ASSESSMENT OF PHARMACEUTICAL QUALITY OF FUROSEMIDE TABLETS FROM MULTINATIONAL MARKETS

This report describes results of a collaborative study in which sample s of the 40-mg strength of furosemide tablets were evaluated following a common protocol based on British (BP), European (Ph. fur), and US P harmacopoeial (USP) specifications. Several tests, including identific ation, uniformity of mass, and dissolution, were performed In total, e xcluding Lasix lots, results for 162 lots obtained from 115 manufactur ers or suppliers were submitted. Also, 23 laboratories identified and submitted data for 34 lots of Lasix products available in their countr ies. There were no reported abnormalities in the physical test require ments of the products analyzed. The summaries (n, mean, and 95% CI) of the assay results for the ''standard sample'' (a common sample), Lasi x lots from participating countries, and for all other furosemide prod ucts, respectively, are as follows: 30, 99.8%, 96-104; 33, 100.0%, 94- 106; and 162, 99.6 94-105. About half (similar to 62%) of the reported uniformity of mass results based on tablet weights were in the range 150-175 mg/tablet. However, there appears to be a notable variability in tablet weights that would result in significant differences in the ratios (0.14 to 0.40) of active ingredient to excipient The reported d isintegration times ranged from 0 (instantaneous) to 18 min, with most less than I min. The drug dissolution testing was conducted with phos phate buffer at pH 5.8 (USP recommended). Another test was conducted w ith acetate buffer at pH 4.6 (noncompendial). There appears to be rema rkable similarity in overall percentage of drug release from the three types of products (standard sample, Lasix lots, and other products). Although apparently there is a very wide spread in dissolution charact eristics of the products tested the analyses of variance did not detec t differences among the products tested and to this extent, would not indicate differences ences in bioavailability characteristics for I-ne st of these products. If is observed that about 20-38% of the variabil ity in dissolution testing is not product related (i.e., if is from th e dissolution testing itself), while the remaining 62-80% variability is product related (manufacturing, formulation, etc). The results of t his multinational collaborative study showed that most of the furosemi de products available in different countries met the required pharmace utical quality standards, including drug-release characteristics. Base d oil an extensive statistical analysis, the main concern front the st udy was that the high variability in drug dissolution testing would re quire wide tolerance standards (e.g., pharmacopoeial standards). This may result in lack of needed discriminating ability of the test in rev ealing the impacts of formulation and manufacturing changes on in vitr o, and perhaps in vivo, drug-release characteristics.