RU2789325C2 - New polymorphic forms of minocycline base and methods of their preparation - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to the preparation of a crystalline form of the IV minocycline base, which can be used in pharmaceutical preparations. A method for obtaining a crystalline form of the IV minocycline base, characterized by a powder radiograph, on which there are peaks at 8.3, 13.46, 14.1, 21.3, 16.62 ± 0.2° 2θ involving the dissolution of the minocycline base in an aliphatic ketone containing 6 carbon atoms or less, followed by precipitation of form IV.

EFFECT: invention provides a crystalline form of the IV minocycline base, which has improved solubility, bioavailability, log P indicators reflecting the distribution of the minocycline base between the organic and aqueous phases in the octanol/water system, and the simplicity of compounding based on it.

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Description

Introduction

The present invention provides two new crystalline minocycline base polymorphs with improved dissolution profiles and favorable log P and describes methods for preparing crystalline minocyclic base polymorphs. These characteristics make these new polymorphs more suitable for use in pharmaceutical formulations.

BACKGROUND OF THE INVENTION

Minocycline is a member of the large family of tetracycline antibiotics with a broader spectrum of activity than other members of this group of compounds. Minocycline is widely used in therapy, mainly for the treatment of acne and rosacea at a single daily dose of 100 mg. Minocycline has a unique biological activity profile: it has both antibacterial and anti-inflammatory properties.

The preparation of minocycline is described, for example, in US 3148212, US 3226436 and US 4849136.

In most cases, minocycline can be used as a base per se , or as an appropriate acid addition salt, for example. Until 2008, minocycline base was known only in amorphous form.

WO2008102161 describes three crystalline forms of the minocyclic base which are more stable than the previously known amorphous product.

The inventors have now found new crystalline forms having a better dissolution profile and a favorable log P, and it has been found that these forms further increase bioavailability and ease of formulation based on them.

In accordance with the present invention, provided is a crystalline form IV of minocycline base, according to the present description. It is characterized in particular by a powder X-ray diffraction pattern which has peaks at 8.3, 13.46, 14.1, 21.3, 16.62 ± 0.2° 2θ. It is also characterized by X-ray powder diffraction, which has peaks at 7.06, 8.3, 10.3, 11.18, 13.46, 14.1, 14.94, 16.62, 20.62, 21.3 , ± 0.2° 2θ.

The crystalline form IV of the minocycline base is conveniently characterized by an x-ray powder diffraction pattern which has the peaks shown in FIG. 1.

The crystalline form IV of the minocycline base according to the present invention preferably has an endotherm at 146° C. in the DTA curve when analyzed by TGA according to the present disclosure.

The invention also provides acid addition salts of a minocycline base formed from, or derived from, crystalline form IV of a minocycline base as described herein.

In a further aspect, a method is provided for preparing a crystalline form IV of a minocycline base of the present invention, and the method is characterized in that it comprises dissolving the minocycline base in an aliphatic ketone containing 8 carbon atoms or less, or 6 carbon atoms or less, accompanied by precipitation and, optionally, isolation, Form IV. The inventors prefer to use secondary aliphatic ketones. Aliphatic ketones containing 4 carbon atoms are preferred. One preferred aliphatic ketone is methyl ethyl ketone (MEK).

The process for preparing Form IV of the minocycline base according to the present invention is preferably characterized by a dissolution/precipitation temperature of 20 to 25°C. The solution is stirred for at least 30 minutes before isolation. For example, the solution can be stirred up to 5 hours, or up to 10 hours to increase the yield of the precipitate.

In a further aspect of the invention, a crystalline form V of minocycline base is provided, characterized in particular by an x-ray powder diffraction pattern which has peaks at 5.34, 16.74, 21.06, 23.02, 22.26 ± 0.2° 2θ. It is also characterized by X-ray powder diffraction, which has 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 the minocycline base of the present invention is conveniently characterized by an x-ray powder diffraction pattern which has the peaks shown in FIG. 4.

The crystalline form V of the minocycline base according to the present invention preferably has an endotherm at 140° C. in the DTA curve when analyzed by TGA according to the present disclosure.

The invention also provides acid addition salts of minocycline formed from, or derived from, crystalline form V of the minocycline base as described herein.

The present invention also provides a process for preparing the minocycline base form V of the present invention, characterized by suspending the minocycline base in 2-methyltetrahydrofuran (THF) and applying a thermal cycling temperature profile for crystallization, optionally followed by isolation of the crystals.

Preferably, the thermal cycling temperature profile includes heating the slurry three times to a temperature of about 40°C (+/-5°C) and cooling each time to about 5°C (+/-5°C). The thermal cycling temperature profile shown in FIG. 8 illustrates a suitable mode.

