Synthesis and characterization of impurities of an anticonvulsant drug, Pregabalin

Somaiah Sripathi; Narender Rao Somesetti; Raju Veeramalla; Nageswar Rao Challa; Srinivasa Rao Peddi; Venugopal Reddy Karnati

doi:10.3998/ark.5550190.0011.a22

PDF
Print
Share+
- Twitter
- Facebook
- Reddit
- Mendeley

Synthesis and characterization of impurities of an anticonvulsant drug, Pregabalin

Somaiah Sripathi; Narender Rao Somesetti; Raju Veeramalla; Nageswar Rao Challa; Srinivasa Rao Peddi; Venugopal Reddy Karnati

Volume 2010, Issue 10, pp. 266-275

DOI: http://dx.doi.org/10.3998/ark.5550190.0011.a22

Paper ID: 10-5093CP

Received on 2010-02-12; Accepted on 2010-08-12; Published on 2010-08-20

Permissions: This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 License. Please contact [email protected] to use this work in a way not covered by the license.

For more information, read Michigan Publishing's access and usage policy.

- 150% +

image text pdf

General Papers ARKIVOC 2010 (x) 266-275 Synthesis and characterization of impurities of an anticonvulsant drug, Pregabalin Somaiah Sripathi,a Narender Rao Somesetti,a Raju Veeramalla,a Nageswar Rao Challa,a Srinivasa Rao Peddi,a and Venugopal Reddy Karnati*b aDepartment of Research and Development, Srini Pharmaceuticals Ltd., Plot No. 10, Type-C, Road No. 8, Film Nagar, Jubilee Hills, Hyderabad-500033, Andhra Pradesh, India bDepartment of Chemistry, Osmania University, Tarnaka, Hyderabad- 500007, Andhra Pradesh, India E-mail: [email protected], [email protected] Abstract During the process development of Pregabalin 1, a known anticonvulsant drug, six potential impurities were identified in the final crude material ranging from 0.01 to 0.15% by LCMS. All six impurities were subsequently synthesized and characterized by IR, MS and NMR spectral data. Four of the six related substances are known as 4-isobutylpyrrolidin-2-one 6, 3isobutylglutaric acid 2, (R)-(-)-3-carbamoylmethyl-5-methylhexanoic acid 5 and (R)-(-)-3aminomethyl- 5-methylhexanoic acid 8, whilst (S)-3-aminomethyl-5-methylhexanoic acid isobutyl ester 9 and (S)-3-aminomethyl-5-methylhexanoic acid isopropyl ester 10 are new compounds reported for the first time in our process. The present work describes the formation, synthesis and characterization of these impurities. Keywords: Pregabalin, anticonvulsant, impurities, synthesis, characterization Introduction Pregabalin 1 ((S)-(+)-3-aminomethyl-5-methylhexanoic acid) is a novel and potent anticonvulsant agent for the treatment of epilepsy and pain.1 It has also been found to be more active than Gabapentin in preclinical models of epilepsy.2 It has more potent and robust activity in various models of epilepsy, neuropathic pain and anxiety.3 The presence of impurities in an active pharmaceutical ingredient (API) can have a significant impact on the quality and safety of the drug products. Therefore, it is necessary to study the impurity profile of the API to be used in the manufacturing of drug substance. International Conference on Harmonization (ICH) guidelines recommended identifying and characterizing all impurities that are present at a level of 0.10% or more.4,5 As Pregabalin 1 is an ISSN 1551-7012 Page 266 ©ARKAT USA, Inc.