Polymorphic forms of olanzapine
First Claim
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1. A process for producing a polymorph of olanzapine comprising:
- dissolving an initial polymorph of olanzapine in aqueous acidic solution;
wherein the aqueous acidic solution comprises an acid selected from the group consisting of organic and inorganic acids; and
precipitating a different polymorph of olanzapine by neutralization;
wherein neutralization is accomplished by the addition of an aqueous or alcoholic solution of a base.
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Abstract
The invention provides three new polymorphic forms of 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thieno[2,3b][1,5]benzodiazepine (Olanzapine) (Formula A), the process for preparing the new polymorphs and pharmaceutical compositions containing the polymorphs. The new polymorphic forms of olanzapine are useful for the treatment of psychotic conditions, mild anxiety and gastrointestinal conditions.
54 Citations
42 Claims
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1. A process for producing a polymorph of olanzapine comprising:
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dissolving an initial polymorph of olanzapine in aqueous acidic solution;
wherein the aqueous acidic solution comprises an acid selected from the group consisting of organic and inorganic acids; and
precipitating a different polymorph of olanzapine by neutralization;
wherein neutralization is accomplished by the addition of an aqueous or alcoholic solution of a base.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
recovering said different polymorph of olanzapine containing less than 5% of the initial form of olanzapine and less than 1% of other impurities.
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8. The process according to claim 1, wherein the initial polymorph of olanzapine is Form I or Form II olanzapine, wherein Form I olanzapine is an olanzapine polymorph having a typical x-ray powder diffraction pattern represented by the following interplanar spacings:
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9. The process according to claim 1, wherein the different polymorph of olanzapine is Form III olanzapine having a typical x-ray powder diffraction pattern comprising the following interplanar spacings:
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10. The process according to claim 1, wherein the different polymorph of olanzapine is Form IV olanzapine having a typical x-ray powder diffraction pattern comprising the following interplanar spacings:
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11. The process according to claim 1, wherein the different polymorph of olanzapine is Form V olanzapine having a typical x-ray powder diffraction pattern comprising the following interplanar spacings:
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12. The process according to claim 1, wherein the precipitation is conducted at a temperature between about 0°
- C. and about 100°
C.
- C. and about 100°
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13. The process according to claim 1, wherein the precipitation is conducted at a temperature between about 0°
- C. and about 35°
C.
- C. and about 35°
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14. The process according to claim 1, wherein the precipitation is conducted at a temperature between about 10°
- C. and about 30°
C.
- C. and about 30°
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15. The process according to claim 1, wherein the precipitation comprises adjusting the pH to between about 6 and about 12.
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16. The process according to claim 1, wherein the precipitation comprises adjusting the pH to between about 8 and about 11.
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17. The process according to claim 1, wherein the acidic solution comprises from about 5% to about 50% acid.
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18. The process according to claim 1, wherein the acidic solution is about 50% acetic acid and the basic solution is about 15% aqueous ammonia.
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19. The process according to claim 1, wherein the acidic solution is about 38% formic acid and the basic solution is about 10% methanolic sodium hydroxide.
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20. The process according to claim 1, wherein the acidic solution is about 10% hydrochloric acid and the basic solution is about 10% aqueous sodium hydroxide.
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21. The process according to claim 1, wherein the acidic solution is about 43% acetic acid and the basic solution is about 25% aqueous ammonia.
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22. The process according to claim 1, wherein the acidic solution is about 40% acetic acid and the basic solution is about 50% aqueous sodium hydroxide.
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23. The process according to claim 1, wherein the acidic solution is about 20% formic acid and the basic solution is about 25% aqueous ammonia.
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24. The process according to claim 1, wherein the acidic solution is about 33% acetic acid and the basic solution is about 50% aqueous ammonia.
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25. The process according to claim 1, wherein the acidic solution is about 50% acetic acid and the basic solution is about 25% aqueous ammonia.
- 26. Form III olanzapine polymorph having a typical x-ray powder diffraction pattern comprising the following interplanar spacings:
- 31. Form IV olanzapine polymorph having a typical x-ray powder diffraction pattern comprising the following interplanar spacings:
- 36. Form V olanzapine polymorph having a typical x-ray powder diffraction pattern comprising the following interplanar spacings:
Specification