ES2306590A1 - Crystalline shapes i and ii of telitromycin (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Crystal forms i and ii of telithromycin. The present invention describes two new pharmaceutically acceptable crystalline forms of telithromycin and methods for their preparation. Two solid crystalline forms of telithromycin, here named form i and form ii, have been found, which differ from each other by their respective powder x-ray diffraction patterns (see figures 1 and 2). In addition to its characterization, ways of obtaining each of them are described in the present invention. (Machine-translation by Google Translate, not legally binding)

Description

Crystal forms I and II of telithromycin.

Object of the invention

The present invention describes two new ways Pharmaceutically acceptable telithromycin crystallines and methods for the preparation of these.

Background of the invention

Telithromycin, of formula I, is designated chemically like 11,12-dideoxy-3-de - [(2,6-dideoxy-3-C-methyl-3-O-methyl-? -L-ribo-hexopyranosyl) oxy] -6-O-methyl-3- oxo-12,11- [oxycarbonyl- [4 - ([4- (3-pirdidinyl) -1-H-imidazol-1-yl] butyl] imino]] erythromycin.

one

The telithromycin compound is an antibiotic of the ketolide family, a new class of macrolides specially designed to fight pathogens of the tract respiratory that have developed resistance to macrolides of second generation (such as clarithromycin, azithromycin and roxithromycin). They are semi-synthetic derivatives prepared from erythromycin that preserve the macrolactone ring structure and deosamine type sugar bound in position 5. The characteristic What defines these compounds is the elimination of sugar L-cladinous position 3 and later oxidation of the hydroxyl released into a carbonyl group. The Cetolides that are currently of greatest interest are those that they also contain a cyclic carbamate group between positions 11 and 12, instead of the two hydroxyl groups of erythromycin, attached to an arylalkyl or arylalkyl chain.

Within this new group of macrolides, the Telithromycin has been the first to be approved for use pharmacist.

The synthesis of telithromycin is described by first time in patent EP0680967, obtained by ether recrystallization a solid with a melting point of 187 ° C-188 ° C.

In WO2005 / 105821 a new synthetic route for the preparation of telithromycin is described, which is isolated as a solid from the final reaction medium by distillation of the solvent and treatment of the resulting concentrate with diisopropyl ether. In another example of this patent, telithromycin is recrystallized from a mixture of cyclohexanone and tert- butyl methyl ether.

The EP1212336 patent describes the formation and preparation of spherical agglomerates of this ketolide and its Application in pharmaceutical formulations. These agglomerates spherical are prepared from a solution of telithromycin in acetone which is subsequently treated with a mixture of cold diisopropyl ether and acetone.

The importance of the polymorphic form in which an active substance of Pharmaceutical use This is characterized by the orientation between adjacent molecules and the interactions that establish each other and affects physical properties as important as stability (sensitivity to heat, humidity, pH or light), solubility, bioavailability and ease of handling (storage, compaction, encapsulation, etc.)

Polymorphs of the same substance, which they share molecular formula but they show differences in their physical properties, can be characterized by different techniques, for having different X-ray diffractograms, points of fusion, infrared spectra, magnetic resonance spectra solid phase nuclear, etc.

The object of the present invention is to describe two crystalline forms of telithromycin as well as the methods for its preparation.

Brief description of the figures

Figure 1: X-ray powder diffractogram of the crystalline form I of telithromycin.

Figure 2: X-ray powder diffractogram of the crystalline form II of telithromycin.

Figure 3: X-ray powder diffractogram of amorphous telithromycin.

Description of the invention

Two solid crystalline forms have been found of telithromycin, in addition to the well-known amorphous form, which in the The present invention is called Form I and Form II. They differ each other for their respective x-ray diffraction patterns in powder (Figures 1 and 2). In addition to its characterization, in the present invention describes ways of obtaining each of they.

Crystalline form I

Form I of the present invention is characterized by the main peaks that appear in the model of X-ray powder diffraction, expressed in 2 ta, and by its relative intensities, shown below:

2

In this case and hereafter the abbreviations in brackets they mean: (f) strong intensity, (m) intensity medium and (d) weak intensity.

