Porous hollow fiber membrane-based continuous cross-flow anti-solvent crystallizer for production of API nanocrystals

• Crossflow around hollow fiber membrane (HFM) was used for antisolvent crystallization. • Nanocrystals of drugs, griseofulvin and L-glutamic acid, were continuously produced. • Continuous crossflow of drug solution in HFM module had low residence time, t res. • For a solvent/nonsolvent flow rate ratio, nanocrystal size grew linearly with t res. • Distributed supersaturation generation allows growth to overshadow nucleation rate. In porous hollow fiber membrane (HFM) based anti-solvent crystallization (AsCr) technique, the anti-solvent is injected from HFM bore into the active pharmaceutical ingredient (API) containing solution flowing in the shell side. Conventionally, shell-side feed solution flows along the HFM. In our compact module design, the shell-side liquid flows perpendicular to the HFMs; the mean flow length is ∼ 3 cm reducing considerably the residence time ( t res ) which strongly influences crystal growth. We investigated AsCr of griseofulvin (GF) from its acetone solution using anti-solvent water injected 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 and 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 ± 0.1 , 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 yields as high as 98 % were achieved. AsCr of L-glutamic acid in water with anti-solvent acetone in the same device illustrated continuous nanocrystal production and similar behaviors vis-à-vis variation s of t res and FRR. The cross-flow HFM based continuous AsCr technique can continuously produce nanocrystals of APIs.