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QUALITY | ISO 9001 | ISO/IEC 17025 ISO 17034 | GMP
Paroxetine impurities:An overview
Acetylation of 2,6-Dimethylaniline during the synthesis of Lidocaine. (Impurity N-(2,6-Dimethylphenyl) acetamide, MM0102.08)
API of the Month: Paroxetine
Paroxetine Impurities – An overview
Paroxetine Hydrochloride Hemihydrate Paroxetine Hydrochloride Anhydrous (MM0264.00) (MM1032.00)
Introduction: Paroxetine, also known as Seroxat or Paxil, is a drug used to treat depression, anxiety, and other mood disorders. The substance acts as selective serotonin reuptake inhibitor (SSRI)1. It belongs to a class of drugs which increases the extracellular level of the neurotransmitter serotonin in the synaptic cleft by limiting of serotonin-reuptake in the presynaptic cell2. Paroxetine has in comparison to the conventional tricyclic antidepressants significantly fewer cardiovascular side effects. Paroxetine is a basic compound, which is commonly used as salt3, the most relevant forms being Paroxetine hydrochloride, Paroxetine hydrochloride hemihydrate, and the corresponding maleate, mesylate, sulfonate salts.
Scheme 1: Synthesis route of Paroxetine
1 Mylan Institutional Inc. (January 2012). "PAROXETINE (paroxetine hydrochloride hemihydrate) tablet, film coated". DailyMed. U.S. National Library of Medicine. Retrieved 5 September 2018. 2 Preskorn SH, Ross R, Stanga CY (2004). "Selective Serotonin Reuptake Inhibitors". In Sheldon H. Preskorn, Hohn P. Feighner, Christina Y. Stanga, Ruth Ross. Antidepressants: Past, Present and Future. Berlin: Springer. pp. 241–62 3 Anti-depressant crystalline paroxetine hydrochloride hemihydrate, Beecham Group p.l.c. - US4721723, 1988, A
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API of the Month: Paroxetine
A representative synthesis route is shown in the scheme4 on page 2.
Starting materials are Arecoline [1] (see scheme 1) and 1-Bromo-4-fluorobenzene [2] which are coupled to form the API’s racemic core structure [4]. Interestingly many impurities seem to stem from substitution of the fluorine. It is reported that the presence of metal alkoxides leads to defluorination and the formation of impurities MM0264.05 and MM0264.04.5 In a similar vein impurities MM1032.10 and MM1032.15 stem from reactions in which access amounts of magnesium Grignard reagent [3] reacts with the already formed core structure [4]. The synthesis is racemic until intermediate [5] for which enantiomeric resolution is realized by esterification with menthol. Hence all possible diastereomers and degradation compounds resulting thereof are relevant impurities for Paroxetine. Desfluoro paroxetine MM0264.03 is likely formed during the reduction with LiAlH4.
In contrast to synthesis related impurities formed in side reactions, also referred to as process impurities, degradation products may further be formed in drug products and may enrich. Most relevant degradation products of paroxetine are given in scheme 2.
4 Kleemann et al. Pharmaceutical Substances Online Database 4.4, 2018 5 Niddam et al., Process for the Preparation of Paroxetine substantially free of alkoxy impurities, 15 Sept, 2005; US2005/0203140A1
Scheme 2: Impurities derived from degradation
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API of the Month: Paroxetine
Stress conditions which need to be taken into account for validations are given in ICH Q3B(R2) and comprise ‘light, heat, humidity, acid/base hydrolysis and oxidation’6. Degradation studies for Paroxetine7 show lability to acids and alkalis, while the API seems to be relatively stable under humidity, light and oxidative conditions.
Acid hydrolysis leads to ether cleavage with formation of impurities MM1032.02, MM1032.08/09/12/20 and MM1032.16/17. These resulting impurities can degrade further by elimination of the methoxy group, yielding impurities MM0264.02 and MM1032.07. The dimeric impurity MM0264.08 is formerly derived from addition of a formaldehyde equivalent. However, it remains unclear where this may come from. Hypothetically, the dimer could be the result of a radical reaction with e.g. methanol.
Authors: Irina Erlin, Moritz Perscheid, Thomas Tautz
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ICH (2006) ‚ Impurities in New Drug Products Q3B(R2), 4th version, 02 June, 2006 Geetharam et al. Int J Pharm 2014; 4(1):448-457
The complete range of pharmaceutical impurity reference standards from Mikromol is listed at lgcstandards.com/mikromol
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