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.