Table 2.

Common methods used for cocrystal screening and synthesis.

Method	Mechanism	Characteristic
Reaction crystallizationa	Solution process based on generating supersaturation with respect to cocrystal by dissolving reactants and or changing pH	Useful for both screening and synthesis; amenable for large and small scales
Solvo-thermalb	Solution process based on generating supersaturation with respect to cocrystal through temperature change	Requires screening for solvents with similar reactant solubilities to minimize their crystallization
Sonic slurryc	Solution process based on generating supersaturation with respect to cocrystal by subjecting a slurry of reactants to ultrasound pulses	May reduce the supersaturation for nucleation and increase nucelation rate
Co-grindingd	Mechanical stresses enhance molecular molibity and lead to transformation of reactants to cocrystal	Solvent free method useful for screening
Liquid assisted grindinge	Cocrystal formation through solution and/or solid phase mediated process	Useful for screening but requires larger amounts of materials than RCM
Moisture/vapor sorptionf	Solution process involves generating supersaturation by exposing solid reactants to deliquescent materials	Suitable for screening by vapor sorption of solid mixtures
Melt crystallizationg	Cocrystal formation occurs through a melted phase	Useful for screening with small quantities of reactants by DSC and microscopy
Tween screw extrusion (TSE) and Hot melt extrusion (HME)h	High screw mixing can lead to cocrystal formation with (HME) or without (TSE) melting reactants	Continuous, single-step, solvent free and readily scalable process

^aRef.[53];

^bRef. [18, 36–39];

^cRef. [56, 63];

^dRef. [41, 42];

^eRef. [43–45];

^fRef. [58–60];

^gRef. [46, 47];

^hRef. [62, 64].