New Cocrystallization Method: Non-photochemical Laser-Induced Nucleation of a Cocrystal of Caffeine–Gallic Acid in Water

Abstract

This paper reports for the first time the crystallization of cocrystals (caffeine -gallic acid) in water using the Non-Photochemical Laser-Induced Nucleation (NPLIN) technique. The nucleation temporal control of NPLIN and the induction time reduction (70 times shorter than spontaneous nucleation) allow the obtention of cocrystals on-demand, with excellent repeatability. Prior to NPLIN experiments, solubility measurements, metastable zone limit determination, and spontaneous nucleation (SN) are carried out. Supersaturated solutions at three different molarities of caffeine (0.0158, 0.0167 and 0.0179 M) are prepared and dissolved at 338 K. Supersaturated solutions are exposed to a 532 nm wavelength nanosecond pulsed laser at 296 K. Some hours later crystals can be filtered. The impact of supersaturation on probability of nucleation has been studied and the result shows a higher supersaturation implies a higher probability of nucleation. Crystalline form characterization has employed a combination of Raman scattering, high-performance liquid chromatography, thermogravimetry, differential scanning calorimetry, and powder X-ray diffraction; the sizes of the cocrystals being too small for a single-crystal X-ray diffraction experiment. Two different cocrystal forms are obtained: a new polymorph of hemihydrate CAFGAL.0.5H2O from spontaneous nucleation by precipitation, and a new hydrate form CAFGAL.1.5H2O from NPLIN and from spontaneous nucleation of a supersaturated solution without evaporation. These results open a promising way to crystallize cocrystals in the context of the pharmaceutical industry.

Thermodynamics of Oiling-Out in Antisolvent Crystallization. I. Extrapolation of Ternary Phase Diagram from Solubility to Instability

“…The calculation of the polymorph solubilities suggests that the points above the β SLE have higher probabilities to be the β phase and those below to be the γ phase. On the left side of the crystallization region, the mixing easily goes into LLPS, as the distance between the LLE and SLE curves decreases exponentially with the fraction of 1,4-dioxane (2). The points of amorphous precipitation below the LLE are transient observations depended on the mixing conditions away from equilibrium, which will be addressed in Section 7.2.…”

“…The microfluidic phase diagram exhibits satisfactory agreement with the thermodynamic calculations: interdiffusion without phase transition was observed mainly in the dissolution region, crystallization in the crystallization region, and amorphous precipitation in the LLPS region. Note that the crystals were only recorded in the upper-right region of the crystallization region, slightly away from the good solvent (2). The calculation of the polymorph solubilities suggests that the points above the β SLE have higher probabilities to be the β phase and those below to be the γ phase.…”

“…Practically water-insoluble (<0.1 mg/mL) chemicals have been estimated to make up ∼70% of the new drugs in development and ∼40% of the drugs established . The need for improving their bioavailability, though in competition with the stability, has spurred extensive research into more soluble phases, cocrystals, and dispersed morphologies. , While the surface-to-volume ratio , is an important factor, it is the polymorphism , that substantially determines the stability, crystal habit, solubility, and dissolution rate. The stable polymorph is favored by thermodynamics; yet, intermediate pathways can be more viable due to kinetics.…”

Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

“…Alternative methods which may hold promise in advancing the discovery of elusive cocrystals include carrier gas-assisted desublimation and non-photochemical laser-induced nucleation. 129,130 Recently, Sanvordenker et al developed a novel process in which cocrystal formers were sublimed and transported by a carrier gas, followed by direct impingement of the gases at high velocities onto a cool targeted substrate, where a fine indomethacin-saccharine cocrystal was formed. 129 This technique, coined "carrier gas-assisted desublimation" allows simultaneous particle size reduction and surface coating of cocrystals, implying its potential in generating inhalable cocrystal powders.…”

Synthetic Strategies toward Higher Cocrystals of Some Resorcinols

“…The study of cocrystals, or more accurately multicomponent molecular crystals, continues to be an active area of research in crystal engineering after 3 decades of investigation and research. − This is so because this subject has been found to be of considerable commercial interest and useful in practical applications in the pharmaceutical industry. , Key to these applications is the fact that cocrystal formation of active pharmaceutical ingredients (APIs) is often accompanied by changes in the solubility and permeability of the drug under consideration. , Since many computationally designed drugs suffer from shortcomings with respect to both these abovementioned properties, cocrystal formation might result in a more bioavailable product. − This is clearly a desired outcome and so there is a continued interest in identifying new cocrystals of APIs. − …”