Membrane Crystallization for the Direct Formulation of Crystalline Bio-active Molecules

The interest to combine membrane operations and solution crystallization is growing since several years. This approach has been put in practice in several forms of membrane-assisted crystallization (MAC) processes, among which is membrane crystallization (MCr) technology [1]. This equipment has been demonstrated to be effective and versatile for the final formulation, in the solid crystalline state, of active pharmaceutical ingredients (APIs) also from multicomponent solutions [2]. The main features of MCr are: (1) the use of membranes as precision devices to control the composition of the crystallizing solution, by opposing a well-defined and tunable resistance to mass flow occurring in vapor phase; (2) the action of the porous surface of the membrane as suitable support to activate heterogeneous nucleation mechanisms; (3) the possibility to induce nucleation and crystal growth in separate sites, thus reducing the risk of membrane fouling even when the same membrane supports heterogeneous nucleation; (4) the opportunity to operate in continuous mode. Thank to these fundamental options, combined together in a unique apparatus, advantages like: (i) improved control of the supersaturation degree and the rate of its generation; (ii) the possibility for the crystallization to be initiated at low supersaturation level; (iii) the enhancement of the crystallization kinetics and (iv) improved overall process efficiency, can be achieved, even in the case of large and complex molecules like proteins. In this presentation, the several aspects related with the membrane-based crystallization technology and their relations with the final properties of the crystalline materials produced will be outlined. The preferential production of specific polymorphs of some relevant APIs, the extension of the concept to antisolvent crystallization in different process configurations, the production of co-crystals of APIs and functional conformers as potential alternative to poorly water-soluble drugs, the application to complex bio-macromolecules for both structural studies and therapeutic delivery, will be discussed. References: [1] Di Profio, G.; Curcio, E.; Drioli, E. Supersaturation Control and Heterogeneous Nucleation in Membrane Crystallizers: Facts and Perspectives. Ind. Eng. Chem. Res. 2010, 49, 11878-11889. [2] Di Profio, G.; Stabile, C.; Caridi, A.; Curcio, E.; Drioli, E. Antisolvent membrane crystallization of pharmaceutical compounds. J. Pharm. Sci. 2009, 98, 4902.