WO2008117123A2

WO2008117123A2 - Process for preparing donepezil hydrochloride polymorphic form i

Info

Publication number: WO2008117123A2
Application number: PCT/IB2007/004566
Authority: WO
Inventors: Nuria Soldevilla Madrid
Original assignee: Medichem, S.A.
Priority date: 2006-10-16
Filing date: 2007-10-16
Publication date: 2008-10-02
Also published as: WO2008117123A3; AR063319A1

Abstract

The invention relates to improved methods for preparing polymorph Form I of 2,3- dihydro-5,6-dimethoxy-2-[[ 1 -(phenylmethy l)-4-piperidinyl]methyl- 1H-inden- 1 -one hydrochloride (i.e., donepezil hydrochloride).

Description

IMPROVED PROCESS FOR PREPARING DONEPEZIL HYDROCHLORIDE

POLYMORPHIC FORM I

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to United States Provisional Application Ns. 60/851,757, (filed October 16, 2006) and 60/929, 195 (filed June 18, 2007), which applications are each expressly incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0001] The invention relates to improved methods for preparing polymorph Form I of 2,3-dihydro-5,6-dimethoxy-2-[[ 1 -(pheny lmethyl)-4-piperidiny ljmethy 1- 1 H-inden- 1 -one hydrochloride (i.e., donepezil hydrochloride).

2. Discussion of the Related Art

[0002] Donepezil hydrochloride is a commercially marketed pharmaceutically active ingredient that is prescribed for treatment of mild to moderate dementia of the Alzheimer's type. Donepezil hydrochloride is also known as 2,3-dihydro-5,6-dimethoxy-2-[[l- (phenylmethyl)-4-piperidinyl]methyl-l H-inden- 1 -one hydrochloride or 2-(l-benzyl- piperidin-4-ylmethyl)-5,6-dimethoxy-indan-l-one and has the following structure:

Donepezil Hydrochloride

[0003] Donepezil hydrochloride is an orally active reversible inhibitor of the enzyme acetylcholinesterase, which is marketed under the name ARICEPT^®.

[0004] According to each of U.S. Patent No. 4,895,841, WO 9839000 Al, EP 0 296

560 Bl and J. Med. Chem., 38, 4821-29 (1995), donepezil hydrochloride can be prepared by hydrogenation of the intermediate 2-(l-benzylpiperidin-4-ylmethyliden)-5,6- dimethoxyindan-1 -one (Scheme 1, Compound 1) with Pd/C followed by treatment with hydrochloric acid. Compound 1 can be obtained by reacting 5,6-dimethoxyindan-l-one (Scheme 1, Compound 2) and l-benzylpiperidine-4-carbaldehyde (Scheme 1, Compound 3) and using LDA (generated in situ by reaction of N,N-diisopropylamine and rc-butyllithium) in a mixture of tetrahydrofuran and hexamethylphosphoramide (HMPA) at - 78° C.

Scheme 1

[0005] U.S. Patent No.4,895,841 discloses five polymorphs of donepezil hydrochloride and processes for making them. In this regard, US Patent No. 4,895,841, as well as EP 0296560 Bl, disclose the production of donepezil hydrochloride polymorphic Form I via crystallization from diisopropylether (DIPE) and methanol. The use of DIPE has a number of disadvantages. DIPE is a class A peroxidizable compound, which means that dangerous explosive peroxides can form without concentration. Thus, DIPE is a very dangerous solvent to handle and use.

[0006] In an effort to overcome the above technical problem, the crystallization leading to the production of donepezil hydrochloride polymorphic Form I can be performed using tert-butyl methyl ether as an alternative to DIPE. In this regard, it has been shown that donepezil hydrochloride polymorphic Form I is obtained successfully via crystallization from tert-bυty\ methyl ether and methanol at laboratory scale. This process, however, has a.significant drawback, namely the wet donepezil hydrochloride polymorphic Form I obtained after crystallization must be rapidly processed to the subsequent drying step, since it is slightly unstable and can convert to other polymorphic forms. Thus, the wet donepezil hydrochloride polymorphic Form I obtained after crystallization is difficult to handle which presents an industrial scale drawback.

