Abstract

Production of micron and submicron size particles for hydrophobic compounds finds a great application in the pharmaceutical industry due to their enhanced surface properties which aid in overcoming dissolution and bioavailability issues. The key to obtaining fine particles is inducing homogeneous precipitation in supersaturated systems. However, batch systems prove to be inefficient for homogenous nucleation due to non-uniform mixing conditions and continuous reduction in driving force as the process progresses over time. Favorable conditions for homogenous nucleation can be easily established in micromixers, due to presence of microchannels they are able to achieve superior mixing conditions with small mixing times (tmix). Over the past few years, micromixers have played an instrumental role in the transition of processes from batch to continuous systems in several sectors, yet very few studies focus on their applications for carrying out liquid antisolvent precipitative reactions of pharmaceutical compounds.

      The current work investigates the application of a lab scale Ehrfeld® valve assisted micromixer (VAMM) technology for generation of micronsized drug compounds which are poorly water soluble. The VAMM has emerged as a promising technology due to its unique construction which splits the fluid stream into multiple microchannels triggering impingement at multiple sites. In addition the unidirectional restrictor valve excludes reverse flow of fluid stream (therefore having an advantage over conventional T-mixers) and the passage of the thin fluid lamellae through the body of the micromixer ensures a well-mixed and highly supersaturated solution. First the mixing efficiency of the VAMM was characterized by developing an empirical correlation for mixing time (tmix) [1], followed by experimentation using a set of competitive parallel reactions (whose kinetics have been well studied) and establishing conversion of key reactant as a function of varying jet velocity. These values were then used, to estimate Damköhler number (Da) and tmix which enables a direct comparison of mixing efficiencies between VAMM and other well established micromixer systems [2].      

Model Biopharmaceutical classification system (BCS) II compounds were identified and highly supersaturated solutions of same were subjected to anti-solvent crystallization process via VAMM in the presence of suitable stabilizer system [3]. Similar crystallizations  were also carried out in batch process, where the results clearly indicated the superior performance of VAMM in generation of fine particles when compared with the batch . In both the cases particles as small as d90 < 5µm were achieved, therefore establishing the Ehrfeld® Valve Assisted Micromixer as a feasible platform for precipitation of fine pharmaceutical compounds. 

References:

1. Wolf A., etl al., Precipitation in a Micromixer –From Laboratory to Industrial Scale. Chemical        Engineering & Technology (2015), 2017-2024

2. Johnson K., and Prudhomme R., Chemical processing and micromixing in confined impinging jets, AIChE J, 2003, 2264-2282

4. Flash nanoprecipitation of organic actives and block copolymers using a confined impinging jets mixer, Australian Journal of Chemistry (2003), 1021-1024.