals from first boot. In an additional study, the crystals are dried in vacuum at ambient temperature for 20 hours and then dried in vacuum for 24 hours at about 70°C. the Spectrum of Raman scattering Fourier transform of the crystal is s after each stage drying coincides with the spectrum of Raman scattering Fourier transform of the first boot.

Example 20

Getting tertrahydrofuran ring crystalline MES S3 on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (150 mg)obtained in accordance with example 4, dissolved in tetrahydrofuran (1.0 ml). The resulting mixture was filtered, and then allow the solvent to evaporate at ambient temperature. Crystallization occurs after evaporation of the relatively large proportion of solvent.

Example 21

Getting methylacetate crystalline MES S4 on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (204,0 mg)obtained in accordance with example 4, is dissolved in methyl acetate (0.5 ml). The initiate recrystallization during dissolution. After 15 minutes the entire volume is filled with needles. The solid product is filtered off. The final crystals are prismatic form.

Example 22

Getting ethylformate crystalline MES S4 on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Polymorphic form II on 20, 23-piperidinyl-5-O-mycaminose-tionalize (of 208.3 mg)obtained in accordance with example 4, dissolved in ethyl formate (0.5 ml). The flask was left open for several minutes while the material is slow crystallis what is with the formation of large needles. The solid product is filtered off. The final crystals are prismatic in shape. Range PXRD for the obtained crystals coincides with the PXRD spectrum for the crystalline product of example 21.

Example 23

Obtaining polymorphic form IV on 20, 23-piperidinyl-5-O-mycaminose-tionalize

Wet from an ethyl acetate solvent crystalline MES on 20, 23 S1-piperidinyl-5-O-mycaminose-tionalize (3.4 g, corresponding to 2.0 g of dry product) is mixed with 27.7 g of heptane (corresponding to a ratio of 14 g of solvent to 1 g of the product). The mixture is distilled at 73-95°C with removal of 8.4 g of solvent (ethyl acetate and heptane unite), which also leads to the dissolution of the product. The solution is cooled to 45°C within 2 hours, which leads to the deposition of a certain amount of sticky solid at 45°C. the Solution is heated to 60°C and add the seed crystals (these seed crystals receive in advance by mixing raw on 20, 23-piperidinyl-5-O-mycaminose-tionalize (0.9 g) with heptane (4.5 g), stirring the mixture at 80°C for 8 hours, stirring the mixture at 23°C for 21 hours and filtering the obtained crystals). The solution is cooled to 45°C, this produces a certain amount of solid product. The mixture is heated to 80°C, and then maintain at this temperature, while stirring during the 8 hours. Subsequently, the mixture is cooled to 22°C, causing the formation of product on the walls of the reaction flask. This product is separated.

The words contain, contains, and containing in this patent (including the claims) should be interpreted inclusive rather than exclusive. This interpretation is, as expected, coincides with the interpretation given to these words under the patent laws of the United States.

The term "pharmaceutically acceptable" is used in this patent as an adjective to denote that the modified noun corresponds to the use in the pharmaceutical product. When it is used, for example, to describe the carrier or salt, it characterizes the media or salt as having the advantage that outweighs any adverse effect(I)that the carrier or salt can have on the estimated animal-recipient.

If it is not otherwise characterized in this patent, the term "ambient temperature" means a temperature of from about 20 to about 25°C.

The term "amorphous" as applied to on 20, 23-piperidinyl-5-O-mycaminose-tionality in this patent refers to the solid, where molecules on 20, 23-piperidinyl-5-O-mycaminose-tionalize are present in a disordered arrangement, and do not form a distinguishable crystal lattice or e is ementary cells. When exposed to the x-ray diffraction on powder amorphous on 20, 23-piperidinyl-5-O-mycaminose-tionale not give any characteristic crystalline peaks.

The term "crystalline form" as applied to on 20, 23-piperidinyl-5-O-mycaminose-tionality in this patent refers to a solid form, where the molecules on 20, 23-piperidinyl-5-O-mycaminose-tionalize are with the formation of distinguishable crystal lattice, which (i) contains a distinguishable unit cell and (ii) gives diffraction peaks when subjected to x-ray radiation on the powder.

The term "crystallization" can refer to crystallization and/or recrystallization, depending on the proposed circumstances relating to the collection of source material on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

The term "direct crystallization" refers to crystallization on 20, 23-piperidinyl-5-O-mycaminose-tionalize directly from the appropriate solvent without education and desolvatation intermediate compound solvated crystalline solid forms on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

The term "particle size" refers to the particle size, as measured by the usual methods of measuring particle sizes, are well known in this field such as laser light scattering, sedimentation the Noah flow fractionation, photon-correlation spectroscopy, or disk centrifugation. A non-limiting example of a technique that can be used to measure particle size, is a technique for liquid dispersions using the analyzer Sympatec particle size.

The term "HPLC" means high performance liquid chromatography.

If it is not otherwise characterized in this patent, the term "purity" refers to the chemical purity on 20, 23-piperidinyl-5-O-mycaminose-tionalize in accordance with the usual analysis using HPLC.

