FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A MONOHYDRATE FORM OF LOXAPINE HYDROCHLORIDE
2. APPLICANT:
(a) NAME: Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS: Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai, Maharashtra India Pin Code: 400055.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
Present invention relates to a monohydrate form of loxapine hydrochloride compound represented by structural formula (I) and process of preparing thereof.

BACKGROUND OF THE INVENTION:
Loxapine hydrochloride is chemically defined as 2-Chloro-11-(4-methyl-1 -piperazinyl)dibenz[b,f][l,4]oxazepine hydrochloride salt and is known from the US patent number 3,546,226 and is represented by structural formula (II).

Loxapine hydrochloride is approved in the US and is indicated for treatment of schizophrenia.
US patent no. 3,546,226 describes preparation of acid addition salts of dibenzoxazepine compounds by reacting with acid wherein loxapine compound represented by structural formula (III) is one of the dibenzoxazepine compounds and loxapine hydrochloride compound represented by structural formula (II) is one of the acid addition salt.


However it does not discloses isolation of loxapine hydrochloride compound represented by structural formula (II) in solid state.
US patent no. 3,412,193 discloses process for preparation of loxapine compound represented by structural formula (III) wherein crude product is treated with hydrochloric acid to provide hydrochloric acid salt which is further treated in-situ with sodium hydroxide solution to provide loxapine compound represented by structural formula (III).

However it does not disclose isolation of loxapine hydrochloride compound represented by structural formula (II) in solid state.
A publication in Indian Journal of Chemistry Vol. 12, March 1974, pp. 258-262 describes that crystallization of loxapine hydrochloride compound represented by structural formula (II) in mixture of ethanol and diethyl ether provides hemihydrate form of loxapine hydrochloride compound represented by structural formula (II), however it does not characterise the hemihydrate form.
The hemihydrate form of loxapine hydrochloride compound represented by structural formula (II) is hygroscopic and it is not a stable form. Hence hemihydrate form is not suitable for use in pharmaceutical products.

Prior art process does not provide stable form of loxapine hydrochloride compound represented by structural formula (II) in solid state and process of preparing thereof.
Polymorphs are crystals of the same molecule having different physical properties as a result of the order of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility, density which are important in formulation and product manufacturing and dissolution rates which is an important factor in determining bio-availability. The polymorphic behaviour of drugs is of crucial importance in pharmacy and pharmacology.
In view of the above the inventors of present invention have invented stable form of loxapine hydrochloride compound represented by structural formula (II) in solid state and process of preparing thereof.
OBJECT OF THE INVENTION:
An object of the present invention is to provide a stable monohydrate form of Loxapine hydrochloride compound represented by structural formula (I).

Another object of present invention is to provide a process for preparation of a monohydrate form of loxapine hydrochloride compound represented by structural formula (I).

SUMMARY OF THE INVENTION:
First aspect of this invention is a stable monohydrate form of Loxapine hydrochloride compound represented by structural formula (I).

Second aspect of this invention is a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2 theta (± 0.2) angles 7.5, 10.6, 11.1, 14.7, 17.1, 19.2,
21.2, 22.9, 25.4 & 27.5.

Third aspect of this invention is a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2 theta (± 0.2) angles:

Position [°2 theta] Relative Intensity [%]
7.5 100.00
10.1 20.65
10.6 17.93
11.1 23.98
13.4 33.45
14.3 4.75
14.7 6.56
15.8 8.05
16.2 2.38
16.5 6.78
17.1 76.50
18.1 19.86

18.6 15.81
19.1 26.13
19.2 33.93
20.2 56.53
20.6 22.42
21.1 61.50
21.2 87.68
21.4 30.03
21.6 14.80
22.2 11.32
22.5 30.08
22.6 35.30
22.9 69.31
23.4 16.44
24.4 9.55
24.7 12.21
25.2 54.68
25.4 66.71
25.8 4.09
26.6 8.36
26.9 18.88
27.1 24.70
27.5 54.20
27.8 14.40
29.1 12.17
Fourth aspect of present invention is a process for preparation of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) by treating loxapine base compound represented by structural formula (III) with hydrochloric acid in solvent to obtain loxapine hydrochloride monohydrate compound represented by structural formula (I).

Fifth aspect of present invention is a process for preparation of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) comprising the steps of:

i. treating loxapine succinate compound represented by structural formula (IV) with base in solvent to obtain loxapine base compound represented by structural formula (III);

ii. treating loxapine base compound represented by structural formula (III) from step i) with hydrochloric acid in solvent to obtain loxapine hydrochloride monohydrate compound represented by structural formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS:
Fig. 1 - XRPD patterns for monohydrate form of Loxapine hydrochloride compound represented by structural formula (I).
XRD diffraction measurement was performed on X-Ray powder diffractometer XPERT-PRO. The analysis conditions are as follows: Scan range [°2Th]: 4.01 to 39.98 Scan Type: Continuous. Step size [°2Th]: 0.0170 Scan Step Time [s]: 101.4374 Anode Material: Cu K-Alpha [A]: 1.54060 Generator Settings: 40mA, 45kV.

