*2.1.2 Cooling co-crystallization*

It is performed by decreasing the temperature of the solution. A mixture of components and a solvent is heated to obtain a clear saturated solution and then, the temperature is decreased to get a supersaturated solution, and finally, co-crystals are

#### **Figure 2.**

*Ternary phase diagrams with unlike solubility of components C1 plus C2 in the solvent S. Area "a" is for solution; "b" is for the component C1 and solvent; "c" is for the component C1 and co-crystal; "d" is for the component C2 and solvent; "e" is for the component C2 and co-crystal, and "f" is for the co-crystal.*

precipitated out [14]. Cooling of crystals technique was used to formulate co-crystals of nicotinamide:carbamazepine using ethyl alcohol in an excess to create an accessible solution co-crystallization approach. Solvent miscellany, desupersaturation kinetics, and requirement of the thermodynamically stable co-crystal functioning series were used in the design of the procedure, which was displayed throughout to have at 1 L gauge the 90% yield. An analogous methodology was used by Holaň et al. in the formation of citric acid:agomelatine co-crystals, and the effect of freezing level and seed quantity on the crystal proportion dissemination in the concluding yield was evaluated [15].

## *2.1.3 Reaction co-crystallization*

This method is based on the above **Figure 2** for components having different solubility in a solvent. A component C1 is added to the solution of a component C2 near its saturation to obtain co-crystals [16]. The reaction co-crystallization is used to harvest co-crystals of carbamazepine:saccharin by mixing different starting solutions of both of the preparatory components. The technique was systematized by the ternary stage illustration and demonstrated a resilient functioning series for the co-crystal development and validated the predictable connection in induction period and supersaturation. Nicotinamide:carbamazepine co-crystal production was also implemented by the reaction co-crystallization using open-air conditions [17].

#### *2.1.4 Isothermal slurry conversion*

In this methodology, slurry is obtained with the conversion time depending on various factors such as nucleation, growth kinetics, relative concentration of coformer and API, and the resultant solubility [18]. This methodology implicates the formation of the mixture of the API and co-crystal former, generally in a stoichiometric ratio, in a solvent with a compact portion of deposit incessantly enduring in excess of a solvent. Technique, the addition of the API to a mixture of co-crystal former in a solvent, can be also adjusted in functional terms. However, this is a solution-based process, which does not entail the production of an immaculate (completely dissolved) preliminary solution, as is the situation of prior approaches *Chemistry and Modern Techniques of Characterization of Co-Crystals DOI: http://dx.doi.org/10.5772/intechopen.108694*

pronounced above. The degree at which the slurry transformation transpires will diverge centered on the solubility, driving force, the comparative amount of the API and co-crystal former, and the cloud seeding and evolutionary kinetics of the system. A kinetic description of the isothermal slurry transformation of arbitrary co-crystals is inadequate. Zhang et al. scrutinized the adaptation time for theophylline to transform into a stoichiometric ratio glutaric acid co-crystal. While the slurry transformation process usually required a more quantity of starting components and will experience some material damage owing to enduring solubility in the solvent, it is considered as one of the best auspicious screening methodologies owing to its extraordinary proficiency [19].

#### **2.2 Solid state co-crystallization**

These methods of co-crystallization involve limited or no use of solvent and are therefore regarded as environment friendly, green, and economically viable. Following procedures are adopted in these methods.

#### *2.2.1 Grinding*

Grinding may be either neat grinding, that is, dry grinding or solvent-assisted grinding [20]. In dry or neat grinding method, stoichiometric amounts of selected solids for co-crystallization are mechanically (using mechanical force to create supramolecular synthons, that is, involving mechanochemistry, which is considered as eco-friendly route as it avoids the use of solvents) or manually mixed at high pressure while avoiding their melting [21]. A major disadvantage of the dry grinding is the absence of heating stage involved in co-crystallization, which is shown by many studies to be important in the co-crystallization process [22]. On the other hand in the liquid-assisted milling the above shortcoming is overtaken through adding little amount of liquid to the solids for the co-crystallization. The little quantity of solvent performs as a catalyst for the co-crystal development; better results have been obtained through this method [23]. Two carboxylic acid:sulfathiazole co-crystals were formed by milling stoichiometric proportions of sulfathiazole and the needed carboxylic acid in a Retsch blender grind at a frequency of 25 Hz and a temperature not exceeding 37°C for 90 min and it was done [22]. Compared with solution-based approaches, solid milling is associated with higher performance because no product is lost due to its solubility in a solvent. Problems with dry milling can comprise impossibility to form a co-crystal, inadequate modifications to the co-crystal, and crystalline flaws with the presence of possible several amorphous compounds [24].

#### *2.2.2 Contact formation*

Co-crystals have been prepared through mixing without using any mechanical force; however, this process requires controlled conditions of temperature and pressure. Various factors affect the formation of co-crystals such as pre-milling, moisture, and size of premixed materials [25, 26]. The extemporaneous production of co-crystals by intermixing an uncontaminated target molecule and co-crystal former using organized conditions has been stated. During co-crystallization, no mechanical forces are employed in this technique. However, in various circumstances, slight milling of untainted constituents separately afore intermixing has been completed. The impact on the co-crystallization rate of pre-milling of the elementary constituents

carbamazepine and nicotinamide was described by Rodriguez-Hornedo et al. It was shown that the co-crystallization rate can be increased by using milled components as compared to unmilled components (12 vs. 80 days, correspondingly). Furthermore, the greater co-crystallization degree has been described for the indistinguishable arrangement at maximum temperatures and comparative dampness, nevertheless of the mechanical stimulation [20]. The formation of an isoniazid benzoic acid co-crystal *via* spontaneous co-crystallization was reported as well [24]. We found that a higher frequency of pre-grinding of uncontaminated components significantly improved the reaction rate [27].
