Physical states of a pharmaceutical drug substance

• US 8,039,461 B1
• Filed: 08/23/2007
• Issued: 10/18/2011
• Est. Priority Date: 11/10/2006
• Status: Active Grant

• Current Assignee: Pisgah Labs, Inc. (IPCA Laboratories Limited), Pisgah Laboratories, Inc.
• Original Assignee: Pisgah Laboratories, Inc.
• Inventors: Mitchener, Joseph Pike Jr., Audia, Vicki Haynes, King, Clifford Riley, Bristol, David William
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US11/843,690
• Time in Patent Office: 1,517 Days
• Field of Search: 514/217, 540/592
• US Class Current: 514/217
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 223/28 having a single bond between positions 10 and 11

Abstract

An amorphous form of imipramine pamoate, morphologically pure forms, and mixtures of amorphous and morphologically pure imipramine pamoate characterized by differential scanning calorimetry, fourier transform infrared, and powder x-ray diffraction, and pharmaceutical compositions formed therefrom.

Claims

1. A polymorphic form of imipramine pamoate having a differential scanning calorimetry (DSC) thermogram exhibiting a phase transition at about 140-170°

C. and a heat of fusion of at least 15 Joules per gram.

2. The polymorphic form of imipramine pamoate of claim 1 having a differential scanning calorimetry (DSC) thermogram exhibiting a phase transition at about 140 to less than 155°

C.

3. A process for preparing imipramine pamoate of claim 2 comprising the steps of:

a) adding pH adjusted solution of imipramine hydrochloride in a gradual, metered manner to the pH adjusted solution of disodium pamoate,

b) warming the solution to about 52°

C. until the polymorphic form appears,

c) cooling and precipitating the solids from the reaction mixture at a temperature less than about 35°

C.,

d) collecting the precipitated solids by filtration or centrifugation,

e) washing the collected solids, and

f) drying the solids.

4. The polymorphic form of imipramine pamoate of claim 1 wherein said heat of fusion is 20-45 Joules per gram.

5. A process for preparing imipramine pamoate of claim 1 comprising the steps of:

a) adding the pH adjusted solution of imipramine hydrochloride in a gradual, metered manner to the pH adjusted solution of disodium pamoate,

b) warming the solution to about 52°

C. until the polymorphic form appears,

c) cooling and precipitating the solids from the reaction mixture at a temperature less than about 35°

C.,

d) collecting the precipitated solids by filtration or centrifugation,

e) washing the collected solids, and

f) drying the solids.

6. The polymorphic form of imipramine pamoate of claim 1 further comprising at least one other polymorphic form of imipramine pamoate.

7. The polymorphic form of imipramine pamoate of claim 6 wherein said at least one other polymorphic form of imipramine pamoate is amorphous imipramine pamoate.

8. A polymorphic form of imipramine pamoate of claim 1 having a differential scanning calorimetric (DSC) thermogram exhibiting a phase transition at about 155-170°

C.

9. A process for preparing imipramine pamoate of claim 8 comprising the steps of:

a) adding the pH adjusted solution of imipramine hydrochloride in a gradual, metered manner to the pH adjusted solution of disodium pamoate,

b) warming the solution to about 52°

C. until the polymorphic form appears,

c) cooling and precipitating the solids from the reaction mixture at a temperature less than about 35°

C.,

d) collecting the precipitated solids by filtration or centrifugation,

e) washing the collected solids, and

f) drying the solids.

10. The polymorphic form of imipramine pamoate of claim 8 with at least one other imipramine pamoate polymorphic form.

11. The polymorphic form of imipramine pamoate of claim 10 wherein said other imipramine pamoate polymorphic form comprises a blend further comprising amorphous imipramine pamoate.

12. A polymorphic form of imipramine pamoate characterized by a powder X-ray diffraction (PXRD) pattern as of FIG. 23.

13. The polymorphic form of imipramine pamoate of claim 12 further characterized by an infrared (IR) absorbance spectrum as of FIG. 24.

14. A process for preparing imipramine pamoate of claim 13 comprising the steps of:

a) adding the pH adjusted solution of imipramine hydrochloride in a gradual, metered manner to the pH adjusted solution of disodium pamoate,

b) warming the solution to about 52°

C. until the polymorphic form appears,

c) cooling and precipitating the solids from the reaction mixture at a temperature less than about 35°

C.,

d) collecting the precipitated solids by filtration or centrifugation,

e) washing the collected solids, and

f) drying the solids.

15. The polymorphic form of imipramine pamoate of claim 13 further comprising at least one other polymorphic form of imipramine pamoate.

16. The polymorphic form of imipramine pamoate of claim 15 wherein said at least one other polymorphic form of imipramine pamoate is amorphous imipramine pamoate.

17. A process for preparing imipramine pamoate of claim 12 comprising the steps of:

a) adding the pH adjusted solution of imipramine hydrochloride in a gradual, metered manner to the pH adjusted solution of disodium pamoate,

b) warming the solution to about 52°

C. until the polymorphic form appears,

c) cooling and precipitating the solids from the reaction mixture at a temperature less than about 35°

C.,

d) collecting the precipitated solids by filtration or centrifugation,

e) washing the collected solids, and

f) drying the solids.

18. The polymorphic form of imipramine pamoate of claim 12 further comprising at least one other polymorphic form of imipramine pamoate.

