Effects of Paddle-Shaft Position and Inclination of Dissolution Apparatus on the Dissolution Rate of Carbamazepine Tablets and the Equivalence Assessment of Generic Drugs

Dissolution testing is useful for controlling the quality of an oral generic equivalent (GE) drug and rejecting a bioinequivalent GE. However, several sources of variability in dissolution tests can affect evaluations of drug quality. Recently, we reported that shifting the paddle shaft off-center significantly changed the dissolution rate of sodium diclofenac tablets, with the result that some GE tablets did not meet the criteria for equivalence. The aim of this study was to confirm the effect of paddle position and to investigate the effect of inclining the dissolution apparatus on the dissolution rates, quality assessment, and equivalence assessment of rapid-release carbamazepine tablets using a brand product (BR) and three GE products. Dissolution tests were carried out on the basis of the Japanese Pharmacopoeia (JP) 15 and Japanese Orange Book paddle methods. The paddle was shifted 5 mm from the center of the vessel, and the dissolution apparatus was inclined backward approximately 4° from the horizontal position. The percentage of drug that dissolved was then calculated. Shifting the paddle significantly increased the dissolution rate for all tablets, whereas inclining the apparatus reduced the dissolution rate for some tablets. All carbamazepine tablets passed the quality evaluation, and all GE products were judged equivalent to the BR product when the paddle was positioned centrally and the apparatus was horizontal. However, the BR product did not meet the criteria of the quality evaluation, and one GE product was judged not equivalent to the BR product in the 5-mm-off-center experiment, suggesting that the position of the paddle affects the quality and equivalence assessment of the rapid-release carbamazepine tablets. In conclusion, offsetting the paddle position from the center could affect the equivalence, as well as the quality assessment, of GEs by enhancing the dissolution rate. Inclining the apparatus reduced the dissolution rate but did not affect the equivalence assessment of GEs. INTRODUCTION Recently, the importance of generic-equivalent (GE) drugs, which are safe and effective lower-cost alternatives to brand-name (BR) prescription drugs, has increased from a medical–financial viewpoint. The use of GEs reduces medical and healthcare costs. However, the 2007–2008 market share of GEs in Japan is 17.2%, which is smaller than that in other developed countries (68.6% in USA, 63.7% in Germany, 60.9% in England, and 39.8% in France) (1). In a questionnaire provided by the Japan Medical Association in November 2007 (2), approximately 20% of physicians would not prescribe GEs, even if their patients requested them to do so. Some 85% of these physicians questioned the quality of GEs. Therefore, quality assurance is extremely important to eliminate anxiety over GEs and to increase their usage in Japan. Dissolution testing is a useful tool for eliminating GE products that are not equivalent and for evaluating the quality of these drugs. However, several factors affect the dissolution rate. Temperature, acidity, or alkalinity of the sample solution (3, 4); accumulation of the sample in the vessel (4); aeration of the test medium (5); rotation and agitation of the paddle shaft (3, 6, 7); sample position (3); *Corresponding author. These authors contributed equally to this report. diss-17-02-06.indd 36 2010-6-1 9:49:59 dx.doi.org/10.14227/DT170210P36