[0007] In view of the foregoing, there is a need for a process for preparing donepezil hydrochloride polymorphic Form I, which (i) does not use dangerous solvents (including, in particular, DIPE), (ii) which provides stable wet donepezil hydrochloride polymorphic Form I obtained after crystallization that can be easily handled, (iii) that does not need to be processed rapidly, and (iv) that can be stored. Consequently, the process of the invention is well suited to industrial implementation. DESCRIPTION OF THE INVENTION

[0008] The invention relates to improved methods for preparing polymorph Form I of 2,3-dihydro-5,6-dimethoxy-2-[[ 1 -(phenylmethyl)-4-piperidinyl]methyl- 1 H-inden- 1 -one hydrochloride (i.e., donepezil hydrochloride).

[0009] More particularly, the invention provides a process for preparing donepezil hydrochloride polymorphic Form I, which (i) does not use dangerous solvents (including, in particular, DIPE), (ii) which provides stable wet donepezil hydrochloride polymorphic Form I obtained after crystallization that can be easily handled, (iii) that does not need to be processed rapidly, and (iv) that can be stored. Consequently, the process of the invention is well suited to industrial implementation.

[0010] In one embodiment, the invention relates to a process for preparing donepezil hydrochloride polymorphic Form I, in which the wet donepezil hydrochloride polymorphic Form I obtained after crystallization is highly stable against conversion to other polymorphic forms. Namely, the obtained wet donepezil hydrochloride polymorphic Form I does not need to be dried rapidly, and can be stored for a time before any subsequent drying step.

[0011] Surprisingly, it has been observed that when the residual methanol content is almost completely removed from wet donepezil hydrochloride polymorphic Form I obtained after crystallization, a highly stable wet donepezil hydrochloride polymorphic From I is obtained. Consequently, wet donepezil hydrochloride polymorphic From I having a low residual content of methanol is obtained which is highly stable against conversion to other polymorphic forms of donepezil hydrochloride. Consequently, the obtained donepezil hydrochloride polymorphic From I does not need to be dried rapidly, and can be stored for a time before any subsequent drying step.

[0012] More precisely, it has been observed that if the residual content of methanol of the wet donepezil hydrochloride polymorphic Form I obtained after crystallization is less than approximately 2% (w/v), the obtained wet donepezil hydrochloride polymorphic From I is highly stable against conversion to other polymorphic forms. For example, it has been observed that wet donepezil hydrochloride polymorphic Form I having a residual content of methanol less than approximately 2% (w/v) is stable for at least 21 hours at room temperature and atmospheric pressure, and at 40° C under vacuum.

[0013] Preferably, the process for preparing the wet donepezil hydrochloride polymorphic Form I having a residual content of methanol of less than approximately 2% (w/v) includes a step of washing the wet donepezil hydrochloride polymorphic. Form I obtained after crystallization with tert-butyl methyl ether or methylcyclohexane or mixtures thereof. More preferably, the step of washing the wet donepezil hydrochloride polymorphic Form I obtained after crystallization with tert-butyl methyl ether or methylcyclohexane or mixtures thereof includes at least 4 washes with tert-buty\ methyl ether or methylcyclohexane or mixtures thereof in order to obtain wet donepezil hydrochloride polymorphic Form I having a residual content of methanol of less than approximately 2% (w/v). The number of washings can be reduced by using a higher volume of washing solvent.