DETAIL DESCRIPTION OF THE INVENTION:
According to an aspect present invention provides a stable monohydrate form of Loxapine hydrochloride compound represented by structural formula (I).

A monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2 theta(± 0.2) angles: 7.5, 10.6, 11.1, 14.7, 17.1, 19.2, 21.2, 22.9, 25.4 & 27.5.

A monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2 theta (± 0.2) angles:

Position [°2 theta] Relative Intensity [%]
7.5 100.00
10.1 20.65
10.6 17.93
11.1 23.98
13.4 33.45
14.3 4.75
14.7 6.56
15.8 8.05
16.2 2.38
16.5 6.78
17.1 76.50
18.1 19.86

18.6 15.81
19.1 26.13
19.2 33.93
20.2 56.53
20.6 22.42
21.1 61.50
21.2 87.68
21.4 30.03
21.6 14.80
22.2 11.32
22.5 30.08
22.6 35.30
22.9 69.31
23.4 16.44
24.4 9.55
24.7 12.21
25.2 54.68
25.4 66.71
25.8 4.09
26.6 8.36
26.9 18.88 •
27.1 24.70
27.5 54.20
27.8 14.40
29.1 12.17
According to another aspect present invention provides a process for preparation of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) by treating loxapine base compound represented by structural formula (III) with hydrochloric acid in solvent to obtain loxapine hydrochloride monohydrate compound represented by structural formula (I).

Loxapine base compound represented by structural formula (III) can be prepared by methods disclosed in prior art such as those described in US patent no. 3,546,226.

Solvent can be water optionally in combination with solvent selected from the group comprising of hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; nitrile solvent such as acetonitrile, propionitrile; ketone solvent such as acetone, methyl isobutyl ketone, cyclopentanone, butanone or combination thereof.
Hydrochloric acid can be in solution form with water or alcohol solvent such as methanol, ethanol, isopropanol, propanol, butanol; ester solvent such as ethyl acetate, propyl acetate, butyl acetate; isopropyl acetate ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether.
Loxapine base compound represented by structural formula (III) can be treated with hydrochloric acid at a temperature in the range of 25°C to 80°C for a period of 15 minutes to 2 hours.
A monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) can be isolated by method such as distillation, concentration, filtration, drying or combination thereof.
A monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) can be dried under vacuum at a temperature in the range of 55°C to 60°C for a period of 3 to 6 hours till moisture content is in the range of 4.5% to 5.5%.
According to yet another aspect present invention provides process for preparation of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) comprising the steps of:
i. treating loxapine succinate compound represented by structural formula (IV) with base in solvent to obtain loxapine base compound represented by structural formula
(in);


4
ii. treating loxapine base compound represented by structural formula (III) from step i) with hydrochloric acid in solvent to obtain loxapine hydrochloride monohydrate compound represented by structural formula (I).

Loxapine succinate compound represented by structural formula (IV) can be prepared by methods disclosed in prior art such as those described in US patent no. 3,546,226.
Base can be selected from the group comprising of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
Solvent used in step i) can be selected from water and other solvent selected from the group comprising of hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ethyl, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; or combination thereof.
Loxapine succinate compound represented by structural formula (IV) can be treated with base at a temperature in the range of 25°C to 80°C for a period of 15 minutes to 1 hour.
Loxapine base can be isolated by method such as extraction, distillation, concentration, filtration or combination thereof and used for the next step.

Solvent used in step ii) can be water optionally in combination with solvent selected from the group comprising of hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; nitrile solvent such as acetonitrile, propionitrile; ketone solvent such as acetone, methyl isobutyl ketone, cyclopentanone, butanone or combination thereof.
Hydrochloric acid can be in solution form with water or alcohol solvent such as methanol, ethanol, isopropanol, propanol, butanol; ester solvent such as ethyl acetate, propyl acetate, butyl acetate; isopropyl acetate ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether.
Loxapine base compound represented by structural formula (III) can be treated with hydrochloric acid at a temperature in the range of 25°C to 80°C for a period of 15 minutes to 2 hours.
A monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) can be isolated by method such as distillation, concentration, filtration, drying or combination thereof
A monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) can be dried under vacuum at a temperature in the range of 55°C to 60°C for a period of 3 to 6 hours till moisture content is in the range of 4.5% to 5.5%.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example-1: Synthesis of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I):
A solution of loxapine succinate compound represented by structural formula (IV) (100 g) in water (400 ml) and toluene (500 ml) was added solution of sodium carbonate (48 g) in water (200 ml) at a temperature in the range of 20°C to 35°C. Resultant reaction mixture was heated to a temperature in the range of 65°C to 75°C and stirred for a period of 30 minutes. Reaction mixture was settled and toluene layer was separated and was washed with water. Toluene layer was distilled and degassed to obtain loxapine base compound represented by structural formula (III). Loxapine base compound represented by structural formula (III) was added with ethyl acetate (400 ml) and water (10 ml) to form a solution. A solution of loxapine base compound represented by structural formula (III) was drop wise added IPA.HCl (17%) (65 ml) at a temperature in the range of 55°C to 60°C. Resultant reaction mixture was stirred at a temperature in the range of 70°C to 75°C for a period of 30 minutes. Ethyl acetate (70 ml) was distilled out atmospherically and reaction mixture was gradually cooled to a temperature in the range of 25°C to 30°C in 1 to 2 hours. Reaction mixture was further cooled to 10°C to 15°C and stirred for 2 hours; Reaction mixture was filtered and solid was washed with cooled ethyl acetate. Wet solid was dried in oven under vacuum at a temperature in the range of 55°C to 60°C for a period of 3 to 4 hours.
Yield: 78.8 g Moisture content: 4.9% Purity: 99.9%
Example-2: Synthesis of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I):

