Abstract:
Poor aqueous solubility of drug molecules is a major challenge for the pharmaceutical scientist involved in drug development. Particle size reduction to nanoscale appears as an effective and versatile option for solubility improvement. Unlike the traditional methods used for particle size reduction, liquid antisolvent (LAS) process offers advantages ranging from superior particle size control to easy scalability. There are number of factors in effect during LAS processing. These factors can be grouped into two main categories; formulation related and process related. In order to design a robust LAS process, it is extremely important to understand impact of all the variables such as solvent to antisolvent ratio, temperature, mixing techniquesetc on the desirable product attributes, such as particle size, particle size distribution, particle morphology, particle stability, nucleation kinetics etc. Although several researchers have studied these variables, there is a widespread disagreement amongst them which makes it difficult to follow a particular methodology reported. Hence, the objective of the thesis is to address the gaps in the literature. Nucleation kinetics of a poorly water soluble drug curcumin during LASprocess in presence of ultrasound and surfactant has been estimated. The induction time and metastable zone width (MSZW) for curcumin precipitation and the effect of ultrasound and stabilizers on these parameters have been estimated. A significant increase in nucleation rates and decrease in induction time and MSZW was observed for LAS precipitation carried out in presence of ultrasound. Solid-liquid interfacial energies were also estimated using induction times obtained experimentally. It shows that the value predicted using Mersmann equation and Bennema&Sohnel equation are higher than the experimental interfacial energies. Additionally, we devised a simple criterion for prediction of a long-term stability of aqueous suspensions of ultrafine particles of curcumin. A new “stability parameter” (ϒ0Ɛ/ϒƐ0) has been defined, which is a ratio of non-dimensional mechanical (mainly ultrasonic) energy (Ɛ/Ɛ0) to the non-dimensional solid-liquid interfacial energy (ϒ/ϒ0). The stability of aqueous suspensions of curcumin particles over a period of one year and nine months have been correlated with this parameter. It was found that precipitations carried out with higher values of 0/0 (more than 100) result into aqueous suspensions with particle size less than 1µm. It was further observed that these suspensions remain stable (i.e. no or negligible change in average particle size) for a period of one year and nine months. On the other hand, the suspensions of particles precipitated at lower values of 0/0 (less than 10) were found to be highly unstable (i.e. the average particle size changes drastically). These results suggest that 0/0 can be used as a parameter to engineer stable aqueous suspensions of curcumin particles. Further, it was found that the use of Mersmann equation to estimate solid-liquid interfacial surface tensions can help in making this criterion predictive. In addition to aspects of nucleation kinetics and stability of aqueous suspensions the precipitation pathways of poorly water soluble drug griseofulvin during liquid antisolvent precipitation were also explored. It was found that griseofulvin particles undergo non-classical crystallization pathway during liquid antisolvent precipitation in presence of ultrasound and stabilizers.Ultrasound was found to facilitate fusion of assemblies formed during non-classical crystallization.