Direct production of carbamazepine–saccharin cocrystals from water/ethanol solvent mixtures by membrane-based crystallization technology

Abstract

This communication reports on the possibility to achieve the direct production of either carbamazepine crystals or carbamazepinesaccharin cocrystals from water/ethanol solvent mixtures by using membrane-based crystallization technology, by choosing the opportune initial conditions.Co-crystallization of active pharmaceutical ingredients (APIs) with cocrystal formers 1 (or conformers) has become increasingly important in the last few years in the drug-development process, primarily because it provides an alternative to the physical properties of the neat API solid phases. [2][3][4] Co-crystals offer a much wider range of solid forms and improved properties than the solid forms of the free API and its salts, such as shelf life, 5 dissolution rate, 6 and bioavailability. 7,8 Furthermore, co-crystallization offers potential to tailor the physicochemical properties of a drug preparation to an optimum specification, with remarkable consequences also in the field of the intellectual properties protection. 9The most economical and easiest method to scale up for cocrystals production is crystallization from solution. 10,11 However, its apparent failure in a number of cases 12,13 has led to the exploration of other approaches, like spray drying involving supercritical fluid, 14 solidstate grinding, and solvent drop grinding 15 techniques, as alternatives to solution crystallization. [16][17][18] These latter processes under several aspects are not well-understood nor adequately controlled, making cocrystals formulation a kind of empirical and mysterious preparative methodology. Such a description demonstrates on the one side the formidable technological/economical implications in enhancing the knowledge about cocrystals preparation procedures but, on the other side, it demands the development of new and more efficient production technologies.

Cocrystal Systems of Pharmaceutical Interest: 2011

“…By controlling the crystallization parameters, it was shown that one could eliminate nucleation of an undesirable metastable crystal form and produce large particles with a minimum content of fines. The use of membrane-based crystallization technology has been investigated for the production of cocrystals of carbamazepine and saccharin . In this approach, as long as the initial composition of the aqueous ethanol solvent system was optimized, the membrane technology enabled one to control the degree of supersaturation during the process and thus obtain the desired product.…”

“…The use of membrane-based crystallization technology has been investigated for the production of cocrystals of carbamazepine and saccharin. 35 In this approach, as long as the initial composition of the aqueous ethanol solvent system was optimized, the membrane technology enabled one to control the degree of supersaturation during the process and thus obtain the desired product.…”

RootProf: software for multivariate analysis of unidimensional profiles

“…A more challenging case is constituted by polycrystalline mixtures such as those composed of polymorph III of carbamazepine (CBZ III), saccharin (SAC), and their co-crystal form (CBZ-SAC), which are typically produced by crystallization processes aiming at obtaining co-crystals from an active pharmaceutical ingredient and a co-former (Di Profio et al, 2011). This mixture was analysed by XRPD and FT-IR spectroscopy, and the corresponding measured profiles after application of pre-processing are plotted in Fig.…”

Preparation and Characterization of Carbamazepine Cocrystal in Polymer Solution

“…Solvent mixtures can reduce the solubility differences between cocrystal components; facilitate nucleation rate and provide improved transformation kinetics for cocrystallization [ 22 , 23 , 24 ]. Di Profio has successfully prepared carbamazepine-saccharin cocrystal in water/ethanol solvent mixtures by membrane-based crystallization technology [ 25 ]. In this study, ethanol-water solvent mixture was also applied to try to prepare CBZ cocrystal through a combination of solution evaporation and the cooling crystallization method.…”