ethyl acetate. Wet solid was dried in oven under vacuum at a temperature in the range of
55°C to 60°C for a period of 3 to 4 hours.
Yield: 79 g
Moisture content: 4.9%
Purity: 99.9%
Example-3: Synthesis of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I):
A solution of loxapine base compound represented by structural formula (III) (75 g) in water (225 ml) was drop wise added aqueous HC1 (35%) (33 ml) at a temperature in the range of 55°C to 60°C. Resultant reaction mixture was stirred at a temperature in the range of 70°C to 75°C for a period of 30 minutes. Reaction mixture was gradually cooled to a temperature in the range of 25°C to 30°C in 1 to 2 hours. Reaction mixture was further cooled to 10°C to 15°C and stirred for 2 hours. Reaction mixture was filtered and solid was washed with cooled water. Wet solid was dried in oven under vacuum at a temperature in the range of 55°C to 60°C for a period of 3 to 4 hours.
Yield: 70 g
Moisture content: 5.1%
Purity: 99.9%

We claim:
1. A monohydrate form of Loxapine hydrochloride compound represented by structural
formula (I).

2. A monohydrate form of Loxapine hydrochloride compound represented by structural
formula (I) as claimed in claim 1 wherein the X-ray powder diffraction pattern
comprises characteristic peaks at the following 2 theta (± 0.2) angles 7.5, 10.6, 11.1,
14.7, 17.1, 19.2, 21.2, 22.9, 25.4 & 27.5.

3. A monohydrate form of Loxapine hydrochloride compound represented by structural
formula (I) as claimed in claim 1 wherein the X-ray powder diffraction pattern
0
comprises characteristic peaks at the following 2 theta (± 0.2) angles:

Position [°2 theta] Relative Intensity [%]
7.5 100.00
10.1 20.65
10.6 17.93
11.1 23.98
13.4 33.45
14.3 4.75
14.7 6.56
15.8 8.05
16.2 2.38
16.5 6.78
17.1 76.50

18.1
19.86
18.6 15.81
19.1 26.13
19.2 33.93
20.2 56.53
20.6 22.42
21.1 61.50
21.2 87.68
21.4 30.03
21.6 14.80
22.2 11.32
22.5 30.08
22.6 35.30
22.9 69.31
23.4 16.44
24.4 9.55
24.7 12.21
25.2 54.68
25.4 66.71
25.8 4.09
26.6 8.36
26.9 18.88
27.1 24.70
27.5 54.20
27.8 14.40
29.1 12.17
4. A process for preparation of a monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) by treating loxapine base compound represented by structural formula (III) with hydrochloric acid in solvent to obtain loxapine hydrochloride monohydrate compound represented by structural formula (I).

5. A process as claimed in claim 4 wherein loxapine base compound represented by structural formula (III) is treated with hydrochloric acid in water optionally in combination with solvent selected from the group comprising of hydrocarbon solvent

such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; nitrile solvent such as acetonitrile, propionitrile; ketone solvent such as acctone, methyl isobutyl ketone, cyclopentanone, butanone or combination thereof at a temperature in the range of 25°C to 80°C.
6. A process for preparation of a monohydrate form of Loxapine hydrochloride
compound represented by structural formula (I) comprising the steps of:
i. treating loxapine succinate compound represented by structural formula (IV)
with base in solvent to obtain loxapine base compound represented by structural formula (III);

ii. treating loxapine base compound represented by structural formula (III) from
step i) with hydrochloric acid in solvent to obtain loxapine hydrochloride monohydrate compound represented by structural formula (I).

7. The process as claimed in claim 6, step-i) wherein Loxapine succinate compound represented by structural formula (IV) is treated with base selected from the group comprising of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.

8. The process as claimed in claim 6, step-i) wherein Loxapine succinate compound represented by structural formula (IV) is treated with base at a temperature in the range of 25°C to 80°C.
9. The process as claimed in claim 6, step-i) wherein solvent is water and other solvent selected from the group comprising of hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ethyl, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; or combination thereof.
10. The process as claimed in claim 1 and claim 6 wherein A monohydrate form of Loxapine hydrochloride compound represented by structural formula (I) is dried under vacuum at a temperature in the range of 55°C to 60°C till moisture content is in the range of 4.5% to 5.5%.