Cannabigerol is a bioactive compound derived from Cannabis sativa. It displays many promising pharmaceutical and nutraceutical properties. Its use and research are complicated by its thermally unstable solid form with low solubility and needle habit, preventing easy formulation into tablets or capsules. To overcome these problems, we conducted a crystallization screening with the aim to discover new crystal forms with enhanced properties. Though polymorph and solvate screenings did not yield new forms, the cocrystal screening was successful. Two cocrystals were discovered, one with piperazine and another with tetramethylpirazine, both in a 1:1 ratio. The latter can exist in three polymorphic forms. Both offer improvements in the melting point and crystal habit, and the cocrystal with tetramethylpirazine also shows a significant enhancement in dissolution rate. The new solid forms were analysed by a combination of methods, including X-ray powder diffraction, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate. Single-crystal X-ray diffraction data were used to solve the crystal structures, which were then compared with that of pure CBG. The crystal morphologies and surfaces were comprehensively analysed using the CSD-Particle suite, with various properties correlated against dissolution rates. While surface attachment energy and roughness (rugosity) did not show significant effects, the concentration of unsatisfied hydrogen-bond donors displayed a positive correlation. There were two parameters with a very strong correlation to dissolution rate: the propensity for interactions with water molecules, determined by the maximum range in the full interaction maps on the surface calculated for the water probe, and also the difference in the positive and negative electrostatic charges. These parameters proved highly predictive of aqueous dissolution, offering immense utility in pharmaceutical development.

Department of Chemical Engineering University of Chemistry and Technology Prague Technická 3 166 28 Prague 6 Czechia

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Abramov, Y. A., Loschen, C. & Klamt, A. (2012). J. Pharm. Sci.101, 3687–3697. PubMed

Adams, T. B., Doull, J., Feron, V. J., Goodman, J. I., Marnett, L. J., Munro, I. C., Newberne, P. M., Portoghese, P. S., Smith, R. L., Waddell, W. J. & Wagner, B. M. (2002). Food Chem. Toxicol.40, 429–451. PubMed

Aitipamula, S., Banerjee, R., Bansal, A. K., Biradha, K., Cheney, M. L., Choudhury, A. R., Desiraju, G. R., Dikundwar, A. G., Dubey, R., Duggirala, N., Ghogale, P. P., Ghosh, S., Goswami, P. K., Goud, N. R., Jetti, R. R. K. R., Karpinski, P., Kaushik, P., Kumar, D., Kumar, V., Moulton, B., Mukherjee, A., Mukherjee, G., Myerson, A. S., Puri, V., Ramanan, A., Rajamannar, T., Reddy, C. M., Rodriguez-Hornedo, N., Rogers, R. D., Row, T. N. G., Sanphui, P., Shan, N., Shete, G., Singh, A., Sun, C. C., Swift, J. A., Thaimattam, R., Thakur, T. S., Kumar Thaper, R., Thomas, S. P., Tothadi, S., Vangala, V. R., Variankaval, N., Vishweshwar, P., Weyna, D. R. & Zaworotko, M. J. (2012). Cryst. Growth Des.12, 2147–2152.

Allen, F. H. (2002). Acta Cryst. B58, 380–388. PubMed

Amidon, G. L., Lennernäs, H., Shah, V. P. & Crison, J. R. (1995). Pharm. Res.12, 413–420.

Anderton, C. (2007). Am. Pharm. Rev.10, 34–40.

Angelidakis, V., Nadimi, S. & Utili, S. (2022). Powder Technol.396, 689–695.

Anokwuru, C. P., Makolo, F. L., Sandasi, M., Tankeu, S. Y., Elisha, I. L., Agoni, C., Combrinck, S. & Viljoen, A. (2022). Phytochem. Rev.21, 1523–1547.

Bernstein, J. (2011). Cryst. Growth Des.11, 632–650.

