385776 Engineering Fine Crystalline API Via High Shear Direct Precipitation with Isolation Using a Thin Film Evaporator
A growing trend moving away from dry milling for active pharmaceutical ingredient (API) particle size control is motivated by concerns including:
-milling induced disorder and the potentially detrimental impact on powder physical properties as well as physical and/or chemical stability
-industrial hygiene associated with fluidization of micronized potent compounds
-increased cost due to yield losses and labor and overhead associated with an additional processing step
There are numerous wet particle engineering options including both bottom up (i.e. nucleation and/or growth based processes) and top down (high shear milling, media milling, high pressure homogenization) processes that address the concerns listed above. A bottom up, high shear direct precipitation route has shown promise based on ability to consistently achieve target particle size, and as a scalable, highly productive, continuous process. Work will be presented focusing evaluating the impact of solvent system, mill speed and anti-solvent and solvent flow rates on resulting particle size. This will also include scale up studies highlighting consistent particle size from a 1L batch process to >600L continuous process.
Fine particles (<5um) introduce a new challenge regarding product isolation. Conventional filtration and drying processes are not feasible due to prohibitively high cake resistances and/or challenges with aggregation of the fine particles. The thin film evaporator was thought to offer a potential solution for isolating fine particles. Data will be presented evaluating several test compounds with experimental input factors including particle size, particle aspect ratio, slurry concentration, solvent system (and commensurate g/L of dissolved API), processing temperature, feed rate and operating pressure. Key responses will be reviewed including isolated product physical properties (i.e. breakage, growth, aggregation), residual solvent level and yield.
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