**4.1 Techniques for development of co-crystals**

Despite the fact that there are several APD-APIs, they lack key pharmacological activities due to poor physicochemical qualities such as low bioavailability, stability, and solubility [97]. Nanoparticles, co-crystallization, liposomal formulations, chemical changes, and changing ADP-APIs into solids such as polymorphs, salts, and hydrates are just a few of the strategies that may be employed to improve physical characteristics of ADP-APIs [98]. Co-crystallization has been praised for its effectiveness in increasing the pharmacological characteristics of APD-APIs. The use of co-crystallization to adjust the physical features of APD-APIs is excellent

#### *Co-Crystallization of Plant-Derived Antimalarial Drugs: An Alternate Technique for Improved… DOI: http://dx.doi.org/10.5772/intechopen.106200*

since co-crystals are not considered as new medications by the US Food and Drug Administration, but rather pro-drugs [99]. Although co-crystallization of APD-APIs improves their biopharmaceutical and physicochemical traits, there is need to screen APD-APIs based co-crystals. The screening of co-crystals efficiency is basically based on emerging techniques including quantitative structure-activity, Hansen solubility parameters calculation, and pKa rule [100, 101].

Co-crystallization involves dissolving APIs and respective coformers in an appropriate solvent at a predetermined stoichiometric ratio and the solvent is then removed to saturate of solutes for co-crystal production [25, 26]. This therefore implies that co-crystallization is based on slow solvent evaporation as well as reaction co-crystallization and slurry and antisolvent diffusion [12, 28]. Basically, co-crystallization is dependent on strong H-bonds between APIs and their respective coformers, thereby facilitating co-crystal formation [27, 29]. Notably, co-crystallization under the solution-based technique can be effectively achieved if the least soluble component is prevented from sole precipitation, and co-crystals' purity can be improved by selecting APIs and coformers with congruent solubilities [28–30]. In addition to this, other factors such as solvent systems, stoichiometric ratio, and crystallization temperature influence co-crystallization process [29]. Costa et al. [102] reported that co-crystal structures from APIs and coformers with similar shapes and polarities co-crystallize easily with each other.

In addition to solution-based technique, solid-state grinding can be applied, and this involves homogenizing APIs and coformers in mortar to prepare co-crystals using mechanical techniques [29, 102]. Solid-state grinding techniques (SSGTs) are based on and depend on molecular mobility and existence complementarity between APIs and coformers [26–30]. Preparation of co-crystals may involve addition of small quantities of solvents before grinding of APIs and coformers, where the solvent facilitates co-crystal formation. This technique is called liquid-assisted method and is highly efficient in the formation of co-crystals [26–30]. APIs (bioactive compounds) generated from antimalarial plants are essential and have received attention in drug discovery and development. However, due to their poor physicochemical and biological qualities, such as solubility, stability, and dissolution performance, the large proportion of antimalarial plant-derived APIs (APD-APIs), such as alkaloids, flavonoids, phenolic acids, and terpenoids, are disregarded [19, 21, 23]. These PDADs-APIs supply a lot of hydrogen bond donors and acceptors for co-crystal formation, which makes it possible for APD-APIs and coformers to interact [29, 102]. Co-crystallization of these APD-APIs with coformers provides distinct advantages in terms of modulating physicochemical features of these compounds while avoiding covalent interactions that might compromise their therapeutic potential [27–29]. These PDADs-APIs supply a lot of hydrogen bond donors and acceptors for co-crystal formation, which makes it possible for APD-APIs and coformers to interact [102].

Co-crystallization can be applied to the production of multicomponent solids with more than two APIs. This combination of APIs has recently improved physical properties of individual APIs and reduced the number of doses given to a patient [103, 104]. It has, however, noted that formulation of APIs-APIs combinations is associated with inherent challenges including chemical interactions, instability, and variations in solubility of different APIs [105]. Though APIs-APIs combinations could potentially address the issues around antimalarial resistance, there is dearth of published information on APIs-APIs co-crystals. As indicated for other APIs-APIs co-crystals, APD-APIs- APD-APIs combinations are presumed to have synergistic as well as additive effects and enhanced bioavailability, among other advantages of biopharmaceuticals (**Figure 5**).

**Figure 5.**

*Theoretical outline of the formation of APD-APIs co-crystals.*
