Dissolution Method for Milnacipran Hydrochloride Capsules: Development, Validation, and Study of Changes in Dissolution Rate after Storage

Abstract

A dissolution test for milnacipran hydrochloride capsules was developed and validated according to international guidelines. After selection of the best conditions, the method was validated using USP Apparatus 1 (baskets), 50-rpm rotation speed, 900 mL of 0.01 N HCl, and test time of 60 min. The drug released was determined by both LC–UV (PDA) and UV–D methods. The kinetic parameters of drug release (mathematical models, t80%, and dissolution efficiency) were investigated, and the stability of the dosage form was evaluated by analyzing changes in the dissolution rate of milnacipran hydrochloride capsules during storage at 40 °C and 75% RH for different periods. INTRODUCTION Dissolution testing can provide information not only on the rate and extent of drug absorption in the body but also on the effects of drug biopharmaceutical properties and formulation principles on the release properties of a pharmaceutical product (1). Therefore, in vitro dissolution tests are usually used to assess the lot-to-lot quality of a drug product, guide development of new formulations, an d ensure continued product quality and performance after certain changes such as formulation, manufacturing process, site of manufacture, and the scale-up of the manufacturing process (2). The dissolution procedure requires an apparatus, a dissolution medium, and test conditions that provide a method that is discriminating yet sufficiently rugged and reproducible for day-to-day operation and capable of being transferred between laboratories. With regard to stability, the dissolution test should appropriately reflect relevant changes in the drug product caused by temperature, humidity, photosensitivity, and other stresses over time (3). Milnacipran hydrochloride (MNC), [101152-94-7], C15H22N2O⋅HCl, molecular weight 282.81 g/mol (Figure 1), is a racemic mixture with the chemical name (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride, and its solubility in water is 19 mg/mL (4–6). MNC is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated as an antidepressant and for the management of fibromyalgia. It shows preferential blockade of norepinephrine reuptake over serotonin and minimal activity at other receptors or transporters (6–8). MNC is well absorbed after oral administration with maximum concentrations reached within 2–4 h, and its absorption is not affected by food. It presents an absolute bioavailability of approximately 85–90% (9). The solubility and absolute bioavailability data for this drug classify it as Class I (high solubility and high permeability) based on the Biopharmaceutical Classification System. This is the case where the drug is well absorbed, and for immediate-release dosage forms that dissolve very rapidly, the absorption rate is controlled by the gastric emptying rate, and some correlation with dissolution rate is expected only if the dissolution is slower than gastric emptying (10). Methods for quantitation of milnacipran in combination with other antidepressants and their metabolites in biological fluids have been proposed (11–17). However, there is no compendial method to assay milnacipran hydrochloride in pharmaceutical dosage forms. A stability-indicating liquid chromatographic method with UV detection (LC–UV) and a second-order derivative UV spectroscopic method (UV–D) for quality control of milnacipran in capsules were developed and validated by the authors (18) according to guidelines (19–21). Therefore, the purpose of this work was to develop and validate a dissolution test for MNC in capsules (50 mg) based on its physicochemical characteristics and apply the LC–UV and UV–D methods to quantify the drug released from the capsules during the dissolution procedure. The kinetic parameters of drug release were investigated, and the stability of the dosage form was evaluated by analyzing changes in the dissolution rate of MNC capsules over time and in various storage conditions. EXPERIMENTAL Chemicals Milnacipran hydrochloride was purchased from Synfine Research (Canada). The pharmaceutical dosage form *Corresponding author. diss-18-03-06.indd 47 8/31/2011 1:38:15 PM dx.doi.org/10.14227/DT180311P47