“Drug–Coformer–Drug” Multicomponent Crystals to Simultaneously Improve the Solubility of Two Insoluble Combined Drugs by Introduction of a Soluble Coformer

Ren, Bo-Ying; Dai, Xiaoling; Zhang, Fang; Long, Xiang-Tian; Huang, Yong‐Liang; Chen, Jiamei; Lu, Tong‐Bu

doi:10.1021/acs.cgd.2c00377

Cited by 7 publications

(5 citation statements)

References 29 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, for cocrystals containing only a single active pharmaceutical ingredient, adding highly soluble CCFs often enhances the solubility of the material [ 29 , 30 ]. Here, the improvement of solubility of the PROG may be attributed to the property of CCF candidates, since all the CCFs in the paper have more than 20 times higher water solubility than PROG.…”

Section: Discussionmentioning

confidence: 99%

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Xiong,

Xu,

Zhang

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

Progesterone (PROG) is a natural steroid hormone with low solubility and high permeability that belongs to biopharmaceutics classification system class II. In this study, novel pharmaceutical cocrystals of PROG were successfully prepared by solvent evaporation or a liquid-assisted grinding process aimed at enhancing its solubility and bioavailability. The cocrystal formers selected based on crystal engineering principles were carboxylic acids, namely, 4-formylbenzeneboronic acid (BBA), isophthalic acid (IPA), and 3-nitrophthalic acid (NPA). The cocrystal structures were characterized using multiple techniques. Single-crystal X-ray diffraction results showed that the carbonyl group, acting as a hydrogen bond acceptor, was pivotal in the cocrystal network formation, with C–H···O interactions further stabilizing the crystals. The cocrystals exhibited improved solubility and dissolution profiles in vitro, with no significant changes in hygroscopicity. The parallel artificial membrane permeability assay (PAMPA) models indicated that the cocrystals retained PROG’s high permeability. Pharmacokinetic studies in Sprague–Dawley rats revealed that all cocrystals increased PROG exposure, with AUC(0~∞) values for PROG–BBA, PROG–IPA, and PROG–NPA being 742.59, 1201.72 and 442.67 h·ng·mL−1, respectively. These values are substantially higher compared to free PROG, which had an AUC(0~∞) of 301.48 h·ng·mL−1. Notably, PROG–IPA provided the highest AUC improvement, indicating a significant enhancement in bioavailability. Collectively, the study concludes that the cocrystal approach is a valuable strategy for optimizing the physicochemical properties and oral bioavailability of PROG, with potential implications for the development of other poor water-soluble drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Xiong,

Xu,

Zhang

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Recently, our group reported GTB−succinic acid−RH ternary crystals with the intention to simultaneously improve the solubility of GTB and RH by the introduction of soluble succinic acid. 25 During the research, we also obtained one binary GTB-RH crystal and noticed that it has diverse polymorphism. It is beneficial to identify and evaluate as many polymorphic forms (including hydrates) as possible, which aids in finding the optimal form of the multidrug crystal in question to achieve its intended role in a combined formulation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Recently, our group reported GTB–succinic acid–RH ternary crystals with the intention to simultaneously improve the solubility of GTB and RH by the introduction of soluble succinic acid . During the research, we also obtained one binary GTB-RH crystal and noticed that it has diverse polymorphism.…”

Section: Introductionmentioning

confidence: 99%

Three Polymorphs and Two Hydrates of a Multidrug Crystal Involving Gefitinib and Rhein: Characterization, Stability, and Solubility Aspects

