A New 1:1 Drug-Drug Cocrystal of Theophylline and Aspirin: Discovery, Characterization, and Construction of Ternary Phase Diagrams

Abstract

A new 1:1 drug-drug cocrystal of theophylline (THP) and aspirin (ASP) was successfully prepared by liquid assisted grinding, evaporative crystallization, and slurry conversion crystallization. The obtained cocrystal was comprehensively characterized by single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, and Fourier transform infrared analysis. Ternary phase diagrams were constructed for the obtained cocrystal in isopropyl alcohol at two different temperatures, i.e., 20 and 40 °C. A narrow stability region was found for the pure THP-ASP cocrystal in the phase diagram at both temperatures. By proper selection of the ratios between THP, ASP, and IPA from the stability region, THP-ASP cocrystals could be purely produced by isothermal slurry conversion in IPA. In addition, molecular modeling was deployed to provide mechanistic insights into the formation of this THP-ASP cocrystal system.

Mechanochemical synthesis insights and solid-state characterization of quininium aspirinate, a glass-forming drug–drug salt

“…Furthermore, aspirin salts of Li + , Na + , K + , and Rb + are known, and various cocrystals, a few clathrates, and combinations with other drugs have been reported. Among those are aspirin carbamazepine (Vishweshwar et al, 2005), aspirin 5-methoxysulfadiazin (Caira, 1994), aspirin meloxicam (Cheney et al, 2012), aspirin pentoxifylline (Stepanovs et al, 2015), and aspirin theophylline (Darwish et al, 2018). The aspirin meloxicam cocrystallization by NG and LAG using CHCl 3 has been used to model the reactant's approach and molecular mixing during mechanochemical treatment in a ball mill by molecular dynamics calculations (Ferguson et al, 2019).…”

“…Multidrug combinations are a relatively unexplored and patentable type of materials of increasing interest (Darwish et al, 2018), not only related to crystal engineering studies and the improvement of the physicochemical properties of drugs, but due to monotherapies (one drug to treat one disease) are currently not always considered effective to manage various complex illnesses such as cancer, diabetes, infectious, and cardiovascular diseases (Thipparaboina et al, 2016). Besides, doctors commonly prescribe together various drugs (Sekhon, 2012) and multidrug combinations offer opportunities for exploring synergistic beneficial effects (Darwish et al, 2018).…”

Investigation of the solid–liquid ternary phase diagrams of 2HNIW·HMX cocrystal

“…The phase behavior of the two pure components in the solvent can provide insights into the thermodynamically stable region of each phase and the co-crystallization process. [33][34][35] From our previous work experience, the size and position of the thermodynamically stable region of the cocrystal phase depend on the choice of solvent. 36 Whether it is a pure solvent or a mixture solvent system, the symmetry of the phase diagram depends on the solubility of two pure components in the selected solvent system.…”

Enhancement of Solubility and Dissolution Rate of Acetylsalicylic Acid via Co-Crystallization Technique: A Novel Asa-Valine Cocrystal

“…Besides, the Carlo patron has reported that aspirin took part in reducing the risk associated with colorectal cancer [35]. Recently, the combinations of aspirin-4,4-bipyridine [36], aspirin-theophylline [37], aspirin-4,4-butane, aspirinpyridinepoly-2-ene [38] were successfully formed stable cocrystals, but none of them have studied the dissolution behavior of aspirin.…”