2.1.3. Bottom-Up Production Approaches

Bottom-up approaches promote the growth of NC from solution via two crucial steps viz., nucleation and crystal growth. Nucleation is crucial in the production of small uniform NC. An increase in nucleation rate results in an increase in the number of nuclei formed from the supersaturated solution, leading to a decrease in supersaturation and thus reduced growth for each nucleus [49]. If a large number of nuclei are produced concurrently during nucleation, a narrow particle size distribution is likely to occur [49]. Therefore, it is essential to promote rapid and homogeneous nucleation when using a bottom-up process. In general, the drug solution and an anti-solventare combined using conventional mixing equipment, e.g., a magnetic stirrer or an agitator blade [55]. Nucleation can be triggered by mixing with an anti-solvent or removal of solvent [18] or introduction of sonic waves to induce sonoprecipitation [55,56]. Sonoprecipitation has been used successfully to develop NCC to produce caffeine-containing co-crystals using a single-solvent approach by separately adding 60 mg caffeine and 48 mg of 2,4-dihydroxybenzoic acid (DHBA) in 7 mL and 242 mL acetone, respectively. The solutions were rapidly injected into 200 mL of hexane at approximately 0 ◦C and sonicated for 15 s in a cleaning bath. A two-solvent approach using the same procedure with 125 mg of caffeine and 99 mg DHBA dissolved separately in 1 mL chloroform and 600 mL acetone and rapidly injected into 100 mL of hexane at approximately 0 ◦C was also successful in the production of co-crystals, with Span® 85 as surfactant stabiliser at a concentration of 5 % *w*/*v* in hexane [57].

A phenazopyridine-phthalimide nano-cocrystal suspension was produced by dissolving 213 mg phenazopyridine and 147 mg phthalimide in 2 mL of dimethyl sulfoxide (DMSO) separately, after which the individual solutions were rapidly injected into 50 mL 0.4 % *w*/*v* SDS aqueous solution at approximately 2 ◦C using ultrasonic conditions resulting in the formation of a NCC suspension after 15–30 s [58].

Liu et al. [59] produced NCC using top-down and bottom-up approaches. NCC produced using a solution approach were obtained by dissolving 311 mg myricetin and 402 mg nicotinamide separately in 7 mL and 3 mL methanol, respectively [59]. The solutions were rapidly injected together into a conical flask at 0 ◦C and sonicated for 30 min using an ultrasonic processor set at a frequency of 40 kHz with a power output of 50 W following which the low-temperature control was stopped but ultrasonic agitation maintained. The resultant precipitate was removed after 10, 20, and 30 min, filtered and dried for 24 h at 25 ◦C [60].

Witika et al. reported the synthesis of lamivudine and zidovudine NCC using a bottom-up technique [19,42]. The NCC were manufactured using a pseudo one solvent cold sonochemical synthesis technique [19,42]. The individual components were dissolved in methanol and water and injected into a precooled conical flask and sonicated.
