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978-3-8439-2549-5, Reihe Thermodynamik
Solubility and Dissolution of Pharmaceuticals (Band 20)
193 Seiten, Dissertation Technische Universität Dortmund (2015), Softcover, A5
In this work the solubility and dissolution of several crystalline APIs as well as amorphous APIs and their formulations were systematically investigated and analyzed using a novel thermodynamic approach.
The temperature-dependent solubility of amorphous API and thus the solubility advantage versus the crystalline form was predicted based on predictions of the API/solvent phase diagrams using PC-SAFT. It was shown for all selected systems that PC-SAFT solubility predictions are significantly more accurate than the results obtained from other methods described in literature.
Additionally, a two-step chemical-potential-gradient model based upon non-equilibrium thermodynamic principles was developed in order to investigate the dissolution mechanism and to predict the dissolution profiles of crystalline and amorphous APIs. Within the model, PC-SAFT was used to calculate the required solubilities and chemical potentials of the investigated APIs. Intrinsic dissolution profiles of several APIs as well as their formulations were measured under various relevant conditions to analyze different influencing factors like temperature, stirring speed, pH value, ionic strength and the presence of excipients. The specific dissolution mechanisms of the APIs were analyzed by applying the proposed model to identify the rate-controlling step. The results show that the dissolution mechanisms of the APIs can change with e.g. varying pH value or in the presence of excipients during dissolution. Based upon the calculated rate constants, it was shown, that the dissolution profiles could be modeled and even predicted with a high degree of accuracy when compared with the experimental data.
Continuative, the model was applied to predict the dissolution profiles of the cylindrical tablets under different conditions based on the analysis of their intrinsic dissolution profiles as well as on the determination of the surface-area reduction of the API tablets during dissolution. It was shown that the predicted dissolution profiles of the tablets under different conditions were in a good accordance to the experimental findings.