Polymorphic forms of minocycline base and processes for their preparation

Abstract

The present invention concerns new forms of crystalline minocycline base. In particular, two new crystalline polymorphic forms, designated Form IV and Form V of minocycline base are provided. These are characterized by XRD, FTIR and TGA. Processes for preparing the new polymorphic forms and their use in pharmaceutical compositions are also provided. Form IV and form V are prepared by dissolving and/or suspending minocycline base in an organic solvent followed by crystallization.

Claims

1. Crystalline minocycline base form IV characterized by an X-ray powder diffraction pattern having peaks at 8.3; 13.46; 14.1, 21.3 and 16.62?0.2? 2?.

2. Crystalline minocycline base form IV according to claim 1 further characterized by an X-ray powder diffraction pattern having peaks at 7.06, 8.3, 10.3, 11.18, 13.46, 14.1, 14.94, 16.62, 20.62, 21.3 and ?0.2? 2?.

3. Crystalline minocycline base form IV according to claim 1 characterized by an X-ray powder diffraction pattern having peaks as given in FIG. 1.

4. Crystalline minocycline base form IV according to claim 1, showing an endotherm at 146? C. from the STDA (Signal differential thermal analysis) signal of a TGA (thermogravimetric analysis) analysis.

5. An acid addition salt formed from crystalline minocycline base form IV according to claim 1.

6. A process for preparing minocycline base form IV according to claim 1 characterized by comprising dissolving minocycline base in an aliphatic ketone having 6 carbon atoms or less followed by the precipitation of, and optionally isolation of, form IV.

7. A process according to claim 5 wherein the aliphatic ketone is methyl ethyl ketone (MEK).

8. A process for preparing minocycline base form IV according to claim 6 characterized by a dissolution/precipitation temperature of from 20 to 25? C.

9. A process according to claim 6, characterized in that the solution is stirred for at least 30 mins.

10. A pharmaceutical composition characterized by comprising crystalline minocycline base form IV of claim 1 characterized by an X-ray powder diffraction pattern having peaks at 8.3; 13.46; 14.1, 21.3 and 16.62?0.2? 2?, or an acid addition salt thereof, and one or more pharmaceutically acceptable excipients.

11. An antibacterial agent comprising a pharmaceutical composition according to claim 10.

12. An anti-inflammatory agent comprising a pharmaceutical composition according to claim 10.

13. A method of treating a bacterial infections, comprising administering to a subject in need thereof, an effective amount of the pharmaceutical composition of claim 10.

14. A method of treating a inflammation, comprising administering to a subject in need thereof, an effective amount of the pharmaceutical composition of claim 10.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1: Crystalline minocycline base form IV is suitably characterized by an X-ray powder diffraction pattern having peaks.

(2) FIG. 2: Crystalline Form IV of minocycline base has a characteristic spectra FTIR (as measured by Fourier Transform Infrared spectroscopy).

(3) FIG. 3: Crystalline Form IV characterized by an Adsorption/Desorption Isotherm.

(4) FIG. 4: Crystalline minocycline base form V according to the invention is suitably characterized by an X-ray powder diffraction pattern having peaks.

(5) FIG. 5: Crystalline Form V of minocycline base has a characteristic FTIR spectra

(6) FIG. 6: Crystalline Form V is characterized by an adsorption/Desorption Isotherm.

(7) FIG. 7: Crystalline Form IV of minocycline base has a characteristic TGA/SDTA (thermogravimetric analysis).

(8) FIG. 8: Crystalline Minocycline Base Form V has a characteristic thermocycling temperature profile.

(9) FIG. 9: Crystalline Form V of minocycline base has a characteristic TGA/SDTA.

DETAILED DESCRIPTION

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

(11) In one aspect, polymorphic Form IV of crystalline minocycline base is provided. This is a new crystalline form of minocycline base with improved bioavailability and ease of formulation.

(12) Crystalline Form IV of minocycline base has a characteristic X-ray diffraction pattern shown in FIG. 1, a FTIR (as measured by Fourier Transform Infrared spectroscopy) spectra of FIG. 2 and TGA/SDTA (Thermogravimetric analysis) as shown in FIG. 7. The SDTA signal is the temperature difference between the temperature measured directly at the sample and the model reference temperature.

(13) For the present invention, the high resolution X-ray powder diffraction patterns were collected on the D8 Advance system equipped with LynxEye solid-state detector. The radiation used for collecting the data was CuK?1 (?=1.54056 ?) monochromatized by germanium crystal. The patterns were collected in the range 4 to 50? 2?, with a step in the range of 0.016? 2? without further processing. All patterns were taken at approximately 295K.

(14) Data collection was carried out at room temperature using monochromatic CuK.sub.? radiation in the 2? region between 1.5? and 41.5?, which is the most distinctive part of the XRPD pattern. The diffraction pattern of each well was collected in two 28 ranges (1.5??2??21.5? for the first frame, and 19.5??2??41.5? for the second) with an exposure time of 90 s for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

(15) The carrier material used during XRPD analysis was transparent to X-rays and contributed only slightly to the background.

(16) For the present invention, mass loss due to solvent or water loss from the crystals was determined by TGA/SDTA. Monitoring the sample weight, during heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve. The TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed into 100 ?l aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25 to 300? C. at a heating rate of 10? C. min.sup.?1. Dry N.sub.2 gas was used for purging.

(17) For FTIR in the present invention, FTIR spectra: 4000 a 18000 cm-1

(18) Crystalline Form IV is further characterized by an X-ray diffraction pattern having peaks at 7.06, 8.3, 10.3, 11.18, 13.46, 14.1, 14.94, 16.62, 20.62, 21.3, ?0.2 2? as depicted in FIG. 1. It is also characterized by an FTIR spectra as shown in FIG. 2 and the SDTA signal of the TGA analysis shows an endotherm at 146? C.

