In this work, a two-step chemical-potential-gradient model based on nonequilibrium thermodynamic principles was developed to investigate the dissolution mechanism of crystalline active pharmaceutical ingredients (APIs). The perturbedchain statistical associating fluid theory was used to calculate the required solubilities and chemical potentials of the investigated APIs. The statistical rate theory was used to describe the mass-transfer rate of the APIs at the solid−liquid interface during the dissolution process. Dissolution profiles of indomethacin, naproxen, and glibenclamide in water and in buffered solutions at pH 5.0, 6.5, and 7.2 were measured using a rotating-disk system (USP II). The specific dissolution mechanisms of the APIs, such as surface reaction and diffusion, were analyzed by applying the proposed model to identify the rate-controlling step. The results show that the dissolution mechanisms of indomethacin, naproxen, and glibenclamide change with varying pH values of the solution medium. On the basis of the calculated rate constants, the dissolution profiles were modeled with a high degree of accuracy when compared with the experimental data.
For the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs) to be improved, the transformation of crystalline APIs to the amorphous state has often been shown to be advantageous. As it is often difficult to measure the solubility of amorphous APIs, the application of thermodynamic models is the method of choice for determining the solubility advantage. In this work, the temperature-dependent solubility advantage of an amorphous API versus its crystalline form was predicted for five poorly soluble APIs in water (glibenclamide, griseofulvin, hydrochlorothiazide, indomethacin, and itraconazole) based on modeling the API/solvent phase diagrams using the perturbed-chain statistical associating fluid theory (PC-SAFT). Evaluation of the performance of this approach was performed by comparing the predicted solubility advantage to experimental data and to the solubility advantage calculated by the commonly applied Gibbs-energy-difference method. For all of the systems considered, PC-SAFT predictions of the solubility advantage are significantly more accurate than the results obtained from the Gibbs-energy-difference method.
The chemical-potential-gradient model combined with PC-SAFT can be used to analyze the dissolution mechanism of solid dispersions and to describe and predict the dissolution profiles of API as function of stirring speed, temperature and pH value of the medium. This work helps to find appropriate ways to improve the dissolution rate of poorly-soluble APIs.
The solubility of cinnarizine has been investigated in acetonitrile, butyl acetate, 1-butanol, 2-propanol, and water in a temperature range from 288.15 K to 313.15 K. During crystallization from these solvents two different crystal morphologies of cinnarizine were observed. The caloric properties (melting temperature, melting enthalpy, and the difference in the heat capacity of solid and liquid cinnarizin) were measured by differential scanning calorimetry. The temperature-dependent solubility of cinnarizine in different organic solvents and in water was modeled using the perturbed-chain statistical associating fluid theory and was in good agreement with the experimental data.
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