Betteridge, P. W., Carruthers, J. R., Cooper, R. I., Prout, K. & Watkin, D. J. (2003). J. Appl. Cryst.36, 1487–1487.

Bonini, S. A., Premoli, M., Tambaro, S., Kumar, A., Maccarinelli, G., Memo, M. & Mastinu, A. (2018). J. Ethnopharmacol.227, 300–315. PubMed

Braun, D. E. & Griesser, U. J. (2016). Cryst. Growth Des.16, 6111–6121. PubMed PMC

Brittain, H. G. (2009). Polymorphism in Pharmaceutical Solids. Drugs and the Pharmaceutical Sciences, Vol. 192, 2nd ed. Informa Healthcare.

Bryant, M. J., Rosbottom, I., Bruno, I. J., Docherty, R., Edge, C. M., Hammond, R. B., Peeling, R., Pickering, J., Roberts, K. J. & Maloney, A. G. P. (2019). Cryst. Growth Des.19, 5258–5266.

Byrn, S. R., Zografi, G. & Chen, X. (2017). Solid State Properties of Pharmaceutical Materials, pp. 38–47. John Wiley.

Chatziadi, A., Skořepová, E., Rohlíček, J., Dušek, M., Ridvan, L. & Šoóš, M. (2020). Cryst. Growth Des.20, 139–147.

Chen, J., Tian, J., Ge, H., Liu, R. & Xiao, J. (2017). Food Chem. Toxicol.109, 930–940. PubMed

Cheney, M. L., Weyna, D. R., Shan, N., Hanna, M., Wojtas, L. & Zaworotko, M. J. (2011). J. Pharm. Sci.100, 2172–2181. PubMed

Clydesdale, G., Docherty, R. & Roberts, K. J. (1991). Comput. Phys. Commun.64, 311–328.

Deiana, S. (2017). Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis and Treatment, pp. 958–967. Elsevier.

Desiraju, G. R. (2003). CrystEngComm, 5, 466.

Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. PubMed PMC

Hilfiker, R. (2006). Polymorphism. John Wiley.

Holaň, J., Skořepová, E., Heraud, L., Baltes, D., Rohlíček, J., Dammer, O., Ridvan, L. & Štěpánek, F. (2016). Org. Process Res. Dev.20, 33–43.

Holland, J. & Eberlin, A. (2021). Patent WO2021046303A1.

International Union of Pure and Applied Chemistry (2011). Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd rev. ed. Wiley-VCH.

Jastrząb, A., Jarocka-Karpowicz, I. & Skrzydlewska, E. (2022). Int. J. Mol. Sci.23, 7929. PubMed PMC

Kanabus, J., Bryła, M., Roszko, M., Modrzewska, M. & Pierzgalski, A. (2021). Molecules, 26, 6723. PubMed PMC

Khadka, P., Ro, J., Kim, H., Kim, I., Kim, J. T., Kim, H., Cho, J. M., Yun, G. & Lee, J. (2014). Asia. J. Pharm. Sci.9, 304–316.

Kopczyńska, K., Kingsbury, C. J., Pidcock, E., Moldovan, A. A. & Madura, I. D. (2024). Cryst. Growth Des.24, 5159–5170.

Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst.53, 226–235. PubMed PMC

McKellar, S. C., Kennedy, A. R., McCloy, N. C., McBride, E. & Florence, A. J. (2014). Cryst. Growth Des.14, 2422–2430.

Moldovan, A. A. & Maloney, A. G. P. (2024). Cryst. Growth Des.24, 4160–4169. PubMed PMC

Nachnani, R., Raup-Konsavage, W. M. & Vrana, K. E. (2021). J. Pharmacol. Exp. Ther.376, 204–212. PubMed

Navarro, G., Varani, K., Reyes-Resina, I., Sánchez de Medina, V., Rivas-Santisteban, R., Sánchez-Carnerero Callado, C., Vincenzi, F., Casano, S., Ferreiro-Vera, C., Canela, E. I., Borea, P. A., Nadal, X. & Franco, R. (2018). Front. Pharmacol.9, 632. PubMed PMC

Palatinus, L. & Chapuis, G. (2007). J. Appl. Cryst.40, 786–790.