The invention also provides a pharmaceutical composition characterized in that it comprises a crystalline form IV of minocycline base, or an acid addition salt thereof, as described herein, and optionally one or more pharmaceutically acceptable excipients.

The invention also provides a pharmaceutical composition characterized in that it comprises a thermocycling form V of minocycline base, or an acid addition salt thereof, as described herein, and optionally one or more pharmaceutically acceptable excipients. Acceptable excipients, as well as types of formulations suitable for delivering minocycline, will be known to those skilled in the art.

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

DETAILED DESCRIPTION

The present invention describes two new crystalline forms of the minocycline base. The present inventors have surprisingly found that minocycline base can be provided in novel, stable crystalline forms with improved bioavailability and ease of formulation.

In one aspect, a form IV crystalline minocycline base polymorph is provided. It is a novel crystalline form of minocycline base with improved bioavailability and ease of formulation.

Form IV crystalline minocycline base has the characteristic X-ray powder pattern shown in FIG. 1, FT-IR spectra (obtained by FT-IR spectroscopy) shown in FIG. 2 and the TGA/DTA (thermogravimetric analysis) data shown in FIG. 7. The DTA signal is the difference between the temperature of the sample itself and the temperature of the reference sample.

In the case of the present invention, high resolution powder X-ray patterns were obtained on a D8 Advance diffractometer with a LynxEye solid state detector. For data collection, CuKα1 radiation (λ=1.54056 Å) monochromatized by reflection from a germanium crystal was used. Radiographs were obtained in the range from 4 to 50°2θ, with a step in the range of 0.016°2θ without additional processing. All radiographs were taken at approximately 295K.

Data collection was carried out at room temperature using monochromatic CuK _α radiation in the 2θ region from 1.5° to 41.5°, which is the most characteristic region of the X-ray powder diffraction pattern. The diffraction pattern of each well was obtained in two intervals 2θ (1.5° ≤ 2θ ≤ 21.5° for the first frame, and from 19.5° ≤ 2θ ≤ 41.5° for the second) with an exposure time of 90 s for each frame. No background subtraction or curve smoothing was applied to powder radiographs.

The carrier material used in the X-ray diffraction analysis was transparent to X-rays and made only a minor contribution to the background.

In the present invention, the weight loss due to evaporation of the solvent or water from the crystals was determined by TGA/DTA. As a result of monitoring the mass of the sample during heating in a TGA/SDTA851e derivatograph (Mettler-Toledo GmbH, Switzerland), a curve of mass versus temperature was obtained. Temperature calibration of the TGA/SDTA851e derivatograph was performed using indium and aluminum samples. Samples were weighed into 100 μL aluminum crucibles and sealed. The sealed lids were pierced and the crucibles were heated in a TGA apparatus from 25 to 300° C. at a heating rate of 10° C. min ^-1 . Gaseous N ₂ was used for purge.

In the case of FT-IR spectroscopy, FT-IR spectra: from 4000 to 18000 cm ^-1

The crystalline Form IV is further characterized by an X-ray diffraction pattern which has peaks at 7.06, 8.3, 10.3, 11.18, 13.46, 14.1, 14.94, 16.62, 20.62, 21, 3 ± 0.2 2θ shown in FIG. 1. It is also characterized by the FT-IR spectra shown in FIG. 2, and the DTA curve in TGA analysis has an endotherm at 146°C.

The results of PRSA are presented below.

PRS Peak Table

Form IV

Angle (2θ) Interplanar distance D Intensity 7.06 12.51 18.99 8.3 10.64 85.38 10.3 8.58 21.8 11.18 7.9 19.28 13.46 6.57 46.64 14.1 6.27 27.28 14.94 5.92 15.2 16.62 5.33 21.33 20.62 4.3 9.24 21.3 4.17 28.75

In a further aspect, the present invention provides a process for preparing a Form IV crystalline minocycline base polymorph, wherein the process comprises dissolving the minocycline base in methyl ethyl ketone (MEK) followed by crystallization as Form IV.

Preferably, this method includes dissolving the minocycline base in methyl ethyl ketone, cooling the solution to a temperature of from 30°C to 35°C, with the preferred temperature being from 20 to 25°C, and isolating form IV from the reaction mixture.

Form IV can also be obtained, for example, by dissolving the minocycline base in a mixture of acetonitrile/isopropyl alcohol (50:50) and evaporating the resulting solution.

Crystal Form IV is further characterized by the adsorption/desorption isotherm shown in FIG. 3. It reflects the dependence of the mass change on the change in relative humidity.

The crystalline form V of the minocycline base has the characteristic X-ray diffraction pattern shown in FIG. 4 and the FT-IR spectra shown in FIG. 5 and the DTA/TGA data shown in FIG. 9.

The crystalline form V is also characterized by an x-ray pattern that has 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 shown in FIG. 4. It is also characterized by the FT-IR spectra shown in FIG. 5, and the DTA curve in TGA analysis shows an endotherm at 140°C.

