FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"NOVEL CRYSTALLINE FORM OF TEMAZEPAM"
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 THE INVENTION:
The present invention relates to novel crystalline form E of Temazepam. The present invention further relate to a processes of preparing novel crystalline form E of Temazepam and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Chemically Temazepam is 7-chloro-l,3-dihydro-3-hydroxy-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and is known from U.S patent no. 3,296,249 and is represented by compound of structural formula I.

TM
The proprietary name of Temazepam in USA is Restoril. Restoril (Temazepam) is indicated for the short-term treatment of insomnia (generally 7 to 10 days).
The marketed dosage form of Temazepam is Oral Capsules having 7.5 mg, 15 mg, 22.5 mg, and 30 mg strengths.
U.S patent no. 3,296,249 discloses process (example no. 15) for the crystallization of Temazepam in ethanol solvent wherein melting point of Temazepam obtained is 119°C-122°C. This crystalline form of Temazepam is referred herein after as form A.

U.S patent no. 3.340,253 discloses processes (example no. 32) for the crystallization of Temazepam in cyclohexane solvent and ether solvent. The product obtained from the crystallization in cyclohexane solvent is referred herein after as form B and the product obtained from the crystallization in ether solvent is referred herein after as form C.
Temazepam form B is having prism shape while Temazepam form C is having needle shape.
U.S. Patent No. 4,412,952 discloses (example no. 1) process for the crystallization of Temazepam in a mixture of water and ethanol solvent wherein melting point of Temazepam obtained is 158°C-160°C. This crystalline form of Temazepam is referred herein after as form D.
PCT publication no 2010/046929 disclose Temazepam crystalline forms I, II, III, IV, V, VI, VII, VIII, IX, X and amorphous form and processes of its preparation.
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.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, 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 solubilities.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a 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.
Accordingly there is provided a novel crystalline form of Temazepam.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel crystalline form of Temazepam herein after referred as Form E.
A second aspect of the present invention is to provide a process for the preparation of crystalline form E of Temazepam comprising the steps of:
a. providing a solution of Temazepam in an organic solvent selected from the group
comprising of alcohol, alky acetate or alkyl nitrile solvent;
b. heating the reaction mixture and
c. isolating crystalline form E of Temazepam.
Another aspect of the present invention is to provide a process for the preparation of crystalline form E of Temazepam comprising the steps of:
a. providing a solution of Temazepam in a solvent selected from the group comprising of
alcohol, alky acetate or alkyl nitrile solvent and
b. isolating crystalline form E of Temazepam.

Another aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form E of Temazepam and a pharmaceutically acceptable carrier.
Another aspect of the present invention is to provide crystalline form E of Temazepam characterized by its Powder X-ray diffraction pattern having peaks at 9.17, 9.54, 10.82, 11.91, 15.00, 15.83, 18.05, 19.19, 20.46, 21.78,23.08,23.51, 24.34, and 26.48 ± 0.2 degrees 20.
Another aspect of the present invention is to provide method of treating insomnia comprising administering in human being a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of crystalline form E of Temazepam and a pharmaceutically acceptable carrier.
DETAIL DESCRIPTION OF THE INVENTION:
A crystalline form E of Temazepam may be characterized by Powder X-ray diffraction pattern as depicted in Figure 1.
A crystalline form E of Temazepam may be characterized by DSC thermogram as depicted in Figure 2.
A crystalline form E of Temazepam may be characterized by its Powder X-ray diffraction pattern having peaks at 9.17, 9.54, 10.82, 11.91, 15.00, 15.83, 18.05, 19.19,20.46,21.78,23.08,23.51, 24.34, and 26.48 ± 0.2 degrees 28.
A crystalline form E of Temazepam may be characterized by its differential scanning calorimetry showing endothermic peak at 161.57°C.
A solution of Temazepam in a solvent selected from the group comprising of alcohol, alkyl acetate or alkyl nitrile may be prepared by dissolving Temazepam in a solvent at a temperature in

