Dissolution Testing for Poorly Soluble Drugs: A Continuing Perspective

The development of a meaningful dissolution procedure for drug products with limited water solubility has been a challenge to both the pharmaceutical industry and the agencies that regulate them. These challenges include developing and validating the test methods, ensuring that methods are appropriately discriminatory, and addressing the potential for an in vivo–in vitro correlation (IVIVC). Dissolution test media selection should be justified for pH (recommended pH range is 1.2–7.5) as well as surfactant type (ionic versus non-ionic) and amount. If the drug is not soluble in the in vivo pH range, with or without surfactants, then the use of nonaqueous media can be preferred with proper justifications. Physical modifications of the drug, such as particle size reduction, use of metastable polymorphs, eutectic mixtures, solid dispersions, or complexation, are being widely used in the industry to enhance the drug dissolution characteristics. In recent years, newer physical modifications (e.g., microemulsions and nanocrystals) are giving promising results in enhancement of drug dissolution and bioavailability of poorly soluble drugs. Whatever method is used by the dissolution scientists, it must aim towards the cheaper but most effective approach to enhance the dissolution behavior of poorly soluble drugs. *Corresponding author. INTRODUCTION Drug dissolution testing is an analytical technique used to assess release profiles of drugs from pharmaceutical products, generally solid oral products such as tablets and capsules. For a dosage form to produce its effect, drug must be released and generally should be dissolved in the fluids of the gastrointestinal tract. Drug dissolution testing plays an important role as a routine quality control test, for characterizing the quality of the product, for accepting product sameness under SUPAC (Scale-Up and Post-Approval Changes) related changes, in waiving bioequivalence requirements for lower strengths of a dosage form, and in supporting waivers for other bioequivalence requirements (1). Dissolution from the dosage form involves mainly two steps: liberation of the drug from the formulation matrix (disintegration) followed by the dissolution of the drug (solubilization of the drug particles) in the liquid medium. The overall rate of dissolution depends on the slower of these two steps. In the first step of dissolution, the cohesive properties of the formulated drug play a key role. For solid dosage forms, these properties include disintegration and erosion. If the first step of dissolution is rate-limiting, then the rate of dissolution is considered disintegration controlled. In the second step of dissolution (i.e., solubilization of drug particles), the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical form (e.g., amorphous or polymorph and primary particle size) play an important role. If this latter step is rate-limiting, then the rate of dissolution is dissolution controlled. This is the case for most poorly soluble compounds in immediate-release (IR) formulations whose solubility is less than 1–2 mg/L in the pH range of 2–8. Recent advanced technologies like combinatorial chemistry and high-throughput screening are effective in the discovery of new drugs with good pharmacological activities (3). About 35–40% of the drugs discovered with these technologies have poor aqueous solubility (4). Dissolution testing of poorly soluble compounds in immediate-release (IR) solid dosage forms poses many challenges. These challenges include developing and validating the test method, ensuring that the method is appropriately discriminatory, and addressing the potential for an in vivo–in vitro relationship (IVIVR) or correlation (IVIVC). Satisfying all of these challenges and developing a meaningful dissolution method is a large task, because the extent of release is too low (i.e., one cannot get 100% of the dosage form dissolved) and secondly, the rate of release is too slow (i.e., one cannot get dissolution fast enough for a convenient test) (5). Here, an attempt has been made to highlight the approaches to improve the dissolution of poorly soluble drugs. To improve the dissolution of poorly soluble drugs, one needs to increase the maximum dissolvable dose in the dissolution media. The maximum dissolvable dose of the drug is given by Maximum Dissolvable Dose = V × CS / Sink where V is the dissolution medium volume, C S is the saturated solubility of the compound in the medium, and diss-17-03-05.indd 24 8/23/2010 11:08:51 AM dx.doi.org/10.14227/DT170310P24