(134c) Continuous Fluidic Fabrication of Uniform Spherical Aggregates for Controlled Dissolution

Crystallization is one of the most important unit operations in the manufacture of active pharmaceutical ingredients, as it determines the size distribution of produced crystals and therefore downstream processing properties (e.g. flow-ability, compressibility). However, most crystalline active pharmaceutical ingredients prepared by standard crystallization processes have poor properties and have to go through energy-intensive operations such as comminution, milling, sieving and granulation, before being tableted. Alternative approach is to produce spherical crystal aggregates of the API and potentially also the excipient in one step, such that they have improved downstream processing properties, required dissolution and bioavailability, and can be directly compressed into tablets or filled into capsules.

A novel continuous fluidic method based on extractive crystallization for producing monodisperse spherical crystal aggregates, single crystals and composite particles with potential use in pharmaceutical engineering is presented. The effect of extraction rate on the morphology and internal pore structure of the spherical aggregates was studied and the dissolution rates of the spherical aggregates and single crystals were measured and compared in order to demonstrate the improved dissolution rate. Produced particles were characterized by optical microscopy, scanning electron microscopy and x-ray micro-tomography.

The possibility of using microencapsulation for spherical crystallization was also demonstrated. The effect of various process parameters on the morphology and size of core-shell particles consisting of a biocompatible polymer shell and oil core was determined. The possible use of two different crystallization methods was studied – extractive and evaporative crystallization. Microencapsulation was also used to prepare ibuprofen microbeads (ibuprofen crystals dispersed in a polymer matrix) and their dissolution rate was measured and compared with pure ibuprofen crystals in order to determine their dissolution profile.