WO2006111983A2

WO2006111983A2 - NOVEL POLYMORPHIC FORM OF (l-BENZYL-4-[(5,6-DIMETHOXY-l- INDANONE)-2-YL]METHYL PIPERIDINE HYDROCHLORIDE AND PROCESS FOR PREPARING THE SAME

Info

Publication number: WO2006111983A2
Application number: PCT/IN2006/000136
Authority: WO
Inventors: Shailendra Kumar Dubey; Poorvi Gupth; Rajesh Kumar Thaper; Sushil Kumar Dubey
Original assignee: Jubilant Organosys Limited
Priority date: 2005-04-21
Filing date: 2006-04-21
Publication date: 2006-10-26
Also published as: WO2006111983A3

Abstract

Disclosed herein are novel and stable polymorphic form of Donepezil Hydrochloride, wherein said polymorphic form is designated as J and are characterized by their powder X-ray diffraction patterns, Infrared absorption spectrums, thermo gravimetric analysis and differential scanning calorimetry. The processes for preparing said polymorphic form and use thereof to prepare another forms is also disclosed.

Description

NOVEL POLYMORPHIC FORM OF (l-BENZYL ^-K^O-DIMETHOXY-l-

INDANONE)-2-YL]METHYL PIPERIDINE HYDROCHLORIDE AND

PROCESS FOR PREPARING THE SAME

Field of the Invention

This invention, in general relates to the novel crystalline polymorphic form of 1- benzyl-4-[(5,6-dimethoxy- 1 -indanone)-2-yl]methyl piperidine hydrochloride (Donepezil Hydrochloride). More particularly, the present invention provides a novel and stable crystalline Form of Donepezil Hydrochloride designated as J form and the process for preparing the same.

Background of the Invention

l-benzyl-4-(5,6-dimethoxy-l-indanon-2-yl)methylpiperidine (Donepezil) represented by the formula 1, is a new drug and has a acetylcholinesterase inhibitory action, due to which it is used in the treatment of mild to moderate cases of SDAT (Senile Dementia of Alzheimers Type) as well as preventing and improving various cerebrovascular disorder associated with cerebral apoplexy (cerebral hamorrhage and cerebral infarction), head injury, logopathy, hypobulia, emotional disorders, memorization disorders, paranoid hallucinatory states, abnormal behavior associated with sequelae of encephalitis, cerebral paralysis etc.

(1)

Many pharmaceutically active compounds have been found to exist in more than one polymorphic form, such as one or more crystalline forms, an amorphous form, and/or sometimes one or more solvated forms. Frequently it is found that the different forms have different physical or chemical properties, such as solubility, hygroscopicity, etc., or have properties that render some form easier to formulate into a pharmaceutical product. In addition, certain forms can have a greater stability than other forms, as shown by a decreased tendency to spontaneously convert into a different polymorphic form.

In the case of Donepezil hydrochloride, which is administrated orally and may be placed for distribution and storage in a period of time before the administration. The stability of this medicinal substance (bulk pharmaceutical chemicals) against heat and humidity during the storage period is very important. A more stable medicinal substance of Donepezil Hydrochloride is, therefore, desired.

US Patent No. 5,985,864, US Patent No. 6,140,321 and US Patent Application No. 20040034057 describe five types of polymorphic crystalline form i.e. Form I, II, III, IV and V, wherein the stability and the physical properties thereof of the same are disclosed.

US Patent No. 6,140,321 discloses the preparation, XRD, IR, TG-DTA, melting points and stability data for crystalline form I, II, III and IV while for amorphous form, except the preparation and melting point, other data is disclosed. However, the above patent only claims the preparation, XRD and IR data of form III.

Further US Patent no. 5,985,864 discloses the preparation, XRD, IR, TG-DTA, melting points and stability data for crystalline forms I, II, III and IV. The said patent also discloses crystalline form V, whereas no stability data or TG-DTA data is disclosed for this crystalline form. However, the above patent only claimed the preparation, XRD, IR data of polymorphs II, IV and V.

US Patent No. 6,140,321 and US Patent No. 5,985,864 disclose, the crystallization of Donepezil hydrochloride using the methanol and isopropyl ether as a solvent system (which is already given in the product patent) afford crystalline form I having a melting point range of 225-226⁰C with a moisture content of 5.17%. US Patent Application No. 20050215591 discloses the Donepezil Hydrochloride crystalline form Hl, H2, sesquihydrate and monohydrate. The said patent has claimed

^' the powder X-ray diffraction pattern of above-mentioned forms along with their process of preparation. Whereas US Patent No. 6,734,195 has claimed chemically stable amorphous form of Donepezil Hydrochloride and its use in formulation.

Objective of the present invention is to provide novel and stable polymorphic form of Donepezil Hydrochloride, which is stable and easy to handle and convenient to operate on commercial scale.

Summary of the Invention

It is the principal aspect of the present invention to provide novel, stable crystalline polymorph of Donepezil Hydrochloride, wherein said polymorphic form is referred to hereinafter as Form J, and is characterized by using analytical tools selected from infrared absorption spectrum, X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), moisture content and/or melting point.

Further aspect of the present invention is to provide a process to prepare novel polymorphic form of Donepezil Hydrochloride designated as Form J, wherein the process provides the novel Form J which exhibits different dissolution characteristics, stability against heat and humidity during storage period and excellent handling properties.

Another aspect of the present invention is to provide a process to prepare different polymorphic forms of Donepezil Hydrochloride designated as Form I, II, III, IV, V and amorphous form employing said Form J of Donepezil Hydrochloride.

The following different embodiments of the present invention further describing the characteristics of the said polymorphic Form J of Donepezil Hydrochloride differ from prior known forms in their physical properties, spectral data employing the above said analytical tools. In accordance with one embodiment, there is provided novel polymorphic Form J of Donepezil Hydrochloride wherein said polymorphic form is characterized by a PXRD pattern having peaks at 11.5, 20.2, 20.4, 21.0, 21.4 + 0.2° 2Θ.

In accordance with one embodiment, there is provided novel polymorphic Form J of Donepezil Hydrochloride wherein said polymorphic form is characterized by a PXRD pattern having peaks at 10.0, 11.3, 11.5, 13.6, 13.9, 14.3, 19.1, 20.2, 20.4, 21.0, 21.4, 22.1, 22.8, 23.3, 23.6, 24.0, 24.3, 24.7, 26.9, 27.5, 28.8, 29.2, 29.9, 32.4 + 0.2° 2Θ.

In accordance with another embodiment, there is provided novel polymorphic Form J of Donepezil Hydrochloride wherein said polymorphic form is characterized by having an infrared spectrum in KBr comprising one or more characteristic peaks selected from absorption bands (Cm⁴) at 3549, 3380, 2940, 1691, 1589, 1497, 1315, 1264, 1116, 1036 and 759.

hi accordance with another embodiment, there is provided novel polymorphic Form J of Donepezil Hydrochloride wherein said polymorphic form is characterized by having an infrared spectrum in KBr comprising one or more characteristic peaks selected from absorption bands (cm^"1) at 3549, 3380, 2940, 2719, 2638, 1691, 1589, 1497, 1541(s), 1470, 1455, 1315, 1264, 1226, 1116, 1036, 945, 861, 759, 708 and 603.

In accordance with yet another embodiment of the present invention, there is provided a process for preparing crystalline polymorphic Form J of Donepezil Hydrochloride, the process comprises of dissolving Donepezil hydrochloride in water, lyophilizing the resultant solution of step (a) to get solid residue, exposing the resultant to relative humidity to get said polymorphic Form J, wherein obtained polymorphic Form J of Donepezil hydrochloride is novel and stable against heat and humidity during storage period.

The novel and stable polymorphic Form J of Donepezil Hydrochloride described herein in the present invention can be effectively used as pharmaceutical active to prepare different pharmaceutical formulations. Brief Description of the Drawing

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the description of preferred embodiments of the present invention which are shown in the accompanying drawing figures.

Fig. 1 depicts a powder X-ray diffractogram of crystalline Form j of Donepezil

Hydrochloride.