[0014] Thus, the invention includes a process for preparing donepezil hydrochloride polymorph Form I, in which the wet donepezil hydrochloride polymorphic Form I obtained after crystallization is highly stable against conversion to other polymorphic Forms, that includes the steps of (i) dissolving donepezil hydrochloride in methanol and a small amount of water under heating, (ii) cooling the solution, (iii) contacting the solution of step (ii) with a non-polar solvent or a mixture thereof, (iv) isolating wet donepezil hydrochloride polymorphic Form I obtained in step (iii), (v) removing at least a portion of the residual methanol from the wet donepezil hydrochloride polymorphic Form I obtained in step (iv), to obtain wet donepezil hydrochloride polymorphic Form I having a methanol residual content of less than approximately 2% (w/v), and, optionally, (vi) drying the obtained wet donepezil hydrochloride polymorphic Form I.

[0015] The non-polar solvent of step (iii) is an aliphatic ether solvent or an aliphatic hydrocarbon solvent, or a mixture thereof, preferably is tert-buty\ methyl ether or n-heptane or methylcyclohexane, or mixtures thereof, and more preferably is a mixture oftert-butyl methyl ether and methylcyclohexane.

[0016] Step (iii) can further include preparing a suspension of seeds of donepezil hydrochloride polymorphic Form (I) in said non-polar solvent, previous to the contacting with the solution of step (ii).

[0017] In another aspect, the process of removing at least a portion of the residual methanol from the wet donepezil hydrochloride polymorphic Form I, includes the steps of (i) washing the wet donepezil hydrochloride polymorphic Form I with a non-polar solvent in order to obtain wet donepezil hydrochloride polymorphic Form I having a reduced concentration of residual methanol, and a mother liquor including methanol, (ii) measuring the methanol content of the mother liquor of step (i), and (iii) repeating step (i) if the methanol content of the mother liquor of step (i) is higher than approximately 2% (w/v), or (iv) isolating wet donepezil hydrochloride polymorphic Form I if the methanol content of the mother liquor of step (i) is less than approximately 2% (w/v).

[0018] The non-polar solvent of step (i) is an aliphatic solvent or a mixture thereof, preferably an aliphatic ether solvent or an aliphatic hydrocarbon solvent or a mixture thereof, and more preferably tert-butyl methyl ether or methylcyclohexane or a mixture thereof.

[0019] The methanol content of the mother liquor of step (i) in step (ii), is measured by conventional gas chromatography.

[0020] In another aspect, the step (vi) of drying the obtained wet donepezil hydrochloride polymorphic Form I having a methanol residual content of less than approximately 2% (w/v), includes drying the obtained wet donepezil hydrochloride polymorphic Form I at approximately 40° C under vacuum.

[0021] The invention includes:

[0022] 1. A process for preparing donepezil hydrochloride polymorph Form I, wherein the wet donepezil hydrochloride polymorphic Form I obtained after crystallization is highly stable against conversion to other polymorphic forms, and wherein the process includes the steps of: i. dissolving donepezil hydrochloride in methanol and a small amount of water under heating; ii. cooling the solution; i. iii. contacting the solution of step (ii) with a non-polar solvent or a mixture thereof; iv. isolating wet donepezil hydrochloride polymorphic Form I obtained in step (iii); v. removing at least a portion of the residual methanol from the wet donepezil hydrochloride polymorphic Form I obtained in step (iv), to obtain wet donepezil hydrochloride polymorphic Form I having a methanol residual content less than approximately 2% (w/v); and vi. drying the obtained wet donepezil hydrochloride polymorphic Form I having a methanol residual content less than approximately 2% (w/v) of step (v).

[0023] In item 1 , the non-polar solvent of step (iii) is an aliphatic ether solvent or an aliphatic hydrocarbon solvent, or a mixture thereof, preferably is tert-butyl methyl ether or n-heptane or methylcyclohexane, or mixtures thereof, and more preferably is a mixture of /er/-butyl methyl ether and methylcyclohexane. [0024] In item 1, step (iii) can further include preparing a suspension of seeds of donepezil hydrochloride polymorphic Form (I) in said non-polar solvent, previous to the contacting with the solution of step (ii).

