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Wyttenbach N, Niederquell A, Ectors P, et al. Study and Computational Modeling of Fatty Acid Effects on Drug Solubility in Lipid-Based Systems. J Pharm Sci. 2021;doi: 10.1016/j.xphs.2021.11.023.
Wyttenbach, N., Niederquell, A., Ectors, P., & Kuentz, M. (2021). Study and Computational Modeling of Fatty Acid Effects on Drug Solubility in Lipid-Based Systems. Journal of pharmaceutical sciences, . https://doi.org/10.1016/j.xphs.2021.11.023
Wyttenbach, Nicole, et al. "Study and Computational Modeling of Fatty Acid Effects on Drug Solubility in Lipid-Based Systems." Journal of pharmaceutical sciences vol. (2021). doi: https://doi.org/10.1016/j.xphs.2021.11.023
Wyttenbach N, Niederquell A, Ectors P, Kuentz M. Study and Computational Modeling of Fatty Acid Effects on Drug Solubility in Lipid-Based Systems. J Pharm Sci. 2021 Dec 02; doi: 10.1016/j.xphs.2021.11.023. Epub 2021 Dec 02. PMID: 34863971.
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J Pharm Sci. 2021 Dec 02; doi: 10.1016/j.xphs.2021.11.023. Epub 2021 Dec 02.

Study and Computational Modeling of Fatty Acid Effects on Drug Solubility in Lipid-Based Systems.

Journal of pharmaceutical sciences

Nicole Wyttenbach, Andreas Niederquell, Philipp Ectors, Martin Kuentz

Affiliations

  1. F. Hoffmann-La Roche Ltd., Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstr. 124, CH- 4070 Basel, Switzerland.
  2. University of Applied Sciences and Arts Northwest. Switzerland, Institute of Pharma Technology Hofackerstr. 30, CH- 4132 Muttenz, Switzerland.
  3. F. Hoffmann-La Roche Ltd., Pharma Technical Development, Grenzacherstr. 124, CH-4070 Basel, Switzerland.
  4. University of Applied Sciences and Arts Northwest. Switzerland, Institute of Pharma Technology Hofackerstr. 30, CH- 4132 Muttenz, Switzerland. Electronic address: [email protected].

PMID: 34863971 DOI: 10.1016/j.xphs.2021.11.023

Abstract

Lipid-based systems have many advantages in formulation of poorly water-soluble drugs but issues of a limited solvent capacity are often encountered in development. One of the possible solubilization approaches of especially basic drugs could be the addition of fatty acids to oils but currently, a systematic study is lacking. Therefore, the present work investigated apparently neutral and basic drugs in medium chain triglycerides (MCT) alone and with added either caproic acid (C6), caprylic acid (C8), capric acid (C10) or oleic acid (C18:1) at different levels (5 - 20%, w/w). A miniaturized solubility assay was used together with X-ray diffraction to analyze the residual solid and finally, solubility data were modeled using the conductor-like screening model for real solvents (COSMO-RS). Some drug bases had an MCT solubility of only a few mg/ml or less but addition of fatty acids provided in some formulations exceptional drug loading of up to about 20% (w/w). The solubility changes were in general more pronounced the shorter the chain length was and the longest oleic acid even displayed a negative effect in mixtures of celecoxib and fenofibrate. The COSMO-RS prediction accuracy was highly specific for the given compounds with root mean square errors (RMSE) ranging from an excellent 0.07 to a highest value of 1.12. The latter was obtained with the strongest model base pimozide for which a new solid form was found in some samples. In conclusion, targeting specific molecular interactions with the solute combined with mechanistic modeling provides new tools to advance lipid-based drug delivery.

Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Keywords: In silico modeling; Lipid; Lipid-based formulation(s); Solid-state; Solubility; Solubilization

Conflict of interest statement

Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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