Drug–Drug Multicomponent Crystals as an Effective Technique to Overcome Weaknesses in Parent Drugs

An interesting multicomponent crystal consisting of drug–drug combination was synthesized. The multidrug crystals consisted of antidiabetic drugs glicalzide and metformin. Single crystal X-ray structure analysis revealed that this multicomponent crystal is salt-type multicomponent crystal. The physicochemical properties of this crystal were significantly different from those of the parent drugs. The multicomponent crystal showed impressive solubility and dissolution rate compared to that of the raw material of gliclazide. Also, the hygroscopicity issue in metformin was tackled by the formation of multicomponent crystal. These physicochemical property alterations were associated with the existence of hydrophilic channel structure, which was confirmed by microscopic analysis. Therefore, the weaknesses of each component were mutually solved

Crystallographic Analysis of Phase Dissociation Related to Anomalous Solubility of Irsogladine Maleate

We report the anomalous solubility of the pharmaceutical salt irsogladine maleate, which is associated with phase dissociation. The anomalous solubility was demonstrated by the similarity of solubility and miscibility between the salt and its base in ethanol solvent. The phase dissociation was revealed and confirmed by distinguishing irsogladine maleate and its free base using single-crystal X-ray analysis. Herein, the crystal structures of irsogladine maleate and its base were reported for the first time, and the plausible mechanism for phase dissociation was established based on the structural correlations between those phases

Crystal Structure Determination of Dimenhydrinate after More than 60 Years: Solving Salt–Cocrystal Ambiguity via Solid-State Characterizations and Solubility Study

Dimenhydrinate (DIM) is an important drug used for the prevention of motion sickness. Surprisingly, the crystal structure of DIM has not been determined over the last 67 years. In this study, we have attempted to determine the structure of DIM through single crystal X-ray structure analysis and confirmed the salt–cocrystal ambiguity. Because of the existence of proton transfer, DIM exists as a salt crystal. The crystal structure of DIM contains the anionic form of 8-chlorotheophylline whose existence was confirmed using density functional theory calculation. Other solid-state characterizations based on spectroscopy and thermal analysis were also conducted in order to fill the vacancy regarding the solid-state characterization. Kinetic and intrinsic solubility tests were also performed to evaluate the physicochemical properties of DIM raw material

Simultaneous Improvement of Epalrestat Photostability and Solubility via Cocrystallization: A Case Study

In this study, we attempt to simultaneously improve the photostability and solubility of epalrestat (a drug used for neuropathy treatment) by preparing epalrestat–betaine zwitterionic cocrystals and characterize the physicochemical property alterations accompanying their formation. Notably, we reveal that the strong hydrogen bonds between epalrestat and betaine molecules in the above cocrystals and the reduced size of the reaction cavity around epalrestat molecules prevent the <i>E</i>,<i>Z</i> to <i>Z</i><u>,</u><i>Z</i> photoisomerization of the latter, resulting in improved photostability. Furthermore, the prepared cocrystals exhibit a higher solubility and larger dissolution rate than pure epalrestat crystals due to featuring a layered structure with alternately arranged epalrestat and betaine coformer molecules

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3‑3 Protein–Protein Interaction

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein–protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3‑3 Protein–Protein Interaction

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein–protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators