In-Silico Screening of Lipid-Based Drug Delivery Systems
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RESEARCH PAPER
In-Silico Screening of Lipid-Based Drug Delivery Systems Joscha Brinkmann 1
&
Lara Exner 1 & Christian Luebbert 1
&
Gabriele Sadowski 1
Received: 22 July 2020 / Accepted: 9 October 2020 # The Author(s) 2020
ABSTRACT Purpose This work proposes an in-silico screening method for identifying promising formulation candidates in complex lipidbased drug delivery systems (LBDDS). Method The approach is based on a minimum amount of experimental data for API solubilites in single excipients. Intermolecular interactions between APIs and excipients as well as between different excipients were accounted for by the Perturbed-Chain Statistical Associating Fluid Theory. The approach was applied to the in-silico screening of lipid-based formulations for ten model APIs (fenofibrate, ibuprofen, praziquantel, carbamazepine, cinnarizine, felodipine, naproxen, indomethacin, griseofulvin and glibenclamide) in mixtures of up to three out of nine excipients (tricaprylin, Capmul MCM, caprylic acid, Capryol™ 90, Lauroglycol™ FCC, Kolliphor TPGS, polyethylene glycol, carbitol and ethanol). Results For eight out of the ten investigated model APIs, the solubilities in the final formulations could be enhanced by up to 100 times compared to the solubility in pure tricaprylin. Fenofibrate, ibuprofen, praziquantel, carbamazepine are recommended as type I formulations, whereas cinnarizine and felodipine showed a distinctive solubility gain in type II formulations. Increased solubility was found for naproxen and indomethacin in type IIIb and type IV formulations. The solubility of griseofulvin and glibenclamide could be slightly enhanced in type IIIb formulations. The experimental validation agreed very well with the screening results. Conclusion The API solubility individually depends on the choice of excipients. The proposed in-silico-screening approach
allows formulators to quickly determine most-appropriate types of lipid-based formulations for a given API with low experimental effort.
* Gabriele Sadowski [email protected]
SUBSCRIPTS i,j component int intersection
1
TU Dortmund University, Laboratory of Thermodynamics, Emil-Figge-Str. 70, D-44227 Dortmund, Germany
KEY WORDS lipid-based formulations . PC-SAFT . solubility . thermodynamic modeling
NOMENCLATURE a h cp M m kB kii N Nassoc R p T u wi xi
Helmholtz energy molar enthalpy heat capacity molar mass segment number Boltzmann constant binary interaction parameter number of data points number of association sites ideal gas constant pressure temperature dispersion energy mass fraction mole fraction
GREEK CHARACTERS γ activity coefficient εAiBi association energy J. ρ density kg m−3 AiBi κ association volume σseg segment diameter Å
SUPERSCRIPTS
J mol−1 mJ mol−1 J (mol K)−1 g mol−1 J K−1 J (mol K)−1 bar K, °C J -
249
assoc disp hc L res S V
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associating dispersion hard chain liquid residual solid vapor
INTRODUCTION Many of the newly-developed active pharmaceutical ingredients (APIs) possess an insufficient solubility in water. If th
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