STABLE POLYMORPH FORM B OF TAPENTADOL HYDROCHLORIDE

Abstract

The present disclosure relates to Tapentadol Hydrochloride in the polymorphic crystalline Form B, which is substantially free of polymorphic Form A as well as essentially free of low alkyl carboxylic acids or esters of such acids. Furthermore, the present disclosure provides a process to produce this polymorphic Form B substantially free of Form A and its preparation and use for pharmaceutical compositions. This process as well as the specific crystalline form is uncommon, improved and industrially advantageous. Furthermore, the disclosure relates to pharmaceutical compositions and uses thereof.

Claims

1. A Tapentadol Hydrochloride in stable polymorphic crystal Form B which is substantially free of polymorphic crystal Form A, wherein the composition exhibits a PXRD pattern in which the intensity of peaks at 2Theta 18.89, 22.58 and 24.28 (+0.3) are each 1.5%, preferably 1% relative to the peak at 2Theta 14.55 (+0.3), more specifically at 2Theta 18.25, 18.89, 22.58 and 24.28 (+0.3) are each 1.5%, preferably 1% relative to the peak at 2Theta 14.55 (+0.3).

2. The Tapentadol Hydrochloride according to claim 1, wherein the composition exhibits a PXRD pattern having peaks at 2Theta 17.99, 19.58 and 21.99 (+0.3), wherein the Full-Width-at-Half-Maximum (FWHM) of each of these peaks is 0.2, preferably 0.16.

3. The Tapentadol Hydrochloride according to claim 2, wherein the composition exhibits a PXRD pattern furthermore has a peak at 2Theta 28.17 (+0.3), wherein the Full-Width-at-Half-Maximum (FWHM) of the peak is 0.2, preferably 0.16.

4. A process of preparing Tapentadol Hydrochloride substantially in a stable polymorphic pure Form B, wherein the process comprises the removal of nucleation centers and subsequent crystallization.

5. A process of preparing Tapentadol Hydrochloride substantially in a stable polymorphic pure Form B, wherein the process comprises the step of filtering a solution of Tapentadol Hydrochloride with an ultrafine filter; and crystallizing from the seeded filtrate a Tapentadol Hydrochloride.

6. The process according to claim 4, wherein the crystallization is performed at elevated temperatures, preferably 50 C., more preferably 52 C.

7. The process according to claim 4, wherein the process comprises the step of refluxing a solution of Tapentadol Hydrochloride at Temperatures between 55-90 C. for 2 hours to 300 hours, preferably for at least 5 hours, more preferably for at least 24 hours.

8. The process according to claim 6, wherein the solution comprises as solvent at least one solvent of the group consisting of alcohols, ethers, esters, hydrocarbons or halogenated hydrocarbons, nitriles, or ketones, as well as mixtures thereof.

9. The process according to claim 6, wherein the solution comprises as solvent at least one solvent of the group consisting of tetrahydrofuran, chloroform, dichloromethane, 3-methyl-1-butanole, methanol, ethanol, isopropanol, butanol, toluene, p-xylene, acetonitrile, 2-methyl-tetrahydrofuran, 1,4-dioxane, methyl isobutyl ketone, 2-methyl-tetrahydrofuran, 1,4-dioxane, methyl isobutyl ketone, methyl isobutyl carbinol, 2-methoxy-2-methylpropane (MTBE), ethylacetate, acetone and 2-butanone.

10. The process according to claim 9, comprising the step of dissolving Tapentadol as free base in the at least one solvent and adding hydrochloric acid to the solution prior to refluxing the solution.

11. The process according to claim 6, wherein during refluxing further Tapentadol is added to the solution, preferably up to the maximum solubility.

12. The process according to claim 5, wherein after filtering the filtrate is seeded with seed crystal of pure polymorphic Form B of a Tapentadol Hydrochloride.

13. Use of a Tapentadol Hydrochloride according to claim 1 for the preparation of a pharmaceutical composition.

14. The use of a Tapentadol Hydrochloride according to claim 11 for the manufacturing of a finished dosage form which is substantially free of Tapentadol Hydrochloride Form A.

15. The use of a Tapentadol Hydrochloride according to claim 12, wherein the finished dosage form is a solid dosage.

16. The use of a Tapentadol Hydrochloride according to claim 13, wherein the solid dosage form is a tablet.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0084] The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations, and are not intended to limit the scope of the present disclosure.