[0025] 2. The process of item 1, wherein the step (v) of removing at least a portion of the residual methanol from the wet donepezil hydrochloride polymorphic Form I, includes the steps of: i. washing the wet donepezil hydrochloride polymorphic Form I with a non-polar solvent to obtain wet donepezil hydrochloride polymorphic Form I having a reduced concentration of residual methanol, and a mother liquor including methanol; ii. measuring the methanol content of the mother liquor of step (i); and iii. repeating step (i) if the methanol content of the mother liquor of step (i) is higher than approximately 2% (w/v); or iv. isolating the wet donepezil hydrochloride polymorphic Form I if the methanol content of the mother liquor of step (i) is less than approximately 2% (w/v).

[0026] ,In item 2, the non-polar solvent of step (i) is an aliphatic solvent or a mixture thereof, preferably an aliphatic ether solvent or an aliphatic hydrocarbon solvent or a mixture thereof, and more preferably tert-baty\ methyl ether or methylcyclohexane or a mixture thereof. Additionally, the methanol content of the mother liquor in step (ii) is measured by conventional gas chromatography.

[0027] 3. The process of item 1 , wherein the step of (vi) drying the obtained wet donepezil hydrochloride polymorphic Form I having a methanol residual content less than approximately 2% (w/v), includes drying the obtained wet donepezil hydrochloride polymorphic Form I at approximately 40° C under vacuum.

[0028] 4. Wet donepezil hydrochloride polymorphic Form I, as obtained after crystallization, having a methanol residual content of less than approximately 2% (w/v), wherein the wet donepezil hydrochloride polymorphic Form I is highly stable against conversion to other polymorphic forms.

[0029] 5. The process of using the wet donepezil hydrochloride polymorphic

Form I of item 4 to obtain donepezil hydrochloride polymorphic Form I. [0030] 6. The process of item 5, wherein the process includes drying the wet donepezil hydrochloride polymorphic Form I at approximately 40° C under vacuum.

[0031] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

[0032] The following examples are for illustrative purposes only and are not intended, nor should they be interpreted, to limit the scope of the invention.

[0033] Example 1: Donepezil hydrochloride (20.26 g, 48.71 mmol) was dissolved in methanol (100 mL) and water (2.0 mL) under heating. After cooling to 15° C, a suspension of seeds of donepezil hydrochloride Form I (0.51 g, 1.23 mmol) in terf-butyl methyl ether (200 mL) was added to the previous solution. The final suspension was stirred at 10-15° C for 15 minutes and filtered to obtain a wet solid and a mother liquor ("Filtration"). The resulting wet solid was washed with tert-butyl methyl ether to obtain a new wet solid and a new mother liquor ("Washing 1"). The washing was repeated 4 additional times ("Washings 2-5"). The methanol content (%w/v) of each mother liquor was analyzed. Further, a sample of each wet solid was collected, kept at room temperature for 21 hours, dried at 40° C under vacuum, and analyzed by X-ray diffraction data to measure the resulting polymorphic form. The obtained results are summarized in Table 1.

Table 1

[0034] Example 2: Donepezil hydrochloride (101.10 g, 243.06 mmol) was dissolved in methanol (500 mL) and water ( 10 mL) under heating. After cooling to about 15° C, a suspension of tert-buty\ methyl ether (1000 mL) containing seeds of donepezil hydrochloride polymorphic Form I (2.51 g, 6.03 mmol) was added to the previous solution. The final suspension was stirred at 10-15° C for 15 minutes and filtered. The resulting solid was washed with tert-butyl methyl ether (6 x 100 mL) and dried at 40° C under vacuum to yield 93.80 g (Yield: 92.78%) of donepezil hydrochloride polymorphic Form I. Water content (by Karl Fischer method): 4.58%.