Fig. 2 depicts infrared absorption spectrum of crystalline Form J of Donepezil Hydrochloride in potassium bromide. [Vertical axis: Transmission (%);• horizontal axis: wave number (cm^"1)].

Fig. 3 depicts Thermo gravimetric analysis of crystalline Form . J of Donepezil

Hydrochloride.

Fig. 4 depicts Differential scanning calorimetry thermogram of crystalline Form J of Donepezil Hydrochloride.

Description of the Invention

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included drawings.

The present invention describes the novel and stable crystalline Donepezil hydrochloride Form J, which may exist in hydrated forms and is intended to be encompassed within the scope of the present invention. Crystalline Form J of Donepezil Hydrochloride differ from prior art forms in their physical properties, spectral data and methods of preparation and characterized by their X-ray powder diffraction patterns, Thermo gravimetric analysis (TGA) and/or by their infra red absorption spectrum (IR). X-ray powder Diffraction

Crystalline Form J of Donepezil Hydrochloride is characterized by its X-ray powder diffraction pattern. Thus the X-ray diffraction patterns of crystalline Form J of Donepezil Hydrochloride is measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of 2Θ, d-spacings and relative intensities.

Methodology

. Continuous Θ/2Θ coupled scan: 5.01° to 45.00° in 2Θ, scan rate of 3°/min.

Infrared absorption spectrometer (IR)

Methodology

Infrared measurement is made on Thermo Nicolet FT IR spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter.

Thermo Gravimetric analysis (TGA)

Methodology

TGA thermogram is recorded on TGA Q50 equilibrated at 25⁰C and with a ramp of , 5°C/min.

Differential Scanning Calorimetry (DSC)

Methodology

DSC analysis is done on DSC QlOO equilibrated at 25⁰C and with a ramp of 5°C/min. Crystalline Form J of Donepezil Hydrochloride is characterized by powder X-ray diffraction pattern as shown in Fig. 1 with major peaks shown in Table 1, which lists the 2Θ, d-spacings and relative intensities (>20%).

Crystalline Form J of Donepezil Hydrochloride is further characterized by IR with absorption bands at 3549, 3380, 2940, 2719, 2638, 1691, 1589, 1497, 1470, 1455, 1315, 1264, 1226, 1116, 1036, 945, 861, 759, 708 and 603 cm^"1 as depicted in Fig. 2.

Table 1

Crystalline Form J of Donepezil Hydrochloride is hydrated having the moisture content of 6.2-8.0%, which is analyzed by its TGA data as shown in Fig. 3. Crystalline Form J is having the melting point of 222-224⁰C analyzed by its DSC analysis data as shown in Fig. 4.

The present invention also provides the process for the preparation of crystalline Donepezil Hydrochloride Form J₅ which comprises dissolving Donepezil Hydrochloride in water, to get the clear solution followed by lyophilization to get the amorphous Donepezil hydrochloride, which is further exposed to different humidity level at different temperature range for a time period of 12-72 hrs. The humidity level used for the conversion of amorphous Donepezil hydrochloride to Form J is in the range of 50-75% preferably 60%, whereas temperature used for this conversion is in the range of 25-4O⁰C preferably 25-3O⁰C.

The polymorphic Form J of Donepezil Hydrochloride prepared by the process according to the present invention exhibits stability against heat and humidity during storage period. The Table 2 describes the stability study of said polymorphic Form J at various temperatures and relative humidity.

Table 2

The present invention also provides the process for the preparation of other crystalline forms i.e. Form I, II, III, IV, V and amorphous form. Form I is prepared by first treating crystalline Form J of Donepezil Hydrochloride with dichloromethane to reduce the moisture content and then the obtained residue is dissolved in methanol followed by the addition of the anti solvent such as isopropyl ether.

