Drug crystallisation in pharmaceutical development英文电子书.pdf

Drug substance crystallisation in pharmaceutical development: key stage for the control of physical properties Myriam Hassoun , Patrick Dorion, Benoit Robert, Magali Sautel, Ante Krstulovic Analytical Sciences Department Sanofi-Aventis Research 5, rue Georges Bizet 9 1160 Longjumeau (France) Knowledge and control of the properties of powders is essential for the development and manufacture of a pharmaceutical product. This concerns not only the bioavailability of the drug substance, but also the effects of mechanical properties on the manufacturing process of the drug substance and drug product. The first and the key stage is the control of the crystallisation process of the drug substance. A full understanding of crystallisation processes and their impact on the properties of a drug substance − particle morphology and size, purity and physical stability − will serve to improve the crystallisation process as well as to control phenomena such as agglomeration and polymorphism. Several illustrative examples will be presented. 1 Effect of the crystallisation process on particle size and morphology 1.1 Notions of crystallisation All processes of crystallisation begin with the creation of a supersaturated state, which can be attained in different ways [2]. Under local fluctuations of concentration in a given solvent at a specific temperature, a cluster appears (nucleation), which may or may not reach a critical size. If the critical size is achieved, the cluster will develop into a stable germ by adjunction of solute molecules; this phase is the crystalline growth step. By the end of the growth stage, one can obtain a crystalline