[0035] Example 3: Donepezil hydrochloride (500 g, 1.20 mol) was dissolved in methanol (2.5 L) and water (50 mL) under heating. After cooling to 25° C, a suspension of seeds of donepezil hydrochloride Form I (14 g, 33.7 mmol) in a mixture of «-heptane (2.5 L) and /er/-butyl methyl ether (2.5 L) was added, and the mixture was cooled to 10-15° C. Stirring was then continued for 15 minutes at 10-15° C. Thereafter, the suspension was filtered, and the solid was suspended in n-heptane (2.5 L) and stirred for 15 minutes at 5- 10° C. The suspension was then filtered and dried at 40° C under vacuum to yield 425 g (Yield: 82.7%) of donepezil hydrochloride polymorphic Form I.

[0036] Example 4: Donepezil hydrochloride (3.60 Kg, 8.65 mol) was dissolved in methanol (13.9 Kg) and water (0.36 Kg) under heating. After cooling to 30-40° C, the solution was filtered and added to a previously cooled (0 ± 3° C ) suspension containing seeds of donepezil hydrochloride polymorphic Form I (0.15 Kg, 0.36 mol) suspended in a mixture of n- heptane (11.9 Kg) and /ert-butyl methyl ether (13.3 Kg). The suspension was then cooled to 10-15° C and filtered. The resulting solid was next suspended twice in w-heptane (2 x 1 1.9 Kg), filtered and dried at 40° C under vacuum to yield 2.15 Kg (Yield: 57.3%) of donepezil hydrochloride polymorphic Form I. Water content (by Karl Fischer method): 4.89%.

[0037] Table 2 illustrates the results of particle size determination, by volume, of donepezil hydrochloride obtained in Example 4 after milling. The notation D_x means that X% by volume of the particles have a diameter less than a specified diameter. Thus, for example, a D₉₀ of approximately 10.00 μm means that 90% of the particles by volume in a composition preferably have a diameter less than approximately 10.00 μm.

Table 2

[0038] Table 3 lists the peak assignments of the X-ray powder diffractogram of donepezil hydrochloride Form I obtained in Example 4 and illustrated in Figure 1. eafc peak position peak intensity background

1 4.90326 1026.51501 48.19777

2 9.82427 98.47187 39.00281

3 10.49738 136.08324 27.31183

4 12.59218 523.04144 34.10876

S 13.04037 352.13791 40.39000

6 13.55683 165.64740 40.44829

7 13.81346 220.59126 37.70670

8 14.77700 262.74042 31.85770

9 15.17453 92.73779 32.46623

10 16.03797 205.05501 33.73114

11 16.83967 198.19063 46.37988

12 17.46691 211.36890 50.51558

13 19.25482 138.15454 53.42312

H 19.79488 196.52361 50.10030

IS 20.02657 146.66881 47.98029

16 21.14858 509.67398 60.90483

17 21.88403 163.47636 69.26287

18 22.33341 164.55412 69.24625

19 22.97124 218.31781 77.13876

20 23.86831 355.34714 89.96654

21 26.37696 153.90871 80.00401

22 29.01291 168.31595 70.95688

23 29.37976 169.17302 79.17776

24 35.05463 206.27510 54.26583

Table 3

[0039] Example 5: Donepezil hydrochloride (20.00 g, 48.08 mmol) was dissolved in methanol ( 100 mL) and water (2.00 mL) under heating. After cooling to approximately 15 ⁰C, a mixture of tert-butyl methyl ether (29.0 mL) and methylcyclohexane (171 mL) was added to the solution. The final suspension was stirred at 10-15° C for 15 minutes and filtered. The resulting solid was washed with /er/-butyl methyl ether (2 x 10 mL) and dried at 40° C under vacuum to yield 9.35 g (Yield: 46.75%) of donepezil hydrochloride polymorphic Form I.

