WO2009047796A1 - Polymorphs of imipramine hydrochloride and pamoate salt - Google Patents

Polymorphs of imipramine hydrochloride and pamoate salt Download PDF

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WO2009047796A1
WO2009047796A1 PCT/IN2008/000641 IN2008000641W WO2009047796A1 WO 2009047796 A1 WO2009047796 A1 WO 2009047796A1 IN 2008000641 W IN2008000641 W IN 2008000641W WO 2009047796 A1 WO2009047796 A1 WO 2009047796A1
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imipramine
pamoate
organic solvent
process according
solution
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PCT/IN2008/000641
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French (fr)
Inventor
Rajesh Kumar Thaper
Yuvraj Atmaram Chavan
Vikas Shivaji Kamble
Smita Shivaji Bhosale
Mahesh Ramkumar Kolekar
Pritesh Ramesh Upadhyay
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Lupin Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11

Definitions

  • the present invention relates to a novel crystalline form of imipramine hydrochloride, a novel crystalline form of imipramine pamoate and a novel amorphous form of imipramine pamoate.
  • the invention further relates to processes for preparing these polymorphs.
  • Imipramine is known by the chemical name 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5- yl)propyldimethylamine. Its hydrochloride salt and pamoate salt can be represented by the structural formula I and formula Il respectively.
  • Imipramine and its hydrochloride salt are disclosed in US patent 2,554,736 and its pamoate salt is in US patent 3,326,896.
  • Imipramine and its salts are orally active dibenzazepine tricyclic antidepressant. It is one of the less toxic and less sedating tricyclics and has moderate antimuscarinic activity.
  • the present invention describes a novel crystalline form of imipramine hydrochloride, a novel crystalline form of imipramine pamoate and a novel amorphous form of imipramine pamoate
  • Imipramine base was converted to imipramine hydrochloride by the addition of hydrochloric acid in an organic solvent.
  • Imipramine hydrochloride was crystallized from a mixture of polar and non-polar organic solvents.
  • Imipramine pamoate was prepared by reacting imipramine or its hydrochloride salt with pamoic acid or its salts in a mixture of water and water miscible organic solvent.
  • Figure 1 is an FT-IR spectrum of crystalline form of imipramine hydrochloride.
  • Figure 2 is an X-ray powder diffraction pattern of crystalline form of imipramine hydrochloride.
  • Figure 3 is an FT-IR spectrum of crystalline form of imipramine pamoate.
  • Figure 4 is an X-ray powder diffraction pattern of crystalline form of imipramine pamoate.
  • Figure 5 is an FT-IR spectrum of amorphous form of imipramine pamoate.
  • Figure 6 is an X-ray powder diffraction pattern of amorphous form of imipramine pamoate.
  • the inventors of the present invention have found novel polymorphs of imipramine salts viz., amorphous and crystalline form of imipramine pamoate, and a crystalline form of imipramine hydrochloride. These polymorphs are characterized by their infrared spectrum and X-ray powder diffraction pattern as shown in FIGS. 1-6.
  • Imipramine base was prepared as per process described in DD 161 ,250 and DD 119,593 by aminoalkylation of iminodibenzyl with dimethylaminopropylchloride in presence of base and ammonium acetate in benzene or toluene.
  • the aminoalkylation is preferably performed in the presence of base such as alkali metal hydroxide or sodamide.
  • the conversion of imipramine base to imipramine hydrochloride was achieved by the addition of hydrochloric acid to a solution of imipramine base in a suitable organic solvent.
