Development of long-acting injectable suspensions by continuous antisolvent crystallization: An integrated bottom-up process

Our present work elucidated the operational feasibility of direct generation and stabilization of long-acting injectable (LAI) suspensions of a practically insoluble drug, itraconazole (ITZ), by combining continuous liquid antisolvent crystallization with downstream processing (i.e., centrifugal filtration and reconstitution). A novel microchannel reactor-based bottom-up crystallization setup was assembled and optimized for the continuous production of micro-suspension. Based upon the solvent screening and solubility study, N-methyl pyrrolidone (NMP) was selected as the optimal solvent and an impinging jet Y-shaped microchannel reactor (MCR) was selected as the fluidic device to provide a reproducible homogenous mixing environment. Operating parameters such as solvent to antisolvent ratio (S/AS), total jet liquid flow rates (TFRs), ITZ feed solution concentration and the maturation time in spiral tubing were tailored to 1:9 v/v, 50 mL/min, 10 g/100 g solution, and 96 h, respectively. Vitamin E TPGS (0.5% w/w) was found to be the most suitable excipient to stabilize ITZ particles amongst 14 commonly used stabilizers screened. The effect of scaling up from 25 mL to 15 L was evaluated effectively with in situ monitoring of particle size distribution (PSD) and solid-state form. Thereafter, the suspension was subjected to centrifugal filtration to remove excess solvent and increase ITZ solid fraction. As an alternative, an even more concentrated wet pellet was reconstituted with an aqueous solution of 0.5% w/w Vitamin E TPGS as resuspending agent. The ITZ LAI suspension (of 300 mg/mL solid concentration) has the optimal PSD with a D10 of 1.1 +/- 0.3 mu m, a D50 of 3.53 +/- 0.4 mu m and a D90 of 6.5 +/- 0.8 mu m, corroborated by scanning electron microscopy (SEM), as remained stable after 548 days of storage at 25 degrees C. Finally, in vitro release methods using Dialyzer, dialysis membrane sac were investigated for evaluation of dissolution of ITZ LAI suspensions. The framework presented in this manuscript provides a useful guidance for development of LAI suspensions by an integrated bottom-up approach using ITZ as model API.