Dissolution of Crystalline Pharmaceuticals: Experimental Investigation and Thermodynamic Modeling

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 perturbed-chain 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

Design of Median Crystal Diameter Using Gassing Crystallization and Different Process Concepts

The reproducibility of product properties of normal batch cooling crystallizations is often insufficient. For a reliable design of product properties like the median diameter, it is essential to control the nucleation process. An innovative technology to induce nucleation during cooling crystallization is gassing. Therefore, quantification of the influence of gassing and process parameters is important. For this purpose, Design of Experiment approaches were used, investigating a linear cooling profile with constant cooling duration and quadratic cooling profiles with varied cooling duration. Succinic acid/water was used as the model system. The supersaturation where gassing is started was identified as most important design parameter using linear cooling profiles. Using quadratic cooling profiles, the median diameter can be mainly designed by adjusting the cooling duration. By the choice of the cooling profile and gassing supersaturation, it is possible to control the median diameter in a range between 300 and 750 μm. The results show also that independent from the cooling profile, gassing crystallization has an enlarging effect on the median diameter of product crystals. This effect can be used to reduce batch time for crystallization processes