A Process for the Formation of Nanocrystals of Active Pharmaceutical Ingredients with Poor Aqueous Solubility in a Nanoporous Substrate

作者：O'Mahony Marcus; Leung Allen K; Ferguson Steven; Trout Bernhardt L; Myerson Allan S^*

来源：Organic Process Research & Development, 2015, 19(9): 1109-1118.

DOI：10.1021/op500262q

A potential process for the formation of nanocrystals of the poorly soluble drug, ibuprofen, within a nanoporous material is demonstrated. Nanocrystalline ibuprofen (IBP) is prepared at <= 106 nm by adding a solution containing IBP to particles of controlled pore glass (CPG) within a column so that the pores contain IBP solution. The imbibed particles of CPG are then rinsed with a minimal amount of solvent to remove excess solution at the surface of CPG, and a flow of air within the column is used to evaporate the solvent, resulting in crystallization of IBP within the pores of CPG. Crystallinity is determined using X-ray powder diffraction. MP is confirmed as being in the nanosize range by observation of a negative shift in the melting point measured by differential scanning calorimetry, and loading of IBP nanocrystals within the pores (% w/w) is determined by thermogravimetric analysis. Parameters were investigated for the process and demonstrate that an increase in percentage loading is achieved with increasing solution concentration and with increasing solvent viscosity. Loading of IBP within CPG was also found to be very sensitive to the volume of rinse solvent used. It is shown that rinsing with a minimal amount of solvent is necessary to avoid the significant presence of bulk micron-sized surface crystals. In vitro dissolution profiles, performed in water, demonstrate the significant dissolution rate increase offered by nanocrystalline IBP relative to bulk micron-sized crystals or even formulated tablets of IBP.

• 出版日期2015-9