FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"NOVEL CRYSTALLINE FORM C OF FLUPHENAZINE
HYDROCHLORIDE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.
Field of Invention
The present invention relates to a novel crystalline form C of Fluphenazine hydrochloride. The present invention further relate to a processes of preparing novel crystalline form C of Fluphenazine hydrochloride.

FIELD OF THE INVENTION:
The present invention relates to novel crystalline form C of Fluphenazine hydrochloride. The present invention further relate to a processes of preparing novel crystalline form C of Fluphenazine hydrochloride.
BACKGROUND OF THE INVENTION:
Chemically Fluphenazine hydrochloride is 4-[3-[2-(Trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-l-piperazineethanol dihydrochloride and is known from U.S patent no. 3,058,979 and is represented by compound of structural formula I.

The proprietary name of Fluphenazine hydrochloride in USA is Prolixin and Permitil. Fluphenazine hydrochloride is an antipsychotic medication. It is used in the treatment of chronic psychoses such as schizophrenia and appears to be about equal in effectiveness to low-potency antipsychotics. It is given by mouth, injection into a muscle, or just under the skin. Fluphenazine is a typical antipsychotic of the phenothiazine class.
The marketed dosage form of Fluphenazine hydrochloride is Oral Tablets having 1 mg, 2.5 mg, 5 mg, and 10 mg strengths. Fluphenazine decanoate is marketed as injectable having 2.5 mg/ml, 5 mg/ml and 25 mg/ml.

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U.S. patent no. 3,058,979 discloses process for the isolation of Fluphenazine hydrochloride in an alcoholic hydrogen chloride solution. Trituration with ether separates crystals of dihydrochloride salt wherein melting point of Fluphenazine hydrochloride obtained is 224°C-226°C.
GB patent no. 833,474 discloses processes for the crystallization of Fluphenazine hydrochloride in anhydrous ethanol gives the pure salt which is hygroscopic. The product obtained from the crystallization in anhydrous ethanol wherein melting point of Fluphenazine hydrochloride obtained is 235°C-237°C.
Crystalline nature of Fluphenazine hydrochloride is described in Analytical Profiles of Drug substances, Volume 2, page no. 263-294, by Klaus Florey. X-ray powder diffraction pattern published in this literature are accompanied with 'd' spacing value. A. DeLeenheer and Heyndrickk, J. Ass. Office. Anal. Chem. 54, 625 and 633 (1971) reported characteristic 'd' spacing values of Fluphenazine hydrochloride at 17.20, 11.50, 8.40, 5.90, 5.50, 5.40, 4.70, 4.50, 4.20, and 4.10 A.
P. Rajeswaran and P. L. Kirk, Bull. Narcotics, 14, 19 (1962), C. A. 57, 7390 (1962) reported characteristic 'd' spacing values of Fluphenazine hydrochloride at 18.20, 9.07, 8.71, 6.07, 5.03, 4.85, 4.32, 4.02 and 3.75 A.
J. Q. Ochs and N. H. Coy, Squibb Institute, personal communication reported characteristic 'd' spacing values of Fluphenazine hydrochloride at 17.65, 9.80, 8.90, 8.70, 6.02, 5.56, 5.46, 5.36, 5.15 and 4.83 A.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric

analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.
Polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility.
The discovery of new crystalline or polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of pharmaceutical. product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. The novel crystalline form C of Fluphenazine hydrochloride have now been discovered.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel crystalline form C of Fluphenazine hydrochloride.
A second aspect of the present invention is to provide a process for the preparation of novel crystalline form C of Fluphenazine hydrochloride comprising the steps of:
a, providing crystallization of Fluphenazine hydrochloride in a solvent selected from the
group comprising of alcohol and ketone;
b. heating the reaction mixture and

c. isolating crystalline form C of Fluphenazine hydrochloride.
Another aspect of the present invention is to provide crystalline form C of Fluphenazine hydrochloride characterized by its X-ray powder diffraction pattern having characteristic 'd' spacing values at about 16.84, 8.46, 8.22, 5.78, 5.45, 4.73, 4.46, 4.24, 3.83, 3.55 A and '20' values at about 5.3, 10.5, 10.8, 15.7, 16.2, 18.7, 19.9, 21.0, 23.2 and 25.0 degree respectively.
DETAIL DESCRIPTION OF THE INVENTION:
A novel crystalline form C of Fluphenazine hydrochloride may be characterized by X-ray powder diffraction pattern as depicted in Figure 1.
A novel crystalline form C of Fluphenazine hydrochloride may be characterized by its X-ray powder diffraction pattern having characteristic 'd' spacing values at about 16.84, 8.46, 8.22, 5.78, 5.45, 4.73, 4.46, 4.24, 3.83, 3.55 A and '20' values at about 5.3, 10.5, 10.8, 15.7, 16.2, 18.7, 19.9, 21.0, 23.2 and 25.0 degree respectively.
A solution of Fluphenazine hydrochloride in a solvent selected from the group comprising of alcohol may be prepared by dissolving Fluphenazine hydrochloride in a solvent at a temperature in the range of 30°C to 85°C. Alternatively, such a solution may be obtained directly from a reaction in which Fluphenazine hydrochloride is formed.
The examples of alcohol solvents may include but not limited to methanol, propanol, isopropanol, butanol, isobutanol, t-butanol and pentanol.
The examples of ketone solvents may include but not limited to acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl amyl ketone (MAK), dimethyl ketone, 2-propanone and cyclohexanone.
The solution of Fluphenazine hydrochloride may be refluxed for a period of 30 minutes to 3 hours and excess organic solvent may be distilled out from the reaction mixture.

