(276d) Precipitation of Poorly Water Soluble Drugs Using Ultrasound and Stabilizers: Controlling Process Parameters

Precipitation of ultra-fine particles of poorly water soluble BCS class II drugs is attempted to improve bioavailability. A technique of liquid antisolvent (LAS) precipitation is chosen as it offers flexibility to control the particle size and distribution by manipulating physicochemical properties of solution and antisolvent phases using the additives. The objective of this work is to develop better understanding through a systematic and detailed study of a potentially scalable, LAS precipitation process for preparation of stable aqueous suspensions of ultra-fine particles of poorly water soluble active pharmaceutical ingredients (APIs). A combination of jets, ultrasound, and stabilizers has been used to achieve Damkohler number (Da) less than 1, which is a ratio of mixing time and precipitation time, for precipitation and stabilization of ultra-fine particles of six different APIs. Use of ultrasound and high stream velocities enhances micromixing and decreases mixing time, whereas addition of stabilizers increases precipitation time by delaying nucleation and inhibiting the particle growth. Particles with mean size ranging from 500 nm- 10 μm have been precipitated. A rationale understanding of precipitation is developed based on governing material and process parameters. The favorable process conditions have been identified to precipitate and stabilize submicron particles.