PT110699B - NEW POLYMORPHIC FORM OF BASE MINOCYCLINE AND PROCESSES FOR ITS PREPARATION - Google Patents

Abstract

THE PRESENT INVENTION IS ABOUT NEW FORMS OF CRYSTALLINE-BASED MINOCYCLINE. IN PARTICULAR, A NEW CRYSTALLINE POLYMORPHIC FORM IS PRESENTED, DESIGNATED AS A V-FORM OF BASE MINOCYCLINE. THIS IS CHARACTERIZED BY X-RAY (RX), FTIR (INFRARED SPECTROSCOPY BY FOURNIER TRANSFORM) AND THERMOGRAVIMETRY (TGA). PROCESSES TO PREPARE THE NEW POLYMORPHIC FORM AND ITS USE IN PHARMACEUTICAL COMPOSITIONS ARE ALSO PRESENTED. FORM V IS PREPARED BY DISSOLVING AND/OR SUSPENDING MINOCYCLINE BASED IN AN ORGANIC SOLVENT, FOLLOWED BY CRYSTALIZATION.

Description

Description

New polymorphic form of base minocycline and processes for its preparation

Introduction

The present invention presents a new polymorphic form of crystalline minocycline base, with improved solubility profiles and a favorable log P (log P) and also describes processes for obtaining this crystalline polymorphic form of minocycline base.

These characteristics make the new polymorphic form more suitable for use in pharmaceutical formulations.

State of the Art

Minocycline is a member of the tetracycline group, broad spectrum antibiotics, having a broader spectrum than the other members of this group of antibiotics.

Minocycline is widely used in therapy, mainly in the treatment of acne and rosacea, with a daily dose of 100 mg. Minocycline has a unique biological activity profile: it has both anti-bacterial and anti-inflammatory properties.

The preparation of minocycline is, for example, disclosed in the following patents: US 3 148 212; US 3 226 436 and US 4 849 136.

In general, minocycline can be used as a base on its own or, for example, in the form of acid addition salts.

Until 2008, minocycline base was known only in the amorphous form. Patent application WO2008102161 describes for the first time three crystalline forms of minocycline base, which are more stable than the previously known amorphous product.

We have now discovered a new crystalline form, which exhibit an improved solubility profile and a favorable log P. This new crystalline form increases bioavailability and facilitates formulation.

In one aspect of the invention, a novel crystalline form of minocycline base, form V, is provided. This crystalline form is characterized in particular by an RX diffractogram which shows peaks at 5.34; 16.74;

21.06; 23.02; 22.26; ± 0.2° 2Θ.

It can be further characterized by an RX diffractogram showing peaks at 2.9; 5.34; 7.9; 12.94; 15.06; 16.74; 18.22; 19.78; 21.06; 22.26; 23.02; 25.42 ± 0.2° 2Θ.

The crystalline form V of minocycline base according to the invention is suitably characterized by means of an RX diffractogram having peaks as shown in Figure 1.

The crystalline form V of minocycline base, according to the invention, shows an endothermic peak at 140°C from the STDA signal of a TGA analysis as described.

The present invention also contemplates acid salts obtained from the crystalline form V of minocycline base in accordance with the present invention.

In another aspect, a process for the preparation of crystalline form V according to the invention is presented, characterized by the suspension of minocycline base in 2-methyl tetrahydrofuran (2-Me THF) applying a heating/cooling cycle profile for the crystallization followed by isolation of the crystals.

Preferably, the heating/cooling cycle profile comprises heating the suspension three times to a temperature of about 40 °C (+/- 5 °C) and cooling to about 5 °C (+/- 5 °C) . A suitable heating/cooling cycle profile is illustrated in Figure 4.

The invention also features a pharmaceutical composition characterized in that it comprises minocycline base crystalline form V, or an acid addition salt thereof, according to the invention, and optionally, one or more pharmaceutically acceptable excipients.

