Apremilast (APR) is an anti-inflammatory drug commonly used in the treatment of psoriasis. In efforts to enhance its solubility, several cocrystals with similar structural features have been developed. This study investigates the cocrystallization of APR with four phenolic-type coformers: phenol, catechol, pyrogallol, and hydroxyquinol. These coformers differ in the number and position of their hydroxyl groups, with their melting points varying by as much as 100 °C. Four novel cocrystal forms were synthesized, purified, and characterized using X-Ray diffraction and thermal analysis techniques. Surprisingly, the resulting cocrystals exhibited minimal differences in their melting points. The molecular packing of APR appears to limit the network-forming potential of the hydroxyl groups, a conclusion supported by the solved crystal structures, Hirshfeld surface analysis, and differential scanning calorimetry (DSC) results.

Chemical Engineering Department National Research Tomsk Polytechnic University Lenin Avenue 30 634050 Tomsk Russia

Department of Solid State Chemistry University of Chemistry and Technology Prague Technicka 5 16628 Prague Czech Republic

Zobrazit více v PubMed

Rahmani M., Kumar V., Bruno-Colmenarez J., Zaworotko M.J. Crystal Engineering of Ionic Cocrystals Sustained by Azolium·Azole Heterosynthons. Pharmaceutics. 2022;14:2321. doi: 10.3390/pharmaceutics14112321. PubMed DOI PMC

Bolla G., Sarma B., Nangia A.K. Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs. Chem. Rev. 2022;122:11514–11603. doi: 10.1021/acs.chemrev.1c00987. PubMed DOI

Guo M., Sun X., Chen J., Cai T. Pharmaceutical Cocrystals: A Review of Preparations, Physicochemical Properties and Applications. Acta Pharm. Sin. B. 2021;11:2537–2564. doi: 10.1016/j.apsb.2021.03.030. PubMed DOI PMC

Groom C.R., Bruno I.J., Lightfoot M.P., Ward S.C. The Cambridge Structural Database. Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater. 2016;72:171–179. doi: 10.1107/S2052520616003954. PubMed DOI PMC

Armstrong A.W. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: Review. JAMA. 2020;323:1945–1960. doi: 10.1001/jama.2020.4006. PubMed DOI

Shetty D., Yarlagadda D.L., Brahmam B., Dengale S.J., Lewis S.A. Investigating the Influence of the Type of Polymer on Sustaining the Supersaturation from Amorphous Solid Dispersions of Apremilast and Its Pharmacokinetics. J. Drug Deliv. Sci. Technol. 2023;84:104520. doi: 10.1016/j.jddst.2023.104520. DOI

Li H., Zuo J., Tang W. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front. Pharmacology. 2018;9:1048. doi: 10.3389/fphar.2018.01048. PubMed DOI PMC

Jirát J., Zvoníček V., Babor M., Ridvan L., Skořepová E., Dušek M., Šoóš M. Formation of the First Non-Isostructural Cocrystal of Apremilast Explained. Cryst. Growth Des. 2020;20:5785–5795. doi: 10.1021/acs.cgd.0c00393. DOI

Jirát J., Ondo D., Babor M., Ridvan L., Šoóš M. Complex Methodology for Rational Design of Apremilast-Benzoic Acid Co-Crystallization Process. Int. J. Pharm. 2019;570:118639. doi: 10.1016/j.ijpharm.2019.118639. PubMed DOI

Dudek M.K., Kostrzewa M., Paluch P., Potrzebowski M.J. π-Philic Molecular Recognition in the Solid State as a Driving Force for Mechanochemical Formation of Apremilast Solvates and Cocrystals. Cryst. Growth Des. 2018;18:3959–3970. doi: 10.1021/acs.cgd.8b00301. DOI

Dudek M.K., Wielgus E., Paluch P., Śniechowska J., Kostrzewa M., Day G.M., Bujacz G.D., Potrzebowski M.J. Understanding the Formation of Apremilast Cocrystals. Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater. 2019;75:803–814. doi: 10.1107/S205252061900917X. PubMed DOI

Jirát J., Babor M., Ridvan L., Skořepová E., Dušek M., Šoóš M. Structure–Property Relations of a Unique and Systematic Dataset of 19 Isostructural Multicomponent Apremilast Forms. IUCrJ. 2022;9:508–515. doi: 10.1107/S2052252522005577. PubMed DOI PMC

Wang F.-Y., Zhang Q., Zhang Z., Gong X., Wang J.-R., Mei X. Solid-State Characterization and Solubility Enhancement of Apremilast Drug–Drug Cocrystals. CrystEngComm. 2018;20:5945–5948. doi: 10.1039/C8CE00689J. DOI

Wu Y.-D., Zhang X.-L., Liu X.-H., Xu J., Zhang M., Shen K., Zhang S.-H., He Y.-M., Ma Y., Zhang A.-H. The Preparation, Characterization, Structure and Dissolution Analysis of Apremilast Solvatomorphs. Acta Crystallogr. C Struct. Chem. 2017;73:305–313. doi: 10.1107/S2053229617002984. PubMed DOI

