(442t) Particle Engineering through Continuous Solvent Precipitation Conference: AIChE Annual MeetingYear: 2015Proceeding: 2015 AIChE Annual MeetingGroup: Particle Technology ForumSession: Poster Session: Particle Technology Forum Time: Tuesday, November 10, 2015 - 6:15pm-8:00pm Authors: Porfírio, T., Hovione Farmaciência SA Duarte,, Hovione Farmaciência SA Vicente, J., Hovione Temtem, M., Hovione FarmaCiência SA Particle Engineering through continuous solvent precipitation T. Porfirio1, I. Duarte1, J. Vicente1, M. Temtem1 1Hovione Farmaciencia SA, Sete Casas, Portugal Up to 90% of the active pharmaceutical substances under development are poorly water soluble, usually resulting in low bioavailability (BCS class II and class IV). To overcome this issue, different engineering and formulation approaches have been developed. Among the different strategies, the use of cocrystals and amorphous solid dispersions is becoming an increasingly relevant platform. It is also known by a skilled in the art that the dissolution rate may be enhanced by increasing the surface area of the particles through size reduction. Most particle size-reduction methods rely on a top-down approach, where larger particles are mechanically processed by milling or high shear processing. In these cases the size of particles is reduced by impact which can introduce impurities and limits the flexibility in controlling particle morphology. In opposition, on bottom-up approaches the control of the particle properties (size, morphology, crystallinity, etc.) is easily achieved due to molecular arrangements. An example is the liquid antisolvent precipitation which allows particle formation through crystallization/precipitation by using a suitable solvent/antisolvent system. The liquid antisolvent precipitation has been used in the production of single drug particles, cocrystals or amorphous solid dispersions. [1, 2, 3] The present work discloses a new continuous process that makes use of a micro-reaction technology to control precipitation in order to produce single drug particles, cocrystals or amorphous solid dispersions in the particulate form. The benefits of this technology are associated with the capacity to achieve homogeneous and rapid mixing of the two or more fluids thus enabling the control of particle characteristics (e.g. particle size, morphology, polymorphic form). Figure 1 ? Simplified scheme of the process  Firstly, the solvent and antisolvent mixtures are prepared, that are able to form precipitates under preferred process conditions. Then both solvent and antisolvent are delivered to an intensifier pump and mixed under controlled conditions in a microreactor to produce a suspension, as depicted in Fig. 1. The said suspension is feed to a membrane system to obtain a concentrate stream which is supplied to a spray drying unit in order to obtain the product in particulate form.  The feasibility of using this process was successfully demonstrated using carbamazepine/ saccharin co-crystals and fluticasone propionate as single drug. In the case of carbamazepine-saccharin cocrystals, the raw materials were dissolved in a molar proportion 1:1 in methanol. As antisolvent, a mass of deionized water corresponding to 2 times that of the solvent was measured. The co-precipitation in the form of cocrystal was performed micro-fluidizer reactor processor. The intensifying pump was set to impose a pressure higher than 1 kPsi. The resulting suspension was fed to an in-line filter. The suspension was also analyzed by X‑ray powder diffraction characterization and presented the target crystalline form of carbamazepine‑saccharin cocrystal as described by Porter III et al. . Fig. 2 depicted the X-ray powder diffraction of the analysis and the corresponding raw materials. The concentrate stream was supplied to a lab scale spray dryer. The obtained product presents the same target crystalline form of carbamazepine‑saccharin cocrystal that was obtained before drying. Figure 2 ? XRPD patterns and normalized intensity of carbamazepine, saccharin and carbamazepine-saccharin cocrystal In the case of the fluticasone propionate, the API was dissolved in acetone. The mass of antisolvent (deionized water) was set as 10 times that of the solvent. The trial was performed with the same setup. The particle size of the isolated product was characterized through scanning electron microscopy. A representative image of the particles is shown in Fig. 3. Roughly, particles with nano- and micro-scale were obtained. Figure 3 ? SEM of spray dried particles of fluticasone propionate As mentioned above, the present work is also suitable for the production of amorphous solid dispersions overcoming the challenges with intermediate stability of the amorphous materials produced using a co-precipitation approach. In conclusion, the present work proposes a continuous process to overcome the shortcoming identified in the art mainly because: i) includes a new separation approach during the isolation of materials produced by co-precipitation; ii) enables a better control of particle characteristics; iii) reduces the use of excipients in the formulation (such as surfactants), iv) supports the continuous production of single drug particles, cocrystals or amorphous solid dispersions in the particulate form in the micro- and/or nano-range, and v) is scalable to high production scales. References  Thorat and Dalvi, "Liquid antisolvent precipitation and stabilization of nanoparticles of poorly water soluble drugs in aqueous suspensions: Recent developments and future perspective," Chem Eng J , pp. 181-182, 2012.  Qiao et al., "Pharmaceutical cocrystals: An overview," Inter J Pharma, vol. 419, no. 1-2, pp. 1-11, 2011.  Shah et al., "Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs," Inter J Pharma, vol. 438, no. 1-2, pp. 53-60, 2012.  Porfírio et al., ?Continuous production of particles through solvent controlled precipitation?, Provisional patent PT108368.  Porter III et al., "Polymorphism in Carbamazepine Cocrystals," Crystal Growth & Design, Vols. 14-16, no. 1, p. 8, 2008.