  • the suitable organic solvent is selected form alcohols such as methanol, ethanol, isopropanol; ketones such as acetone, ethyl methyl ketone; ethyl acetate and mixtures thereof.
  • the hydrochloride salt is separated out which was isolated by standard method such as filtration and evaporation of the solvents.
  • the crude imipramine hydrochloride was crystallized from mixture of polar organic solvent and non-polar organic solvent.
  • Polar organic solvent is selected from alcohols such as methanol, ethanol, isopropanol; ketones such as acetone and ethyl methyl ketone.
  • Non-polar organic solvent is selected form ether such as diisopropyl ether, diethyl ether and hexane.
  • Crude imipramine hydrochloride was dissolved in polar organic solvent by heating to reflux and cooled to 25-30°C. Non-polar organic solvent was added, the content were cooled to 0-5° and the crystals were filtered off.
  • Pamoic acid is also known as embonic acid has chemical name 2,2'-dihydroxy-1 ,1'- dinaphthylmethane-3,3'-dicarboxylic acid, which is used in the free form or in the form of a soluble salt, particularly an alkali metal salt e.g. the sodium salt.
  • Crystalline form of imipramine pamoate was prepared by the reaction of disodium pamoate with imipramine hydrochloride.
  • the reaction is preferably performed in an aqueous medium or in mixtures of water and water miscible organic solvents.
  • the water miscible solvent is selected from the group comprising alcohols e.g. methanol and ethanol, ketones e.g. acetone, dioxane, dimethyl formamide, dimethyl sulfoxide, propylene glycol and the mixtures thereof.
  • Amorphous imipramine pamoate was obtained by the reaction of imipramine base or its hydrochloride salt with pamoic acid or its sodium salt in water.
  • the ratio of pamoic acid or salt thereof to the imipramine base or salt thereof can vary greatly, preferably 2 moles of base (or salt) are used for each 1 mole of pamoic acid (or salt).
  • the resulting polymorphs of imipramine salts may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc.
  • the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • the present invention is further illustrated by the following examples, which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention.
  • the crude imipramine hydrochloride was added to acetone and refluxed for 30 minutes. It was treated with activated carbon, filtered and washed with hot acetone. To the filtrate was added diisopropyl ether and cooled slowly to 0-5 0 C. The crystals were filtered, washed with mixture of acetone and DIPE 1 and dried to afford crystalline imipramine hydrochloride.
  • Disodium pamoate (68.21 g) was dissolved in 800 ml of water and the solution is poured slowly into a solution of 100 g of imipramine hydrochloride in a mixture of 200 ml of water and 1000 ml of acetone at 50-55°C. The contents were cooled slowly to room temperature, stirred to commence crystallization and then filtered. The solid mass was poured into distilled water (2 liters), stirred, filtered and washed with water. The product was added in water (2 liters) and heated to 65-70°C. The contents were cooled to 40-45°C, filtered, washed with water and then dried under reduced pressure at about 70°C till moisture content was less than 1.0%.
  • lmipramine hydrochloride (20 g) was dissolved in 100 ml of water and the solution is poured slowly into a solution of 13.66 g of disodium pamoate in 300 ml of water. The contents were cooled to 5-10°C and then filtered. The solid was washed with 1.4 liter of distilled water and then dried under reduced pressure at about 70°C till moisture content was less than 2.0%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to novel polymorphs of imipramine salts and the processes for their preparation.