Form II is prepared by treating the Form J with alcohol and then heated at 50-55⁰C, followed by cooling to get solid material as form II. The alcohols used herewith is selected form the group consisting of but not limited to methanol, ethanol, isopropanol and butanol preferably isopropanol. Whereas Form III is prepared by treating Donepezil hydrochloride form J with alcohol in refluxing conditions and then cooled followed by filtration to get form III. The alcohols used herewith is selected form the group consisting of but not limited to methanol, ethanol, isopropanol and butanol preferably isopropanol. Donepezil Hydrochloride form IV is also prepared from crystalline form J by exposing to 100% relative humidity at room temperature for 3-12 hrs and dried the solid material under vacuum at 50-55⁰C. In contrast to this when form J is exposed to 75% relative humidity at 4O⁰C for 15 days it gets converted to form V.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way.

Example 1

Donepezil Hydrochloride (0.5 gm) was taken in water (5 ml) and stirred. The reaction mixture was heated to 50-60⁰C to get clear solution and then cooled. The reaction mixture was lyophilized to get the amorphous Donepezil hydrochloride, which was further exposed to relative humidity level of 60% at a temperature of 25⁰C for 24 hrs to get crystalline form J.

Example 2

Donepezil Hydrochloride (0.5 gm) was taken in water (5 ml) and stirred. The reaction mixture was heated to 50-60⁰C to get clear solution and then cooled. The reaction mixture was lyophilized to get the amorphous Donepezil hydrochloride, which was further exposed to relative humidity level of 75% at a temperature of 4O⁰C for 12 hrs to get crystalline form J.

Example 3

Donepezil hydrochloride form J (0.5 gm) was dissolved in dichloromethane (10 ml). Dichloromethane! was distilled under vacuum, followed by degassing to get residue. The obtained residue was dissolved in methanol (3 ml) and distilled under vacuum to get residue. The residue was redissolved in methanol, followed by addition of isopropyl ether (9 ml) and agitated for 30 min. The obtained solid was filtered and dried under vacuum at 50-55⁰C to get form I. Example 4

Donepezil hydrochloride form J (0.5 gm) and IPA (5 ml) were mixed and heated to 50- 55⁰C. Then the solid material was cooled and filtered, which was dried under vacuum at 50-55⁰C to get form II.

Example 5

Donepezil hydrochloride form J (0.5 gm) was dissolved in isopropanol (3 ml) and refluxed. The resulting solution was then cooled. The obtained solid was filtered and dried under vacuum at 50-55⁰C to get form III.

Example 6

Donepezil hydrochloride form J (0.5 gm) was dissolved in dichloromethane (10 ml). The solvent was distilled under vacuum, followed by degassing under vacuum to get solid material as an amorphous form of Donepezil hydrochloride.

Example 7

Donepezil Hydrochloride form J was exposed to 100% humidity at room temperature for 3-12 hrs and then the material was dried at 5O⁰C under vacuum to get form IV.

Example 8

Donepezil Hydrochloride form J was exposed to 40⁰C and 75% humidity for 15 days to get form V.

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We Claim:

1. Novel crystalline form of Donepezil Hydrochloride wherein said crystalline form is stable polymorphic form designated as J.

2. The crystalline form according to claim 1, wherein said polymorphic form J is having a powder X-ray diffraction pattern comprising characteristic peaks at about 11.5, 20.2, 20.4, 21.0, 21.4 ± 0.2° 2Θ.

3. The crystalline form according to claim 2, wherein said polymorphic form J is having a powder X-ray diffraction pattern comprising characteristic peaks at about 10.0, 11.3, 11.5, 13.6, 13.9, 14.3, 19.1, 20.2, 20.4, 21.0, 21.4, 22.1, 22.8, 23.3, 23.6, 24.0, 24.3, 24.7, 26.9, 27.5, 28.8, 29.2, 29.9, 32.4 ± 0.2° 2Θ.

4. The crystalline form according to claim 3, wherein said polymorphic form J is having a powder X-ray diffraction pattern essentially as depicted in Fig. 1.

5. The crystalline form according to claim 1, wherein said polymorphic form J is having an infrared spectrum comprising one or more characteristic peaks ^' selected from absorption bands (cm^"1) at 3549, 3380, 2940, 1691, 1589, 1497, 1315, 1264, 1116, 1036 and 759.

