Pharmaceutical Cocrystals: A Perspective on Development and Scale-up of Solution Cocrystallization

Understanding drug cocrystal formation and its competitive mechanism is important for improving the physicochemical properties of drugs. In this article, the cocrystal formation of polyhydroxy natural products and their competitive mechanisms are discussed through experimental screening and theoretical calculations. The formation conditions and types of cocrystals were determined based on efficient screening experiments of polyhydroxy natural product cocrystals. To investigate the difficulty and stability of cocrystal formation, competitive cocrystal experiments of polyhydroxy natural products were carried out simultaneously. By simulation of the electrostatic potential surface of molecules and the Hirshfeld surface of crystals, the mode of hydrogen bonding within the crystals was determined. The strength of hydrogen bonding was assessed based on the intermolecular interactions and energy framework within the crystal structure. A “substitution model” was constructed based on experimental results and theoretical calculations, which is of great significance for the prediction and design of natural product cocrystals and provides a feasible solution for improving the physicochemical properties of drugs.

Section: Experimental and Theoretical Calculationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uncovering Cocrystal Formation and Competition Mechanism of Polyhydroxy Natural Products: Cases of Quercetin, Hesperidin, Resveratrol, and Curcumin

Li,

Chen,

Zhou

et al. 2024

“…Drug cocrystals are specifically defined as containing one or more active pharmaceutical ingredients (API), and both the API and the cocrystal former (CCF) are solid at room temperature, where the CCF must be a biologically acceptable small molecule former . Generally, drug cocrystals can be prepared by various methods, such as solution crystallization, comilling, , suspension crystallization, and hot melt extrusion . Drug cocrystals can significantly improve the dissolution behavior, dissolution rate, and stability of drugs, and the study of drug cocrystals can help to improve the physicochemical properties of drugs and promote the entry of insoluble drugs into clinical applications.…”

Section: Introductionmentioning

confidence: 99%

Determination of the Asymmetric Ternary Phase Diagram and Preparation of Theophylline–Isonicotinamide Cocrystals

Liu,

Yang,

Wang

et al. 2024

The solid−liquid phase equilibrium data of theophylline and isonicotinamide in selected solvents (isopropanol, N,Ndimethylformamide, and n-pentanol) were determined by using the static method at 298.15 and 308.15 K under 101.325 kPa. The ternary phase diagram was plotted, and it was concluded that it is an asymmetric phase diagram. The mechanism of solid-phase formation of cocrystals during the determination of the ternary phase diagram is discussed. Excessive amounts of THE and INA cause the system to become supersaturated. As the cocrystal forms, the solubility of THE and INA decreases. When the system is on the solvation curve of the cocrystal, the activity coefficients of THE and INA drop to critical values and cocrystal formation stops. Based on the analysis of phase solubility diagrams for cocrystals, two routes for obtaining the cocrystal of THE-INA from solution have been proposed and validated. For route 1, concentrations of THE and INA in the solution are adjusted to the appropriate concentrations, and then, solvent evaporation is performed to achieve crystallization. For route 2, an amount of THE was added to a highly concentrated INA solution. The variation of the main constitutive forces of cocrystal formation is explored by molecular simulation simulations. The types of interaction forces and their interaction energies in ternary systems are identified. In addition, the melting temperature and enthalpy of fusion of the THE-INA cocrystal obtained during ternary phase diagram determination were determined to be 462.26 K (onset) and 131.69 J/g, respectively.

“…Multicomponent crystals have also been successfully utilized to address the solubility limitations of the existing drugs. , The approach is a facile way for the improvization of existing and discovery of new drugs, as besides addressing the physicochemical limitations the cocrystals can be utilized to induce novel biological tendencies in the resultant molecular complexes . The first pharmaceutical salt–cocrystal drug, Entresto, introduced by Novartis and accepted by the US-FDA in July 2015, followed by many other approved cocrystal drugs, validated the significance of the cocrystallization approach in the area of drug discovery. − …”

Section: Introductionmentioning

confidence: 99%

Sulfonate–Pyridinium Ionic Cocrystal Solvates: Improved Material and Antimicrobial Properties

Ahmad,

Malik,

Ahmad

et al. 2024

Self Cite

Organic cocrystals are attracting the attention of researchers from diverse fields and are the focus of interdisciplinary research. Cocrystals provide a convenient opportunity to realize the property tuning of precursors through an easy and green approach. We extend the scope of sulfonate−pyridinium supramolecular synthons to design ionic cocrystals/molecular salts based on a functionalized sulfonated Schiff base with bipyridyl (1) and bipyridyl ethane (2). The resultant products have been characterized, and their optical properties, including the vaporfluorochromism, have been reported. Structural characterization validates the existence of products in high Z′ ionic form and proton transfer between crystal formers. Hirshfeld studies have been carried out to understand the role and evaluate the contribution of intermolecular interactions toward molecular packing. Improved thermal stability and aqueous solubility, plausibly arising due to their ionic nature, are observed for 1 and 2. A remarkable increase in the aqueous solubility of the Schiff base precursor by a margin of nearly 325 and 400% is observed in the new solid forms 1 and 2, respectively. Cell toxicity studies validate the bioviability of the crystal forms. Improved aqueous solubility and lower cell toxicity studies of 1 and 2 prompted us to investigate them further for their antimicrobial studies, and their antibacterial and antifungal studies are reported.