ES2311391A1 - Crystalline form of moxifloxacin base - Google Patents

Abstract

The present invention relates to a crystalline form of moxifloxacin base, to a process for its preparation, to pharmaceutical compositions containing it, and to its use as an antibacterial agent.

Description

Crystalline form of moxifloxacin base.

Field of the Invention

The present invention relates to a form crystalline moxifloxacin base, to the procedure of its preparation, to pharmaceutical compositions containing it and their Use as an antibacterial agent.

Background of the invention

Moxifloxacin is a therapeutic agent that It presents broad spectrum antibacterial action. Moxifloxacin is the international common name of acid 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7 - [(4aS, 7aS) -octahydro-6H-pyrrole [3,4-b] pyridin-6-yl] -4-oxo- 3-quinolin carboxylic, and has the following chemical structure.

one

Racemic moxifloxacin was described by first time in European patent EP 350733-B and in European application EP-A-550903 is specifically describes moxifloxacin, configuration product (H.H).

In experimental example 19 of the request for European patent EP-A-550903 SE describes a method to prepare and isolate moxifloxacin base. The EP-A-592862 and EP-A-592808 describe the same method. These patent publications do not describe or suggest the possible existence of a crystalline form of moxifloxacin base. Similarly, the international patent application WO-A-2004091619 does not describe methods to prepare a crystalline form of moxifloxacin base.

In European patent applications EP-A-550,903, EP-A-592862 and EP-A-592808, moxifloxacin base se purify and isolate by chromatography using as a system of solvents methylene chloride / methanol / aqueous ammonia 17%. It has been reproduced the purification process described in the memory of these documents and only the obtaining of Moxifloxacin base in the form of an amorphous solid. This procedure For purification and isolation of moxifloxacin base is complex and difficult to perform on an industrial scale due to the need to purify the product by chromatography on column.

Moreover, the authors of this invention have shown that reproducing the reference example of the application WO 04/091619-A1 for obtaining and base moxifloxacin isolation, based on a pH adjustment to 7.0-7.2, no moxifloxacin base is obtained crystalline.

There is, therefore, the need to provide Moxifloxacin base in a form that allows synthesis with a good performance, achievable on a large scale and whose elaboration, purification and isolation overcome the disadvantages previously mentioned.

The authors of the invention have developed a procedure for preparing moxifloxacin base in crystalline form with improved and constant physical properties, enough stable and pure to be used in the preparation of pharmaceutical compositions

Summary Description of the Invention

The present invention aims at provide a crystalline form of moxifloxacin base.

Another object of the present invention is provide a procedure for preparing such form crystalline moxifloxacin base.

It is also object of the present invention provide pharmaceutical compositions that understand the form crystalline object of the invention.

The object of the invention is also part of the use of the crystalline form of moxifloxacin base for the preparation of a medication for treatments antibacterials

Brief description of the figures

Figure 1 shows the diffraction diagram of X-ray powder for the crystalline form object of the invention. In ordinates the number of accounts is presented and in abscissa the position from the peaks to angles 2?

Figure 1A shows the diffraction diagram X-ray powder for the form obtained by reproducing the example of European application EP-A-550903 (for comparative purposes). In ordinates the number of accounts and in abscissa the position of the peaks at angles 2 \ theta.

Figure 2 shows the NMR spectrum of the 13 C in solid state of the crystalline form object of the invention.

Figure 3 shows the infrared spectrum of the crystalline form object of the invention. In ordinates are it presents the transmittance and in abscissa the wavelength.

Figure 4 shows the analysis chart thermogravimetric made with the crystalline form object of the invention. The abscissa indicates the temperature in ºC and the ordered indicate the percentage by weight of the variation of mass.

Figure 5 shows the graph of the analysis of differential scanning calorimetry of the object crystalline form of the invention. The abscissa indicates the temperature in ºC and the Ordered indicate heat flow in W / g.

Detailed description of the invention

According to one of the objects of this invention, a crystalline form has surprisingly been discovered Moxifloxacin base, suitable for use as a principle active in pharmaceutical compositions.

The crystalline form of moxifloxacin base, object of the invention, is characterized by a diagram of X-ray powder diffraction shown in Figure 1 bearing characteristic peaks at the angles 2 ta shown in the table one.

