N-formyl derivatives of paroxetine

Details N-formyl derivatives of paroxetine N-formyl derivatives of paroxetine

2002-10-21

2004-03-09

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S197000

Reexamination Certificate

active

06703408

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to N-formyl paroxetine compounds, to compositions containing the same and to uses thereof as an intermediate, as a reference marker or standard, and/or as a pharmaceutical active ingredient.
U.S. Pat. No. 4,007,196 describes 4-phenyl-piperidine derivatives including a compound that is now known as paroxetine. Paroxetine is a selective serotonin re-uptake inhibitor used to treat, inter alia, depression, obsessive-compulsive disorder, and panic disorder and has the following formula:
U.S. Pat. No. 4,721,723 and EP 223403 describe crystalline paroxetine hydrochloride hemihydrate. This particular form of paroxetine is the active ingredient in a commercial pharmaceutical tablet sold/made by SmithKline Beecham under such brand names as PAXIL® and SEROXAT™.
Pharmaceutical products are regulated in most countries by a government agency. For example, the U.S. Food & Drug Administration (FDA) generally requires an applicant to show safety and efficacy of the pharmaceutical product during the approval/review phase and requires monitoring of the safety of the drug post-approval. Similar requirements exist in many European countries and elsewhere in the world. In order to satisfy safety concerns, the regulatory agencies generally require a manufacturing specification that sets the maximum amount of each identified impurity as well as the maximum amount for all remaining unidentified impurities. Once approved, each batch or lot of the pharmaceutical product is tested to insure that the specification is met. Further, stability testing is performed on the pharmaceutical product in order to show that the composition does not substantially or materially change over time; i.e. over its indicated shelf-life. Good practice warrants keeping a sample from each batch which has been released to the public so that the stability of the product can be monitored over time and any defect uncovered and corrective action can be taken as appropriate.
Accordingly, pharmaceuticals are tested for purity both during manufacture and subsequently during its shelf-life. Typically, the product is tested by comparing certain analytical results with those of a standard reference result. For impurity detection, this normally means assaying the pharmaceutical product and comparing the result to the result obtained for a substantially pure form of the suspected impurity in the same assay. Sources of potential impurities in a pharmaceutically active agent or formulation include:
residual amounts of synthetic precursors
side product arisen from the synthesis and elaboration of the active substance
residual solvents
degradation products appearing during storage including products resulted from interactions with excipients in formulations
isomers of the active agent
trace contaminants e.g. from equipment and environment.
In terms of synthesis, paroxetine is most commonly described as being produced from either a carbamate derivative of formula (B), wherein R can be inter alia a phenyl group, or a methylenephenyl derivative of formula (C). Specifically, in the last step, using conditions that often employ high temperatures or expensive catalysts, a hydrolysis of the carbamate derivative or hydrogenolysis of the methylenephenyl derivative is performed to produce paroxetine.
Thus, these compounds would be suspected as possible impurities in the paroxetine product produced according to these methods.
Several impurities for paroxetine hydrochloride were specifically identified in the published draft Monograph in Pharmeuropa Vol. 10, No. 2, June 1998, including desfluoroparoxetine, p-methoxyparoxetine, methylene bridged paroxetine dimmer, and N-methyl-4-(p-fluorophenyl)-tetrahydropyridine. This list is not exhaustive as other impurities, both identified therein and unidentified may exist within the tablet. Without identification of the potential impurity and a synthetic route to make a reference standard therefor, it is difficult or impossible to efficiently assay for a particular impurity or to otherwise monitor its level in the pharmaceutical product. Hence the need for a specification limit on the amount of unidentified impurities.
SUMMARY OF THE INVENTION
The present invention relates to the discovery/identification of a new compound, namely N-formyl paroxetine compounds, and to various uses thereof including the use of the compound in a new synthetic route for obtaining paroxetine and salts thereof. Accordingly, a first aspect of the present invention relates to a compound or composition comprising an N-formyl paroxetine of formula (1)
and 0 to 99.97% of a paroxetine compound, based on the combined weight of the N-formyl paroxetine and the paroxetine compound, if any. The N-formyl paroxetine compound can be an isolated, substantially pure single substance or part of a multi-component composition. The only limitation is that when a composition contains a paroxetine compound, then the amount of paroxetine is not greater than 99.97% based on the combined weight of both the paroxetine and the N-formyl paroxetine; i.e., at least 0.03% N-formyl paroxetine compound. Other than this proviso, the amount of N-formyl paroxetine is not limited. One specific compositional form relates to a pharmaceutical composition comprising an effective amount of the N-formyl paroxetine compound of formula (1) and optionally a paroxetine compound for treating a selective serotonin reuptake inhibitor-treatable disease or condition along with at least one pharmaceutically acceptable excipient.
A second aspect of the present invention relates to a process which comprises treating an N-formyl paroxetine compound of formula (1) with a de-formylation agent. The de-formylation agent can be acidic or basic and is preferably a pharmaceutically acceptable acid. In preferred embodiments, the treatment with the de-formylation agent directly produces a paroxetine salt such as a pharmaceutically acceptable salt. In some embodiments, this step completes a synthesis of paroxetine or a salt thereof. In these embodiments, the synthesis preferably uses a novel intermediate of formula (2) as is more fully described hereinafter.
A third aspect of the present invention relates to a process for determining the stability or purity of a paroxetine substance or composition, which comprises assaying a paroxetine substance or composition for the presence of an N-formyl paroxetine of formula (1). The process can use TLC or HPLC and can be used for determining initial purity for product release or for stability testing.
In all aspects of the present invention, the N-formyl paroxetine compound is preferably the trans 3S, 4R enantiomer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the discovery and identification of an impurity that can be associated with paroxetine, especially paroxetine pharmaceutical compositions as well as to the discovery of various uses thereof including as an intermediate in the synthesis of a paroxetine compound. In particular, an N-formyl paroxetine compound of formula (1)
was isolated and identified as an impurity in a paroxetine mesylate pharmaceutical composition. The same impurity has also been found by the present inventors in commercially available paroxetine hydrochloride tablets from various European countries, albeit in small amounts that never exceed 0.02%. This is surprising in that N-formyl paroxetine is not a known intermediate in the synthesis of paroxetine nor is it otherwise a suggested or known potential impurity associated with paroxetine. Further, in some cases, storage of the paroxetine composition under accelerated conditions causes an increase in the amount of the N-formyl paroxetine compound.
Without wishing to be bound, it is theorized that the N-formyl paroxetine compound of formula (1) is formed by an interaction of paroxetine with excipients, particularly with calcium phosphate. In a model experiment, 5 g of paroxetine free base was mixed with 6.2 g CaHPO
4
and stored at approx. 80° C. for several days. The mixture was then stirred with 50 ml

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