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-didenz[b,f]azepin-5-
yl)propyldimethylamine. Its hydrochloride salt and pamoate salt can be represented by
the structural formula I and II respectively

Imipramine and its hydrochloride salt are disclosed in US patent 2,554,736 while its
pamoate salt is disclosed 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 very little efforts are directed towards polymorphs
of imipramine salts as indicated by a couple of references towards this topic.
The publication, Post and Kennard, ACTA CRYST. Volume B31, p 1008-1013, 1975,
reports the crystal structure of crystalline imipramine hydrochloride as a monoclinic on
the basis of single crystal X-ray study.
2

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 crystalline 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 organic solvent. Imipramine hydrochloride was then purified by
crystallization from a mixture of polar and non-polar organic solvents.
Imipramine pamoate was prepared by reacting imipramine base or its hydrochloride salt
with pamoic acid or its salts in water or water miscible organic solvent or mixture thereof
to obtain a crystalline imipramine pamoate or amorphous imipramine pamoate.
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.
DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have found novel polymorphs of imipramine salts
viz a crystalline form of imipramine hydrochloride, a crystalline form of imipramine
pamoate and an amorphous form of imipramine pamoate. These polymorphs are
characterized by their infrared spectrum and X-ray powder diffraction pattern as shown
in FIGS. 1-6.
3

Imipramine base (3) was prepared as per process described in DD 161,250 and DD
119,593 by aminoalkylation of iminodibenzyl (1) with dimethylaminopropylchloride (2) 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 (3) to imipramine hydrochloride of formula I 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 from alcohols such as
methanol, ethanol, isopropanol; ketones such as acetone, ethyl methyl ketone; ethyl
acetate and mixtures thereof preferably mixture of ethyl acetate and acetone. The
hydrochloride salt is separated out which was isolated by standard method such as
filteration 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, preferably acetone. Non-polar organic solvent is selected form ether such as
diisopropyl ether, diethyl ether and hexane, preferably diisopropyl ether. The ratio of
acetone to diisopropyl ether is in the range of 1:99 to 99:1, preferably 40:60 to 60:40,
most preferably 50:50 (volume/volume). The ratio of imipramine hydrochloride to solvent
is in the range 1:5 to 1:20, preferably 1:8 to 1:10 (weight/volume).
Crude imipramine hydrochloride was crystallized by dissolving in polar organic solvent
by heating to reflux temperature then cooling to 25-30°C followed by addition of non-
polar organic solvent and then cooling to 0-5°C.
4

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.
Imipramine pamoate of formula II was prepared by the reaction of disodium pamoate
with imipramine base or its hydrochloride salt of formula I. 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, dimetyl formamide, dimethyl
sulfoxide, propylene glycol and the mixtures thereof, preferably acetone.
The crude imipramine pamoate was crystallized from water by heating to 50-90°C,
preferably 65-70°C followed by cooling to 40-45°C and filtration. The ratio of imipramine
pamoate to water is in the range 1:2 to 1:20 preferably 1:8 to 1:10 (weight/volume).
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 followed by isolation of
amorphous solid after cooling to 5-10°C.
The ratio of pamoic acid or salt thereof to the imipramine base or salt thereof can vary
greatly, preferably two moles of base (or salt) are used for each one 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 example, which is provided
merely to be exemplary of the invention and is not intended to limit the scope of the
invention.
5

Example 1: Preparation of imipramine base
Iminodibenzyl (100 g) was added in a mixture of potassium hydroxide (344.15 g),
ammonium acetate (59.15 g) and toluene (300 ml) at room temperature. N,N-
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 contents 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.
Example 2: Preparation of imipramine hydrochloride
Ethyl acetate solution (obtained from example-1) was taken in acetone and pH was
adjusted to 3.5-4.0 by the addition of biphasic mixture of hydrochloric acid-ethyl acetate
(1:2). The solid was filtered and dried to give crude imipramine hydrochloride (130-
135 g). The crude imipramine hydrochloride (100 g) was added to acetone (2800 ml)
and refluxed for 30 minutes. It was treated with activated carbon (3 g), filtered and
washed with hot acetone (200 ml). Solvent was distilled off till about five volumes of
acetone was left. To the slurry diisopropyl ether (500 ml) was added and then cooled
slowly to
0-5°C. The crystals were filtered, washed with mixture of acetone and diisopropyl ether,
and dried. Yield 85 g.
Example 3: Preparation of crystalline imipramine pamoate
Solution of disodium pamoate (68.21 g) in 800 ml of water was 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 to give 200 g of wet imipramine pamoate.
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%. Yield 125 g.
6

Example 4: Preparation of amorphous imipramine pamoate
Imipramine 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 imipramine pamoate was 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%. Yield 24 g.
Dated this 10th day of October 2007

7

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 organic solvent. Imipramine hydrochloride was then purified by
crystallization from a mixture of polar and non-polar organic solvents.
Imipramine pamoate was prepared by reacting imipramine base or its hydrochloride salt
with pamoic acid or its salts in water or water miscible organic solvent or mixture thereof
to obtain a crystalline imipramine pamoate or amorphous imipramine pamoate.