The results of PRSA are presented below.

PRS Peak Table

Form V

Angle (2θ) Interplanar distance D 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 a further aspect, the invention provides a process for preparing a Form V crystalline minocycline base polymorph, comprising suspending the minocycline base in 2-methyl THF (2-methyltetrahydrofuran), followed by crystallization as Form V.

Preferably, the method comprises suspending the minocycline base in 2-methyl THF and applying a thermal cycling temperature profile for crystallization.

The thermal cycling temperature profile preferably includes heating the solution three times to a temperature of about 40°C and cooling each time to about 5°C.

The crystalline forms IV and V of the minocycline base obtained by the methods described above have a better dissolution profile and a more favorable log P than other known crystalline forms.

Crystal Form V also has an adsorption/desorption isotherm shown in FIG. 6. It reflects the dependence of the mass change on the change in relative humidity.

The solubility of the new polymorphs IV and V is comparable to that of the known form III (WO2008102161) and this comparison is presented in Table 1. The values shown indicate the higher solubility of the new polymorphs.

The solubility determination was carried out using buffer solutions prepared at pH=1.2, pH=4.5 and pH=6.8 at 37°C.

Table 1 - Solubility of crystalline forms of minocycline base

Crystalline minocycline base pH 1.2 Temp. 37°C pH 4.5 Temp. 37°C pH 6.8 Temp. 37°C Form IV 0.025 g/ml 0.022 g/ml 0.0148 g/ml Form V 0.036 g/ml 0.023 g/ml 0.0143 g/ml Form III (WO2008102161) 0.033 g/ml 0.018 g/ml 0.00398 g/ml

log P values (i.e. values based on the distribution ratio of the minocycline base between two liquid phases, with the log P value being the logarithm of the ratio of solute concentrations in the liquid phases) reflecting the distribution of the minocycline base between the organic and aqueous phases (octanol/water ) are shown in Table 2. The new polymorphs IV and V are comparable to the known form III (WO2008102161) in Table 2. The values shown indicate a higher solubility of the new polymorphs in water.

Log P determinations were made in octanol/water at 25° C. and pH=7.4, in batch mode. Concentrations were calculated from UV readings at 246 nm.

table 2

Sample log P Crystal form IV minocycline base 0.05 Crystal form V of the minocycline base 0.09 Crystal form III minocycline base 0.12

In the present invention, minocycline can be used as the base per se , or, for example, as its acid addition salt. Preferably, the acid addition salt is non-toxic and can be prepared, for example, using suitable organic or inorganic acids, for example sulfonic acid, trichloroacetic acid or hydrochloric acid. Other suitable acids may be used.

The following examples are intended to illustrate the present invention without limiting it in any way.

Example 1 - Obtaining a crystalline form IV minocycline base

Under an inert atmosphere, minocycline base (5 g of form II described in WO2008102161) is dissolved in methyl ethyl ketone (50 ml) at 20°C to 25°C.

The resulting solution is stirred at a temperature of from 20°C to 25°C.

After about 30 minutes, Form IV crystalline minocycline base precipitates out of solution.

The suspension is stirred for about 10 hours and the product is filtered off and dried in vacuo at about 45° C. to give 3.2 g of crystalline minocycline base Form IV.

Received 3.2 g of minocycline base - crystalline form IV.

The new crystalline form IV has an endotherm at about 146° C. in the DTA curve when analyzed by TGA, as shown in FIG. 7.

Example 2 - Preparation of crystalline form V of the minocycline base

Under an inert atmosphere, minocycline base (5 g of Form II described in WO2008102161) is slowly added to 2-methyl THF (50 ml) at 20°C to 25°C.

A slurry is prepared and the thermal cycling temperature profile shown in FIG. 8.

The product is filtered off and dried in vacuo at about 45°C to give 3.1 g of crystalline minocycline base Form V.

The new crystalline form V has an endotherm at about 140° C. in the DTA curve when analyzed by TGA, as shown in FIG. 9.

Claims (7)

1. Method for obtaining crystalline form IV of the minocycline base of the formula

characterized by an x-ray powder diffraction pattern that has peaks at 8.3, 13.46, 14.1, 21.3, 16.62 ± 0.2° 2θ, including dissolution of the minocycline base in an aliphatic ketone containing 6 carbon atoms or less, followed by precipitation of form IV. 2. The method of claim 1 further comprising isolating Form IV. 3. The method according to claim 1 or 2, wherein the aliphatic ketone is methyl ethyl ketone (MEK). 4. The method of obtaining form IV minocycline base on PP. 1, 2 or 3, characterized in that the temperature of dissolution/precipitation is from 20 to 25°C. 5. The method according to any one of the preceding claims, characterized in that the solution is stirred for at least 30 minutes.

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