María Guillermina Volonté

Dissolution Studies of Generic Medications: New Evidence of Deviations from the Transitivity Principle

Current international criteria to guarantee that tw o equivalent pharmaceutical medications are interchangeable establish that substitution may be done whenever studies indicate that a generic or similar product is bioequivalent to the reference product. The principle of transitivity defines interchangeability between approved pharmaceutical equivalents (i.e., given two generic products B and C and a reference A, if B and C are bioequivalent to A, then B and C are assumed to be bioequivalent although bioequivalence between them has not been actually assessed). In this study, the goal was to test the applicability of the transitivity principle in establishing interchangeability between pharmaceutical equivalents. We obtained the dissolution profiles of all the products corresponding to tablets of ranitidine 300 mg and cephalexin 500 mg (Biopharmaceutics Classification System Class III), furosemide 40 mg (Class IV), and ibuprofen 400 mg and 600 mg (BCS Class II) available in the Argentinean pharmaceutical market. Dissolution profiles of all possible pairs were compared through similarity factor f2. The results obtained bring into question the general validity of the transitivity principle, as many examples were observed to have dissolution profiles similar to the reference product, yet were not equivalent. Although this has only been assessed through in vitro tests, our results are potentially important, as a number of recent reports have suggested the extension of biowaivers to certain BCS Class II and Class III products, including ranitidine hydrochloride and ibuprofen.

Biopharmaceutical Relevance of Dissolution Profile Comparison: Proposal of a Combined Approach

The aims of the present study were to evaluate the performance of the main methods proposed for the comparison of percentage dissolved versus time curves and to recommend a more biorelevant combined approach for the comparison of dissolution profiles of multisource drug products. In vitro dissolution tests of four brands of oxcarbazepine (OxCBZ) tablets were performed, and the resulting profiles were compared by model-independent, model-dependent, and ANOVA-based statistical methods. After a careful analysis of the results, some methods were chosen and applied to the comparison of dissolution profiles of four brands of carbamazepine (CBZ) tablets and two brands of phenytoin (PHT) capsules. Finally, these in vitro results were qualitatively correlated with the corresponding in vivo results previously obtained with the same CBZ and PHT products assayed in healthy volunteers. The analysis of the dissolution data obtained with OxCBZ tablets allowed discarding the ANOVA-based statistical methods since in all cases they were over-discriminating from a biopharmaceutical point of view. The remaining comparison methods were applied to in vitro profiles of CBZ and PHT products and the results correlated with in vivo data. The most suitable methods for the biopharmaceutical comparison of in vitro dissolution profiles were the model-independent ones, and among them, the best correlations were the f2 similarity factor along with a measure of the dissolution extent (e.g., area under the curve). This combined approach gives a robust and informative result with the most biopharmaceutical relevance.

A derivative UV spectrophotometric method for the determination of levothyroxine sodium in tablets

A derivative UV (D-UV) spectrophotometric method was developed for the determination of Levothyroxine Sodium (L-T4) in tablets of different doses. Quantification was performed using the second derivative of the absorption spectrum at 253 nm (2D253) in methanol: water (50: 50; v/v) (pH 11.2). The method was validated and compared with an HPLC procedure carried out using a RP-18 column (125 × 4 mm, 5 μm) and methanol: phosphoric acid (0.1%) (70: 30, v/v) (pH 3) as mobile phase. Flow rate was set at 1.5 mL/min, and detection was performed at 225 nm. The proposed D-UV method was linear in the range 3.0–40.0 μg/mL with an appropriate precision and accuracy, and it was selective for the drug under study. On the other hand, results obtained by 2D253 analysis were similar to those obtained by HPLC, with no statistically significant differences between them. Therefore, it was concluded that the developed method is suitable for the determination of L-T4 in tablets at the tested doses.

Comparative bioavailability of diltiazem in prolonged-release oral preparations.

This study was conducted to compare the bioavailability of two prolonged-release pharmaceutical forms containing 300 mg of diltiazem. The test formulation is a new design of tablets with a hydrophilic matrix, and the reference formulation is capsules containing prolonged liberation microgranules, in the same dose, that are commercially available in the pharmaceutical market. Diltiazem plasma concentrations were analyzed by high-performance liquid chromatography (HPLC), which involves solid-phase extraction for plasma sample preparation. Twelve healthy volunteers participated in the study, which had a single-dose, two-treatment, two-sequence-crossover, randomized design. The preparations were compared using pharmacokinetic parameters such as the area under the plasma concentration-time curve AUC(0–36), peak plasma concentration Cmax, and Cmax/AUC(0–36) ratio as a measure for the absorption rate. No statistically significant difference was observed for any of the parameters, and the 90% confidence intervals calculated for the ratio of the logarithmically transformed AUC(0–36) and Cmax/AUC(0–36) values of both formulations were within the bioequivalence limit of 0.80–1.25. Moreover, an in vitro study of dissolution according to USP 23 was conducted, and the in vitro parameters were calculated.