(184n) Thermodynamics Analysis with Molecular Informatics for Understanding Pharmaceutical Cocrystallization Promoted in Fatty Acid Media

Pharmaceutical cocrystal is one of the crystal engineering techniques to improve the physical-chemical properties of active pharmaceutical ingredients (APIs) such as solubility, bioavailability and stability. [1] Cocrystal is a crystal composed of API and other molecules called as coformer. The crystal structure of cocrystal maintains the non-covalent bond between API and coformer, which allows the cocrystallization technique to be applied to API and coformer with no dissociable group. To achieve the development of pharmaceutical cocrystal, it is necessary to design both suitable combination of API and coformer and cocrystallization media.

Liquid-assist grinding has been known for the representative cocrystallization method. In liquid-assist grinding, the API and coformer are stirred with small amounts of organic solvent. The cocrystal formation depends on the kinds of solvent added. [2] The toxic organic solvents are sometimes used as auxiliary to promote cocrystallization. However, the use of toxic organic solvents is a serious issue that they may remain in the products.

To overcome the issue of liquid-assist grinding, our group has developed the cocrystallization method to use liquefied fatty acid as auxiliary species, instead of organic solvents [3]. Fatty acid is a safe material and generally included in oils. Linoleic acid (LA), which was one of the general fatty acids, was applied to the theophylline (TPL) cocrystallization [3]. Our proposal method achieved TPL cocrystallization by the addition of LA successfully, but our method remains an issue that the effect of fatty acid on cocrystallization is still unknown. Therefore, this research aims to analyze the effect of fatty acid on cocrystallization from both experiment and modelling.

Methods

[Experiment] TPL (1 mmol) as API and nicotinamide (NA, 1 mmol) as coformer were added to the vessel. Fatty acid and hydrocarbon are used as liquid auxiliaries. After adding LA (0.4 g) as fatty acid or 1-octadecene (1-OD, 0.4 g) as hydrocarbon used reference, the mixture was stirred during 120 min under 22 ^oC. The crystal structure was evaluated by Powder-Xray diffraction (PXRD). The ratio of cocrystal formation was also evaluated as the ratio of the characteristic peak intensity of cocrystal to the sum of characteristic peak intensities of API, coformer and cocrystal.

[Modelling] To investigate the effect of cocrystallization promotion given by liquid auxiliaries, the cocrystallization under liquid auxiliaries is composed of the four phases: (A) exist as raw materials (B) active API and coformer by auxiliaries, (C) make the pair and (D) crystallize them. We focused on the phase B in this work because the phase B seems to be the phase that receives the influence of liquid auxiliaries. The energy of each phase A and B was calculated by thermodynamics and molecular information [4].

Results & Discussion

[Experiment] The crystal structures were evaluated for products that were fabricated by stirring TPL and NA with LA and 1-OD by PXRD measurements. The peak attributed to cocrystal [5] of the product stirred with LA was bigger than that of the product stirred with 1-OD where the peaks attributed to raw materials of the product stirred with LA were smaller than those of the product stirred with 1-OD. The cocrystallization ratio of the product using LA was much larger than that of the product using 1-OD. These results mean that LA plays a role to enhance cocrystal composed of TPL and NA more than 1-OD.

[Modelling] The Gibbs free energy difference between the phase A to B (ΔG₁) was calculated by thermodynamic model combined with molecular information. ΔG₁ was smaller with LA as auxiliaries than that with 1-OD. The auxiliary whoseΔG₁ was small value means that the fatty acid assist the formation of API and coformer pair. The result of ΔG₁ calculation means that LA is more suitable auxiliary to active raw materials than 1-OD. It was also confirmed that the addition of LA promoted the cocrystallization than that of 1-OD from the experimental results. Therefore, the developed model is expected to estimate the effect of liquid auxiliary on the promotion of cocrystallization.

Conclusion

We investigated the effect of fatty acids on cocrystallization from both experiment and modelling. From experiments, the addition of fatty acid promoted TPL cocrystallization in the comparison of hydrocarbon. Additionally, from modelling based on thermodynamic model combined with molecular information, fatty acid may activate raw materials more than hydrocarbon. These results mean that fatty acid is more suitable auxiliary to form API and coformer pair promote their cocrystallization than hydrocarbon. Therefore, the effect of auxiliary can be explained by the model based on thermodynamic model combined with molecular information, which is expected that the suitable auxiliary is estimated without any experiments.

References

[1] Sithmi, N. M.; Aruna M.; Ranjit T.; Nadeesh M. A. Org. Process Res. Dev. 27 (2023) 409−422.

[2] David R. W.; Tanise S.; Peddy V.; Michael J. Z. Cryst. Growth Des. 9, (2009) 1106−1123.

[3] Yuna T.; Yasuhiko O.; Yusuke S.; Cryst. Growth Des. 22, (2022) 5176–5181.

[4] Shiang-Tai L.; Stanley I. S.; Ind. Eng. Chem. Res. 41 (2002) 899-913.

[5] Jie, L.; Sohrab, R. Preparation and Characterization of Theophylline-Nicotinamide Cocrystal. Org. Process Res. Dev. 2009, 13, 1269−1275.