Rochele Cassanta Rossi

Development and validation of discriminating method of dissolution for fosamprenavir tablets based on in vivo data

The aim of this work is to develop and validate a dissolution test for fosamprenavir tablets (Telzir(®)) based on in vivo data. The appropriate conditions were determined after testing sink conditions in dissolution medium, rotation speed and stability of the drug. In vivo release profiles were obtained from the literature. The fraction (and percentage) of dose absorbed (FA) was calculated by deconvolution, using the Wagner-Nelson method. For this formulation, the best dissolution conditions were achieved using a USP apparatus 1 900 ml of medium containing HCl 0.01 M at a rotation speed of 75 rpm. Under these conditions a significant linear relationship between fraction of drug absorbed versus dissolved was obtained (R(2)=0.984) and a level-A IVIVC was established. The in vitro dissolution samples were analyzed using a HPLC method and the validation was performed according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. The discriminatory power of the dissolution method was challenged. The kinetics of dissolution was determined using model-dependent methods. The dissolution profiles were best described by the Hixson-Crowell model. The dissolution test was validated and could be applied to evaluate the dissolution profile of fosamprenavir tablets.

Comparative Validation Study to Assay Milnacipran Hydrochloride in Capsules by a Stability-Indicating LC and a Second Order Derivative UV Spectroscopic Methods

A selective stability-indicating LC method and a second order derivative UV spectroscopic method (UV-D 2 ) were developed to assay milnacipran in pharmaceutical formulation. The LC method was developed with a Nucleosil C8 analytical column and a mobile phase consisting of acetonitrile, water and triethylamine (at 210 nm). The validation of UV-D 2 (zero-crossing method) was based on recording the second-derivative spectra for milnacipran hydrochloride at 268.5 nm of its solutions in 0.1 N HCl and the parameters specificity, linearity, precision, and accuracy were evaluated to both methods. The linear dynamic range was 20–100μg-mL -1 (R 2 ≥0.999). The validation data showed that both methods are reproducible, providing an accurate (98.5% to 101.6%) and precise (RSD ≤ 1.0%) quantitation of milnacipran in capsules. The methods proposed showed satisfactory results and were statistically equivalent.

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

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

Stability-indicating comparative methods using mekc and lc for determination of olmesartan medoxomil

A stability-indicating method using MEKC was validated for the analysis of olmesartan medoxomil in tablets. Successful separation was achieved using a fused silica capillary (40 cm x 50 µm i.d.); background electrolyte consisted of a combination of 10 mmol L-1 borate buffer and 5 mmol L-1 anionic detergent sodium dodecyl sulfate (95:5; v/v) pH 6.5; hydrodynamic mode at 50 mBar for 5 s; 25 kV separation voltage at 25 oC; and column temperature 25 oC with detection at 257 nm. The proposed method, validated following ICH guidelines, was applied to the determination of this antihypertensive with good results compared with an LC method.