Revathi S., Hakkim F.L., Ramesh Kumar N., Bakshi H.A., Sangilimuthu A.Y., Tambuwala M.M., Changez M., Nasef M., Krishnan M., Kayalvizhi N. In Vivo Anti Cancer Potential of Pyrogallol in Murine Model of Colon Cancer. Asian Pac. J. Cancer Prev. 2019;20:2645–2651. doi: 10.31557/APJCP.2019.20.9.2645. PubMed DOI PMC

Wong S.N., Hu S., Ng W.W., Xu X., Lai K.L., Lee W.Y.T., Chow A.H.L., Sun C.C., Chow S.F. Cocrystallization of Curcumin with Benzenediols and Benzenetriols via Rapid Solvent Removal. Cryst. Growth Des. 2018;18:5534–5546. doi: 10.1021/acs.cgd.8b00849. DOI

Sathisaran I., Dalvi S.V. Crystal Engineering of Curcumin with Salicylic Acid and Hydroxyquinol as Coformers. Cryst. Growth Des. 2017;17:3974–3988. doi: 10.1021/acs.cgd.7b00599. DOI

Nijhawan M., Santhosh A., Babu P.R.S., Subrahmanyam C.V.S. Solid state manipulation of lornoxicam for co-crystals—Physicochemical characterization. Drug Dev. Ind. Pharm. 2014;40:1163–1172. doi: 10.3109/03639045.2013.804834. PubMed DOI

Guo C., Zhang Q., Zhu B., Zhang Z., Ma X., Dai W., Gong X., Ren G., Mei X. Drug–drug cocrystals provide significant improvements of drug properties in treatment with progesterone. Cryst. Growth Des. 2020;20:3053–3063. doi: 10.1021/acs.cgd.9b01688. DOI

Sanphui P., Goud N.R., Khandavilli U.B.R., Nangia A. Fast Dissolving Curcumin Cocrystals. Cryst. Growth Des. 2011;11:4135–4145. doi: 10.1021/cg200704s. DOI

Rohlicek J., Skorepova E., Babor M., Cejka J. CrystalCMP: An easy-to-use tool for fast comparison of molecular packing. J. Appl. Cryst. 2016;49:2172–2183. doi: 10.1107/S1600576716016058. DOI

Lide D.R. CRC Handbook of Chemistry and Physics. CRC Press; Boca Raton, FL, USA: 2005. pp. 3–422.

O’Neil M.J. The Merck Index—An Encyclopedia of Chemicals, Drugs, and Biologicals. Royal Society of Chemistry; Cambridge, UK: 2013. p. 1482.

Lide D.R. CRC Handbook of Chemistry and Physics. 88th ed. CRC Press; Boca Raton, FL, USA: 2007. pp. 3–36.

Zhang L., Bandy B., Davison A.J. Effects of metals, ligands and antioxidants on the reaction of oxygen with 1,2,4-benzenetriol. Free Radic. Biol. Med. 1996;20:495–505. doi: 10.1016/0891-5849(95)02089-6. PubMed DOI

Bruker S. SAINT. Bruker AXS Inc.; Madison, WI, USA: 2002.

Sheldrick G.M. SHELXT—Integrated Space-Group and Crystal-Structure Determination. Acta Crystallogr. A Found. Adv. 2015;71:3–8. doi: 10.1107/S2053273314026370. PubMed DOI PMC

Altomare A., Cascarano G., Giacovazzo C., Guagliardi A., Burla M.C., Polidori G., Camalli M. SIR92 a program for automatic solution of crystal structures by direct methods. J. Appl. Cryst. 1994;27:435. doi: 10.1107/S002188989400021X. DOI

Betteridge P.W., Carruthers J.R., Cooper R.I., Prout K., Watkin D.J. CRYSTALS Version 12: Software for Guided Crystal Structure Analysis. J. Appl. Crystallogr. 2003;36:1487. doi: 10.1107/S0021889803021800. DOI

Cooper R.I., Thompson A.L., Watkin D.J. CRYSTALS enhancements: Dealing with hydrogen atoms in refinement. J. Appl. Cryst. 2010;43:1100–1107. doi: 10.1107/S0021889810025598. DOI

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., et al. Mercury 4.0: From Visualization to Analysis, Design and Prediction. J. Appl. Crystallogr. 2020;53:226–235. doi: 10.1107/S1600576719014092. PubMed DOI PMC

Degen T., Sadki M., Bron E., König U., Nénert G. The HighScore suite. Powder Diffr. 2014;29((Suppl. S2)):S13–S18. doi: 10.1017/S0885715614000840. DOI

Spackman P.R., Turner M.J., McKinnon J.J., Wolff S.K., Grimwood D.J., Jayatilaka D., Spackman M.A. CrystalExplorer: A program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals. J. Appl. Cryst. 2021;54:1006–1011. doi: 10.1107/S1600576721002910. PubMed DOI PMC

Sparkman M.A., Jayatilaka D. Hirshfeld surface analysis. CrystEngComm. 2009;11:19–32. doi: 10.1039/B818330A. DOI

McKinnon J.J., Spackman M.A., Mitchell A.S. Novel tools for visualizing and exploring intermolecular interactions in molecular crystals. Acta Cryts. B. 2004;60:627–668. doi: 10.1107/S0108768104020300. PubMed DOI