(W1130-12-83) Exploring the Mechanism of Mechanochemically Induced Cocrystal Formation with Terahertz Spectroscopy

Purpose: Mechanochemical reaction refers to a type of chemical reaction that occurs in the solid state when mechanical force is applied, which plays a vital role in green chemistry. This method reduces energy consumption and waste production compared to traditional synthesis routes. Although this method has been introduced and implemented for decades, its fundamental mechanism has not been fully investigated [1].

Methods: This study used terahertz time-domain spectroscopy to examine the mechanochemical growth of theobromine and anhydrous oxalic acid 1:1 w/w cocrystals. The cocrystal growth kinetics were investigated during storage under three different humidity conditions (RH 23%, RH 55%, RH 75%) following the initial mechanical activation using a variety of precisely defined compaction forces (from 5kN to 40kN). The mechanical activation was triggered using a compaction simulator, and the force profiles and compaction forces were controlled tightly.

Results: The results obtained from this study revealed that the formation of cocrystals did not occur immediately after compaction, but rather after a certain period of time when the samples were stored in a humid environment. This finding is consistent with the outcomes observed using the traditional mixer mill method. However, in contrast to the fully ground mixture, which exhibited a roughly monotonously increasing absorption spectrum, the compacted mixture retained the crystalline peak feature at 1.82THz. During the process of crystallisation, the peak at 1.28THz underwent evolution, while the peak at 1.82THz shifted towards higher frequencies. This overall change can be attributed to both the crystallisation effect and the scattering caused by an increase in particle size. The degree of crystallinity was quantified based on the absolute absorption coefficient of the peak at 1.28THz [2]. Hence, samples compressed at 30kN and stored under RH23% were found not to exhibit significant changes. However, samples stored under RH55% and RH75% displayed an increase in the absorption coefficient, with the transformation process taking approximately 15 and 7 days to complete, respectively.

Conclusion: Humidity was the essential and dominant factor in the growth process that influences the overall kinetics. A higher compaction force results in a more stable structure, which leads to a slower growth rate. Having a better understanding of how the mechanochemical reaction is influenced by the molecular aspects and the inter-particle interaction will enable us to control the process more effectively during pharmaceutical manufacturing [3].

References: [1] Friščič, T., & Jones, W. (2009). Recent advances in understanding the mechanism of cocrystal formation via grinding. In Crystal Growth and Design (Vol. 9, Issue 3, pp. 1621–1637)
[2] Sibik, J., Löbmann, K., Rades, T., & Zeitler, J. A. (2015). Predicting Crystallization of Amorphous Drugs with Terahertz Spectroscopy. Molecular Pharmaceutics, 12(8), 3062–3068.
[3] Karimi-Jafari, M., Padrela, L., Walker, G. M., & Croker, D. M. (2018). Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. In Crystal Growth and Design (Vol. 18, Issue 10, pp. 6370–6387). American Chemical Society.

Absorption spectra of sample compressed by 15kN and stored under RH75%.

Absorption coefficient spectra of samples compressed by 30kN and stored under varying humidity conditions.

Change in the absolute absorption coefficient at 1.28THz for samples compressed at 30kN and stored under different humidity conditions.