Description

POLYMORPHS OF IMIPRAMINE HYDROCHLORIDE AND PAMOATE SALT
FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of imipramine hydrochloride, a novel crystalline form of imipramine pamoate and a novel amorphous form of imipramine pamoate. The invention further relates to processes for preparing these polymorphs.
BACKGROUND OF THE INVENTION
Imipramine is known by the chemical name 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5- yl)propyldimethylamine. Its hydrochloride salt and pamoate salt can be represented by the structural formula I and formula Il respectively.
Formula I
Figure imgf000002_0001
Formula II
Figure imgf000002_0002
Imipramine and its hydrochloride salt are disclosed in US patent 2,554,736 and its pamoate salt is in US patent 3,326,896. Imipramine and its salts are orally active dibenzazepine tricyclic antidepressant. It is one of the less toxic and less sedating tricyclics and has moderate antimuscarinic activity.
From literature survey, it appears that efforts for explanation of polymorphs of imipramine salts are ignored except for a couple of references. The publication, Post and Kennard, ACTA CRYST. Volume B31 , p 1008-1013, 1975, reports the crystal structure of imipramine hydrochloride as a monoclinic on the basis of single crystal X-ray study.
Another publication ANALYTICAL PROFILES OF DRUG SUBSTANCES AND EXCIPIENTS, volume 14, p 37-75, 1985, Academic Press, discloses the infrared spectra and X-ray powder diffraction pattern of imipramine hydrochloride.
SUMMARY OF THE INVENTION
The present invention describes a novel crystalline form of imipramine hydrochloride, a novel crystalline form of imipramine pamoate and a novel amorphous form of imipramine pamoate
Imipramine base was converted to imipramine hydrochloride by the addition of hydrochloric acid in an organic solvent.
Imipramine hydrochloride was crystallized from a mixture of polar and non-polar organic solvents.
Imipramine pamoate was prepared by reacting imipramine or its hydrochloride salt with pamoic acid or its salts in a mixture of water and water miscible organic solvent.
DESCRIPTION OF THE DRAWINGS
Figure 1 is an FT-IR spectrum of crystalline form of imipramine hydrochloride.
Figure 2 is an X-ray powder diffraction pattern of crystalline form of imipramine hydrochloride.
Figure 3 is an FT-IR spectrum of crystalline form of imipramine pamoate.
Figure 4 is an X-ray powder diffraction pattern of crystalline form of imipramine pamoate. Figure 5 is an FT-IR spectrum of amorphous form of imipramine pamoate.
Figure 6 is an X-ray powder diffraction pattern of amorphous form of imipramine pamoate.
DESCRIPTION OF THE INVENTION
The inventors of the present invention have found novel polymorphs of imipramine salts viz., amorphous and crystalline form of imipramine pamoate, and a crystalline form of imipramine hydrochloride. These polymorphs are characterized by their infrared spectrum and X-ray powder diffraction pattern as shown in FIGS. 1-6.
Imipramine base was prepared as per process described in DD 161 ,250 and DD 119,593 by aminoalkylation of iminodibenzyl with dimethylaminopropylchloride in presence of base and ammonium acetate in benzene or toluene. The aminoalkylation is preferably performed in the presence of base such as alkali metal hydroxide or sodamide.
Novel crystalline form of imipramine hydrochloride
The conversion of imipramine base to imipramine hydrochloride was achieved by the addition of hydrochloric acid to a solution of imipramine base in a suitable organic solvent. The suitable organic solvent is selected form alcohols such as methanol, ethanol, isopropanol; ketones such as acetone, ethyl methyl ketone; ethyl acetate and mixtures thereof. The hydrochloride salt is separated out which was isolated by standard method such as filtration and evaporation of the solvents.
