madrid2i

Resumen

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).

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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[deg.] 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.

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