Incomplete cocrystalization of ibuprofen and nicotinamide and its interplay with formation of ibuprofen dimer and/or nicotinamide dimer: A thermodynamic analysis based on DFT data

A molecularly enhanced proof of concept for targeting cocrystals at molecular scale in continuous pharmaceuticals cocrystallization

“…S1 . The labels DI, DN, and CO represent the ibuprofen dimer, nicotinamide dimer ( 49 , 73 ), and cocrystals, respectively.…”

“…1 indicate the possibility of coexistence/mixing of the pair involved. Following our previous recommendation to mitigate dimer formation ( 49 ), during this initial examination we focused on the coexistence of cocrystals. There was coexistence compatibility between CO-6 and CO-7 but they had slow emergence kinetics, and the weak established electrostatic interaction made their presence rare.…”

“…The convergence tolerances were 2.0 × 10 −5 kcal/mol in energy, 10 −3 kcal/mol/Å in force, maximum iterations of 10 4 , and displacement of 10 −5 Å. The reasons for choosing this functional and these criteria were discussed in our previous work ( 49 ). We calculated surface electrostatic charges ( 91 ) using the Hirshfeld partitioning scheme ( 92 ).…”

“…The Raman spectra were calculated as described by Porezag and Pederson ( 50 ). We ignored the spectra below 400 cm −1 as those high frequencies are associated with phonons ( 69 ), and we strived to include frequencies as low as 3,750 cm −1 to account for solvent effects ( 49 ). In the current calculation of Raman data, the incident light had an intensity of 532 nm and the spectra were extracted at 20 cm −1 intervals, which corresponded to a laser power of 150 mW.…”

“…In contrast, in the current study we used signals from the Raman spectrometer equipped on the twin-screw granulator to quantify interactions between compounds throughout the granulator. Depending on the identified interactions, the intensity of a specific interaction affecting the target cocrystal in formulation can be controlled, provided that one knows how to affect the stability and kinetics of that interaction through macroscopic processing parameters (such as the temperature and screw rotation speed) ( 49 ). This molecular-level information can bridge the gap between the micro- and mesoscales of continuous cocrystallization processing.…”