Acceptable excipients, as well as suitable formulation types for minocycline, will be known to those skilled in the art.

The invention also features a pharmaceutical composition as described herein for use in medicine. Preferably, the pharmaceutical composition is used as an antibacterial agent or an anti-inflammatory agent.

Detailed Description

The present invention describes a new crystalline form of minocycline base. The inventors have now found that, surprisingly, minocycline base can be provided in new stable crystalline forms showing improved bioavailability and ease of formulation.

For the present invention, the high resolution RX diffractogram was obtained on a D8 Advance system equipped with a high resolution LynxEye detector. The radiation used was CuKal (λ=1.54056 Â) monochrome germanium crystal. Standards were obtained in the range 4 to 50° 2 Θ. All defaults were used at 295K.

Data were obtained at room temperature using CuKa monochromatic radiation, in the region between 1.5° and 41.5°. The diffraction pattern was obtained in two intervals (1.5 ° 2θ ^ ^ 21.5 for ^the I frame and 19.5 ° 2θ ^ ^ 41.5 ° for ^the second frame) with an exposure of 90 seconds for each frame.

In the present invention, the mass loss due to solvent or water of the crystals was determined by TGA/SDTA. By monitoring the sample weight during heating in a TGA/SDTA851 instrument (Mettler-Toledo GmbH, Switzerland) a curve of weight vs. temperature. The TGA/SDTA851 was temperature calibrated with indium and aluminum. The samples were weighed in aluminum containers and closed. Dry N2 was used for purges.

In the present invention the FTIR spectra: 4000 - 18000cm-1.

In one aspect of the invention, crystalline base minocycline form V is shown. This is a new crystalline form of minocycline base with improved bioavailability and ease of formulation.

The crystalline form V of minocycline base has a characteristic X-ray diffractogram shown in Figure 1, a FTIR spectrum shown in Figure 2 and TGA/SDTA as shown in Fig. 5.

Crystal form V is further characterized by an X-ray diffractogram having peaks at 2.9; 5.34; 7.9, 12.94; 15.06; 16.74; 18.22; 19.78; 21.06; 22.26; 23.02; 25.42 ± 0.2 °2θ, as shown in Fig.1. It is also characterized by an FTIR spectrum shown in Fig. 2. and the STDA signal from the TGA analysis shows an endothermic peak at 140°C.

RX results are shown below.

Table 1 RX Form V peaks

Angle (2Θ) D-Space Intensity 2.9 30.43 15.6 5.34 16.53 64.63 7.9 11.18 21.42 12.94 6, 83 60.3 15.06 5.88 23.17 16, 74 5.29 44.26 18.22 4.86 12.36 19, 78 4.48 33.21 21.06 4.21 14.73 22.26 3.99 53 23.02 3.86 15.72 25.42 3.5 9.9

In another aspect, the invention features a process for preparing polymorphic Form V of crystalline minocycline base which comprises suspending minocycline base in 2-methyl THF (2-methyl tetrahydrofuran) followed by crystallization of crystalline form V.

Preferably, the process comprises suspending the minocycline base in 2-methyl THF followed by applying a heating/cooling cycle profile and isolating the crystals.

Preferably, the heating/cooling cycle profile comprises heating the suspension three times to a temperature of about 40 °C (+/- 5°C) and cooling to about 5 °C (+/- 5 °C) .

The crystalline form V is further characterized by an adsorption/desorption isotherm, as shown in Figure 3. Figure 3 shows the variation in weight as a function of relative humidity.

The crystalline base minocycline in the V form obtained by the processes described above has a more favorable solubility profile and a log P than the other known crystalline forms.

The solubility of the new polymorphic form V is compared with the known solubility form of the crystalline form III (WO2008102161) and the comparison is shown in Table 2. The values show a better solubility of the new polymorphic form.

Solubilities were performed using buffer solutions prepared at pH=1.2, pH=4.5 and pH=6.8 and at a temperature of 37°C.