Pallikara, I., Skelton, J. M., Hatcher, L. E. & Pallipurath, A. R. (2024). Cryst. Growth Des.24, 6911–6930. PubMed PMC

Peters, E. N., Yardley, H., Harrison, A., Eglit, G. M. L., Antonio, J., Turcotte, C. & Bonn-Miller, M. O. (2023). J. Int. Soc. Sports Nutr.20, 2280113. PubMed PMC

Petříček, V., et al. (2023). Z. Kristallogr. Cryst. Mater.238, 271–282.

Prandini, E., Calì, E., Maloney, A. G. P., Parisi, E. & Simone, E. (2024). Powder Technol.443, 119927.

Rohlíček, J. & Hušák, M. (2007). J. Appl. Cryst.40, 600–601.

Rohlíček, J. & Skořepová, E. (2020). J. Appl. Cryst.53, 841–847. PubMed PMC

Rohlíček, J., Skořepová, E., Babor, M. & Čejka, J. (2016). J. Appl. Cryst.49, 2172–2183.

Skořepová, E. (2013). Cryst. Growth Des.13, 5193–5203.

Skořepová, E. (2014). J. Cryst. Growth, 399, 19–26.

Skořepová, E. (2017). Cryst. Growth Des.17, 5283–5294.

Skořepová, E., Hušák, M., Ridvan, L., Tkadlecová, M., Havlíček, J. & Dušek, M. (2016). CrystEngComm, 18, 4518–4529.

Sládková, V., Dammer, O., Sedmak, G., Skořepová, E. & Kratochvíl, B. (2017). Crystals, 7, 13.

Sládková, V., Cibulková, J., Eigner, V., Šturc, A., Kratochvíl, B. & Rohlíček, J. (2014). Cryst. Growth Des.14, 2931–2936.

Sládková, V., Skalická, T., Skořepová, E., Čejka, J., Eigner, V. & Kratochvíl, B. (2015). CrystEngComm, 17, 4712–4721.

Storey, R. A. & Ymén, I. (2011). Solid State Characterization of Pharmaceuticals. John Wiley & Sons.

Tahir, M. N., Shahbazi, F., Rondeau-Gagné, S. & Trant, J. F. (2021). J. Cannabis Res.3, 7. PubMed PMC

Tesson, N., Castaño, M. T. & Comely, A. C. (2020). Patent WO2020089424A1.

Tieger, E., Kiss, V., Pokol, G., Finta, Z., Dušek, M., Rohlíček, J., Skořepová E. & Brázdac, P. (2016a). CrystEngComm, 18, 3819–3831.

Tieger, E., Kiss, V., Pokol, G., Finta, Z., Rohlíček, J., Skořepová E. & Brázdac, P. (2016b). CrystEngComm, 18, 9260–9274.

Vardanyan, R. S. & Hruby, V. J. (2006). Synthesis of Essential Drugs, edited by R. S. Vardanyan & V. J. Hruby, pp. 583–593. Elsevier.

Xu, T., Chen, G., Tong, X., Wu, Y., Xu, H., Han, X., Zhang, G., Ding, W., Liu, B. & Zhou, Y. (2022). Pharmacol. Res. Mod. Chin. Med.5, 100171.

Zingg, T. (1935). PhD Thesis. ETH Zurich, Switzerland.

Zvoníček, V., Skořepová, E., Dušek, M., Babor, M., Žvátora, P. & Šoóš, M. (2017). Crystal Growth Des.17, 3116–3127.

Zvoníček, V., Skořepová, E., Dušek, M., Žvátora, P. & Šoóš, M. (2018). Crystal Growth Des.18, 1315–1326.