For the registration of the X-ray diffractogram in powder an automatic powder diffractometer has been used XPERT PRO lens from PANALYTICAL with the following features:

Copper tube, at 40KV and 40 mA. X detector CELERATOR

2-45º angular scan

Graphite Monochromator Automatic slit

Automatic interpretation with the HIGH software SCORE

Table 1 shows the spaces d interplanes and the relative intensities that characterize the crystalline form of moxifloxacin base.

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TABLE 1 X-ray diffraction peaks

2

4

The crystalline form of moxifloxacin base, object of the invention, it is also characterized by resonance 13 C nuclear magnetic solid state.

The 13 C NMR spectrum in solid state of the crystalline form object of the invention is shown in the Figure 2 and is characterized by chemical shifts shown in table 2. The spectrum of figure 2 was obtained in a Bruker Advance DSX300 75,488 MHz spectrometer.

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TABLE 2 Chemical shifts in 13 C NMR in solid state

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Additionally, the crystalline form of Moxifloxacin base, object of the invention, has a spectrum infrared that contains peaks shown in table 3.

The infrared spectrum was obtained in pill of potassium bromide using a Perkin Elmer spectrometer Spectrum One FT-IR. Table 3 provides infrared transmitters for the crystalline form of the K. invention.

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TABLE 3 FT-IR peaks

7

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The crystalline form of moxifloxacin base, object of the invention, it is further characterized by thermogravimetry (TG) and differential scanning calorimetry (DSC)

The results of the thermogravimetric analysis are presented in Figure 4. The TG curve shows weight loss in two stages. The first of the order of 1.4% takes place in the temperature range 40-130 ° C. Later, The sample is stable up to an approximate temperature of 225ºC, at from which a continued loss begins that becomes of the order, approximately, of 20% at 310 ° C. The equipment used to carry out this analysis was a TGA 7 Perkin Elmer in standard open platinum crucible, at a speed of heating of 5 ° C per minute, in a temperature range of 20 to 315 ° C under argon gas atmosphere.

The results of the DSC analysis are presented in Figure 5, which shows a pronounced endotherm in the interval 210-218 ° C and a weak endotherm approximately at 150-165 ° C when subjected to a speed of heating of 10 ° C per minute, in a temperature range of 35 to 275 ° C, using a DSC 7 Perkin Elmer, standard crucible Aluminum with perforated lid under argon gas atmosphere.

Another object of the present invention is provide a procedure for the preparation of moxifloxacin crystalline base, which is effective, simple and suitable for industrial scale getting a good performance. Saying Procedure comprises the following stages:

i)

adjust a suspension or solution of moxifloxacin at a pH approximately within the range 8.0-8.5;

ii)

isolate moxifloxacin base from the medium of reaction by conventional methods.

In stage i) of the procedure subject to the invention, the pH adjustment is performed by adding a base, preferably sodium hydroxide, when starting from a suspension or moxifloxacin acid salt solution. Alternatively, the adjustment pH is performed by adding an acid, preferably acid hydrochloric, when starting from a suspension or solution of Basic salt moxifloxacin.

In stage ii) of the procedure object of the invention, moxifloxacin base is isolated by extraction and evaporation of the organic solvent or is isolated by filtration of a solvent organic, aqueous or mixture of both.

Preferably the solvents used are acetonitrile, ethanol, acetone, water and ethanol / water mixtures.

The moxifloxacin or moxifloxacin HCl used as a starting product they can be prepared by any of the procedures described in the literature.

Also part of the invention are the pharmaceutical compositions comprising the crystalline form of Moxifloxacin base object of the invention.

The pharmaceutical compositions comprising The product of the invention may include excipients, adjuvants, pharmaceutically acceptable carriers and / or diluents, for formulate forms of presentation well known to the expert in the matter.

Still another object of the invention is the use of the crystalline form of moxifloxacin base, object of the invention, for the preparation of a medicine for the treatment of diseases caused by bacteria.

The examples that follow are set forth for the purpose of providing the person skilled in the art with a detailed explanation of a specific embodiment of the procedure to obtain the compound of the invention.

