Crystallization of Pharmaceutical Substances


  • B. Kratochvíl Department of Solid State Chemistry, Institute of Chemical Technology, Prague


The theoretical background and crystallization techniques used in pharmaceutical manufacture are reviewed. Processes of primary and secondary nucleation, thermodynamics and kinetics of crystal growth and the phenomenon of polymorphism and polymorphic transitions are introduced. Polymorphism is a keyword of considerable importance in the pharmaceutical industry. Most pharmaceutical substances crystallize in more than one solid state form, whether they are polymorphs or solvates or both. Crystallization of the required polymorph from a solvent must be under kinetic and thermodynamic control because possible polymorph transformations are influenced by many parameters of the crystallizer. The phase nucleated during a primary (spontaneous) nucleation is a typically metastable polymorph. Unstable polymorphs have a tendency to transform to more stable ones, and finally to the thermodynamically stable form. Crystallizations in the pharmaceutical industry are often carried out batchwise. Changes in the polymorphic form of the batches produced are seen as indicative of changes in the crystallizing conditions, so seeding techniques are used for batch reproducibility. The development of seeding strategies is facilitated by certain data on the system (polymorphic behaviour, solubility curves, widths of metastable zones). Special attention is paid to the preparation of the seed, optimisation of the seeding strategy and the amount of the seed added. The quality of the product (crystal size, shape, purity) and the choice of the solvent are also discussed. An example of the patent suit between Monsanto and Ajimoto companies concerning the crystal shape of aspartam is mentioned for illustration.



Jak citovat

Kratochvíl, B. (2007). Crystallization of Pharmaceutical Substances. Chemické Listy, 101(1). Získáno z




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