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The novel crystalline form C of Fluphenazine hydrochloride may be isolated by the steps of cooling, filtering of reaction mixture, washing, drying under controlled condition and the combination thereof.
DRIEF DESCRIPTION OF THE DRAWING:
Figure 1 depicts X-ray powder diffraction pattern of novel crystalline form C of Fluphenazine hydrochloride.
X-Ray Powder Diffraction Pattern (XRPD) of the product of Examples 1 to 3 were obtained on PANalytical, XPert PRO, Netherland diffractometer equipped with X-celerator detector using Copper Ka (λ= 1.5406 A) radiation with scanning range between 4.00-40°2θ at scanning speed of 1.26°/min.
EXAMLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way. Fluphenazine base used for example was prepared as per published prior art US 833,474.
Example: 1
A solution of Fluphenazine base (10gm) in Toluene (100ml) was stirred and added methanolic hydrogen chloride solution (15ml) at 25-30°C temperature. The resulting reaction mixture was heated at 60-64°C for 30 minutes. The reaction mixture was cooled to 20-55°C and stirred for one hour. The resulting solids were filtered, washed with Toluene (10ml), slurry in acetone. Solid was filtered and dried at 55°C under reduced pressure. Yield=10.1gm
Purity by HPLC= 99.97%

Example: 2
A solution of Fluphenazine hydrochloride crude (5gm) prepared as per example 1 in methanol (40ml) was heated at 60-65°C for 30 minutes. The methanol solvent (25ml) was distilled out from the reaction mixture and pH of resulting solution was adjusted below 2 with methanolic hydrogen chloride solution. The resulting solution cooled to 0-5°C and stirred for one hour. The resulting solids were filtered, washed with chilled methanol (5ml) and slurry in acetone. Solid was filtered and dried at 55°C under reduced pressure. Yield=4.5 gm
Purity by HPLC= 99.99%
XRD: As depicted in Figure 1
Example: 3
A solution of Fluphenazine hydrochloride crude (5gm) prepared as per example 1 in isopropanol (60ml) was heated at 60-65°C for 30 minutes. The isopropanol solvent (50ml) was distilled out from the reaction mixture and pH of resulting solution was adjusted below 2.0 with methanolic hydrogen chloride solution. The resulting solution cooled to 0-5°C and stirred for one hour. The resulting solids were filtered, washed with chilled isopropanol (5ml) and slurry in acetone. Solid was filtered and dried at 55°C under reduced pressure. Yield= 4.6 gm
Purity by HPLC= 99.98%
XRD: As depicted in Figure 1

WE CLAIM:
1. The novel crystalline form C of Fluphenazine hydrochloride characterized by its X-ray powder diffraction pattern having characteristic '2θ' values at about 5.3, 10.5, 10.8, 15.7, 16.2, 18.7, 19.9, 21.0, 23.2 and 25.0 degree as depicted in figure no.1.
2. A process for the preparation of novel crystalline form C of Fluphenazine hydrochloride comprising the steps of:
a. providing crystallization of Fluphenazine hydrochloride in a solvents selected from
the group comprising of alcohol and ketone;
b. heating the reaction mixture and
c. isolating novel crystalline form C of Fluphenazine hydrochloride.
3. The process according to claim nos. 2 wherein solution of Fluphenazine hydrochloride is refluxed for a period of 30 minutes to 3 hours and excess organic solvent is distilled out from the reaction mixture.
4. The process according to claim nos. 2 wherein alcohol solvent is selected from the group comprising of methanol, propanol, isopropanol, butanol, isobutanol, t-butanol or pentanol. The examples of aromatic hydrocarbons is selected from the group comprising of toluene, benzene, monochlorobenzene and xylene.
5. The process according to claim nos. 2 wherein ketone is selected from the group comprising of acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl amyl ketone (MAK), dimethyl ketone, 2-propanone and cyclohexanone.
6. A pharmaceutical composition comprising novel crystalline form C of Fluphenazine hydrochloride and a pharmaceutically acceptable carrier.

7. A method of treating insomnia comprising administering in human being a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of novel crystalline form C of Fluphenazine hydrochloride and a pharmaceutically acceptable carrier.