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Example 1

Raw Moxifloxacin was suspended over water and adjusted to pH> 11 with 30% sodium hydroxide. Dissolution basified was washed with toluene and then adjusted to pH = 8.0-8.2 with 35% HCl. It was then extracted with methylene chloride and the resulting organic phase was dried reduced pressure The solid thus obtained was recrystallized from acetonitrile obtaining Moxifloxacin crystalline base.

Challenge: 85%.

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Example 2

A mixture of 70 g of moxifloxacin hydrochloride and 350 ml of water was basified to pH> 11 with 30% NaOH. The basified solution was washed with toluene and then adjusted to pH = 8.0-8.2 with 35% HCl. It was then extracted with  methylene chloride and the resulting organic phase was dried reduced pressure The solid thus obtained was recrystallized from alcohol. ethyl obtaining Moxifloxacin crystalline base.

Challenge: 90%.

Claims (14)

1. Crystalline form of moxifloxacin base characterized by an X-ray diffraction diagram with peaks at the 2? Angles of: 9.7; 10.2; 11.7; 13.4; 14.2; 14.9; 15.4; 15.9; 16.8; 18.1; 18.4; 18.7; 19.2; 19.5; 20.0; 20.4; 21.2; 21.8; 22.4; 23.3; 24.5; 25.1; 26.1; 26.4; 27.1; 27.8; 28.8; 29.3; 30.1; 31.4; 32.8; 33.5; 35.0; 35.6; 37.4; 39.6; 41.1; 41.9; 42.9; 43.6 ± 0.2. 2. Crystalline form according to claim 1, characterized by: the fact that it presents an X-ray diffraction diagram substantially in accordance with Figure 1. 3. A crystalline form of moxifloxacin base according to claim 1 characterized by a 13 C NMR spectrum in solid state having the following chemical shifts δ (ppm): 8.4; 9.95; 11.3; 19.8; 23.9; 25.0; 35.7; 38.7; 40.9; 45.2; 51.7; 56.0; 57.4; 60.6; 61.1; 105.2; 106.3; 116.7; 134.9; 135.9; 141.1; 150.6; 153.7; 165.3; 166.6; 175.2. 4. Crystalline form according to claim 3, characterized in that it substantially exhibits the 13 C NMR spectrum in solid state according to Figure 2. 5. Crystalline form according to claims 1 to 4, characterized by an infrared spectrum presenting the peaks: IR (cm -1): 3437, 3072, 3008, 2947, 2889, 2852, 1728, 1621, 1511, 1435, 1369, 1343, 1321, 1266, 1187, 1149, 1125, 1109, 1046, 1029, 985, 960, 941, 883, 865, 830, 805, 772, 750, 722, 653, 591, 563, 547, 484. 6. Crystalline form according to claim 5, characterized in that it has substantially an infrared spectrum according to Figure 3. 7. A procedure to obtain the crystalline form of moxifloxacin base according to any of the claims 1 to 6, comprising:

iii)

adjust a suspension or solution of moxifloxacin at a pH approximately within the range 8.0-8.5;

iv)

isolate moxifloxacin base from the medium of reaction by conventional methods.

8. A process for obtaining the crystalline form of moxifloxacin base according to claim 7, characterized in that a suspension or solution of moxifloxacin acid salt is adjusted to a pH of 8.0-8.5 by the addition of a base, preferably hydroxide sodium 9. A process for obtaining the crystalline form of moxifloxacin base according to claim 7, characterized in that a suspension or solution of moxifloxacin basic salt is adjusted to a pH of 8.0-8.5 by the addition of an acid, preferably acidic hydrochloric. 10. A process for obtaining the crystalline form of moxifloxacin base according to claim 7, characterized in that moxifloxacin base is isolated by extraction and evaporation of the organic solvent. 11. A process for obtaining the crystalline form of moxifloxacin base according to claim 7, characterized in that moxifloxacin base is isolated by filtration of an organic, aqueous solvent or mixture thereof. 12. A process for obtaining the crystalline form of moxifloxacin base according to claim 11, characterized in that the solvent used is acetonitrile, ethanol, acetone, water or ethanol / water mixtures. 13. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of the crystalline form of moxifloxacin base according to any one of claims 1 to 6 in association with at least one suitable pharmaceutically acceptable inert diluent. 14. The use of the crystalline form of moxifloxacin base according to any one of claims 1 to 6 for the preparation of a medicine for the treatment of diseases caused by bacteria.