The term "phase purity"as used in this patent, means the purity of the solid on 20, 23-piperidinyl-5-O-mycaminose-tionalize in relation to a particular crystalline or amorphous form on 20, 23-piperidinyl-5-O-mycaminose-tionalize, as determined using analytical methods based on diffraction of x-rays on the powder described in this patent. The term "phase-pure" refers to a purity with respect to other forms of solid on 20, 23-piperidinyl-5-O-mycaminose-tionalize and does not necessarily imply a high degree of chemical purity with respect to other compounds. The term "essentially phase-pure" refers, at least about 90% purity (e.g., at least about 95% purity) in relation to the other firm is ormam on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

All references cited in this patent are included as references in this patent.

The above-mentioned detailed description of the preferred embodiments is intended only to inform other specialists in this field with the present invention, its principles and its practical application to another specialist in this area could adapt and apply the invention in its numerous forms, as they can best meet the requirements of a particular use. The present invention is therefore not limited to the above implementation options and can be modified in various ways.

1. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize that has the following characteristics:
range of x-ray diffraction on powder containing at least one peak selected from the group consisting of 5,0 (±0,2) and 5.6 (±0,2) degrees of angle 2θ.

2. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize according to claim 1, having the following additional features:
the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2935, about 1633, about 1596, about 1712, when is Erno 1683 and approximately 781 cm ^-1;
the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2932, about 1711, about 1682, about 1635, about 1599, about 1442, about 1404, about 1182, about 1079, about 1053, about 1008, about 985, approximately 842 and approximately 783 cm^-1;
melting point from about 192 to about 195°C.

3. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize that has the following characteristics:
range of x-ray diffraction on powder containing peak at (6,5±0,2) degrees 2θ.

4. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize according to claim 3, having the following additional features:
the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2929, about 1625, about 1595, about 1685, and 783 cm^-1;
the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2935, about 1736, about 1668, about 1587, about 1451, about 1165, about 1080, about 1057, about 1042, about 1005, approximately 981, approximately 838 and p is IMEMO 755 cm ^-1.

5. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize that has the following characteristics:
range of x-ray diffraction on powder containing at least one peak selected from the group consisting of (5,6±0.2) and (6,1±0,2) degrees of angle 2θ.

6. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize according to claim 5, having the following additional features:
the spectrum of Raman scattering Fourier transform containing the absorption band at one or more frequencies selected from the group consisting of a frequency of about 2943, about 2917, about 1627, about 1590, about 1733, about 1669, about 1193, approximately 1094 and approximately 981 cm^-1;
the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group consisting of a frequency of about 2931, about 1732, about 1667, about 1590, about 1453, about 1165, about 1081, about 1057, about 1046, about 1005, approximately 981, approximately 834 and approximately 756 cm^-1.

7. Crystalline form on 20, 23-piperidinyl-5-O-mycaminose-tionalize that has the following characteristics:
the infrared spectrum of frustrated total internal reflection, containing an absorption band at one or more frequencies selected from the group sotoyama the frequency of about 3559, approximately 2933, about 1743, about 1668, about 1584, about 1448, about 1165, about 1075, about 1060, about 1045, about 1010, about 985, approximately 839 and approximately 757 cm^-1;
the melting temperature from about 149 to about 155°C.

8. The crystalline form of MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize, which includes at least one of the following forms:
crystalline form of an ethyl acetate MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize;
crystalline form ethanol MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize;
crystalline form diethylketone of MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize;
crystalline form of MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize with tert-butylmethylamine ether;
crystalline form tertrahydrofuran ring of MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize;
crystalline form methylacetate of MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize or
crystalline form ethylformate of MES on 20, 23-piperidinyl-5-O-mycaminose-tionalize.

9. Pharmaceutical composition for the treatment of hemorrhagic septicemia, respiratory diseases of ruminants and respiratory diseases of pigs, containing on 20, 23-piperidinyl-5-O-mycaminose-tionale in solid form, where therapeuti the Eski effective amount on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition consists of a crystalline form according to any one of claims 1 to 8.

10. The pharmaceutical composition according to claim 9, where at least 50% on 20, 23-piperidinyl-5-O-mycaminose-tionalize in the composition consists of a crystalline form according to any one of claims 1 to 8.

11. The pharmaceutical composition according to claim 9, where on 20, 23-piperidinyl-5-O-mycaminose-tionale is present in the composition, essentially, in the pure phase crystalline form according to any one of claims 1 to 8.

12. The use of a therapeutically effective amount of the pharmaceutical composition of claim 10, for obtaining a medicinal product for the treatment of hemorrhagic septicemia, respiratory diseases of ruminants and respiratory diseases of pigs.

13. The application indicated in paragraph 12, in which:
respiratory disease in ruminants is associated, at least. with one of Mannheimia haemolytica, Pasteurella multocida and Histophilus somni and
respiratory disease of pigs is associated at least with one of Actinobacillus pleuropneumoniae, Pasteurella multocida and Bordetella bronchiseptica.

14. Pharmaceutical composition for the treatment of hemorrhagic septicemia, respiratory diseases of ruminants and respiratory diseases of pigs, which is obtained by a process comprising combining at least one carrier with a composition according to claim 9.

15. Pharmaceutical composition, which contains a suspension obtained by the method including the suspension therapeutically effective choicestvsomali according to claim 9, at least one carrier.