[0040] Example 6: Donepezil hydrochloride (20.00 g, 48.08 mmol) was dissolved in methanol (100 mL) and water (2.00 mL) under heating. After cooling to about 15° C, a mixture of /er/-butyl methyl ether (100 mL) and methylcyclohexane (100 mL) was added to the solution. The final suspension was stirred at 15° C for 10 minutes and filtered. The resulting solid was washed with methylcyclohexane (2 x 10 mL) and dried at 40° C under vacuum to yield 15.69 g (Yield: 78.45%) of donepezil hydrochloride polymorphic Form I.

[0041] Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.

Claims

1. A process for preparing donepezil hydrochloride polymorph Form I that is highly stable against conversion to other polymorphic forms comprising: i. dissolving donepezil hydrochloride in methanol and a small amount of water under heating; ii. cooling the solution; iii. contacting the solution of step (ii) with at least one non-polar solvent or mixtures thereof; iv. isolating wet donepezil hydrochloride polymorphic Form I obtained in step (iii); and v. removing at least a portion of the residual methanol from the wet donepezil hydrochloride polymorphic Form I obtained in step (iv).

2. The process of claim 1, wherein said non-polar solvent of step (iii) comprises at least one of an aliphatic ether solvent, an aliphatic hydrocarbon solvent and a mixture thereof.

3. The process of claim 1, wherein said non-polar solvent of step (iii) is at least one of tort-butyl methyl ether, n-heptane, methylcyclohexane and mixtures thereof.

4. The process of claim 1, wherein said non-polar solvent of step (iii) is a mixture of tert-butyl methyl ether and methylcyclohexane.

5. The process of claim 1, wherein said step (iii) further comprises preparing a suspension of seeds of donepezil hydrochloride polymorphic Form (I) in said non-polar solvent prior to contacting the solution of step (ii) with said non-polar solvent.

6. The process of claim 1 , further comprising drying the obtained wet donepezil hydrochloride polymorphic Form I.

7. The process of any of claims 1 through 6, wherein said donepezil hydrochloride polymorphic Form I has a methanol residual content of less than approximately 2% (w/v).

8. The process of claim 1, wherein step (v) comprises: i. washing the wet donepezil hydrochloride polymorphic Form I with at least one non-polar solvent or mixture thereof in order to obtain wet donepezil hydrochloride polymorphic Form I having a reduced concentration of residual methanol, and a mother liquor including methanol; ii. measuring the methanol content of the mother liquor of step (i); and iii. repeating step (i) if the methanol content of the mother liquor of step (i) is higher than approximately 2% (w/v), or iv. isolating wet donepezil hydrochloride polymorphic Form I if the methanol content of the mother liquor of step (i) is less than approximately 2% (w/v).

9. The process of claim 8, wherein said at least one non-polar solvent or mixture thereof of step (i) comprises at least one aliphatic solvent or a mixture thereof.

10. The process of claim 8, wherein said at least one non-polar solvent or mixture thereof of step (i) comprises at least one of an aliphatic ether solvent, an aliphatic hydrocarbon solvent and mixtures thereof.

1 1. The process of claim 8, wherein said at least one non-polar solvent or mixture thereof of step (i) comprises at least one of ter/-butyl methyl ether, methylcyclohexane and mixtures thereof.

12. The process of claim 8, wherein said measuring the methanol content of the mother liquor of step (i) comprises measuring the methanol content by gas chromatography.

13. The process of any of claims 1-12, further comprising drying the obtained wet donepezil hydrochloride polymorphic Form I at approximately 40° C under vacuum.

14. Wet donepezil hydrochloride polymorphic Form I obtained by the process of any of claims 1-13 having a methanol residual content of less than approximately 2% (w/v) and wherein the wet donepezil hydrochloride polymorphic Form I is highly stable against conversion to other polymorphic forms.

15. Use of the wet donepezil hydrochloride polymorphic Form I of claim 14 or made by the processes of claims 1-13 to obtain donepezil hydrochloride polymorphic Form I.

16. A formulation comprising donepezil hydrochloride polymorphic Form I obtained by the process of any of claims 1-13 and 15.