Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System.

The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development. Over the years, physiologically adapted media and buffers were introduced with the intention to better predict the in vivo solubility and dissolution of drug substances. Water, buffer solutions, compendial media, micellar solubilization media, and biorelevant media are reviewed. At this time point, there is no universal medium available which can be used to predict every drug substance's solubility or a drug product's in vivo dissolution behavior. However, there have been many improvements and additions made to media to optimize their in vivo predictability; for example, the current phosphate concentrations in buffers seem to be too high to correlate with the carbonate buffer concentrations in vivo. Biorelevant media were updated to correlate them better with the composition of human intestinal fluids. The BCS was introduced into regulatory sciences as a scientific risk management tool to waive bioequivalence studies under certain conditions. Today's different guidance documents define the dose-solubility ratio differently. As shown for amoxicillin, this can cause more confusion than certainty for globally operating companies. Harmonization of BCS guidelines is highly desirable.

Enzymatic activity in the presence of surfactants commonly used in dissolution media, Part 1: Pepsin.

The United States Pharmacopeia (USP) General Chapters Dissolution 〈711〉 and Disintegration and Dissolution of Dietary Supplements 〈2040〉 allows the use of enzymes in dissolution media when gelatin capsules do not conform to dissolution specifications due to cross linking. Possible interactions between enzymes and surfactants when used together in dissolution media could result in loss of the enzymatic activity. Pepsin is an enzyme commonly used in dissolution media, and in this work, the activity of pepsin was determined in the presence of different surfactants as usually found in case of dissolution tests of certain gelatin capsule formulations. Pepsin enzymatic activity was determined according to the Ninth Edition of the Food Chemicals Codex (FCC) 9 method, in dissolution conditions: simulated gastric fluid, 37 °C and 50 rpm. Sodium dodecyl sulfate (SDS), cetyltrimethyl ammonium bromide (CTAB), polysorbate 80 (Tween 80) and octoxynol 9 (Triton X100) in concentrations above and below their critical micellar concentrations were selected. Results showed a significant reduction in the activity of pepsin at all the concentrations of SDS assayed. On the contrary, CTAB, Tween 80, and Triton X100 did not alter the enzymatic activity at of pepsin any of the concentration assayed. This data demonstrates a rational selection of the surfactant to be used when pepsin is required in dissolution test.

The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers.

PURPOSE: Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. METHODS: Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. RESULTS: The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. CONCLUSION: The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.

Toward global standards for comparator pharmaceutical products: case studies of amoxicillin, metronidazole, and zidovudine in the Americas.

This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.

Development of a performance verification test for USP apparatus 4.

PURPOSE: To evaluate salicylic acid tablets as a candidate reference material in a Performance Verification Test (PVT) when a USP performance test for dissolution (General Chapter <711>) relies on USP Apparatus 4 (flow-through cell). METHODS: We developed a dissolution procedure relying on Apparatus 4 and salicylic acid tablets. Thereafter, a designed experiment was conducted to identify operational variables that significantly affect salicylic acid dissolution in this apparatus. RESULTS: Four variables (size of glass beads, cell temperature, flow rate, level of deaeration) and one combination effect (deaeration/bead size) were significant for mean percent dissolved. Two variables (tablet orientation, level of deaeration) were significant for standard deviation results, but these effects were less pronounced than those for mean percent dissolved results. Three variables (analyst, tester manufacturer, amount of glass beads) had no statistically significant effects on either the mean or standard deviation of the responses. CONCLUSIONS: The proposed PVT is capable of probing effects of changes in several critical operational parameters of Apparatus 4. Salicylic acid tablets were shown to be a suitable reference material for the PVT. The PVT using salicylic acid tablets satisfies important aspects of a PVT.

Establishing new acceptance limits for dissolution performance verification of USPC apparatus 1 and 2 using USPC prednisone tablets reference standard.

PURPOSE: On 1 March 2010, the US Pharmacopeial Convention released into commerce Lot P1I300 of its Prednisone Tablets Reference Standard for use in periodic performance verification testing (PVT) of dissolution Apparatus 1 and 2. This report presents the collaborative study data, development of the acceptance limits, and results from supporting work for this Lot. METHODS: The collaborative study involved 25 collaborators who provided data for Apparatus 1 and 31 who provided data for Apparatus 2. These limits are for the geometric mean and percent coefficient of variation (%CV) instead of per-individual results as for prior lots. Stability of results and sensitivity to test performance parameters were also studied. RESULTS: To determine new PVT acceptance limits, the authors calculated geometric mean and variance components as percent coefficient of variation. The move to the geometric mean and %CV criteria brings the acceptance criteria in line with current accepted statistics and provides a more realistic assessment of the system's performance. Results for Apparatus 1 are stable over time, but for Apparatus 2, the mean decreases over time. Acceptance criteria are adjusted for this trend. Lot P1 demonstrates sensitivity to test performance parameters (vessels and degassing). CONCLUSIONS: Apparatus 1 results are stable over time. Those in Apparatus 2 show a decrease over time in the geometric mean but show no trend in variability. The current tablets are shown to remain sensitive to two operational parameters, degassing and vessel dimensions, not covered by mechanical calibration. The new acceptance limits for Lot P1 are based on geometric mean and %CV for Prednisone Tablets Reference Standard Lot P1I300. The limits better control variability than the prior per-individual-result limits.

Change in criteria for USP dissolution performance verification tests.

The US Pharmacopeial Convention has been evaluating its performance verification tests (PVT) for several years. These tests help ensure the integrity of the US Pharmacopeia performance test when a dissolution procedure, as described in General Chapter Dissolution <711>, is relied upon to test a nonsolution orally administered dosage form. One result of the evaluation is a change in the PVT criterion from one based on individual tablet results to one based on the mean and variability of a set of tablets. This paper describes the new PVT and its criterion and how its acceptance limits are derived from results of a collaborative study, explains a two-stage option for the test, and presents operating characteristics.