6. The crystalline form according to claim 5, wherein said polymorphic form J is having an infrared spectrum comprising one or more characteristic peaks selected from absorption bands (cm^"1) at 3549, 3380, 2940, 2719, 2638, 1691, 1589, 1497, 1541(s), 1470, 1455, 1315, 1264, 1226, 1116, 1036, 945, 861, 759, 708 and 603.

7. The crystalline form according to claim 6, wherein said polymorphic form J is having an infrared spectrum essentially as depicted in Fig. 2.

8. The crystalline form according to claim 1, wherein said polymorphic form J is containing 6.2-8.0% water.

9. A process for preparing crystalline polymorphic form J of Donepezil Hydrochloride as claimed in claim 1, the process comprising:

(a) dissolving Donepezil hydrochloride in water;

(b) lyophilizing the solution of step (a) to get solid residue; and (c) exposing the residue to relative humidity to get final product.

10. The process according to claim 9, wherein the Donepezil hydrochloride is of any form.

11. The process according to claim 9, wherein the relative humidity is in the range of 50-75%.

12. The process according to claim 11, wherein the relative humidity is of 60%.

13. The process according to claim 9, wherein exposing is done at a temperature of 25-4O⁰C.

14. The process according to claim 13, wherein exposing is done at a temperature of 25-3O⁰C.

15. The process according to claim 9, wherein said polymorphic form J of Donepezil hydrochloride is further employed in preparing crystalline form I of Donepezil hydrochloride, the process comprising: a. dissolving form J of Donepezil hydrochloride in dichloromethane; b. evaporating to get residue; c. dissolving the residue in methanol; and d. adding isopropyl ether to the solution.

16. The process according to claim 9, wherein said polymorphic form J of Donepezil hydrochloride is further employed in preparing crystalline form II of Donepezil hydrochloride, the process comprising: a. treating the crystalline form J with alcohol at 50-55⁰C; b. cooling the solution to get solid material; and c. filtering the solid material and drying.

17. The process according to claim 16, wherein said alcohol is selected from the group consisting of methanol, ethanol, isopropanol or butanol.

18. The process according to claim 17, wherein said alcohol is preferably isopropanol.

19. The process according to claim 9, wherein said polymorphic form J of Donepezil hydrochloride is further employed in preparing crystalline form III of Donepezil hydrochloride, the process comprising: a. treating the crystalline form J with alcohol; b. refluxing the solution; c. cooling the solution to get solid material; and d. filtering the solid material and drying.

20. The process according to claim 19, wherein said alcohol is selected from the group consisting of methanol, ethanol, isopropanol or butanol.

21. The process according to claim 20, wherein said alcohol is preferably isopropanol.

22. The process according to claim 9, wherein said polymorphic form J of Donepezil hydrochloride is further employed in preparing crystalline form IV of Donepezil hydrochloride by exposing the crystalline form J to 100% relative humidity.

23. The process according to claim 22, wherein exposing is done at room temperature.

24. The process according to claim 22, wherein exposing is done for 3-12 hrs.

25. The process according to claim 9, wherein said polymorphic form J of Donepezil hydrochloride is further employed in preparing crystalline form V of v Donepezil hydrochloride by exposing the crystalline form J to 75% relative humidity at a temperature of 4O⁰C.

26. The process according to claim 25, wherein exposing is done for 15 days.

27. A process for preparing crystalline polymorphic form J of Donepezil Hydrochloride, the process comprising: a. dissolving Donepezil hydrochloride in water; b. lyophilizing the resultant solution of step (a) to get solid residue; and c. exposing the resultant to relative humidity to get final product, wherein obtained polymorphic form J of Donepezil hydrochloride is novel and v stable against heat and humidity during storage period.

28. The process according to claim 27, wherein Donepezil hydrochloride is of any form.

29. The process according to claim 27, wherein relative humidity is in the 5 range of 50-75%.

30. The process according to claim 29, wherein relative humidity is of 60%.

31. The process according to claim 27, wherein exposing is done at a temperature of 25-4O⁰C.

32. The process according to claim 31, wherein exposing is done at a temperature of 25-3O⁰C.