Cocrystallized

Cocrystallized refers to the formation of a cocrystal, a crystalline solid composed of two or more molecular components in a fixed stoichiometric ratio that are held together by relatively weak, non-covalent interactions. In pharmaceutical contexts, one component is typically an active pharmaceutical ingredient (API) and the other a coformer chosen to participate in the crystal lattice. The components do not undergo a permanent chemical change, unlike salts formed by proton transfer.

The lattice is defined by hydrogen bonds, π–π interactions, and other non-covalent forces, creating a new crystalline phase with properties derived from both constituents. Coformers are often carboxylic acids, amides, amino acids, or other small molecules that can form complementary bonding motifs. The term “cocrystallized” describes the API or other component that has been incorporated into such a crystal structure.

Cocrystallization is used to tune solid-state properties such as solubility, dissolution rate, hygroscopicity, stability, and mechanical properties. These changes can improve drug formulation and processing, enabling enhanced bioavailability, reduced variability, or easier manufacturing, while maintaining the molecular integrity of the API.

Cocrystals can be prepared by solution crystallization, grinding (mechanochemical synthesis), slurry conversion, and anti-solvent crystallization, as well as by melt-based methods. They may also form during spray drying or hot-melt extrusion. Characterization relies on X-ray diffraction (single-crystal or powder) to confirm crystal structure, along with differential scanning calorimetry, thermogravimetric analysis, infrared or Raman spectroscopy, and solid-state NMR.

Examples include carbamazepine–nicotinamide and caffeine–oxalic acid cocrystals, among others, which illustrate how cocrystallization can tailor properties without altering the chemical identity of the components.