The possibility of solid solution behavior of diastereomeric salts, containing multiple resolving agents of the same family (Dutch Resolution), is predicted by molecular modeling. Super-cells containing different ratios of resolving agents in the diastereomeric salt are constructed and optimized, and their lattice energy is computed. The energy difference between these "simulated solid solutions" and the native structures is related in an understandable fashion to the probability of solid solution formation. This procedure is applied to a family of diastereomeric salts of ephedrine and cyclic phosphoric acids, for which the ternary diagrams have been determined experimentally at 25 degrees C in ethanol. Good agreement between experimental and computational results indicates that this relatively simple and fast method could predict the stable character of solid solution behavior in binary systems.

Real-time Raman spectroscopy was used to characterize the solvent-mediated polymorphic transition and cooling crystallization of carvedilol. Kinetically preferred Form II was transformed into thermodynamically stable Form I during solvent-mediated phase transitions in ethyl acetate. The transition rate into Form I increased with rising temperature; however, at 0 °C a solvate form (Form VII) appeared. In the case of cooling crystallizations, the Form II polymorph was formed at 16−9 wt % drug concentration, while metastable solvates crystallized from a diluted, 2.9 wt % solution. A new solvate form, Form V*, was identified during crystallization in ethyl acetate, which is presumably related to Form V (known as an ethyl methyl ketone solvate in the literature). This study demonstrates the advantages of in-line Raman spectroscopy for monitoring in situ pharmaceutical crystallization by detecting the intermediate polymorphic transitions, which is fundamental in the development and operation of industrial crystallization processes.

Chiral recognition in the coordination sphere of a calcium ion that is coordinated to a simple tartaric acid derivative offers new possibilities for the preparative‐scale resolution of nonbasic compounds. An example of a mixed calcium salt formed upon resolution of racemic carboxylic acids is shown on the right.

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Crystallization as the most widespread purification, separation, and morphology-determining method is a critical technology that could be made safer and more economical by using continuous crystallization alternatives. Accordingly, this study aims to develop the continuous crystallization method for direct processing of a flow reaction mixture of acetylsalicylic acid (ASA) and to provide pure, homogeneous crystalline products for further formulation steps. The solid−liquid separation and the purification of the acetylsalicylic acid from the multicomponent mixture were accomplished in a single stage mixed suspension mixed product removal (MSMPR) continuous crystallizer equipped with an overflow and an inner buffer element to ensure the representative withdrawal of the product suspension. The effect of process parameters such as the operating temperature and the length of residence time (RT) on product quality and quantity were studied at two and three levels, respectively. Investigating these parameters, we found that higher operating temperatures (25 °C) and longer residence time (47 min) favor appropriate purity (>99.5%), and narrow crystal size distribution. By reducing the operating temperature (2.5 °C), the yield improved slightly (approximately 77%) and polydisperse products were characterized. The developed crystallization process can link the flow synthesis with the continuous formulation, and consequently serves a further step toward end-to-end production.

During an optical resolution it is the resolving agent that has the strongest influence on the outcome of the process. Applying a mixture of resolving agents can result either in antagonism or in synergy. We found that using mixtures of tartaric acid and its derivatives chiral selectivity is at least the same, but in several cases markedly better (synergistic effect), than the sum of the effect of the individual resolving agents. Thus, the "Dutch method," reported for the crystallization method, also works for distillation. A calculation method is applied for measuring the synergistic effect. Interestingly, an individually inactive resolving agent can be a useful contributor to the mixture of the resolving agents.

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The optimization of filling up crystallization of a specific active pharmaceutical ingredient (APIe) is presented and discussed. Filling up crystallization is a special cooling crystallization method the main goal of which is to narrow the crystal size distribution (CSD) of the product. Fast cooling of the solution is achieved in the first section of the cooling profile as the hot solution of the API for crystallization is fed into the crystallizer, where a constant but significantly lower temperature is maintained by choosing a suitable addition rate of the hot solution and utilizing the cooling efficiency of the crystallizer. The process of determination for formulation of the crystals occurs during the filling up period of the crystallization. As a result of optimization, a parameter range is specified from which the process parameters can be chosen ensuring that the product specifications comply with the limitations.