A New Crescent-shaped Spindle for Drug Dissolution Testing—But Why a New Spindle?

Abstract

Assessment of drug dissolution from solid oral dosage forms such as tablets and capsules is an established practice,and an integral part of pharmaceutical product development and quality evaluation. The rationale for conducting such a test is based on the fact that for a drug to be absorbed from gastrointestinal (GI) tract to systemic circulation, it must be released from the product and dissolved in aqueous based GI tract fluid. In general, without dissolution in aqueous based medium, absorption of the drug in the body may not occur, resulting in lack of anticipated therapeutic effects. Thus drug and drug product dissolution characteristics may directly be related to efficacy of a pharmaceutical product. Considering its critical importance and extensive use, the testing aspect for measuring dissolution is surprisingly simple in concept and practice. In fact, drug dissolution measurement may be considered as a specific form of solubility measurement. However a critical difference between solubility determination and dissolution testing is that solubility is measured once the solution becomes saturated, a single point answer, but dissolution is measured at single and/or multiple times and usually below saturation. Commonly, solubilities are determined in pure solvents (aqueous solution or organic) at room temperature (~20oC) in a beaker or Erlenmeyer flask with a magnetic stirrer. Drug dissolution is measured at 37oC in water or aqueous based buffers (pH range of 1 to 7) in round bottom containers with special stirrers known as Paddle and Basket [1]. A schematic representation of dissolution vessels and stirrers is shown in Figure 1. Generally known as dissolution apparatuses, they are commercially available with accessories to conduct testing under precisely controlled mechanical and operational parameters. Generally, drug dissolution tests are conducted using Paddle or Basket apparatuses containing 900 mL of medium, with spindle rotation speeds between 50 and 150 rpm, most often 50 or 100 rpm. The choice of spindle type and rpm appears to be based on traditional use rather than from scientific rationale. The tests are conducted for various durations from 15 minutes to 24 hours, with frequent sampling, depending on the nature of products. The results are reported as cumulated percent drug dissolved in appropriate times, e.g., 75% Q in 45 minutes. Based on experimental details and observations during the product development phase, the test, or a simpler version of the test, becomes a quality control tool to ascertain lot-to-lot consistency of drug release. Up to this stage there are generally no issues in explaining the need for dissolution testing, conducting it and reporting the results. This is where simplicity of the drug dissolution testing ends. The main difficulty and complexity in dissolution testing is not in conducting the experiments, but obtaining reproducible results and interpreting and relating the results to product attributes and their biological response (e.g. bioavailability of drug), commonly referred to as in vitro/in vivo correlation (IVIVC). This is where no, or limited, successes have been achieved. Unfortunately, this issue has been with us since the early days, with the hope that if enough controls and strict guidance for conducting dissolution studies are established, these shortcomings will either be eliminated or at least be controlled.