**1.1 Crystal engineering and supramolecular chemistry in co-crystals formation**

Crystal engineering can be used to create pharmaceutical co-crystals with the goal of enhancing an API's solid-state characteristics without changing its fundamental structure. A model for the quick development of medicinal co-crystals was created through crystal engineering. It can be described as an application of supramolecular chemistry concepts to solid states, with a focus on the notion that crystalline solids are real-world examples of self-assembly [20, 21] Co-crystals are created through intermolecular interactions such as hydrogen bonds, stacking interactions, and van der Waals contact forces. By changing the intermolecular interactions that regulate the breaking and formation of non-covalent bonds, such as hydrogen bonding, van der Waals force, stacking, electrostatic interactions, and halogen bonding, crystal engineering involves changing the crystal packing of a solid material [22, 23]. In the study of co-crystals, the term supramolecular synthon is widely employed. It is referred to as structural units inside supramolecular that can be created by known hypothetical synthetic procedures involving intermolecular interactions. This guarantees generality, which subsequently results in the predictability of one-, two- and three-dimensional patterns produced by intermolecular interactions. Supramolecular chemistry is nothing more than noncovalent molecular bonding that is recognized as a lock and key principle in biological processes through the concept of complementarity and selectivity. Carboxylic acids,

**Figure 3.** *Typical hydrogen bond utilized in crystal engineering [24].*

*Modification of Physicochemical Properties of Active Pharmaceutical Ingredient… DOI: http://dx.doi.org/10.5772/intechopen.110129*

#### **Figure 4.**

*Indomethacin: Saccharine co-crystal structure [33].*

amides, carbohydrates, alcohols and amino acids are good examples of pharmaceutically approved crystallizers that can be combined with APIs. **Figure 3** depicts the most prevalent supramolecular synthon used in pharmaceutical co-crystals.

The carboxylic acid functional group, which is present in many medications, has been extensively researched in the field of pharmaceutical co-crystals. The synthesis of carboxylic acid homosynthon through the C∙O⋯H∙O hydrogen bond is highly frequent when the hydrogen bond donor and acceptor are self-complementary [25]. A second popularly researched homosynthon is the amide homodimer, which forms co-crystals *via* the CO⋯H∙N hydrogen bond.

A part from homosynthons, some favourable heterosynthons are carboxylic acidpyridine, carboxylic-amide and alcohol-ether. Recently, studies of hydrogen bonds competition have attracted increasing interest from a number of researchers [26, 27]. Heterosynthons are stronger than homosynthons; for example, the acid-amide heterosynthons favoured over both carboxylic acid and amide homodimer [28]. Through analysis of the Cambridge Structural Database (CSD) [29], it is discovered that the competitive hydroxyl-hydroxyl homosynthon is substantially favoured over the hydroxyl-pyridine and hydroxyl-cyano heterosynthons. One of the most popular heterosynthons, carboxylic acid-pyridine heterosynthons, contains an O∙H⋯N hydrogen bond, which is generated when the carboxylic acid reacts with a suitable N-containing heterocycle [30, 31]. In contrast to carboxylic acid homodimer, carboxylic acid-pyridine heterosynthons were preferred, according to the CSD study [32]. These empirical findings about the hierarchy of supramolecular synthons are very helpful for designing co-crystals. Reality, however, does not always support this. The structure of the indomethacin and saccharin (IND-SAC) co-crystals revealed that, contrary to the more advantageous indomethacin carboxylic acid saccharin imide heterosynthons predicted by empirical rules, the indomethacin carboxylic acid dimer interacts with the saccharin imide dimer synthon through a weak N∙H⋯O bond in **Figure 4** [33].
