Influence of solvent evaporation rate and formulation factors on solid dispersion physical stability.
New chemical entities (NCEs) often show poor water solubility necessitating solid dispersion formulation. The aim of the current study is to employ design of experiments in investigating the influence of one critical process factor (solvent evaporation rate) and two formulation factors (PVP:piroxicam ratio (PVP:PRX) and PVP molecular weight (P(MW))) on the physical stability of PRX solid dispersion prepared by the solvent evaporation method. The results showed the rank order of an increase in factors contributing to a decrease in the extent of PRX nucleation being evaporation rate>PVP:PRX>P(MW). The same rank order was found for the decrease in the extent of PRX crystal growth in PVP matrices from day 0 up to day 12. However, after 12days the rank became PVP:PRX>evaporation rate>P(MW). The effects of an increase in evaporation rate and PVP:PRX ratio in stabilizing PRX were of the same order of magnitude, while the effect from P(MW) was much smaller. The findings were confirmed by XRPD. FT-IR showed that PRX recrystallization in the PVP matrix followed Ostwald's step rule, and an increase in the three factors all led to increased hydrogen bonding interaction between PRX and PVP. The present study showed the applicability of the Quality by Design approach in solid dispersion research, and highlights the need for multifactorial analysis.
Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Denmark.
Jian X
JX
Wu
Mingshi
M
Yang
Frans van den
Fv
Berg
Jari
J
Pajander
Thomas
T
Rades
Jukka
J
Rantanen
D000096:Acetone / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D000432:Methanol / Q000737:chemistry; D008853:Microscopy; D008970:Molecular Weight; D010894:Piroxicam / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D033362:Powder Diffraction; D025341:Principal Component Analysis; D012997:Solvents / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D013818:Thermogravimetry; D014961:X-Ray Diffraction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012997:Solvents; D000096:Acetone; D010894:Piroxicam; D011205:Povidone; D000432:Methanol