*2.2.4 Hot melt extrusion (HME)*

Hot melt extrusion is a comparatively modern addition to the co-crystal grounding options. Using a warmed screw extruder, this special technique achieves simultaneous softening and combining of the API and co-crystal former. Usually, the initial components are combined in the definite stoichiometric ratio and supplied to the warmed extruder. The complete intermixing of the starting components in the stoichiometric ratio occurs by melting. The co-crystal nucleates amenably in the melt and the uncontaminated co-crystal extrudate is separated from the extruder constantly. The benefits of the technique are as follows: the purging using organic solvents, rapid working times, improved adaptation compared with the solution-based techniques, reduced leftover, and the tools offering itself well to the constant drug manufacturing [8]. **C**o-crystal formation of carbamazepine:cinnamic acid by a single screw and twin screw extruder is reported by Moradiya et al. Co-crystals prepared by the twin screw extruder presented improved suspension characteristics as compared with those gained *via* single screw/solution-based procedures. Extrusion melt as an incessant engineering performance was applied to harvest indomethacin:saccharin co-crystals. Their studies demonstrated the three critical process parameters (CPP): temperature

#### *Chemistry and Modern Techniques of Characterization of Co-Crystals DOI: http://dx.doi.org/10.5772/intechopen.108694*

profile, screw speed, and forage rate, which are desired in the engineering of goodquality co-crystals. Furthermore, the rate of dissolution of co-crystals is not affected by temperature. However, as was established on Rietveld investigation the co-crystal uniform crystallinity is affected by temperature. It has been shown that in the conditions of unevenness in the crystal-form quality because of the process temperature, the dissolution degree will be affected successively. Moreover, the dissolution profile can be affected by the unit size of co-crystals.

This method helps in avoiding solvents and saves time due to the increased conversion to co-crystals. Besides other benefits of HME, this method falls within the requirement of US FDA practice analytical expertise for controlling, analyzing, and designing the engineering of pharmaceuticals. For example, drugs such as Rezulin, Kaletra, and Norvir have been prepared through this method and got FDA approval [28]. Other benefits include scaling-up of production to an industrial scale and being more economical because it is a continuous process.

#### **2.3 Miscellaneous methods of co-crystal preparation**

#### *2.3.1 Heat-induced co-crystallization*

Co-crystallization method using heat is a novel method to form co-crystals. It has several advantages compared with the solvent evaporation method such as it does not need any organic solvent and can be used without drug coformer solubility determination that is a time-consuming and laborious work [29].

### *2.3.2 Spray drying method*

Spray drying is an instant and incessant method for solid manufacturing, generating dry fine particles from precursor *via* a warm air torrent [30, 31]. For drug-coformer different solubility systems, where an uncontaminated co-crystal cannot be designed by the solvent evaporation technique, co-crystallization *via* spray drying process can be used as an alternative process. Theophylline: nicotinamide, carbamazepine:glutaric acid, caffeine:glutaric acid, and succinic acid:urea co-crystals, as instances of different schemes, their untainted co-crystals cannot be produced by the solvent evaporation process; however, when spray drying process is employed, it efficaciously produces uncontaminated co-crystals. Patil et al. reported the cocrystallization *via* the spray drying process using carbamazepine and nicotinamide as drug and coformer models respectively in a stoichiometric ratio. Accidentally, nicotinamide:carbamazepine co-crystal produced by the spray drying methodology has an analogous characteristic with a co-crystal produced by the liquid facilitating grinding [32].