the range of 30°C to 80°C.AIternatively, such a solution may be obtained directly from a reaction in which Temazepam is formed.
The examples of alcohol solvents may include but not limited to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol orpentanol.
The examples of alkyl acetate solvents may include but not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate or pentyl acetate.
The examples of nitrile solvents may include but not limited to acetonitrile or propionitrile.
The solution of Temazepam may be refluxed for a period of 30 minutes to 3 hours and excess
organic solvent may be distilled out from the reaction mixture.
The crystalline form E of Temazepam may be isolated by the steps of cooling, filtering of reaction mixture, washing, drying and the combination thereof.
The crystalline form E of Temazepam may be washed with chilled organic solvent selected from the group of alcohols, alky acetates or alkyl nitrile solvent.
The crystalline form E of Temazepam may be dried under reduced pressure at a temperature in the range of 40°C to 60°C.
DRIEF DESCRIPTION OF THE DRAWING:
Figure 1 depicts Powder X-ray diffraction pattern of crystalline form E of Temazepam. Figure 2 depicts DSC thermogram of crystalline form E of Temazepam
X-Ray Powder Diffraction (XRPD) pattern of the product of Examples 1 to 4 were obtained on PANalytical, X'Pert PRO, Netherland diffractometer equipped with X-celerator detector using Copper Kal (λ= 1.5406 A) radiation with scanning range between 4-4O°20 at scanning speed of 1.26°/min.

Differential Scanning Calorimetry (DSC) thermogram of the product of examples 1 to 4 were obtained on Mettler Toledo DSC 823e Switzerland calorimeter equipped with STARe software using endothermic measurement range from 40° to 250°C at rise 10°C/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.
Example: 1
A solution of Temazepam (lOgm) in methanol (100ml) was heated at 60-64°C for 30 minutes. The methanol solvent (45 ml) was distilled out from the reaction mixture and resulting solution was cooled to 0-5oC and stirred for one hour.The resulting solids were filtered, washed with chilled methanol (10ml) and dried at 55°C under reduced pressure. Yield-9.1 gm
XRD: As depicted in Figure 1 DSC: As depicted in Figure 2
Example: 2
A solution of Temazepam (lOgm) in isopropanol (110ml) wa$ heated at 80-82°C for 30 minutes. The isopropanol solvent (60ml) was distilled out from the reaction mixture and resulting solution was cooled to 0-5°C and stirred for one hour. The resulting solids were filtered, washed with chilled isopropanol (10ml) and dried at 55°C under reduced pressure. Yield- 9.4 gm
XRD: As depicted in Figure 1 DSC: As depicted in Figure 2
Example: 3

A solution of Temazepam (lOgm) in ethyl acetate (70ml) was heated at 75-80°C for 30 minutes. The ethyl acetate solvent (30ml) was distilled out from the reaction mixture and resulting solution was cooled to 0-5°C and stirred for one hour. The resulting solids were filtered, washed with chilled ethyl acetate (5ml) and dried at 55°C under reduced pressure. Yield- 9.2 gm
XRD: As depicted in Figure 1 DSC: As depicted in Figure 2
Example: 4
A solution of Temazepam (lOgm) in acetonitrilre (30ml) was heated at 75-80°C for 30 minutes. Resulting solution was cooled to 0-5°C and stirred for one hour. The resulting solids were filtered, washed with chilled acetonitrilre (5ml) and dried at 55°C under reduced pressure. Yield=8.2 gm XRD: As depicted in Figure 1
DSC: As depicted in Figure 2

WE CLAIM:
1. A crystalline form E of Temazepam characterized by its Powder X-ray diffraction pattern as depicted in figure no.l.
2. A crystalline form E of Temazepam characterized by its differential scanning calorimetry showing endothermic peak at 161.57°C.
3. A process for the preparation of crystalline form E of Temazepam comprising the steps of:
a. providing a solution of Temazepam in an organic solvent selected from the group
comprising of alcohol, alkyl acetate or alkyl nitrile solvent;
b. heating the reaction mixture and
c. isolating crystalline form E of Temazepam.
4. A process for the preparation of crystalline form E of Temazepam comprising the steps
of:
a. providing a solution of Temazepam in a solvent selected from the group comprising
of alcohol, alkyl acetate or alkyl nitrile solvent and
b. isolating crystalline form E of Temazepam.
5. The process according to claim nos. 3 and 4 wherein alcohol solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol orpentanol.
6. The process according to claim nos. 3 and 4 wherein alkyl acetate solvent is selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate or pentyl acetate.

7. The process according to claim nos. 3 and 4 wherein alkyl nitrile solvent is selected from the group comprising of acetonitrile or propionitrile.
8. The crystalline form E of Temazepam characterized by its Powder X-ray diffraction pattern having peaks at 9.17, 9.54, 10.82, 11.91, 15.00, 15.83, 18.05, 19.19,20.46,21.78, 23.08,23.51, 24.34, and 26.48 ± 0.2 degrees 29.
9. A pharmaceutical composition comprising crystalline form E of Temazepam and a
pharmaceutics 11 y acceptable carrier.
10. A method of treating insomnia comprising administering in human being a
pharmaceutical composition comprising a therapeutically or prophylactically effective
amount of crystalline form E of Temazepam and a phannaceutically acceptable carrier.