19. The polymorphic form of imipramine pamoate of claim 18 wherein said at least one other polymorphic form of imipramine pamoate is amorphous imipramine pamoate.

20. A process for preparing a mixture of polymorphic forms of imipramine pamoate comprising the steps of:

a) preparing the individual forms to be blended selected from the group defined as Form I, Form II, Form III, Form IV, Form V, Form VI and Form

b) combining the desired forms of imipramine pamoate in a pre-determined weight ratio of each component in a common vessel,

c) mixing, blending, tumbling, rotating, or by other mechanical action to insure and assure homogenous intermixing of the two forms, and

d) assessing the quality of the polymorphic blend by analytical methodology selected from differential scanning calorimetry (DSC), Infrared absorption (IR), powder x-ray diffraction (PXRD) and chromatographic methodology.

21. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 20 wherein said Form I has a phase transition as determined by DSC of 105-113°

C. with a heat of fusion of at least 0.5 joules per gram.

22. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 20 wherein said Form II has phase transitions as determined by DSC of 108-115°

C. and 137-151°

C. with a heat of fusion of at least 0.5 and 8 joules per gram respectively.

23. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 20 wherein said Form III has a phase transition as determined by DSC of 160-171°

C. with a heat of fusion of at least 2 joules per gram.

24. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 20 wherein said Form IV has a phase transition as determined by DSC of 140-160°

C. with a heat of fusion of at least 18 joules per gram.

25. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 24 wherein said Form IV has a phase transition as determined by DSC of 140 to less than 155°

C.

26. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 20 wherein said Form V has phase transitions as determined by DSC of 60-110°

C. and 150-170°

C. with a heats of fusion of at least 10 joules per gram each.

27. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 20 wherein said Form VI has phase transitions as determined by DSC of 98-118°

C. and 128-145°

C. with a heat of fusion of at least 50 and 8 joules per gram respectively.

28. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 20 wherein said Form VII has a phase transition as determined by DSC of 140-170°

C. with a heat of fusion of at least 15 joules per gram.

29. The process for preparing a mixture of polymorphic forms of imipramine pamoate of claim 28 wherein said Form VII has a phase transition as determined by DSC of at least 155 to 170°

C.

30. A pharmaceutical composition comprising imipramine pamoate polymorphic forms wherein one form of said forms one is imipramine pamoate Form VII suitable for use in treating depression, fibromyalgia, childhood nocturnal enuresis and adult urinary incontinence, trichotillomania, post-traumatic stress disorder, panic disorder and to provide analgesic-like relief for neuropathic pain.

31. A pharmaceutical composition comprising a polymorphic form of imipramine pamoate comprising at least one material selected from the group consisting of imipramine pamoate Form I, imipramine pamoate Form II, imipramine pamoate Form III, imipramine pamoate Form IV, imipramine pamoate Form V, imipramine pamoate Form VI and imipramine pamoate Form VII, adapted for use in treating depression, fibromyalgia, childhood nocturnal enuresis and adult urinary incontinence, trichotillomania, post-traumatic stress disorder, panic disorder and to provide analgesic-like relief for neuropathic pain.

32. A pharmaceutical composition comprising 1 to 95 wt % amorphous imipramine pamoate and 5-99 wt % of at least one material selected from imipramine pamoate Form II, imipramine pamoate Form III, imipramine pamoate Form IV, imipramine pamoate Form VI and imipramine pamoate Form VII.

33. A pharmaceutical composition according to claim 32 exhibiting resistance to ratio changes of the at least one polymorphic form of imipramine pamoate compared to the amorphous imipramine pamoate when subjected to time, temperature and humidity.

34. A pharmaceutical composition according to claim 32 and presented in a human dosage.

35. A pharmaceutical composition comprising at least one imipramine pamoate selected from:

imipramine pamoate with a phase transition of about 105-133°

C. and a heat of fusion of at least 0.5 joules per gram;

imipramine pamoate with a phase transition of about 108-115°

C. with a heat of fusion of at least 0.5 joules per gram and a phase transition of about 137-151°

C. with a heat of fusion of at least 8 joules per gram;

imipramine pamoate with a phase transition of about 160-171°

C. and a heat of fusion of at least 20 joules per gram;

imipramine pamoate with a phase transition of about 140-160°

C. and a heat of fusion of 18 joules per gram;

imipramine pamoate with a phase transition of about 60-110°

C. with a heat of fusion of at least 15 joules per gram and a phase transition of about 150-170°

C. with a heat of fusion of at least 15 joules per gram;

imipramine pamoate with a phase transition of about 98-118°

C. with a heat of fusion of at least 30 joules per gram and a phase transition of about 128-145°

C. with a heat of fusion of at least 5 joules per gram; and

imipramine pamoate with a phase transition of about 140-170°

C. with a heat of fusion of at least 15 joules per gram.

36. The pharmaceutical composition of claim 35 comprising 20-80 wt % of said imipramine pamoate with a phase transition of about 140-170°

C. with a heat of fusion of at least 15 joules per gram.

37. The pharmaceutical composition of claim 36 wherein said imipramine pamoate has a phase transition of about at least 155-170°

C.

38. The pharmaceutical composition of claim 36 comprising 40-60 wt % of said imipramine pamoate with a phase transition of about 140-170°

C. with a heat of fusion of at least 18 joules per gram.

39. The pharmaceutical composition of claim 38 wherein said imipramine pamoate has a phase transition of 140 to less than 155°

C.