|Title of Invention||A NOVEL RECRYSTALLIZATION PROCESS FOR THE PREPARATION OF FORM-V OF SERTRALINE HYDROCHLORIDE|
|Abstract||The present invention provides a novel recrystallization process for the preparation of Form V of Sertraline Hydrochloride of formula 1. The present invention is also directed to a cost effective process for preparation of Sertraline hydrochloride Form-V by a commercially viable and industrially scaleable process.|
|Full Text||The present invention relates to novel method for preparing known pbiymorophic Form-V of
Sertraline Hydrochloride, which is chemically identified as cis-(lS)-N-methyl-4-(3,4-
dichlorophenyl)-! ,2,3,4-tetrahydro-l-naphthalenamine hydrochloride.
More specifically, the present invention relates to novel process for preparation of Form V of
The drug is represented by the formula:
Sertraline hydrochloride is useful as an anti-depressant and anorectic agent and is also useful in the treatment of chemical dependencies, anxiety related disorders and premature ejaculation.
The method of preparation of cis-(lS)-N"methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride was first described and claimed in US Pat No. 4,536,518. Sertraline hydrochloride exists in a number of polymorphic forms. The polymorphic forms of Sertraline hydrochloride viz., Form I to Form V and their methods of preparation are disclosed in US Pat No. 5,248,699. The claimed Form I is described as thermodynamically more stable polymorph at room temperature and hence useful active ingredient for a commercial pharmaceutical product.
The basic patent, US 4,536,518 does not refer to any specific polymorphic crystalline form of Sertraline hydrochloride.
us Pat No. 5^48,699 discloses the method of preparation of Form V stating that "The form V may be prepared by the sublunation of Sertraline hydrochloride at a reduced pressure at a temperature of about 180^C to about 190*^C (Column 10, lines 56-58). The exact experimental details for preparation of Sertraline hydrochloride polymorphs (except for Form-I) or elaborate description are not reported in US Pat 5^48,699. As a result' reproducibility of polymorphs without detailed information becomes extremely difficult. Also, sublimation of Sertraline hydrochloride to obtain Form V under reduced pressure and high temperature renders the process hazardous and industrially less viable.
Since Sertraline hydrochloride is useful as an anti-depressant and anorectic agent and is also useful in the treatment of chemical dependencies, anxiety related disorders and premature ejaculation the objective of present invention is to provide a novel, simple and cost effective process for preparation of Sertraline hydrochloride Form-V by a commercially viable and industrially scaleable process. The objective of the present invention is also to provide a detailed process for the same.
The present invention is hence directed to an improved reciystallization process for the preparation of Form V of Sertraline hydrochloride, which comprises dissolution of Sertraline hydrochloride in an alcohol (Ci-Cs) such as methanol, ethanol or propanol or mixture thereof, preferably methanol at reflux temperature, accompanied by rapid cooling of clear solution to -10 to lO°Cand. stirring at same temperature for a period of 3 -6 hours. The separated solid on filtration and drying renders Form V of Sertraline hydrochloride.
It is noteworthy to mention that Sertraline hydrochloride is prepard according to the procedure disclosed in US Pat. 4,536,518, for our studies.
As referred earlier, the exact experimental details for preparation of Form V of Sertraline hydrochloride is not reported in US Pat. 5,248,699. The present invention is hence directed to a novel, simple, detailed and commercially viable recrystallization technique for the / preparation of Form V of Sertraline hydrochloride which is different from prior art processes. The present invention does not involve reduced pressure and high temperatures, as suggested in prior art wherein the process is hazardous and industrially less viable. Our copending application number 765/MAS/2000 is also directed to a novel, robust, detailed and commercially viable method for the preparation of Form II of Sertraline hydrochloride, for which, again, the exact experimental details are not flimished in US Pat. 5,248,699.
Brief Description of Accompanying Drawings:
Fig. 1 is X-ray Powder Diffraction pattem of Sertraline hydrochloride Form V obtained
recrystallisation from methanol. The significant 2 theta values are 5.22, 10.46, 10.98, 14.24,
16.24, 17.20, 20.84, 25.30, 25.98 and 29.10 and are in accordance with 2 theta values for
Form V specified as 5.2, 10.4, 10.9, 14.2, 16.3, 17.2, 20.1, 25,3, 25.9, 29.1 in US Pat No.
Fig 2 is the infrared spectrum of Sertraline hydrochloride Form V obtained by
recrystallisation from methanol.
The present invention is described in detail in the examples, which are provided by way of
illustration and does not limit the scope of the invention.
Example-1 Preparation of Form-V
A solution of Sertraline hydrochloride (prepared as per procedure disclosed in US Pat. 4,536,518; 5.0 g) in methanol (30.0 ml) is heated to reflux. Upon completion of this step, the resultant clear solution is rapidly cooled to 0 to -6°C. The separated solid stirred at -9 to - / 5°C for 3 14 hours. Subsequent filtration of the separated solid accompanied by drying renders desired Form V of Sertraline hydrochloride. (Yield : 4.0 g ,76%).
The aforementioned polymorph described herein is characterized by Powder X-Ray Diffraction Patterns set using Rigaku D / Max -2200 X-Ray Powder Diffractometer having copper Ka radiation source of wave length A, = 1.54 A° . The samples were scanned between 3-45 degrees 20. The polymorph is also examined by infrared spectra.
The present invention hence provides a novel method for preparation of Form Vof Sertraline
> hydrochloride, which does not involve sublimation of Sertraline hydrochloride under
pressure and at elevated temperatures as disclosed in US 5,248,699. Instead it provides a simple recrystallisation technique, which is commercially viable in terms of industrial scale-up and is more cost effective. The recovery of methanol used also renders the process environment friendly.
1. A novel recrystallization process for the preparation of Form V of Sertraline
Hydrochloride, by recrystallization of Sertraline hydrochloride (crude or polymorphic
forms other than Form V) in alcohol or mixture thereof, by a process which
a. suspending Sertraline hydrochloride (crude or polymorphic forms other
than Form V) in alcohol containing C1 C3 carbon atoms selected from
methanol, ethanol or propanol or mixture thereof and heating to reflux for
b. rapidly cooling the clear solution to -10 to lO°C;.
c. stirring the separated solid at -10 to 10°C for 3 to 6 hours;
d. isolating the desired Form V of Sertraline hydrochloride by conventional
2. A process as claimed in claim 1 for preparation of Form V of Sertraline
hydrochloride, substantially as herein exemplified.
Dated this 18 day of July 2001.
Dr. R. B.Reddy,
Director R& D
For Dr. Reddy's Laboratories
Dr. R. B.Reddy,
Director R& D
For Dr. Reddy's Laboratories
|Indian Patent Application Number||768/MAS/2000|
|PG Journal Number||02/2006|
|Date of Filing||15-Sep-2000|
|Name of Patentee||DR. REDDY'S LABORATORIES LIMITED|
|Applicant Address||7-1-27, AMEERPET HYDERABAD, A.P., 500 016|
|PCT International Classification Number||C07C87/46|
|PCT International Application Number||N/A|
|PCT International Filing date|