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Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 3: Understanding Supersaturation Versus Precipitation Potential During the In Vitro Digestion of Type I, II, IIIA, IIIB and IV Lipid-Based Formulations

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Abstract

Purpose

Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation – precipitation balance for a range of LBFs.

Methods

Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases.

Results

Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SRM) was >3. This threshold SRM value was remarkably consistent across all LBF and was also consistent with previous studies with danazol.

Conclusions

The maximum supersaturation ratio (SRM) provides an indication of the supersaturation ‘pressure’ exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

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Acknowledgments AND DISCLOSURES

This study results from a joint collaboration between members of the LFCS Consortium funded primarily by Capsugel and Sanofi R & D, with additional funding from Gattefossé, Merck Serono, NicOx, Roche, Bristol-Myers Squibb and Actelion. The authors would like to thank Dr. Laura Gordon and the Chemical Engineering department at Melbourne University for the XRPD analysis, and Rhiannon Smythe and Samuel Wood for determining the fenofibrate solubilities in the digested lipid formulations.

Author information

Author notes

  1. Hywel D. Williams

    Present address: Capsugel R&D, Strasbourg, France

Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, 3052, Australia

    Hywel D. Williams & Christopher J. H. Porter

  2. Department of Pharmaceutics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Philip Sassene, Karen Kleberg & Anette Müllertz

  3. Sanofi Research and Development, Montpellier, France

    Marilyn Calderone & Ross Blundell

  4. Capsugel R&D, Strasbourg, France

    Annabel Igonin, Jan Vertommen & Hassan Benameur

  5. Capsugel Product Development Center, Cambridge, Massachusetts, USA

    Eduardo Jule

  6. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, 3052, Australia

    Colin W. Pouton

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Correspondence to Colin W. Pouton or Christopher J. H. Porter.

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Williams, H.D., Sassene, P., Kleberg, K. et al. Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 3: Understanding Supersaturation Versus Precipitation Potential During the In Vitro Digestion of Type I, II, IIIA, IIIB and IV Lipid-Based Formulations. Pharm Res 30, 3059–3076 (2013). https://doi.org/10.1007/s11095-013-1038-z

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