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Eutectic Freeze Crystallization

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Eutectic is a single-phase crystalline compound consisting of two or more molecules combined in a certain stoichiometric ratio by non-covalent bonding. Compared with APIs, eutectic crystals have advantages in solubility, dissolution rate, bioavailability, and stability. Therefore, eutectic crystals are an effective method to improve the solubility of BSC class II and class IV compounds.

Drug eutectic refers to the formation of novel co-crystals with specific physicochemical properties by the action of hydrogen or other non-covalent bonds between APIs and eutectic formers. The formation of eutectic provides room for the transformation of amorphous or difficult-to-crystallize APIs into easily handled and stable solid crystals. Co-crystallization of drugs can improve the physicochemical properties (e.g., solubility, dissolution, bioavailability, stability, etc.) of drugs without changing the covalent bonds between APIs molecules.

Micrographs of: (a,b) pure LOV) (c) pure BEN, (d) LOV-BEN eutectic mixture, (e) pure SAL, (f) LOV-SAL eutectic mixture, (g) pure CIN and (h) LOV-CIN eutectic mixture.Figure 1. Micrographs of: (a,b) pure LOV) (c) pure BEN, (d) LOV-BEN eutectic mixture, (e) pure SAL, (f) LOV-SAL eutectic mixture, (g) pure CIN and (h) LOV-CIN eutectic mixture. (Araya-Sibaja, A. M., et al., 2019)

Various methods such as solvent volatilization, freezing crystallization, vapor diffusion, liquid-liquid diffusion, sublimation, and eutectic generation are often used in crystal culture. Among them, freezing crystallization is a crystallization method that takes advantage of the difference in freezing points between different compounds in solution and achieves separation and purification by cooling the whole system and precipitating substances in a different order according to different temperature gradients.

The general technical method

Workflow of eutectic freeze crystallization method.Figure 2. Workflow of eutectic freeze crystallization method.

Cryo-crystallization can be coupled with other techniques to form new crystallization technologies, such as ultrasonic cryo-crystallization and magnetic field cryo-crystallization. By introducing static or variable magnetic fields of different strengths into the conventional crystallization incubation process, magnetic fields have been found to increase the subcooling of aqueous solutions, and the time in the subcooled state, and to affect the nucleation process of ice crystals.

Studying the pocket region of "protein-ligand" by studying its eutectic structure is important for understanding protein function, drug design, and analysis of biomolecular interaction mechanisms. Eutectic structures are needed for the development of small molecule drugs, antigen-antibody complexes, PROTAC, and enzyme catalytic mechanisms, among other fields.

In addition to the conventional co-crystallization method, Creative Biostructure also has a mature MicroED technology, which can break the bottleneck that the size of co-crystal of complexes is not enough for analysis, and only nanometer-sized crystals are needed to obtain the analysis data and obtain the complete structure. Please contact us for more information on eutectic freeze crystallization.

Ordering Process

Ordering Process

Reference

  1. Araya-Sibaja A M, et al. Drug solubility enhancement through the preparation of multicomponent organic materials: Eutectics of lovastatin with carboxylic acids. Pharmaceutics. 2019. 11(3): 112.

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