Active pharmaceutical ingredients crystallization process

CASE STUDY DEVELOPMENT OF AN ACTIVE PHARMACEUTICAL INGREDIENT CRYSTALLIZATION PROCESS D... 

This chapter provides an introduction to the pharmaceutical sector, and the business of developing new active pharmaceutical ingredients (API). Crystallization is the preferred method of isolating commercial API products because it offers a highly efficient means of purification. The crystallization process is also where the physical properties of the drug substance are defined. These properties can have a significant impact on the formulated product and process, and eventually on the drug release profile in the patient. 

The design of crystallization processes for the manufacture of Active Pharmaceutical Ingredients is a significant technical challenge to Process Research and Development groups throughout the Pharmaceutical and related industries. It requires an understanding of both the thermodynamic and kinetic aspects of crystallization, to ensure that the physical properties of the product will consistently meet specification. Failure to address these issues may lead to production problems associated with crystal size, shape and solubility, and to dissolution and bioavailability effects in the formulated product. 

V. Liotta and V. Sabesan, Monitoring and feedback control of supersaturation using ATR-ETIR to produce an active pharmaceutical ingredient of a desired crystal size, Org. Process Res. Dev., 8, 488-494 (2004). 

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

Final product isolation in a form suitable for further processing into the final dose form of the pharmaceutical, e.g., as a tablet or an injectable solution. Secondary production of this type is sometimes done in a separate facility, with the raw material referred to as the bulk product or, more recently, the active pharmaceutical ingredient. Examples of unit operations at this stage of processing include lyophilization, precipitation, or crystallization followed by solid isolation using filtration and drying techniques. In some cases, the final product must be produced in a sterile form, which introduces additional complications when selecting suitable process equipment. 

Crystallization plays an important role in the synthesis, scale-up, processing, formulation, and stability of active pharmaceutical ingredients (API) (Rodriguez-Hornedo and Murphy, 1999 Shekunov and York, 2000 Rodriguez-Hornedo and Sinclair, 2002). Crystallization from solvent is a particularly important process, as this is the primary means of purihcation during the intermediate and hnal stages of drug synthesis. Moreover, solution crystallization determines the hnal solid-state modihcation of the API namely polymorphs, solvates, and hydrates. 

Crystallization Processes for Active Pharmaceutical Ingredients —From Art to Science... 

During the early 1990s, crystallizations were considered more of an art than a science. During that time, process chemists would design a process that delivered an active pharmaceutical ingredient (API) with a certain particle size, and formulation chemists would use it to design a tablet or a capsule suitable for clinical trials or the marketplace. Since then, several events have changed that business model ... 

Bench chemists developed a preliminary process for the production and purification by crystallization of an active pharmaceutical ingredient (API) as follows ... 

Chatterji, A. Desai, D. Miller, D.A. Sandhu, H.K. Shah, N.H. A Process for Controlled Crystallization of an Active Pharmaceutical Ingredient from Supercooled Liquid State by Hot Melt Extrusion World InteUeetnal Property Organization, W02012110469. 2012. 

Besides distillation, absorption and extraction, crystallization processes are often applied in separation sequences. This is particularly the case if the components have a very low vapor pressure (e.g., salts, active pharmaceutical ingredients (APIs)) or decompose at higher temperature. Furthermore, crystallization has advantages compared to distillation if the separation factor shows values near unity and cannot be influenced by an entrainer as in the case of isomers, for example, m-xylene/p-xylene. 

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