Crystalline form II

Form II of the present invention is characterized by angular positions (expressed in 2 the) of the most representative peaks with their relative intensities in The X-ray powder diffraction pattern shown at continuation:

4

The registration conditions of the models of X-ray powder diffraction are as follows:

Sample preparation:

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Inside 0.5 mm diameter Lindemann glass capillaries.

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Equipment and experimental conditions:

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PANalytical X'Pert PRO diffractometer with 240 mm radius the / 2 g goniometer, parallel optics with hybrid monochromator and transmission geometry with sample holder for spinner capillaries.

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Radiation Kα1 of Cu (λ = 1.5406 Å).

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Working power: 45 kV - 40 mA.

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Window that determines the height of the beam 0.19 mm.

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Soller windows of 0.02 rad in incident beam and diffracted beam.

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X'Celerator detector with active length of 2,122º.

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Sweepings \ theta / 2 \ theta from 2 to 50º 2 con with step size of 0.017 ° and measurement time of 300 seconds per step

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Form I is obtained from telithromycin in amorphous form or by recrystallization in any other way crystalline when applying the following methods:

Method 1. Amorphous or crystalline telithromycin is treated with an organic solvent in which it is slightly soluble of the R 1 OR 2 type (where R 1 and R 2 are linear or branched alkyl chains from 2 to 4 carbon atoms, the same or different), such as diethyl ether, diisopropyl ether or tert- butyl methyl ether, or linear, branched or cyclic alkane type of 5 or more carbon atoms, such as hexane, cyclohexane or heptane The resulting suspension is stirred hot for a while and then allowed to cool gradually to room temperature or lower. The solid formed is isolated by filtration and dried. Telithromycin is obtained in its Form I.

Method 2. Alternatively, amorphous or crystalline telithromycin is treated with an organic solvent in which it is soluble of the AcOR 3 type (where R 3 is an alkyl chain of 1 to 4 carbon atoms), such as ethyl acetate, or cyclic ether type , such as tetrahydrofuran, or with acetone . To the resulting solution is added an organic insolubilizer in which telithromycin precipitates, of the alkane type, for example pentane, hexane or heptane. The solid formed is isolated by filtration and dried. Telithromycin is thus obtained in its Form I.

Method 3. Alternatively, a mixture of Form I and Form II is treated in an organic solvent in which they are slightly soluble and the resulting suspension is stirred for several hours, cold or hot. The resulting suspension is filtered and the isolated solid is dried. Telithromycin is thus obtained in its Form I.

Form II is obtained from telithromycin amorphous following the following method:

Method 4. Amorphous telithromycin is treated with an alkane-type organic solvent, such as hexane or pentane, preferably pentane. The resulting suspension is kept under stirring at a temperature not exceeding 50 ° C for a while, and then cooled progressively. The suspension is filtered and the isolated solid is dried. Telithromycin is thus obtained in its Form II.

The following examples illustrate, but not limit, the scope of the present invention.

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Method one

Preparation of telithromycin Form I in heptane and in tert-butyl methyl ether

Example 1.1

0.500 g of amorphous telithromycin are treated with 4 ml of heptane . The resulting mixture is refluxed. A precipitate is formed that is allowed to mature by gradually cooling the mixture to 20 ° C. Filter and dry at 40 ° C with a vacuum oven for 10 h. 0.455 g of telithromycin is isolated in its Form I.

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Example 1.2

0.500 g of amorphous telithromycin are treated with 5 ml of tert- butyl methyl ether. The resulting mixture is refluxed and kept under stirring at this temperature for 2 h. The suspension is progressively cooled to 20 ° C. Filter and dry at 40 ° C with a vacuum oven for 10 h. 0.465 g of telithromycin is isolated in its Form I.

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Method 2

Preparation of telithromycin Form I in ethyl acetate and hexane

Example 2.1

0.500 g of amorphous telithromycin is treated with 3 ml of ethyl acetate at room temperature. At dissolution resulting hexane is slowly added. A precipitate forms that it is allowed to mature keeping the system under agitation for 1 h at the same temperature Filter and dry at 40 ° C with an oven empty for 10 h. 0.450 g of telithromycin is isolated in its form I.

