Improvement of theophylline anhydrate stability at high humidity by surface-physicochemical modification.
To improve the stability of theophylline anhydrate (THA) at high humidity and temperature, the surface of THA was modified by adsorption of n-butanol and phase transformation kinetics and dissolution kinetics were investigated. Hydration kinetics was evaluated using differential scanning calorimetry. The samples were stored in various saturated salt solutions at 30, 40 and 50 degrees C. A dissolution test was performed in distilled water at 37 degrees C, 100rpm. Hydration of THA and surface-modified THA (STHA) at various levels of RH at 40 degrees C followed a two-dimensional growth of nuclei equation (Avrami equation) including an induction period (IP). The IP of STHA was significantly longer (p<0.05) than that of THA at each RH, but the k of STHA was not significantly different (p>0.05) from that at each relative humidity (RH). The IP of STMA was significantly longer at 40 and 50 degrees C, 93% RH (p<0.05) than at 30 degrees C, but there was no significant difference between 40 and 50 degrees C. The k of THA and STHA increased with the increase in storage temperature at 30-50 degrees C. Arrhenius plots of the k of THA and STHA showed a straight line. The activation energy of hydration of THA and STHA was 17.60+/-1.38 and 28.92+/-5.56J/mol, respectively. Dissolution of THA and STHA followed the Hixson-Crowell equation, and the dissolution rate constant, K', was 0.0306+/-0.0041 and 0.0269+/-0.0034mg(1/3)s(-1) (n=3), respectively.
Otsuka
Makoto
M
Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Shinmachi, Nishi-Tokyo, Japan. motsuka@musashino-u.ac.jp
Ishii
Mika
M
D000327:Adsorption; D000440:Butanols / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D055598:Chemical Phenomena; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006813:Humidity; D013499:Surface Properties; D013696:Temperature; D013806:Theophylline / Q000737:chemistry*; D017155:Wettability
D000440:Butanols; D013806:Theophylline