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M. Sc. Raj Schneider

M. Sc. Raj Schneider Foto von M. Sc. Raj Schneider

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+49(231)755-3008

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Fakultät Bio- und Chemieingenieurwesen
Emil-Figge-Str. 70
44227 Dortmund

Raum G2-516

Supersaturation behavior of amorphous formulations of active pharmaceutical ingredients (API)

Abstract
The low aqueous solubility of crystalline APIs often leads to their slow dissolution and insufficient oral bioavailability. Amorphous formulations, where the amorphous API is incorporated into hydrophilic polymeric excipients, have been demonstrated to yield concentrations above equilibrium solubility of the crystalline API, thus enhancing intestinal absorption [1]. To prevent API recrystallization in the intestinal tract upon dissolution of the amorphous form, it is essential to develop theoretical models to understand and even predict the dissolution/recrystallization phenomena at API supersaturation.

Schneider_Figure_1



Description:
During amorphous formulation dissolution the supersaturation phenomenon actually is a coupling behavior of dissolution and recrystallization of the amorphous API which occur simultaneously. The effect of the polymeric excipient of the formation during these processes is not really understood so far.  It might act as a solublizer (co-solvent), which increases API dissolution and decreases API crystallization from thermodynamic point-of-view.  On the other hand, the polymer might also inhibit the recrystallization of a specific amorphous API from kinetic point-of-view.

Ji, Paus and Sadowski [3] developed a two-step chemical-potential-gradient model integrated with Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) [4] to quantitatively model/predict dissolution kinetics of amorphous API/polymer formulations at concentrations far below the crystalline solubility of the API. To model/predict dissolution behavior in the supersaturation range it is necessary to simultaneously account for the recrystallization kinetics. 

The aim of this project is to investigate the influence of polymeric excipients on the supersaturation behavior of amorphous formulations. A theoretical model which considers the simultaneous dissolution and recrystallization of API and combines PC-SAFT [4] will be developed to predict the supersaturation behavior of amorphous formulations.

Schneider_Figure_2

The completion of this project will provide important information for choosing a suitable excipient to reach sufficient bioavailability.



References:

[1] J. Brouwwers, M. E. Brewster, P. Augustijns:
"Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? "
Journal of Pharmaceutical Sciences, vol. 98, pp. 2549-2572, 2009.
[2] W. Curatolo, J. A. Nightingale, S. M. Herbig:
"Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu."
Pharmaceutical Researchvol 26, pp. 1419-1432, 2009.
[3] Y. Ji, R. Paus, A. Prudic, C. Lubbert, G. Sadowski:
"A Novel Approach for Analyzing the Dissolution Mechanism of Solid Dispersions"
Pharmaceutical Research, vol. 32, pp. 2559-78, 2015.
[4] J. Gross, G. Sadowski:
"Perturbed-chain SAFT: An equation of state based on a perturbation theory for chain molecules"
Industrial & Engineering Chemistry Research, vol. 40, pp. 1244-1260, Feb 21 2001.