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Preparation of telithromycin Form I in tetrahydrofuran and hexane

Example 2.2

0.500 g of amorphous telithromycin is treated with 3 ml of tetrahydrofuran at room temperature. At dissolution resulting hexane is slowly added. A precipitate forms that it is allowed to mature keeping the system under agitation for 1 h at the same temperature Filter and dry at 40 ° C with an oven empty for 10 h. 0.450 g of telithromycin is isolated in its form I.

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Method 3

Preparation of telithromycin Form I from a mixture of Forms I and II

Example 3.1

0.250 g of telithromycin Form I and 0.250 telithromycin Form II and treated with 5 ml low hexane stirring for 16 h at 20 ° C. The final suspension is filtered and Dry at 40 ° C with 10 h vacuum oven. 0.430 mg of Telithromycin in its Form I.

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Method 4

Preparation of telithromycin Form II in pentane

Example 4.1

0.500 g of amorphous telithromycin is treated with 3 ml of pentane The mixture is heated until reflux. Be keep the suspension under stirring for 1 h. It is filtered and it Dry the isolated solid in a vacuum oven for 10 h. They are isolated 0.480 g of telithromycin in Form II.

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Example 4.2

0.500 g of amorphous telithromycin is treated with 3 ml of pentane The suspension is stirred for 15 hours at 25 ° C. Be Filter and dry the isolated solid in a vacuum oven for 10 h. 0.450 g of telithromycin is isolated in Form II.

Claims (11)

1. Crystalline form of telithromycin, called Form I, characterized in that it has the main peaks of the X-ray powder diffraction model, expressed in 2 ta, and the relative intensities shown below: 6 where (f) means intensity strong, (m) medium intensity and (d) intensity weak.

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2. Method of obtaining telithromycin crystalline according to claim 1 consisting of:

(one)

treat telithromycin in the form amorphous or crystalline with an organic solvent in which partially soluble, type R 1 OR 2 (where R 1 and R 2 they are linear or branched alkyl chains of 2 to 4 atoms of carbon, the same or different from each other);

(2)

reflux the suspension previous resulting;

(3)

allow the resulting mixture to cool (2) progressively to room temperature or lower;

(4)

isolate the solid formed by vacuum filtration and drying,

to obtain the crystalline telithromycin characterized according to claim 1.

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3. Method of obtaining crystalline telithromycin according to claim 2, characterized in that the solvent of type R1 OR2 is diethyl ether, diisopropyl ether or tert -butyl methyl ether. Method of obtaining crystalline telithromycin according to claim 3, characterized in that the solvent of type R 1 OR 2 is tert- butyl methyl ether. 5. Method of obtaining telithromycin crystalline according to claim 1 consisting of:

(one)

treat telithromycin in the form amorphous or crystalline with an organic solvent in which soluble of type AcOR 3 (where R 3 is an alkyl chain of 1 to 4 carbon atoms) or of the cyclic ether or acetone type;

(2)

add to the resulting solution a organic alkane type solvent in which telithromycin does not be soluble;

(3)

isolate the solid formed by filtration and vacuum drying,

to obtain the crystalline telithromycin characterized according to claim 1.

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6. Method of obtaining crystalline telithromycin according to claim 5, characterized in that in the organic solvent type AcOR3 is ethyl acetate. 7. Method of obtaining crystalline telithromycin according to claim 5 characterized in that the organic solvent type cyclic ether is tetrahydrofuran. 8. Method of obtaining crystalline telithromycin according to claim 5, characterized in that the alkane-type organic solvent is cyclohexane, hexane or heptane. 9. Crystalline form of telithromycin, called Form II, characterized in that it has the main peaks of the X-ray powder diffraction model, expressed in 2 ta, and the relative intensities shown below: 7 8 where (f) means intensity strong, (m) medium intensity and (d) intensity weak.

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10. Method of obtaining telithromycin crystalline according to claim 9 consisting of:

(one)

treat telithromycin in the form amorphous or crystalline with an organic solvent of the alkane type in the which is poorly soluble or insoluble;

(2)

shake the resulting suspension for 10 hours or more at a temperature between 20 ° C and 30 ° C or for 1 to 3 hours at a temperature between 35 ° C and 40 ° C;

(3)

isolate the solid by filtration and vacuum drying,

to obtain crystalline telithromycin characterized according to claim 9.

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11. Method of obtaining crystalline telithromycin according to claim 10 characterized in that the alkane type solvent is pentane.