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ABSTRACT:
Synthesis of two novel impurities in the manufacturing process of Paroxetine.HCl. ½H^sub 2^O is described. They were characterized by spectroscopic techniques like ^sup 1^HNMR, ^sub 13^CNMR and MS. Synthesis and reaction mechanism is also explained in details.
KEYWORDS: Impurity synthesis and characterization, QbD, Environmental protection
INTRODUCTION:
Paroxetine hydrochloride,trans(-)-3-[(1,3-benzodioxol-5- yloxy)methyl]-4-(4-fluorophenyl) piperidine, is an antidepressant[1] developed by Smithkline beecham and also used in treatment of Obsessive compulsive disorder under brand name Paxil®. Synthesis and characterization of impurities in drug substance is a current topic of interest as per ICH guidelines [3]. Impurity limits in final API are getting stringent and regulatory authorities are focusing in depth towards control of process related impurities. Quality of drug substance /API need to be ensured by following QbD principles par se [4]. Information related to characterization of impurities is an integral part of DMF filling process in highly regulated markets of US, Europe and Japan.
The prediction of formation of impurities in a particular process needs an in depth knowledge and understanding of manufacturing process of intermediates and drug substance and sound scientific principles involved based on reaction mechanisms of organic chemistry. Such a proactive approach would be an added advantage towards building QbD in the process and would assure quality of drug substance consistently during commercial manufacturing. It has been stated that quality of product is not ensured by mere in process controls/ testing, but needs to be inbuilt in the process[5].The aim of the presnt study was to synthesis and characterize two novel impurities in the process of Paroxetine as it is necessary to identify impurities above 0.1%.[6, 9]
RESULTS AND DISCUSSION:
Synthesis of Paroxetine hydrochloride hemihydrates[7] involves multi step organic transformations [Scheme 1].Typical sequence may begin with resolution of racemic intermediate 4-(4-fluorophenyl)-3-hydroxymethyl-Nmethyl- piperidine "carbinol" to get chirallly pure (-) carbinol, Stage-I: (-) carbinol is converted into "in situ mesylate" [2] or tosylate and then condensed with 3,4- methylenedioxyphenol "sesamol" in presence of strong alkali to get an advanced intermediate N-Methyl Paroxetine( NMP). Stage-II: NMP on further demethylation using carbamate chemistry generates free base of Paroxetine and treatment with HCl finally gives Paroxetine Hydrochloride API.
Synthesis of ether type impurity:[Scheme 2] Condensation of sesamol with mesylate intermediate generates (-) carbinol due to hydrolysis of mesylate functional...