In Vitro Dissolution Testing with Flow-Through Method: A Technical Note

Abstract

In vitro dissolution testing is important for providing process control and quality assurance, determination of stability release characteristics of the product over time, and facilitating certain regulatory determinations (e.g., absence of effect of minor formulation changes or of change in manufacturing site on performance). In the past two decades, the dissolution test has also been widely discussed to serve as an indicator of how the formulation will perform in vivo (1–3). Although basket and paddle methods are currently the most popular methods for many drug products, both methods are operated under closed finite sink condition and cannot mimic the conditions present in the digestive system. A flow-through method using the official USP 4 apparatus operated in open-loop mode is capable of maintaining a continuous flow of fresh dissolution medium, thus, maintaining infinite sink conditions (3–6). This operational mode provides an environment potentially closer to that of the digestive tract. Thus, this technique may offer advantages for establishing in vitro and in vivo correlations (IVIVCs). To compare dissolution testing under finite and infinite sink conditions, this study applied both paddle and flow-through methods for dissolution testing with disintegrating prednisone and nondisintegrating salicylic acid tablets. The closed- and open-loop configurations of the flow-through method were used to provide comparisons with the paddle method. In addition to studies based on the official USP dissolution apparatus, several authors have reported development of novel, multicompartment dissolution apparatus in their efforts to develop good IVIVCs (7–9; Hughes et al., private communication). The reported novel systems have potential to simulate in vivo condition such as gastric volume and pH, gastric emptying to the intestine, and intestinal volume and pH etc., which may give a good in vivo and in vitro correlation. However, these novel apparatus require special configurations or parts, which may be difficult to duplicate in other labs. This study applies the idea of a multicompartment dissolution apparatus but attempts to minimize modifications to the current official USP apparatus so as to facilitate adoption by other labs for application to their specific studies. In this study, the flow-through apparatus with open-loop configuration has been modified by adding a flow-through reservoir after the flow-through cell. This reservoir is maintained at intestinal pH. Disintegrating prednisone and nondisintegrating salicylic acid were used as test drugs.