Analysis of nucleation kinetics of poorly water-soluble drugs in presence of ultrasound and hydroxypropyl methyl cellulose during antisolvent precipitation

In this paper, nucleation kinetics of four poorly water-soluble drugs namely, itraconazole (ITZ), griseofulvin (GF), ibuprofen (IBP) and sulfamethoxazole (SFMZ) when precipitated by liquid antisolvent precipitation using water as antisolvent is examined in order to identify thermodynamic and kinetic process parameters as well as material properties that affect nucleation rate and hence, the particle size. The nucleation rates have been estimated for precipitation with and without ultrasound and hydroxypropyl methyl cellulose (HPMC). It is found that the nucleation rates increase significantly in presence of ultrasound and HPMC. Analysis of nucleation kinetics indicates that an increase in diffusivity due to ultrasound and a decrease in solid-liquid interfacial surface tension due to HPMC result in higher nucleation rates. Analysis also shows that reduction in interfacial surface tension due to HPMC is higher for a drug with lowest aqueous solubility (such as ITZ) as compared to drugs with higher aqueous solubility. It is also observed that it is easy to precipitate submicron particles of a drug with lowest aqueous solubility (such as ITZ) compared to drug molecules (such as SFMZ) with higher aqueous solubility in presence of HPMC.