Zhang,

Long,

Ren

et al. 2024

Crystal Growth & Design

Self Cite

View full text Add to dashboard Cite

Multidrug crystals, comprising multiple drugs in the same crystal lattice, can be used to develop drug combinations with improved physicochemical properties. The investigation on polymorphism of a given multidrug crystal aids in finding the optimal solid form for the development of combined formulations. In this work, three polymorphs (GTB−RH I, GTB−RH II, and GTB−RH III) and two hydrates (GTB−RH·4.25H 2 O and GTB−RH·1.25H 2 O) of a multidrug crystal involving gefitinib (GTB) and rhein (RH) were successfully obtained and fully characterized by X-ray diffraction (XRD), 1H nuclear magnetic resonance (1H NMR), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR), and dynamic vapor sorption (DVS) measurements. Thermal analysis reveals that GTB−RH I and GTB−RH II are monotropically related, while GTB−RH II and GTB−RH III are enantiotropically related. GTB−RH I is a metastable form, GTB−RH II is the stable form at lower temperature, and GTB−RH III is the stable form at higher temperature. The transition of GTB−RH II to GTB−RH III occurs upon heating to 190 °C. Slurry conversion experiments indicate that GTB−RH·4.25H 2 O is the stable form in aqueous solutions, while GTB−RH II is the stable form in nonaqueous solutions. Accelerated stability tests show that GTB−RH·1.25H 2 O and GTB−RH I converted to GTB−RH·4.25H 2 O, while GTB−RH·4.25H 2 O, GTB−RH II, and GTB−RH III remained intact up to three months. In addition, dissolution experiments demonstrate the apparent solubility of GTB and RH in the following order: GTB−RH III > GTB−RH II > GTB−RH I > GTB−RH·1.25H 2 O > GTB−RH·4.25H 2 O. This work shows that GTB−RH III has great potential to be developed into a combined formulation as it exhibits simultaneously and significantly improved solubility for both GTB and RH.

show abstract

“…cocrystals, salts, hydrates/solvates). , In particular, cocrystals offer many possibilities when it comes to crystal engineering since there are various coformers which can be assembled with target compounds by noncovalent interactions, such as hydrogen-bonding interactions, π–π interactions, halogen bonds, etc . These interactions can manipulate the molecular arrangement in crystal structures, resulting in the modification of the physicochemical properties, such as solubility, luminescence, stability, etc. − …”

Section: Introductionmentioning

confidence: 99%

Experimental and Theoretical Investigation of Hydrogen-Bonding Interactions in Cocrystals of Sulfaguanidine

Huang

Cheemarla

Tiana

et al. 2023

Crystal Growth & Design

View full text Add to dashboard Cite

Pharmaceutical cocrystals, a type of multicomponent crystalline material incorporating two or more molecular and/or ionic compounds connected by noncovalent interactions (such as hydrogen bonds, π–π interactions, and halogen bonds), are attracting increasing attention in crystal engineering. Sulfaguanidine (SGD), one of the most frequently used sulfonamide compounds, was chosen as a model compound in this work to further investigate the hydrogen bond interactions in cocrystals, since it possesses various hydrogen bond donor and acceptor sites. Five cocrystals of SGD, synthesized successfully by slurry and slow evaporation methods, were fully characterized by thermal analysis, X-ray techniques, and Fourier transform infrared spectroscopy. To gain insight into the nature of hydrogen-bonding interactions, theoretical calculations including the analysis of Hirshfeld surface, MEPS (molecular electrostatic potential surface), and QTAIM (quantum theory of atoms in molecules) were conducted. The results are a part of a systematic study of cocrystals of sulfonamides that aims to establish synthon hierarchies in cocrystals containing molecules with multiple hydrogen-bonding functional groups.

show abstract

“Drug–Coformer–Drug” Multicomponent Crystals to Simultaneously Improve the Solubility of Two Insoluble Combined Drugs by Introduction of a Soluble Coformer

Cited by 7 publications

References 29 publications

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Three Polymorphs and Two Hydrates of a Multidrug Crystal Involving Gefitinib and Rhein: Characterization, Stability, and Solubility Aspects

Experimental and Theoretical Investigation of Hydrogen-Bonding Interactions in Cocrystals of Sulfaguanidine

Contact Info

Product

Resources

About