276740 Selecting the Desired Solid Form by Membrane Crystallization: Crystals or Cocrystals
In the last years, membrane crystallization technique has been recognized as a useful means for producing pharmaceutical crystals in controlled manner. Indeed, the interest in membrane technology arises from the possibility to improve control in the course of the crystallization process, particularly in the supersaturation stage, by using the right combination of membrane characteristics and operating parameters. The possibility to exploit membrane crystallization technology, operating in antisolvent configuration, to produce pharmaceutical cocrystals was recently verified for the Carbamazepine (CBZ) – Saccharin (SAC) system.
Cocrystallization of active pharmaceutical ingredients (APIs) with cocrystal formers (or coformers) is gaining increasing interest in the drug-development area since the resulting new solid forms are characterized by different physical-chemical properties compared to the original API. Indeed cocrystallization increases the diversity of solid state forms of an API and enhances pharmaceutical properties by modification of chemical stability, moisture uptake, mechanical behavior, solubility, dissolution rate, and bioavailability. Therefore, cocrystallization can directly impact scientific and legal aspects of drug development and life cycle management of the marketed products by providing alternative solid dosage forms and extended patent life.
Despite of its great potentialities, cocrystallization is by now mainly considered as an empirical technique based on “trial and error” strategies; this is because the basic mechanisms involved in cocrystals - and more general in crystal - formation are poorly understood to date; moreover cocrystallization process requires a special control in solution composition in order to avoid the overrunning in the phase diagram of the thermodynamic stability region of a specific specie, thus producing undesired or impure solid products. Such situation demands for the development of new robust and more efficient production technologies of solid dosage forms and, among them, particularly cocrystals .
In this paper, the application of membrane cocrystallization process was further investigated by performing a systematic study about the conditions promoting pure CBZ-SAC cocrystals or single components (CBZ/SAC) crystals from water/ethanol solvent mixtures. Particular attention has been devoted to verify the possibility to improve control during the supersaturation stage, operating in the proper zone of the solubility phase diagram of the chosen API/coformer/solvent system, in order to achieve full control in the crystallization of a specific solid form with the desired degree of purity.
Precipitates characterizations revealed that products from experimental trials where extremely sensitive to solution composition. When decreasing the initial CBZ/SAC molar ratio from 1.1 to 0.01 (while keeping all the other parameters constant) the composition of the precipitate drastically changes. CBZ 100% pure crystals are obtained for CBZ/SAC molar ratio higher than 0.3; further decreasing the molar ratio in the range 0.3-0.22 produces a mixture of cocrystals/CBZ; 100% pure CBZ-SAC cocrystals form I are obtained for solution composition consisting in 0.12-0.22 molar ratio, while a further decrease of molar ratio from 0.12 to 0.01 allowed to produce first cocrystals/SAC (up to 0.05) and then pure SAC crystals.
This observation confirms the great importance of the initial solution composition in addressing the final outcome of the cocrystallization process and it can be explained exploring the phase solubility diagram of the cocrystal system. However, in order to achieve the desired product with the right level of purity, it is necessary to operate in the proper conditions without overcoming its region of thermodynamic existence. To achieve this purpose, the role of the membrane was crucial to control the concentration mechanism of solution limiting the maximum level of supersaturation. The operating mechanism of the membrane-based strategy involves using a porous membrane as mean to control the solvent/antisolvent demixing in the crystallizing solution, by finely modulating solvent removal in vapor phase. Accordingly, the specific role of the membrane is to limit the maximum level of supersaturation reached in solution by controlling the solvent evaporation, so as providing specific routes in the phase diagram, thus avoiding the overrunning of the thermodynamic stability region of a specific specie, giving rise to the desired solid form.
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