[0085] FIGS. 1 to 5 show PXRDs of Polymorphic Form A as well as B and/or mixtures thereof.

DETAILED DESCRIPTION

[0086] Example embodiments will now be described more fully with reference to the accompanying drawings.

[0087] In FIG. 1 the PXRD pattern of a stability sample experiment 1 are shown as well as PXRD pattern of Tapentadol hydrochloride in polymorphic crystal structure A and in polymorphic crystal structure B. The upper most pattern results from a sample (experiment 1) after a 4 month stability test at 27 C. and 42% RH (relative humidity). The second of top pattern results from the initial sample prior to the stability testing. The second last pattern represents the mono-crystal structure of pure Tapentadol Hydrochloride in polymorphic crystal Form B. The last pattern represents the mono-crystal structure of pure Tapentadol Hydrochloride in polymorphic crystal Form A. What can be derivate from figure I is that the inventive Tapentadol Hydrochloride in stable polymorphic crystal Form B does not show any tendency to disintegrate or to transform to polymorphic crystal Form A. Furthermore, the comparison of the PXRD pattern of the inventive Tapentadol Hydrochloride in stable polymorphic crystal Form B with the mono-crystal structure of crystal Form B of Tapentadol Hydrochloride let derivate that the inventive composition is essentially free of low alkyl carboxylic acids and/or esters of such low alkyl carboxylic acids. FIG. 2 shows in the upper pattern PXRD pattern of Tapentadol hydrochloride Form B from a scale up experiment. The second last pattern represents the mono-crystal structure of pure Tapentadol Hydrochloride in polymorphic crystal Form B. The last pattern represents the mono-crystal structure of pure Tapentadol Hydrochloride in polymorphic crystal Form A.

[0088] FIG. 3 shows Tapentadol Hydrochloride PXRD pattern of polymorphic Form A as well as B. The exemplified experimental polymorphic Form B in this case comprises some impurities of polymorphic Form A. After 2 month under ambient temperature storage conditions the amount of polymorphic Form A obviously increased. This is in contrast to behavior of pure Form B as exemplified in figure I. After several months of storage under ambient conditions polymorphic pure Form B without any seeds of Form A showed no transformation to polymorph A.

[0089] FIG. 4 shows Tapentadol Hydrochloride PXRD pattern of polymorphic Form A as well as B. Form B results the from a 1,4-Dioxan solution as explained in detail in example 4.

[0090] FIG. 5 shows Tapentadol Hydrochloride PXRD pattern of polymorphic Form A as well as B. Form B results the from a 2-methyl-tetrahydrofuran solution as explained in detail in example 5.

EXPERIMENTAL EXAMPLES

[0091] Tapentadol as free base is dissolved in a mixture of solvents. Hydrochloric acid is added and the reaction mixture is heated under reflux temperature. Alternatively, Tapentadol hydrochloride can be dissolved in a mixture of solvents.

[0092] Further Tapentadol Hydrochloride might be added during refluxing, until a solid appears. The resulting hot dispersion is filtered with a preheated Whatman filter (0.2 m) and the resulting solution is heated for 1 week at reflux temperature. The solvent is evaporated at temperatures above 60 C. and the resulting solid is isolated. This solid consist of polymorphic Form B substantially free of polymorph A.

[0093] Stable Form B without any additional stabilizing components is advantageous in terms of technical feasibility at ambient or elevated temperatures during processing into pharmaceutical compositions and storage of the API and pharmaceutical compositions. Stable Form B might have a lower hygroscopicity and improved flow behavior.

[0094] For Powder X-Ray Diffraction (PXRD) the samples were placed onto a Si-wafer (Bragg-Brentano) or into a standard glass capillary (=0.7 mm) (Example 2). The measurements were performed at room temperature with a D8 Bruker Advance Diffractometer (Cu-K1=1.54059 , Johansson primary beam monochromator, position sensitive detector) in transmission mode with rotation of the sample.

Example 1

[0095] Tapentadol Hydrochloride is dissolved in chloroform, and then heated to boiling point under reflux. Tapentadol Hydrochloride Form A and B was added under stirring until sediment is visible. The resulting dispersion (total mass 30 mg in 13 mL chloroform) was filtered through a preheated Buchner funnel (Whatman filter paper, white) and the solution stirred for one week at boiling temperature under reflux. The solvent is distilled off at atmospheric pressure gently to dryness. The solid phase afterwards was characterized by X-ray powder diffraction.

