**1. Introduction**

Co-crystals are crystalline complexes containing neutral molecular components combined by non-covalent forces forming a crystal framework [1]. Co-crystals are also defined as the combination of ionic or molecular pharmaceutical active ingredient (API) and co-crystal former that are solid at room temperature [2]. A comparison can also be drawn about the selection of salt. In this instance, the pKa controversy concerns the selection the acid-base duos that combine to form salts. Study displays that a pKa variance of minimum two digits (in base and acid) is essential to generate a salt that is solid in H2O. The formation of co-crystals can roughly be predicted by the value of ∆pKa; that is, if

**Figure 1.** *Common solid-state systems and their respective components.*

the ∆pKa is more than 3, then this monophasic homogeneous material usually falls in the category of salts, whereas if the ∆pKa is less than 2, then co-crystals are usually observed [3]. Accordingly, solvates hydrates, clathrates, or inclusion compounds (host and guest molecules), and pseudopolymorphs are excluded from the definition of co-crystals because all the mentioned species contain a liquid or gas component under ambient conditions, whereas a co-crystal contains only the solid constituents at room temperature. A general representation of various solid-state systems is given in **Figure 1** [1].

Synthesis of co-crystals is a formidable task due to numerous constrictions like the nature of a solvent, the reactants, (1:1) equivalent of the co-crystal former and API, stirring, pH, heat, sort of glassware, etc., which are the effective variables associated with the mechanism of co-crystallization. The question here is how the neutral molecules interact to form a single state of same union (co-crystal) rather than a collection of untainted crystals [4]. The answer to this question is that the force responsible for co-crystal formation is electrostatic in nature; that is, it involves the attraction affinity of negative charge for positive charge. Intermolecular forces like X⋅⋅⋅X interactions (X = F, Cl, Br, I), hydrogen bonding, π⋅⋅⋅π stacking, and van der Waal interactions are involved for the development of co-crystals [5]. Thus, non-covalent interactions are the key factor in designing of co-crystal systems.

Many methods are available for the co-crystal production in which grinding is the pioneer one that was used the first time in 1893 when equal molarities of p-benzoquinone and hydroquinone produced quinhydrone co-crystals [6]. In the interim, numerous new well-defined co-crystals have been formed by both wet grinding and neat methods.

In this chapter, co-crystallization techniques and co-crystallization characterization techniques such as SC-XRD and powder X-ray diffractometry (P-XRD) which are two techniques extensively used for the structure determination of solids having single large crystal and solid in the powder form, respectively, density functional theory (DFT), spectroscopic analysis (UV/IR/FTIR), and morphological (PXRD, SEM, SXRD) and thermal analysis (DSC, TGA) are reviewed.