The crude imipramine hydrochloride was crystallized from mixture of polar organic solvent and non-polar organic solvent. Polar organic solvent is selected from alcohols such as methanol, ethanol, isopropanol; ketones such as acetone and ethyl methyl ketone. Non-polar organic solvent is selected form ether such as diisopropyl ether, diethyl ether and hexane. Crude imipramine hydrochloride was dissolved in polar organic solvent by heating to reflux and cooled to 25-30°C. Non-polar organic solvent was added, the content were cooled to 0-5° and the crystals were filtered off.
Novel crystalline form of imipramine pamoate
Pamoic acid is also known as embonic acid has chemical name 2,2'-dihydroxy-1 ,1'- dinaphthylmethane-3,3'-dicarboxylic acid, which is used in the free form or in the form of a soluble salt, particularly an alkali metal salt e.g. the sodium salt.
Crystalline form of imipramine pamoate was prepared by the reaction of disodium pamoate with imipramine hydrochloride. The reaction is preferably performed in an aqueous medium or in mixtures of water and water miscible organic solvents. The water miscible solvent is selected from the group comprising alcohols e.g. methanol and ethanol, ketones e.g. acetone, dioxane, dimethyl formamide, dimethyl sulfoxide, propylene glycol and the mixtures thereof.
Novel amorphous form of imipramine pamoate
Amorphous imipramine pamoate was obtained by the reaction of imipramine base or its hydrochloride salt with pamoic acid or its sodium salt in water.
The ratio of pamoic acid or salt thereof to the imipramine base or salt thereof can vary greatly, preferably 2 moles of base (or salt) are used for each 1 mole of pamoic acid (or salt).
The resulting polymorphs of imipramine salts may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients. The present invention is further illustrated by the following examples, which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention.
Example 1: Preparation of imipramine base
Iminodibenzyl (100 g) was added in a mixture of KOH (344.15 g), ammonium acetate (59.15 g) and toluene (300 ml) at room temperature. N1N- dimethylaminopropylchloride (435.2 g) was added and heated to reflux. Reaction mixture was cooled, added water and pH was adjusted between 3.5 and 4.0 by using HCI (1 :1). Organic layer was separated and the pH of aqueous layer was adjusted between 8.5 and 9.0 by using 20 % sodium hydroxide solution. The content were extracted with ethyl acetate and the organic layer was treated with activated carbon. Filtered off the carbon and the filtrate was used for the next steps. Ethyl acetate solution thus obtained was taken in acetone and pH was adjusted to 3.5-4.0 by the addition of hydrochloric acid-ethyl acetate (1 :2). The solid was filtered and dried.
Example 2: Preparation of crystalline imipramine hydrochloride
The crude imipramine hydrochloride was added to acetone and refluxed for 30 minutes. It was treated with activated carbon, filtered and washed with hot acetone. To the filtrate was added diisopropyl ether and cooled slowly to 0-50C. The crystals were filtered, washed with mixture of acetone and DIPE1 and dried to afford crystalline imipramine hydrochloride.
Example 3: Preparation of crystalline imipramine pamoate
Disodium pamoate (68.21 g) was dissolved in 800 ml of water and the solution is poured slowly into a solution of 100 g of imipramine hydrochloride in a mixture of 200 ml of water and 1000 ml of acetone at 50-55°C. The contents were cooled slowly to room temperature, stirred to commence crystallization and then filtered. The solid mass was poured into distilled water (2 liters), stirred, filtered and washed with water. The product was added in water (2 liters) and heated to 65-70°C. The contents were cooled to 40-45°C, filtered, washed with water and then dried under reduced pressure at about 70°C till moisture content was less than 1.0%.
Example 4: Preparation of amorphous imipramine pamoate
lmipramine hydrochloride (20 g) was dissolved in 100 ml of water and the solution is poured slowly into a solution of 13.66 g of disodium pamoate in 300 ml of water. The contents were cooled to 5-10°C and then filtered. The solid was washed with 1.4 liter of distilled water and then dried under reduced pressure at about 70°C till moisture content was less than 2.0%.