Example 2 Scale Up

[0096] Tapentadol Hydrochloride is dissolved in chloroform, and then heated to boiling point under reflux. Tapentadol Hydrochloride Form A and B was added under stirring until sediment is visible. The resulting dispersion (total mass 455 mg in 200 mL chloroform) was filtered through a preheated Buchner funnel (Whatman filter paper, white) and the solution stirred for one week at boiling temperature under reflux. The solvent is distilled off at atmospheric pressure gently to dryness. The solid phase afterwards was characterized by X-ray powder diffraction.

Example 3

[0097] The investigated sample shows Form B and traces of Form A of Tapentadol Hydrochloride after preparation. After two months of storage an increase of Form A in Form B was observed.

[0098] While the disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the disclosure is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word comprising does not exclude other elements or steps, and the indefinite article a or an does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Example 4

[0099] A solution of 360 mg Tapentadol free base in 5 ml 1,4-Dioxan are cooled to 15 C. To this solution 5 mg of Tapentadol HCl Form B are added under vigorous stirring. 0.5 ml of a 4 N HCl in Dioxan solution are added dropwise with a syringe within ca. 3 min while the internal temperature did not exceed 20 C. Immediately a colorless precipitate is formed. After completion of the HCl addition the suspension is stirred for additional 5 min at ambient temperature before the solid is filtered off. The wet product is dried in high vacuum yielding into pure Form B as per pXRD measurement. Yield: 300 mg (71%).

Example 5

[0100] A solution of 0.75 g of Tapentadol free base 40 ml of 2-Methyl-tetrahydrofuran (2-MeTHF, water content <0.05%) was stirred in a three necked 250 ml round bottom flask equipped with a reflux condenser, CaCl.sub.2-tube, thermometer and a aeration tube for introduction of the gas. The IT was kept at ambient temperature (23 C.). 20 mg Tapentadol HCl Form B were added and the suspension was vigorously stirred, HCl gas was bubbled directly into the solution. The precipitation of a very fine solid started immediately with the first gas flow. The internal temperature (IT) raised to approx. 29 C. and spontaneously a yellowish/colorless solid precipitates. The gas addition was stopped after 20 seconds. The apparatus was flushed for two minutes with nitrogen before the filtration of the solid was started. The solid collected by filtration. The filter cake was washed with 5 ml of 2-MeTHF at ambient temperature. The solid was sucked dry on the filter and the wet product submitted to high vacuum drying in a round bottom flask at 75 C. for 12-15 h, delivering pure form B as per pXRD measurement. Yield: 0.89 g (ca. 100%).

Example 6

[0101] 0.9 g of Tapentadol free base was dissolved in 45 ml of Methyl-isobutyl-ketone (MIBK) in a three necked round bottom flask equipped with a reflux condenser, CaCl.sub.2-tube, thermometer and an aeration tube for introduction of the gas. The IT was kept at ambient temperature. 25 mg Tapentadol HCl Form B were added and the suspension was vigorously stirred. HCl gas was bubbled through the solution. The precipitation of a very fine solid started immediately with the first gas flow. The temperature was raised to approx. 29 C. and spontaneously a yellowish/colorless solid precipitates. The gas addition was stopped after 30 seconds. The apparatus was flushed for two minutes with nitrogen before the filtration of the solid was started. The solid collected by filtration. The filtrate was washed with 5 ml of MIBK at ambient temperature. The solid was sucked dry on the filter and was submitted to high vacuum drying at 75 C. for 17 h, delivering pure form B as per pXRD measurement. Yield: 0.85 g. (99%).

Example 7

[0102] A solution of Tapentadol HCl salt (6.0 g) in methyl-isobutyl-carbinol (MIBC) (300 mL) was refluxed for 30 min to give a clear solution. Additional 90 mL of MIBC was added into the solution, then about 60 mL of MIBC was distilled off (to remove H.sub.2O) and the clear solution was refluxed for 3 days. About 250 mL of MIBC was distilled off to give a slurry, which was cooled to ambient temperature over 3 h. The solid was collected and dried at 80 C. under vacuum to give 4.3 g, delivering pure Form B as per pXRD measurement. Yield: 4.3 g (60%).