Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices

Leia Dwyer,Allan Myerson,Samir Kulkarni,Luzdary Ruelas

doi:10.3390/cryst7050131

Leia Dwyer, Allan Myerson + Show 2 more

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https://doi.org/10.3390/cryst7050131

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Abstract

While porous silica supports have been previously studied as carriers for nanocrystalline forms of poorly water-soluble active pharmaceutical ingredients (APIs), increasing the loading of API in these matrices is of great importance if these carriers are to be used in drug formulations. A dual-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer was designed in which the poorly soluble API fenofibrate was loaded into the porous matrices of pore sizes 35 nm–300 nm in the first stage, and then fed to a second stage in which the crystals were further grown in the pores. This resulted in high loadings of over 50 wt % while still producing nanocrystals confined to the pores without the formation of bulk-sized crystals on the surface of the porous silica. The principle was extended to another highly insoluble API, griseofulvin, to improve its loading in porous silica in a benchtop procedure. This work demonstrates a multi-step crystallization principle API in porous silica matrices with loadings high enough to produce final dosage forms of these poorly water-soluble APIs.

Highlights

The low bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) is a challenge for API formulation and even selection in the drug discovery phase [1,2]
These methods include milling [5], high-pressure homogenization [12], hydrosol methods [5,13], freeze-drying [14], supercritical fluid methods [14,15,16], and evaporative or antisolvent precipitation [17,18,19,20,21]. These methods have associated problems with contamination, high surfactant requirements, complex and energy-intensive procedures, difficulties controlling particle size distribution and polymorphism, and low production rates [22]. Many of these challenges are addressed with the confined crystallization approach, in which crystallization of the API is restricted to a micro- or nanoporous environment to form nanocrystals
FEN nanocrystals confined to rigid porous silica matrices have been shown to have well-behaved thermal properties and enhanced dissolution rates [7,40]

Summary

Introduction

The low bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) is a challenge for API formulation and even selection in the drug discovery phase [1,2]. Approaches that control the nanosizing of larger crystals or “bottom-up” technologies which control the size of the crystal formed directly These methods include milling [5], high-pressure homogenization [12], hydrosol methods [5,13], freeze-drying [14], supercritical fluid methods [14,15,16], and evaporative or antisolvent precipitation [17,18,19,20,21]. These methods have associated problems with contamination, high surfactant requirements, complex and energy-intensive procedures, difficulties controlling particle size distribution and polymorphism, and low production rates [22] Many of these challenges are addressed with the confined crystallization approach, in which crystallization of the API is restricted to a micro- or nanoporous environment to form nanocrystals. Of particular interest and widely studied for drug delivery applications are rigid silica matrices including ordered

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