An improved kinetics approach to describe the physical stability of amorphous solid dispersions.
The recrystallization of amorphous solid dispersions may lead to a loss in the dissolution rate, and consequently reduce bioavailability. The purpose of this work is to understand factors governing the recrystallization of amorphous drug-polymer solid dispersions, and develop a kinetics model capable of accurately predicting their physical stability. Recrystallization kinetics was measured using differential scanning calorimetry for initially amorphous efavirenz-polyvinylpyrrolidone solid dispersions stored at controlled temperature and relative humidity. The experimental measurements were fitted by a new kinetic model to estimate the recrystallization rate constant and microscopic geometry of crystal growth. The new kinetics model was used to illustrate the governing factors of amorphous solid dispersions stability. Temperature was found to affect efavirenz recrystallization in an Arrhenius manner, while recrystallization rate constant was shown to increase linearly with relative humidity. Polymer content tremendously inhibited the recrystallization process by increasing the crystallization activation energy and decreasing the equilibrium crystallinity. The new kinetic model was validated by the good agreement between model fits and experiment measurements. A small increase in polyvinylpyrrolidone resulted in substantial stability enhancements of efavirenz amorphous solid dispersion. The new established kinetics model provided more accurate predictions than the Avrami equation.
ISP Pharma Technologies, 9176 Red Branch Rd., Suite R, Columbia, MD 21046, USA. jyang@ispcorp.com
Jiao
J
Yang
Kristin
K
Grey
John
J
Doney
D000480:Alkynes; D048588:Benzoxazines / Q000737:chemistry / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003521:Cyclopropanes; D004355:Drug Stability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D011205:Povidone / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D004364:Pharmaceutical Preparations; D011205:Povidone; C098320:efavirenz