In Vitro Therapeutic Equivalence of Two Multisource (Generic) Formulations of Sodium Phenytoin (100 mg) Available in Peru

Abstract

This in vitro study evaluated the therapeutic equivalence of two multisource (generic) formulations of 100-mg phenytoin as immediate-release tablets available in the Peruvian pharmaceutical market, compared with the reference medicine, to establish interchangeability. The mean weight, hardness, and content of active substance were evaluated, prior to analyzing the dissolution profile. USP dissolution apparatus 2 (paddle) was used at 75 rpm with 900 mL of dissolution medium at 37 ± 0.5 °C at pH levels of 1.2, 4.5, and 6.8. The generic and reference formulations had similar weight or drug content, but hardness values were significantly different (p = 0.029). At pH 1.2, the generic products were considered therapeutically equivalent to the reference product based on similarity factor (f 2 ) and dissolution efficiency values; however, at pH 4.5 and 6.8, there were differences in dissolution performance based on f 2 values below the acceptable range.

In Vitro Biopharmaceutical Equivalence of 5-mg Glibenclamide Tabletsin Simulated Intestinal Fluid Without Enzymes

“…SPSS 23 and Microsoft Office Excel 2007 were used for statistical analysis. As a statistical indicator of the in vitro biopharmaceutical equivalence, f2, DE%, and MDT were used (10,35). DE% was determined with the formula: DE% = (AUCot × 100) / Q∞ × t∞, where AUCot is the area under the release curve from the initial time to the final time of the experiment; Q∞ is the mean amount of drug obtained at the end time (t∞) of the experiment.…”

“…Bioequivalence studies for multisource drugs are essential to ensure that the active pharmaceutical ingredient (API) is available at the site of action (4). In vivo bioequivalence studies assess relative bioavailability (pharmacokinetic), pharmacodynamics, or therapeutic effectiveness and are performed for class 2 and 4 high health-risk drugs; in vitro bioequivalence studies are carried out for class 1 and 3 highly soluble drugs, according to the Biopharmaceutical Classification System (BCS) (7)(8)(9)(10). Because glibenclamide is a class 2 drug with low aqueous solubility and high membrane permeability, it must be evaluated very rigorously through in vitro biopharmaceutical equivalence studies, including tests of weight, hardness, friability, content, disintegration, and dissolution (11)(12)(13)(14)(15).…”

“…To establish in vitro bioequivalence, various statistical models are applied, such as the difference factor (f1), which measures the percentage of error between two dissolution profiles at pre-established sampling times; if the result is zero, then the two profiles are considered equal, if f1is 0-15, then the two profiles are similar, and if the f1is greater than 15, then the profiles are different (10,16,17). The similarity factor (f2), proposed by Moore and Flanner, measures the similarity between two dissolution curves (17)(18)(19).…”

“…The similarity factor (f2), proposed by Moore and Flanner, measures the similarity between two dissolution curves (17)(18)(19). This factor is calculated from the mean percentage of dissolution at each sampling time (9,10,17). If the result is 100, the two dissolution profiles are identical, if f2is 50-100, then the two profiles are considered to be similar, with some differences.…”

“…For example, an f2 value of 83.5 means that there is a difference of 2%, 65 means the difference is 5%, 50 means the difference is 10%, 41 indicates a difference of 15%, and 36 is a difference of 20% (8,20). Another parameter used to measure bioequivalence is dissolution efficiency (DE%), which is the area under the dissolution curve at a predetermined time, expressed as a percentage of the rectangle described for 100% dissolution at the same time; the resulting value should optimally be 90% for immediate-release drugs, which indicates that rapid dissolution of the API occurs in the early stages of the dissolution profile (9,10). Additionally, mean dissolution time (MDT) determines how fast the drug (solid form) dissolves in the dissolution medium (9,10).…”