Suitability of the z-Factor for Dissolution Simulation of Solid Oral Dosage Forms: Potential Pitfalls and Refinements.

Parameterization of dissolution profiles for subsequent use in in silico modeling and simulation is a crucial element for the success of extrapolating in vitro to in vivo release from solid oral dosage forms. The z-factor dissolution model is an option that can be utilized in commercial software such as GastroPlus™ to simulate the release from solid oral dosage forms. However, several aspects that can confound particle dissolution, such as disintegration and coning, are currently not taken into consideration in this model. To promote a more comprehensive use of the z-factor dissolution model, we discuss the scope of the model in its current modus operandi, highlight problems associated with the current approach and present potential solutions. Taking into account disintegration of dosage forms together with a calculation of the theoretical mass available for dissolution allows for a more realistic z-factor estimate that considers the dissolution process in terms of its two core components, dosage form disintegration and particle dissolution, independently. It is shown that separating these two elements allows for more flexible evaluation and use of the z-factor approach in modeling softwares, as both elements can then be scaled independently to describe the behavior in a range of simulated physiological environments.

Evaluation of Differences in Dosage Form Performance of Generics Using BCS-Based Biowaiver Specifications and Biopharmaceutical Modeling-Case Examples Amoxicillin and Doxycycline.

Drug products containing the antibiotics amoxicillin (500 mg as trihydrate) or doxycycline (200 mg as hyclate or monohydrate) with varying qualitative excipient composition were obtained from the German market and their biopharmaceutical properties were characterized in compendial quality control tests, dissolution tests run under BCS-based biowaiver conditions and dissolution tests using biorelevant media. Observed differences in disintegration time and dissolution rate were assessed according to BCS-based biowaiver dissolution specifications and in virtual bioequivalence trials using GastroPlus™. Great variation was observed in dosage form performance, and 2 out of 5 drug products for each active ingredient failed to demonstrate in vitro similarity using the BCS-based biowaiver specifications, with coning being identified as a key hindrance. Nonetheless, all drug products investigated were found to be equivalent in virtual trials, concordant with their market approval status, indicating that the current BCS-based biowaiver criteria are over-discriminating. To bridge the gap between in vitro and pharmacokinetic assessment of bioequivalence, modification of the experimental setup with the use of Peak Vessels™ and the validation of dissolution specifications with virtual bioequivalence trials appear to be promising approaches. However, neither approach is currently foreseen by the harmonized ICH M9 BCS-based biowaiver guidance.

The Discriminatory Power of the BCS-Based Biowaiver: A Retrospective With Focus on Essential Medicines.

This article summarizes historic developments, recent expert opinions, and (currently) unresolved challenges concerning the Biopharmaceutics Classification System (BCS)-based Biowaiver. An overview of approval statistics and application potential, case examples addressing the discriminatory power of the procedure, as well as an outlook on possible refinements in the future are provided and critically discussed. Over the last decade, regulatory guidance documents have been harmonized, for example, following scientific consent on allowing biowaivers for BCS class III drugs, making over 50% of orally administered drugs on the World Health Organization Essential Medicines List eligible for an abbreviated approval. Biowaiver monographs that present a complete risk-benefit evaluation for individual drugs have been issued by the International Pharmaceutical Federation for more than 25% of those drugs with the long-range aim of covering all essential drugs. Unresolved issues that have emerged from reported examples of false-negative and false-positive outcomes in the literature demand further adjustments to the regulatory requirements. Possible solutions for resolving these issues are the use of modeling and simulation and refined biorelevant in vitro tests that are better able to discriminate between dosage forms with unequal performance in vivo, potentially allowing biowaivers for selected BCS II drugs.

Solubility Determination of Active Pharmaceutical Ingredients Which Have Been Recently Added to the List of Essential Medicines in the Context of the Biopharmaceutics Classification System-Biowaiver.

Since the publication of Lindenberg et al., which classified orally administered active pharmaceutical ingredients (APIs) on the 2004 Essential Medicines List (EML) of the World Health Organization according to the Biopharmaceutics Classification System (BCS), various APIs have been added to the EML. In this work, BCS classifications for 16 of the orally administered APIs which were added to the EML after 2004 were determined. To establish a reliable solubility classification for all these compounds, a miniaturized shake-flask method was introduced. This method enables a fast, economical determination of the BCS solubility class while reliably discriminating between "highly soluble" and "not highly soluble" compounds. Nine of the 16 APIs investigated were classified as "highly soluble" compounds, making them potential candidates for an approval of multisource drug products via the BCS-based biowaiver procedure. The choice of dose definition (which currently varies among the guidances pertaining to BCS-based bioequivalence published by various regulatory authorities) had no effect on the solubility classification of any of the 16 substances evaluated. BCS classification of the compounds was then completed using permeability data obtained from the literature. As several APIs decomposed at one or more pH values, a decision tree for determining their solubility was established.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid.

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 µg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid.