High pressure homogenization of pharmaceutical solids

The comminution of different pharmaceutical solids by high pressure homogenization in various dispersion media has been investigated. First, the influence of two important process parameters, namely the pressure drop and the number of passes across the homogenizer, has been investigated through the homogenization of aqueous suspensions. Applying pressure drops ranging from 250 to 1000 bar and up to 200 passes across the homogenizer, it was found that smaller particles can be obtained either by working at an increased homogenization pressure or by further increasing the number of passes. The smallest particles, obtained for one of the two pharmaceutical compounds investigated by applying 50 passes at 1000 bar homogenization pressure, exhibited a very narrow size distribution with a median x50 of 1.14 μm. Moreover, experimental results could be adequately described using an empirical relationship that allows estimating a priori the median x50 of the product size distribution as a function of the aforementioned operating parameters. Furthermore, the performance of different homogenizers has been evaluated, thus showing that valve homogenizers have favorable properties as compared to static homogenizers regarding the comminution of solids. Finally, the present study demonstrates successfully the feasibility of this novel process option by applying two different pressurized dispersion fluids, namely liquid carbon dioxide or 1,1,1,2-tetrafluoroethane (Solkane R134a), in the homogenization of phenytoin and of another proprietary pharmaceutical solid. These fluids are subject to residue-free evaporation upon pressure release, and at the end of the process the micronized product particles could be directly recovered in form of a dry powder.

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► We present a novel milling method for pharmaceutical solids, relying on pressurized fluids.
► Crystalline particles in the low micron range are obtained for two different drugs.
► Particle size depends on the pressure drop and # of passes across the homogenizer.
► Valve homogenizers outperform static homogenizers in the comminution of solids.
► The feasibility of using pressurized dispersion fluids is demonstrated successfully.