Claims

1. A crystalline form of imipramine hydrochloride, which has FT-IR spectrum as depicted in Figure 1.
2. A crystalline form of imipramine hydrochloride of claim 1 , which exhibits X-ray diffraction pattern as depicted in Figure 2.
3. A process for the preparation of the crystalline imipramine hydrochloride, comprising the steps of: a) preparing a solution of imipramine hydrochloride in a polar organic solvent; b) adding a non polar organic solvent to the solution obtained in step (a); c) cooling the reaction mixture; and d) isolating the product.
4. The process according to claim 3, wherein the polar organic solvent is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol; ketones such as acetone and ethyl methyl ketone, preferably acetone and the non-polar organic solvent is selected from diisopropyl ether, diethyl ether and hexane, preferably diisopropyl ether.
5. The process according to claim 3, wherein the reaction is performed at a temperature ranging from 0-800C, preferably at reflux temperature of the polar organic solvent.
6. Crystalline imipramine pamoate.
7. A crystalline form of imipramine pamoate of claim 6, which has FT-IR spectrum as depicted in Figure 3.
8. A crystalline form of imipramine pamoate of claim 6, which exhibits X-ray diffraction pattern as depicted in Figure 4.
9. A process for the preparation of the crystalline imipramine pamoate, comprising the steps of: a) preparing a solution of disodium pamoate in a water miscible organic solvent; b) preparing a solution of either imipramine free base or its salt in a mixture of water and water miscible organic solvent; c) adding imipramine solution obtained in step (b) to the disodium pamoate solution obtained in step (a) or vice versa; and d) isolating the product.
10. The process according to claim 9, wherein the ratio of imipramine base or a salt thereof to pamoic acid is in the range of 5:1 to 2:1 , more preferably 2:1.
11. The process according to claim 9, wherein the organic solvent is selected from group consisting of alcohols such as methanol and ethanol; ketones such as acetone; and dioxane, dimethyl formamide, dimethyl sulfoxide, propylene glycol, preferably acetone.
12. The process according to claim 9, wherein the reaction is performed at a temperature ranging from 0-700C, preferably at 50-55°C.
13. Amorphous form of imipramine pamoate.
14. Amorphous form of imipramine pamoate of claim 13, which has FT-IR spectrum as depicted in Figure 5.
15. Amorphous form of imipramine pamoate of claim 13, which exhibits X-ray diffraction pattern as depicted in Figure 6.
16. A process for the preparation of the amorphous imipramine pamoate, comprising the steps of: a) preparing a solution of disodium pamoate in water; b) preparing a solution of either imipramine free base or its salt in water; c) adding imipramine solution obtained in step (b) to the disodium pamoate solution obtained in step (a) or vice versa; and d) isolating the product.
17. The process according to claim 16, wherein the ratio of imipramine base or a salt thereof to pamoic acid is in the range of 5:1 to 2:1 , more preferably 2:1.
18. The process according to claim 16, wherein the reaction is performed at a temperature ranging from 0-50°C, preferably at 25-3O0C.
PCT/IN2008/000641 2007-10-10 2008-10-06 Polymorphs of imipramine hydrochloride and pamoate salt WO2009047796A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8716278B1 (en) * 2010-07-30 2014-05-06 Pisgah Laboratories, Inc. Abuse deterrent and anti-dose dumping pharmaceutical salts useful for the treatment of attention deficit/hyperactivity disorder
US9334240B2 (en) 2014-02-13 2016-05-10 R.L. Fine Chem Method of preparation of imipramine pamoate and novel crystalline form of imipramine pamoate thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2554736A (en) * 1951-05-29 Tertiary aminoalkyl-iminodibenzyls
US3326896A (en) * 1964-01-24 1967-06-20 Geigy Chem Corp Embonic acid addition salts of 10, 11-dihydro-5h-dibenz[b, f]azepines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2554736A (en) * 1951-05-29 Tertiary aminoalkyl-iminodibenzyls
US3326896A (en) * 1964-01-24 1967-06-20 Geigy Chem Corp Embonic acid addition salts of 10, 11-dihydro-5h-dibenz[b, f]azepines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KENDER, D.N. ET AL., ANALYTICAL PROFILE OF DRUG SUBSTANCES, vol. 14, 1985, pages 37 - 75, XP009111245 *
POST, M.L ET AL., ACTA CRYSTALLOGRAPHICA SECTION B, vol. 31, 1975, pages 1008 - 1013, XP002512014 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8980880B1 (en) * 2006-11-10 2015-03-17 Pisgah Laboratories, Inc. Abuse deterrent and anti-dose dumping pharmaceutical salts useful for the treatment of attention deficit/hyperactivity disorder
US8716278B1 (en) * 2010-07-30 2014-05-06 Pisgah Laboratories, Inc. Abuse deterrent and anti-dose dumping pharmaceutical salts useful for the treatment of attention deficit/hyperactivity disorder
US9334240B2 (en) 2014-02-13 2016-05-10 R.L. Fine Chem Method of preparation of imipramine pamoate and novel crystalline form of imipramine pamoate thereof

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