A Discriminatory and Biorelevant Dissolution Test Method for Simvastatin Drug Products

Biorelevant in vitro dissolution is a useful technique for qualitative forecasting of the in vivo behavior of a formulation. A biorelevant dissolution medium for simvastatin was developed with a lower concentration of surfactant (0.1% sodium lauryl sulfate, SLS) in the medium as compared with the 0.5% SLS concentration stated in the USP monograph. The slower dissolution rate of simvastatin tablets in 0.1% SLS relative to a self-emulsifying formulation of simvastatin correlated with the enhanced bioavailability of the self-emulsifying formulation in albino rats. INTRODUCTION The dissolution test is utilized as either a research tool for optimizing new formulations or a quality control test to routinely monitor the uniformity and reproducibility of production batches. In biological systems, drug dissolution is an important attribute before systemic absorption (1). The dissolution test should reflect significant differences in bioavailability arising from differences in dissolution (2) and discriminate formulation factors such as polymers, particle surface area, or physical and chemical characteristics of the drug (3, 4). When dissolution testing is used to forecast the in vivo performance of a drug, it is critical that the in vitro test should mimic the in vivo conditions as closely as possible. The nature of the dissolution medium affects the dissolution rate. The preferred media are pH 4.5 acetate/phosphate buffer, pH 6.8 phosphate buffer, pH 7.2/7.4 phosphate buffer, water, or 0.1 N hydrochloric acid (3). For poorly water-soluble drugs that do not show pH-dependent solubility, an approach to increase the dissolution rate is the addition of wetting agents, solubilizing agents, or surfactants to the dissolution media (5). The use of surfactants in the dissolution media for sparingly soluble drugs is physiologically relevant and well-documented. Sodium lauryl sulfate is a surfactant commonly used in dissolution media for poorly soluble drugs (6). A dissolution medium containing surfactant can better simulate the environment of the gastrointestinal tract than a medium containing organic solvents or other nonphysiological substances. The addition of a small amount of surfactant below its critical micelle concentration is often sufficient to solubilize certain drug products (7). In those cases where a higher concentration of surfactant leads to faster dissolution, any potential correlation with in vivo performance is lost; therefore, a low concentration of surfactant is a modifier of choice. The dissolution test is generally performed under sink conditions (i.e., the material already in solution should not exert a modifying effect on the rate of dissolution). Sink conditions occur in a volume of dissolution medium that is 3–10 times greater than the saturation volume for the drug. Drug dissolution or release-rate data based on a discriminating and well-designed test is of tremendous value in formulation development. The USP monograph for dissolution testing of simvastatin tablets lists pH 7.0 phosphate buffer with 0.5% SLS as the medium (8). SLS-containing Fasted State Simulated Gastric Fluid (FaSSGFSLS) is probably the most commonly used FaSSGF, having 0.25% (8.67 mM) SLS. A medium containing 0.5% (17.34 mM) SLS may result in solubility overestimation (9). Therefore, the objective of our study was to evaluate different concentration levels (0.1–0.5%) of SLS in the dissolution medium for two solid oral dosage formulations of simvastatin and to determine any effect on the biorelevance of the dissolution method. EXPERIMENTAL Materials Reagent grade disodium hydrogen phosphate and sodium hydroxide were obtained from S.D. Fine-Chem Ltd. Simvastatin was obtained from Ranbaxy Labs, India. Sodium lauryl sulfate and buffer ingredients were purchased from CDH, India. Distilled water was used in the preparation of all test media. Simvastatin (Zocor) 40-mg tablets were obtained from Merck, USA. A self-microemulsifying formulation of simvastatin 40 mg was manufactured in our lab; the formulation is described in Table 1. Corresponding author. diss-16-04-03.indd 11 11/22/2009 11:35:38 AM dx.doi.org/10.14227/DT160409P11