The expiry date is thus 40.9 months after initial preparation.

Although accelerated storage testing based on the use of the Arrhenius equation has resulted in a very significant saving of time, it still involves the time-consuming step of the initial determination of the order of reaction for the decomposition. While most investigators have emphasised the need for a knowledge of the exact kinetic pathway of degradation, some have bypassed this initial step by assuming a particular decomposition model. At less than 10% degradation and within the limits of experimental error involved in stability studies, it is not possible to distinguish between zero-, first- or simple second-order kinetics using curve-fitting techniques; consequently, the assumption of firstorder kinetics for any decomposition reaction should involve minimum error. In fact, it was shown that there was a linear relationship between the logarithm of t0.9 (the time taken for the concentration of the reactant to decompose to 90% of its original value) and the reciprocal temperature, which was independent of the order of reaction for the decomposition of a series of drugs.28 On the basis of these findings it was suggested that the use of such linear plots to determine t0.9 at the required temperature would provide a rapid, and yet sufficiently accurate, means of studying decomposition rate during the development stage.

Even with the modifications suggested above, the method of stability testing based on the Arrhenius equation is still time-consuming, involving as it does the separate determination of rate constants at a series of elevated temperatures. Experimental techniques have been developed29,30 which enable the decomposition rate to be determined from a single experiment. Such methods involve raising the temperature of the product in accordance with a predetermined temperature-time programme and are consequently referred to as nonisothermal stability studies.

Any suitable temperature-time programme may be used. In the method of Rogers25 the k

0 0

Post a comment