Crystal16 and Crystalline for Combined Cooling and Anti-solvent Crystallization

Crystallization is the most important separation and purification method in the pharmaceutical industry. More than 80% of the active pharmaceutical ingredients are produced via crystallization and about 70% of solid chemicals. In crystallization of active ingredients (AIs), the solubility curve helps to choose a suitable crystallization process (e.g. cooling, anti-solvent or evaporative crystallization) and determines the yield. Therefore, knowledge of the solubility is essential for the design of the crystallization process. Additionally, it is estimated that 40% of the new drug compounds may be regarded as poorly soluble with that percentage even higher for certain therapeutic classes. Combined cooling and anti-solvent crystallization is a critical step in pharmaceutical manufacturing, especially for poorly soluble active ingredients.
The solubility of a compound in organic solvents or water is equally important for screen design and later for process development. For designing a screen, for instance around cooling crystallization, you need to select solvents that have sufficient solubility and that have a high dependency of solubility on temperature. In addition, a selection of solvents and mixtures that spans the range of possible chemical functionalities will maximize the chances of finding new, interesting and developable solid forms.
Measuring the solubility requires accurate control of temperature and sharp observation of the phase transition, i.e. full dissolution of the solid phase, combined with information regarding the composition of the system. For many compounds, the solubility increases with temperature. A compound may have considerably different solubility depending on the investigated solvent/solvent system. Solubility data are used to take critical decisions from the earliest stages of drug discovery, throughout the entire process development and up to formulation. Since generally a reproducible solubility dataset over a temperature or compositional range is required, many data points need to be determined separately. This can be labor intensive and time consuming. Crystal16 and Crystalline instruments offer invaluable tools to automate the execution of solubility measurements in quick, controllable and reproducible manner.
Moreover, when solubility data is required at constant temperature, which is often the case in multicomponent mixtures, solvent addition (SA) is the method of choice. In the solvent addition method, the temperature is kept constant. Upon dilution of a suspension of known composition by the addition of solvent, a clear point is detected when the equilibrium concentration is reached. The clear point can be detected by a decrease in solution concentration or by the disappearing of crystals. Crystalline instrument is used to monitor the suspension by using the particle viewer cameras. The cameras take pictures at regular intervals and the clear point is determined as the first picture without crystals. In the Crystalline, eight measurements may be conducted simultaneously. The cameras of the Crystalline clearly capture the thinning of the suspension upon the addition of solvent, until no crystals are detected anymore.
Knowledge of solubility is essential in order to reach the supreme goal of crystallization: provide customers with a product having acceptable cost, yield, purity, and material properties.

If you would like to learn more about this topic, please check these references or check our publication database for the poster on chiral compounds:
1. Variankaval, N.; Cote, A. S.; Doherty, M. F. Aiche J. 2008, 54 (7), 1682–1688;
2. Giulietti, M.; Seckler, M.; Derenzo, S.; Ré, M.; Cekinski, E. Braz. J. Chem. Eng. 2001, 18(4), 423–440;
3. Reus, M.A.; van der Heijden A.E.D.M.; ter Horst J.H. Org. Process. Res. Dev. 2015, 19 (8), 1004-1011;
4. White paper on Solubility - Technobis Crystallization Systems.