Easymax 102 advanced synthesis workstation

All reactions were performed in Mettler-Toledo Easymax 102 Advanced Synthesis Workstation using 25 mL reactor tubes. NMR spectra were recorded on Varian Inova 300 spectrometer (300 MHz ¹H, 75 MHz ¹³C, 285 MHz ¹⁹F) at 25 °C. ¹H-NMR spectra were obtained as solutions in CDCl₃ with TMS as the internal standard. ¹⁹F-NMR spectra were obtained as solutions in CDCl₃ with CFCl₃ as the internal standard. N-bromosuccinimide was freshly recrystallized before use. All other chemicals used for synthetic procedures were obtained from commercial sources and were of reagent grade purity or better (Merck, Sigma Aldrich, Carlo Erba, Fluka, Fisher Scientific, Apollo Scientific, etc.). Reactions were monitored by TLC with silica gel coated plates Silica gel/TLC cards, DC-Alufolien-Kieselgel with 60 Å medium pore diameter (Sigma Aldrich) and detection was conducted by UV absorption (254 nm). Purification of certain products was conducted on preparative silica gel glass plates PLC Kieselgel 60 F254 with 2 mm layer thickness. Succinimide, isolated at the end of the reaction, can easily be recycled back to N-bromosuccinimide according to the standard procedure by NaOH, as elaborated in other reports [56 (link)]. Copies of ¹H-NMR, ¹³C-NMR and ¹⁹F-NMR spectra of isolated final products are available in Supplementary material file online.

Gelatin from bovine skin, phytic acid sodium salt hydrate, and Pluronic^® F-127 were purchased from commercial sources Sigma-Aldrich (Sigma Aldrich, St. Louis, MO, USA; and Sigma-Aldrich Chemie GmbH, Steinheim, Germany, Merck, Darmstadt, Germany) without additional purification processes. The heating of mixtures was performed in a Mettler-Toledo Easymax 102 Advanced Synthesis Workstation using 25 mL closed reactor tubes.

In vitro studies like solubility and dissolution were performed for the prepared samples. Concerning dissolution experiments, the initial step was to grind CBZ cocrystals in mortar and pestle to obtain uniform particle size range. In the next step, the instrument (EasyMax 102 Advanced Synthesis Workstation) devised by Mettler Toledo provided with a temperature monitor and a stirrer rotating at 150 rpm to prepare supersaturated CBZ solution by pouring large quantity of sample powder in a flask (100 mL) having a medium (ethanol) of 40 mL at 25°C. Online “React IR iC 10” manufactured by Mettler Toledo AutoChem having an ATR crystal (AgX DiComp Fiber Conduit probe) with a size 6.5 mm attached to the crystallization reactor was used for recording of CBZ IR signature in solution every 15 seconds (50 scans) from 2800 cm⁻¹ to 650 cm^–1 till equilibrium. Finally, the React IR data was monitored using the “IR iC 10” software. The samples for solubility measurement were collected when the cocrystal solution reached the saturated state during dissolution experiment. Samples were analyzed by high-performance liquid chromatography (HPLC).