Active pharmaceutical ingredient crystallization

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

In Structural analysis of active pharmaceutical ingredients, crystal polymorphism is an important subject of study. Crystal structures are determined by X-ray diffraction studies. Once the correlation between crystal polymorphs and their infrared spectra has been established, it can then become a relatively easy task to distinguish polymorphs by measuring their microphotographs and corresponding microscopic infrared spectra, as infrared microspectrometric measurements can be conveniently performed within a much shorter time than X-diffraction analysis. 

The Role of Solubility Modeling and Crystallization in the Design of Active Pharmaceutical Ingredients... 

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)-... 

R. Banerjee, P.M. Bhatt, N.V. Ravindra, G.R. Desiraju, Saccharin salts of active pharmaceutical ingredients, their crystal structures, and increased water solubilities, Cryst. Growth Des. 5 (2005) 2299-2309. 

The topic of polymorphism is of tremendous and increasing academic and industrial importance in modern crystal chemistry and crystal engineering. The industrial interest stems from the pharmaceutical industry and has stimulated wide-ranging academic study. Legally, a molecule (termed an active pharmaceutical Ingredient, API) with particular biological activity in vivo can be patented as a new invention. Moreover, particular crystal forms of that molecule (polymorphs) can be separately patented as distinct inventions. If particular polymorphs are patented after the original API patent then upon the... 

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. 

Drug substance-. The drug substance (DS), also known as a new chemical entity (NCE) or the active pharmaceutical ingredient (API), in early phases of drug development consists of the following components (a) active moiety, (b) counter-ion, and (c) water or solvent molecules that are known components of the DS crystal structure. If the single crystal structure of the DS is unavailable, the DS can be defined as a hydrate or solvate based on the results of other analytical tests and the scientific judgment of the scientist. 

In cases where drug formulations containing more than one polymorph are marketed it is required that the composition is fixed in relation to each polymorphic form. The issue is complicated by the conversions between polymorphs in the solid state. It is clear that the conversion of a crystal structure in a more stable polymorph has to be inhibited, to preserve the composition of the drug formulation. In terms of morphological stability, the production of the more stable polymorph of an active pharmaceutical ingredient is the more convenient option however, other issues may play critical roles. 

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. 

Banga, S., Chawla, G., and Bansal, A.K. 2004. New trends in the crystallization of active pharmaceutical ingredients. Business Briefing Pharmagenerics 1-5. 

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 ... 

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