In Vitro Evaluation of an Anticholinergic Agent in a Timed-Release Solid Dosage Formulation

Abstract

Determinations of intact drug content and in vitro dissolution tests were carried out on a commercially available brand of the anticholinergic drug propantheline in 15-mg single-dose and 30-mg sustained-release tablets. These tests were made following a report of unsatisfactory therapeutic response in human subjects after ingestion of the 30-mg sustained-release dosage form. A chemical assay, specific for intact drug, showed that all tablets contained essentially the labeled amount of active drug species (±4%). However, the slow dissolution of the first 15mg of drug (a usual single dose) from the 30-mg dosage form, as observed in acidic solution (0.1N HC1), was unexpected based on manufacturer claims. Older and fresher lots of the 30-mg formulation, both of which fell within a recently revised 2-year expiration period at the time of testing, released only 6.0±1.4mg of active ingredient during the 1st hr compared to 14.5±0.7mg from regular 15-mg tablets. Of the 30-mg tablets, the fresher lot released consistently more drug with time; the difference reached a statistically significant level of p<0.01 at 2hr. The dissolution rates of all tablets were enhanced in more alkaline media, and little difference (p>0.2) was evident between the older and fresher sustained-release lots at any time during 4-hr dissolution trials when the medium had been adjusted to pH 6.38 or above at 1hr. In vitro dissolution test results correlated well with in vivo findings and showed that rapid dissolution of the initial 15mg of propantheline from solid dosage forms in acidic gastric juices is critical to its therapeutic effectiveness. It was concluded that reformulation of the 30-mg sustained-release dosage form to promote more rapid release of the first 15mg of drug or full reliance on single-dose tablets is necessary to ensure therapeutic efficacy.