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A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol

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Abstract

Purpose

To examine the effect of common excipients such as sugars (sorbitol versus sucrose) on bioequivalence between pharmaceutical formulations, using ranitidine and metoprolol as model drugs.

Methods

Two single-dose, replicated, crossover studies were first conducted in healthy volunteers (N = 20 each) to compare the effect of 5 Gm of sorbitol and sucrose on bioequivalence of 150 mg ranitidine or 50 mg metoprolol in aqueous solution, followed by a single-dose, nonreplicated, crossover study (N = 24) to determine the threshold of sorbitol effect on bioequivalence of 150 mg ranitidine in solution.

Results

Ranitidine Cmax and AUC(0–∞) were decreased by ∼50% and 45%, respectively, in the presence of sorbitol versus sucrose. Similarly, sorbitol reduced metoprolol Cmax by 23% but had no significant effect on AUC(0–∞). An appreciable subject-by-formulation interaction was found for ranitidine Cmax and AUC(0–∞), as well as metoprolol Cmax. Sorbitol decreased the systemic exposure of ranitidine in a dose-dependent manner and affected bioequivalence at a level of 1.25 Gm or greater.

Conclusions

As exemplified by sorbitol, some common excipients have unexpected effect on bioavailability/bioequivalence, depending on the pharmacokinetic characteristics of the drug, as well as the type and amount of the excipient present in the formulation. More research is warranted to examine other ‘common’ excipients that may have unintended influence on bioavailability/bioequivalence.

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Acknowledgments

This work was supported, in part, by a contract from the Food and Drug Administration to the University of Tennessee, Memphis, Tennessee. The authors would like to thank Lawrence Lesko, Rabindra Patnaik and Lawrence Yu for their helpful discussion on the related topics during the early phase of this investigation.

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Author notes

  1. A. S. Hussain

    Present address: Sandoz, Inc., 506 Carnegie Center, Suite 400, Princeton, New Jersey, 08540, USA

Authors and Affiliations

  1. Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue Building 21, Rm. 3644, Silver Spring, Maryland, 20993-0002, USA

    M.-L. Chen

  2. Health Science Center, University of Tennessee, 874 Union Avenue, Memphis, Tennessee, 38163, USA

    A. B. Straughn, B. Meibohm & C. R. Yates

  3. Food and Drug Administration, 10903 New Hampshire Avenue, Life Sciences Building 64, Silver Spring, Maryland, 20993-0002, USA

    N. Sadrieh, P. J. Faustino, A. B. Ciavarella & A. S. Hussain

  4. 1700 SW 6th Ave., Boca Raton, Florida, 33486, USA

    M. Meyer

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Chen, ML., Straughn, A.B., Sadrieh, N. et al. A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol. Pharm Res 24, 73–80 (2007). https://doi.org/10.1007/s11095-006-9120-4

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