(504e) Continuous Production of API Nanocrystals By a Porous Hollow Fiber Membrane-Based Anti-Solvent Crystallizer

In porous hollow fiber membrane (HFM) based anti-solvent crystallization (AsCr) technique developed by us and investigated by others, the anti-solvent is injected from the HFM bore into the active pharmaceutical ingredient (API) containing solution flowing in the shell side. In this design, the shell-side feed solution flows parallel to the length of the HFM. We have studied a totally different membrane module configuration and design, where the flow path length of the API-containing solution is ~ 3 cm reducing considerably the residence time (t_res) which strongly influences crystal growth. It allowed us to obtain API nanocrystals which strongly enhance the bioavailability for a majority of APIs which are hydrophobic. The technique is highly suitable for fast crystallizations. We investigated AsCr of griseofulvin from its acetone solution using anti-solvent water coming through HFM pores. The range of t_res was 5-30 s; the volume flow rate ratio (FRR) of acetone/water ranged between 0.35 to 1.66; griseofulvin concentration was varied between saturation (3.73 g/100 g acetone) to 0.4 g GF in 100 g of solution having 50 wt% acetone in the total solution. Low t_res yielded nanocrystals <100 nm. The average API crystal size (D_avg) remained around 230 nm in a three-hour-long experiment. At a fixed mass FRR of 1.34, D_avg increased linearly from 48 to 280 nm as t_res increased from 5 to 28 s. For two HFM modules in series with the nanocrystal suspension from one module fed to the next module independently fed with anti-solvent water, GF crystallization yield as high as 98% was achieved. AsCr of L-glutamic acid in water with anti-solvent acetone in the same device illustrated continuous nanocrystal production and similar behavior vis-à-vis variation of t_res and FRR. This HFM module based AsCr technique can continuously produce nanocrystals of API.