Development of a Discriminating In Vitro Dissolution Method for the Poorly Soluble Drug Rimonabant: Effect of Formulation Variables on Dosage Form Release Profiles

Abstract

The effect of formulation parameters on the in vitro release profile of a poorly soluble drug was investigated using rimonabant as model drug. A dissolution test was developed to evaluate the release profile of rimonabant from both 20mg film-coated tablet and capsule dosage forms. The test was applied to compare dissolution profiles of different dosage forms and to evaluate the effect of formulation parameters on the in vitro release profile of the drug. Four different commercially available products were evaluated, and the results obtained show very distinct rates and extent of dissolution among them. The type of excipients used in the capsule formulation significantly influenced the dissolution rate of the formulations studied. INTRODUCTION Many drugs are poorly soluble or insoluble in water, which results in poor bioavailability because the solubility of a drug is an important factor in determining the rate and extent of its absorption (1). Drug release rate is one of the most important parameters for solid oral drug delivery systems; therefore, the therapeutic response is a function of the concentration of drug available to be absorbed and reach the bloodstream (2). Physical factors important to drug dissolution include particle size, molecular size, hydrophilicity, and crystalline structure. The volume of medium into which the drug must dissolve can also play a role in determining the dissolution rate (3). Physical modifications often aim to increase the surface area, solubility, and wettability of the powder particles and, therefore, typically focus on particle size reduction or generation of amorphous states. Classically, particle size reduction is performed by milling, and a wide variety of apparatus is available. The increase in bioavailability after micronization of drugs is well known, and the technique has been applied to a variety of poorly water-soluble compounds (4). Another approach for improving solubility is the complexation and incorporation of drugs into cyclodextrins (5). The incorporation of adjuvants (e.g., diluents, lubricants, and surfactants) into the formulation of a solid oral dosage form can cause significant effects on the dissolution rate of drugs, especially those that are hydrophobic and poorly soluble (6). In the case of Class 2 drugs in the Biopharmaceutics Classification System (BCS), dissolution may be the ratelimiting step for drug absorption, so suitable dissolution tests can be used to predict differences in bioavailability among different formulations (7). The choice of formulation is often of critical importance in establishing a successful product for oral administration of this class of drugs (8). In this context, the purpose of the present study was to evaluate and compare the dissolution profiles of several compounded formulations to that of a reference product using rimonabant as a model drug. This drug is poorly soluble in water and has high in vitro permeability; it is therefore classified as BCS Class 2 (9). To date, there is no published dissolution test for the evaluation of in vitro release profiles of this drug from immediate-release solid oral dosage forms. Therefore, we also developed a dissolution method for rimonabant to determine its release profiles from pharmaceutical formulations. We prepared several formulations containing different types and proportions of excipients and variations in drug particle size to assess the influence of formulation and drug physical properties on the dissolution kinetics of the drug MATERIALS AND METHODS Chemicals Rimonabant reference substance (99.5%) was purchased from Sequoia Research Products (Pangbourne, UK). Acomplia (Sanofi–Aventis, Paris, France) film-coated tablets and compounded capsules containing 20 mg of rimonabant were obtained from commercial sources. Gradient grade LiChrosolv acetonitrile and methanol were *Corresponding author. Current address: Departamento de Farmacia Industrial, Universidade Federal de Santa Maria, Av. Roraima 1000, 97105900 Santa Maria, RS, Brazil. e-mail: crolim@smail.ufsm.br dx.doi.org/10.14227/DT190312P30