We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV−vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have designed, 3D-printed, and characterized a stainless steel static mixer. This approach enabled the evaluation of different configurations and ensured efficient scale-up across development and commercial facilities that should allow for enhanced portability of mixing-sensitive processes.
Despite the many benefits that flow chemistry brings in the context
of commercial manufacturing, a major issue for such continuous processing
can be the clogging of flow equipment. In the case of verubecestat
(MK-8931), the development of a flow chemistry process for the Mannich
step greatly increased the reaction yield and the purity of the isolated
product. However, in one of the plant-scale solvent runs in advance
of process validation, an unforeseen and isolated clogging incident
occurred. Herein, we report the methodical troubleshooting leading
to the location of the clog, the structural elucidation of the solids,
and eventual root cause analysis. The culprit was eventually tied
to poly(THF), which was present in extremely low levels in a specific
lot of THF solvent used. An interesting observation with regards to
the deposition of solids in the filter cartridge and static mixer
element with respect to solvent flow led us to speculate that the
precipitation of the solids is caused by a phenomenon known as hydrodynamic
cavitation.
Investigational drugs are increasingly becoming less soluble in aqueous media, thus, presenting real challenges during development. Previous work has successfully demonstrated the manufacturing of pharmaceuticals using fluidized bed (FB) impregnation of APIs onto porous carriers. This study demonstrates the usefulness of FB impregnation in formulating poorly soluble drugs. We show that dissolution of Fenofibrate is greatly improved by FB impregnation onto Neusilin V R (Fuji Health Science Inc, Burlington, NJ USA), a synthetic amorphous form of magnesium alumino-metasilicate. We impregnate Neusilin V R for range of loadings and examine Fenofibrate's physical state. Dissolution of impregnated formulations is drug loading dependent and loadings below 40% show great improvement (decrease) in release time compared to physical blend. Release times are further improved by milling. We also examine feasibility of coimpregnating Fenofibrate with additives and observe stability (1.5 years) of the amorphous form of Fenofibrate inside Neusilin V R . This stabilization significantly improves Fenofibrate's dissolution kinetics, making our formulation comparable to one of the current market formulations, TriCor
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