Table 2

Crystalline based minocycline solubilities

Crystalline based minocycline pH 1.2 TEMP. 37°C pH 4.5 TEMP. 37°C pH 6.8 TEMP. 37°C Form V 0.036g/ml 0.023g/ml 0.0143g/ml Form III (WO2008102161) 0.033g/ml 0.018g/ml 0.00398g/ml

The log P values (ie, based on the partition coefficient for the base minocycline between the two liquid phases, the log P value being the logarithm of the ratio of solute concentrations in the liquid phases), shows the distribution of minocycline base between the organic phase and aqueous phase (octanol / water) are shown in table 3. The new polymorphic form V is compared with the known form 10 III (WO2008102161) in table 4. The values show a better water solubility of the new polymorphic form.

Log P measurements were made in octanol/water at 25°C and pH=7.4, in batch and concentrations were calculated based on UV readings at 246nm.

Table 3 Log P

Log P Crystalline based minocycline V shape 0.09 Crystalline based minocycline form III 0.12

In the present invention, minocycline can be used as a base or, for example, as a salt of an acid. Preferably the salts are non-toxic, and can be formed, for example, from an organic or inorganic acid, such as sulfonic acid, trichloroacetic acid or hydrochloric acid. Other suitable acids can be used. The following examples are intended to illustrate the invention without limiting it in any way.

Example 1 - Preparation of crystalline based Minocycline Form V

In an inert atmosphere, minocycline base (5 g) (form II of WO2008102161) is added portionwise to 2-methyl THF (50 ml) at a temperature between 20°C and 25°C.

Heating/cooling cycles, shown in Fig.4 are applied to the suspension.

The product is filtered and dried under vacuum at a temperature of about 45°C.

3.1 g of crystalline base minocycline - Form V are obtained.

The new crystal form V shows an endothermic peak at about 140°C from the STDA signal from the TGA analysis shown in Fig.5.

Brief description of the figures

Figure 1 - Form V - X-ray diffractogram

Figure 2 - Form V - FTIR spectrum.

Figure 3 - Adsorption/desorption isothermal Form V

Figure 4 - Thermocycle temperature profile

The isothermal segments shown in correspond to 31 minutes at 40°C, one hour at 5°C and hours at 25°C

Figure 5 - Shape V - TGA/SDTA figure latest

Claims (8)

Claims 1- Minocycline crystalline base in crystalline form V characterized by an X-ray diffractogram having peaks at 2.9; 5.34; 7.9; 12.94; 15.06; 16.74; 18.22; 19.78; 21.06; 22.26; 23.02; 25.42 ± 0.2 ⁰ 2Θ. 2-Minocycline crystalline base in crystalline form V according to claim 1, characterized in that it presents an endothermic peak at about 140°C, from the differential thermal analysis (STDA) of a thermogravimetric analysis (TGA). 3-Process for the preparation of minocycline base in crystalline form V according to any one of claims 1 and 2, characterized by suspending minocycline base in 2-methyl tetrahydrofuran (2-Me THF) followed by heating/cooling cycles for crystallization. 4. Process for the preparation of minocycline base in crystalline form V according to claim 3 characterized by carrying out 3 heating/cooling cycles comprising heating the suspension to a temperature of about 40°C ± 5°C followed by cooling to a temperature of about 40°C ± 5°C. temperature of 5 °C ± 5 °C. 5-Minocycline crystalline base in crystalline form V according to any one of claims 1 to 2, for obtaining an acid salt of minocycline. 5 Pharmaceutical composition characterized in that it comprises crystalline minocycline base in crystalline form V, according to any one of claims 1 to 2, or a salt thereof of an acid according to claim 5 and optionally one or more pharmaceutically acceptable excipients. A pharmaceutical composition as claimed in claim 6 for use in medicine. 8. Pharmaceutical compositions for use according to claim 7 characterized in that the use is as an antibacterial or anti-inflammatory agent.