(19) The XRPD results are given below.

(20) TABLE-US-00001 XRPD peak table Form IV ANGLE (2?) D-SPACING 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

(21) In another aspect, the invention provides a process for the preparation of polymorphic Form IV of crystalline minocycline base, which process comprises dissolving minocycline base in methyl ethyl ketone (MEK), followed by crystallization as Form IV. Preferably, the process comprises dissolving minocycline base in methyl ethyl ketone cooling the solution to a temperature of from 30? C. to 35? C., the preferred temperature being from 20 to 25? C., and isolating Form IV by crystallization.

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

(23) Crystalline Form IV is further characterized by an Adsorption/Desorption Isotherm as shown in FIG. 3. This shows the weight change against change in relative humidity.

(24) Crystalline Form V of minocycline base has a characteristic X-ray diffraction pattern shown in FIG. 4 and an FTIR spectra of FIG. 5 and TGA/SDTA as shown in FIG. 9.

(25) Crystalline Form V is further characterized by an X-ray diffraction pattern 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 2?, as depicted in FIG. 4. It is also characterized by a FTIR spectra depicted in FIG. 5. and the STDA signal of the TGA analysis shows an endotherm at 140? C.

(26) The XRPD results are given below.

(27) TABLE-US-00002 XRPD peak table Form V ANGLE (2?) D-SPACING 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

(28) In another aspect the invention provides, a process for the preparation of polymorphic Form V of crystalline minocycline base comprises suspending minocycline base in 2-methyl THF (2-methyl tetrahydrofuran) followed by crystallization as Form V.

(29) Preferably, the process comprises suspending minocycline base in 2-methyl THF and applying a thermocycling temperature profile for crystallization.

(30) The thermocycling temperature profile preferably comprises heating the solution three times to a temperature of about 40? C. and cooling each time to about 5? C.

(31) The crystalline minocycline base in Forms IV and V, obtained by the processes described above have a better solubility profile and a more favorable log P than the other known crystalline forms.

(32) Crystalline Form V is further characterized by an adsorption/Desorption Isotherm as shown in FIG. 6. This shows the weight change against change in relative humidity.

(33) The solubility of new polymorphic forms IV and V is compared with the solubility known form III (WO2008102161) and the comparison is shown in Table 1. The values show a better solubility of the new polymorphic forms.

(34) Solubility measurements were carried out with buffered solutions prepared at pH=1.2, pH=4.5 and pH=6.8 at a temperature of 37? C.

(35) TABLE-US-00003 TABLE 1 Solubilities of crystalline forms of minocycline base Crystalline pH 1.2 TEMP. pH 4.5 TEMP. pH 6.8 TEMP. Minocycline base 37? C. 37? C. 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 0.033 g/ml 0.018 g/ml 0.00398 g/ml (WO2008102161)

(36) Log P values (i.e. based upon the partition coefficient for minocycline base between the two liquid phases; the Log P value being the logarithm of the ratio of the concentrations of the solute in the liquid phases), showing the distribution of minocycline base between organic and aqueous phase (octanol/water), are depicted in Table 2. The new polymorphic forms IV and V are compared with known form III (WO2008102161) in the table 2. The values show a better solubility in water of the new polymorphic forms. Log P measurements were done in octanol/water at 25? C. and at pH=7.4, with a batch mode. Concentrations were calculated based on UV readings at 246 nm.

(37) TABLE-US-00004 TABLE 2 SAMPLE Log P Minocycline base crystalline form 0.05 IV Minocycline base crystalline form 0.09 V Minocycline base crystalline form 0.12 III

(38) In the present invention, minocycline may be used as the base per se or, for example, as an acid addition salt thereof. Preferably, the acid addition salt is non-toxic, and may for example be formed using suitable organic or inorganic acids, for example, sulfonic acid, trichloroacetic acid or hydrochloric acid. Other suitable acids may be used.

(39) The following examples are intended to illustrate the invention, without limiting it in any way.

EXAMPLE 1

Preparation of Crystalline Minocycline Base Form IV

(40) In an inert atmosphere, minocycline base (5 g of Form II as described in WO2008102161) is dissolved in methyl ethyl ketone (50 ml) at a temperature of from 20? C. to 25? C.

(41) The resultant solution was stirred at a temperature of from 20? C. to 25? C.

(42) After about 30 minutes Form IV of crystalline minocycline base precipitates from the solution.

(43) The suspension is stirred for about 10 hours and the product is filtered and dried under vacuum at about 45? C. to yield 3.2 g of crystalline minocycline baseForm IV.

(44) 3.2 g of Minocycline basecrystalline Form IVwas obtained.

(45) The new crystalline Form IV shows an endotherm of about 146? C. from the SDTA signal of the TGA analysis depicted in FIG. 7.

EXAMPLE 2

Preparation of Crystalline Minocycline Base Form V

(46) In an inert atmosphere, minocycline base (5 g of Form II as described in WO2008102161) is added slowly to 2 methyl THF (50 ml) at a temperature of from 20? C. to 25? C.

(47) A suspension is obtained and a thermocycling temperature profile is applied as shown in FIG. 8.

(48) The product is filtered and dried under vacuum at about 45? C. to yield 3.1 g of crystalline minocycline baseForm V.

(49) The new crystalline Form V shows an endotherm at about 140? C. from the SDTA signal of the TGA analysis depicted in FIG. 9.