Crystallization-Based Integrated Process for the Resolution of a Pharmaceutically Relevant Intermediate

Monday, October 17, 2011: 3:40 PM
Marquette V (Hilton Minneapolis)
Jan von Langermann1, Heike Lorenz1, Malte Kaspereit1, Martin Hedberg2, Matthew J. Jones2, Björn Herschend3, Kerstin Larson3, Mozzafar Shakeri4, Jan-Erling Bäckvall4, Achim Kienle1 and Andreas Seidel-Morgenstern1, (1)Max Planck Institute for dynamics of complex technical systems, Magdeburg, Germany, (2)Pharmaceutical Development, Process Engineering, AstraZeneca AB, Södertälje, Sweden, (3)AstraZeneca AB, Södertälje, Sweden, (4)Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden

2,6-Pipecoloxilidide (PPX) is an important intermediate for the synthesis of mepivacaine, ropivacaine and bupivacaine, which are frequently used local anesthetics of the amide type for several purposes in medicine[1]. Based on its chiral nature, an enantioseparation of PPX is needed to exclude additional negative side effects from the counter-enantiomer. By combining three different techniques, chromatography, enantioselective crystallization and racemization, an improved process with a higher yield was achieved in comparison to the use of a single full-separation process. All 3 unit operations were executed within a jointly used solvent system with full recycling (counter-enantiomer of PPX and solvents) including a minimum requirement of solvent exchanges / removals. The target molecule was obtained with an enantiopurity of >99.5% in multi-gram scale.

Within this contribution the design of the integrated process is presented with a focus on the final enantioselective crystallization process. The relevant physical chemical properties of PPX are presented, e.g. binary and ternary phase diagrams, polymorphism study, and finally the successful design of an effective crystallization processes on industrial scale.

 [1]      Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances -Synthesis, Patents and Applications of the most relevant APIs, 5th ed.; Georg Thieme Verlag KG: Stuttgart, New York, 2009.

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See more of this Session: Crystallization Process Development II - Case Studies
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