Carbamazepine and nicotinamide were purchased from Energy Chemical (Shanghai, China). Solvents were purchased from Shanghai Lingfeng Chemical Reagent Co., Ltd. (Shanghai, China).

CBZ-NCT cocrystal was synthesized using grinding, solvent-Assisted grinding and ultrasound-assisted cocrystallization [15].

Fourier Transform Infrared Spectroscopy (FT-IR) spectra were recorded on a Perkin-Elmer Spectrum BX FTIR system, equipped with a deuterium triglycine sulfate detector. The scanrange was 500 - 4000 cm⁻¹, using eight scans per spectrum with a resolution of 1 cm⁻¹. Spectra were obtained in the transmission mode in KBr pellets.

Powder X-ray diffraction (PXRD) patterns were collected using Rigaku X-ray polycrystalline diffractometer. Samples were placed onto a silicon wafer slide. Generator settings were 40 kV with a current of 40 mA used for the measurement. Data were collected (n = 3) in the range 2θ = 5˚ to 40˚ at a scanning rate of 5˚/min with a scan rate of 0.04˚/time and a slit width of 6.0 mm.

Microscopy was performed using Bai Datong wireless connection high-definition digital wifi microscope.

Also known as dry grinding or solid state grinding, mechanochemical grinding was the more typically used method of cocrystal synthesis. The FT-IR spectra of commercial CBZ and CBZ USP grade, recorded in KBr pellets. Figure 1 shows the FT-IR spectrum of CBZ, NCT, their physical mixture, and cocrystal prepared by solvent-free grinding.

It can be seen from Figure 1 that through simple solvent-free grinding, CBZ and NCT cannot form a cocrystal. One huge drawback with mechanochemical grinding in the solid state is that, with no heating stage involved in the process, there are numerous cases where the energy required to complete the cocrystallization of compounds is lacking. One method to overcome this is the induction of a small amount of water or a solvent to the ball milling mechanism, which acts as a catalyst assisting the process in a process known as Liquid-assisted grinding (LAG). LAG (also known as solvent-drop grinding or wet granulation) is mediated by a liquid phase.

Then we use solvent-assisted grinding, and the result is shown in Figure 2. Figure 2 shows the FT-IR spectrum of CBZ, NCT, their physical mixture, and cocrystal prepared by grinding with solvent. Dichloromethane (DCM), acetone (CP), n-butyl alcohol (NBA), n-propyl alcohol (NPA), Acetonitrile (ACN), ethyl alcohol (EA).

It can be seen from Figure 2 that the method of adding liquid to assist grinding cannot be CBZ and NTC to form a cocrystal.

Figure 3 shows the FTIR spectrum of CBZ, NCT, their physical mixture, and cocrystal prepared by ultrasound-assisted cocrystallization.

Figure 3 shows the FTIR spectrum of CBZ, NCT, and ultrasound-assisted cocrystallization prepared by different solvents. The stretching of the primary amide group in CBZ was represented by absorption bands at 3464 and 3163 cm⁻¹, respectively, which could be assigned to the free anti-NH (asymmetrical) and hydrogen-bonded syn-NH (symmetrical) vibration. The absorption band at 1679 cm⁻¹ was due to carbonyl (−C=O) stretching. It indicated that when form cocrystal, absorption bands at 3446, 3391 and 3210 cm⁻¹. Absorption bands due to carbonyl (−C=O) andvibrations appeared at 1683 and 1660 cm⁻¹, respectively.

Figure 4 shows the PXRD spectrum of CBZ, NCT, their physical mixture prepared by solvent-free grinding.

It can be seen from Figure 4 that the grinding is only physical mixing.

Figure 5 shows the PXRD spectrum of CBZ, NCT, their physical mixture by grinding with solvent.

It can be seen from Figure 5 that the grinding by adding a solvent is only a physical mixing.

It can be seen from Figure 6 that through ultrasound induction, CBZ and NCT have formed cocrystal. The PXRD of CBZ forms showed sharp peaks at 2θ values of 13.0˚, 15.2˚, 15.8˚, 18.6˚, 19.4˚, 23.8˚, 26.68˚, and 27.52˚, respectively. Similarly, the diffractogram of NCT showed peaks at 2θ values of 14.72˚, 22.12˚, 25.72˚, 27.24˚, and 40.28˚. Cocrystal showed sharp peaks at 6.68˚, 8.92˚, 10.2˚, 13.32˚, 20.44˚, 23.04˚, 26.48˚, 28.12˚.

Solvent is the fundamental and foremost important factor for promoting or inhibiting certain crystal motif and to produce correlated effects to the success of required drug material compatibility for the end-user. The use of different solvents during crystallization profoundly affects the crystal habit of the purifified drug, leading to the variation in raw material characteristics such as flowability, compaction, chemical stability, dissolution and packing. Ultrasound-assisted cocrystallization in different solvent are shown in Figure 7.

The effect of solvents on ultrasound-assisted cocrystallization in solution is discussed here. From the captured microscopic images, crystals in different solvents show different morphologies CBZ has polar functional groups as hydroxyl, amide and carbonyl groups and CH as the non-polar. Among the selected solvents, polar protic solvents such as isopropyl alcohol strongly allow them to dissolve both positively and negatively charged species to participate in intermolecular force via hydrogen bonding. Whereas the polar aprotic solvents such as acetone, ethylacetate and acetonitrile solvate only positive ions but not negative ions which results in the lack of hydrogen bonding. This result indicates that the type of solvent dramatically influences the shape of cocrystal with respect to the solubility of solute, solvent polarity, evaporation number of solvent and rate of generation of supersaturation in the solution.