Correlation and prediction of moisture-mediated dissolution stability for benazepril hydrochloride tablets.
OBJECTIVE
This report investigated dissolution stability of benazepril hydrochloride tablets.


METHODS
Reduction in dissolution rate was observed for benazepril hydrochloride tablets when they were subjected to stressed storage condition (40 degrees C/75% RH) for prolonged periods of time (1-3 months). Moisture contents of initial and stressed tablets were measured by Karl Fischer method. Comparative thermal and physical characterizations of initial and stressed tablets were also performed. A mathematical model that was used to predict possible reduction in dissolution rate was proposed and validated using experimental data.


RESULTS
It was found that there was a direct correlation between moisture content of benazepril hydrochloride tablets and their percentage of dissolution at 10 min. At moisture content below 3.5%, there were no significant changes in dissolution values. Beyond that point, however, a close to linear decrease in dissolution was observed as a function of increase in moisture content. Results from thermal and X-ray analysis have ruled out possible changes in drug substance. Other physical characterization, such as scanning electron microscope and mercury porosimetry measurements, revealed changes in core structure of stressed tablets vs. initial tablets. Based on results from these measurements, "preactivation" of disintegrant was identified as the mechanism for reduction in dissolution rate above critical moisture content. A simple physical model for moisture uptake of benazepril hydrochloride tablets was also proposed for predicting when, based on water vapor transmission and critical moisture content, dissolution rate will decline.


CONCLUSIONS
Physical changes of tablets mediated by moisture were the main cause for reduction in dissolution. Inclusion of desiccant, although beneficial, cannot prevent reduction in dissolution completely. The simple physical model proposed in this report was found to be useful in predicting the dissolution stability of the dosage form.
Li
Shoufeng
S
Pharmaceutical and Analytical Development, Novartis Pharmaceuticals, East Hanover, New Jersey 07936, USA. shoufeng.li@pharma.novartis.com
Wei
Bill
B
Fleres
Santo
S
Comfort
Ann
A
Royce
Alan
A
D001552:Benzazepines / Q000737:chemistry* / Q000493:pharmacokinetics*; D004355:Drug Stability; D011237:Predictive Value of Tests; D012995:Solubility / Q000187:drug effects; D013607:Tablets; D014867:Water / Q000737:chemistry* / Q000378:metabolism
D001552:Benzazepines; D013607:Tablets; D014867:Water; C044946:benazepril