Covalent organic frameworks: spotlight on applications in the pharmaceutical arena.

Covalent organic frameworks (COFs) have much potential in the field of analytical separation research due to their distinctive characteristics, including easy modification, low densities, large specific surface areas and permanent porosity. This article provides a historical overview of the synthesis and broad perspectives on the applications of COFs. The use of COF-based membranes in gas separation, water treatment (desalination, heavy metals and dye removal), membrane filtration, photoconduction, sensing and fuel cells is also covered. However, these COFs also demonstrate great promise as solid-phase extraction sorbents and solid-phase microextraction coatings. In addition to various separation applications, this work aims to highlight important advancements in the synthesis of COFs for chiral and isomeric compounds.

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Monophasic coamorphous sulpiride: a leap in physicochemical attributes and dual inhibition of GlyT1 and P-glycoprotein, supported by experimental and computational insights.

Study aimed to design and development of a supramolecular formulation of sulpiride (SUL) to enhance its solubility, dissolution and permeability by targeting a novel GlyT1 inhibition mechanism. SUL is commonly used to treat gastric and duodenal ulcers, migraine, anti-emetic, anti-depressive and anti-dyspeptic conditions. Additionally, Naringin (NARI) was incorporated as a co-former to enhance the drug's intestinal permeability by targeting P-glycoprotein (P-gp) efflux inhibition. NARI, a flavonoid has diverse biological activities, including anti-apoptotic, anti-oxidant, and anti-inflammatory properties. This study aims to design and develop a supramolecular formulation of SUL with NARI to enhance its solubility, dissolution, and permeability by targeting a novel GlyT1 inhibition mechanism, extensive experimental characterization was performed using solid-state experimental techniques in conjunction with a computational approach. This approach included quantum mechanics-based molecular dynamics (MD) simulation and density functional theory (DFT) studies to investigate intermolecular interactions, phase transformation and various electronic structure-based properties. The findings of the miscibility study, radial distribution function (RDF) analysis, quantitative simulations of hydrogen/π-π bond interactions and geometry optimization aided in comprehending the coamorphization aspects of SUL-NARI Supramolecular systems. Molecular docking and MD simulation were performed for detailed binding affinity assessment and target validation. The solubility, dissolution and ex-vivo permeability studies demonstrated significant improvements with 31.88-fold, 9.13-fold and 1.83-fold increments, respectively. Furthermore, biological assessments revealed superior neuroprotective effects in the SUL-NARI coamorphous system compared to pure SUL. In conclusion, this study highlights the advantages of a drug-nutraceutical supramolecular formulation for improving the solubility and permeability of SUL, targeting novel schizophrenia treatment approaches through combined computational and experimental analyses.Communicated by Ramaswamy H. Sarma.

Forced degradation study of baricitinib and structural characterization of its degradation impurities by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy.

RATIONALE: Baricitinib (BARI), an inhibitor of Janus kinases 1 and 2 (JAK 1/2), is used for the treatment of rheumatoid arthritis and COVID-19. The present study focuses on establishing the forced degradation behavior of BARI under different degradation conditions (hydrolysis, oxidation, and photolysis) following International Council for Harmonization (ICH) guidelines of Q1A (R2)-Stability testing of new drug substances and products and Q1B-Photostability testing of new drug substances and products. This study helps in monitoring the quality and safety of BARI and its product development. METHODS: Prior to conducting the study, the in silico degradation profile of BARI was predicted by Zeneth. Reversed-phase high-performance liquid chromatography employing a gradient program was used for the identification and separation of degradation impurities with an InertSustain C8 column (4.6 × 250 mm, 5 µm). The mobile phases used were 10 mM ammonium formate (pH 2.89) and acetonitrile. High-resolution mass spectrometry (HRMS) was used for the structural elucidation of the degradation impurities. RESULTS: BARI was labile to hydrolytic (acidic, basic, and neutral) and photolytic degradation conditions which yielded 10 new degradation impurities and it was stable under oxidative (H2 O2 ) conditions. The separated degradation impurities were characterized by HRMS and the respective degradation pathways were proposed. The generated information helped to propose a mechanism for the formation of the degradation impurities. Additionally, one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy were used for the characterization of two major degradation impurities. CONCLUSION: The forced degradation study of BARI was carried out in accordance with ICH Q1A and Q1B guidelines, which resulted in the formation of 10 new degradation impurities. In our analysis, three degradation impurities were matching with the Zeneth predictions. In silico tools, DEREK Nexus® and SARAH Nexus®, were used for predicting the toxicity and mutagenicity of BARI and its degradation impurities. Overall, this study sheds light on BARI's safety monitoring and storage circumstances.

Structural characterization and in silico toxicity prediction of degradation impurities of roxadustat.

Roxadustat is the first drug approved for anemia due to chronic kidney disease. Drug degradation profile is very crucial for assessing the quality and safety of the drug substances and their formulations. Forced degradation studies are conducted for quick prediction of drug degradation products. Forced degradation of roxadustat was carried out as per ICH guidelines, and nine degradation products (DPs) were observed. These DPs (DP-1 to DP-9) were separated using the reverse phase HPLC gradient method with an XBridge column (250 mm × 4.6 mm, 5 µm). The mobile phase consisted of 0.1% formic acid (solvent A) and acetonitrile (solvent B) at a flow rate of 1.0 ml/min. The chemical structures of all the DPs were proposed by using LC-Q-TOF/MS. DP-4 and DP-5, the two major degradation impurities, were isolated, and NMR was used to confirm their chemical structures. Based on our experiments, the roxadustat was found stable to thermal degradation in solid state and oxidative conditions. However, it was unstable in acidic, basic, and photolytic conditions. A very remarkable observation was made about DP-4 impurity. DP-4 was generated as a common degradation impurity in alkaline hydrolysis, neutral hydrolysis as well as photolysis conditions. DP-4 has a similar molecular mass to roxadustat but is structurally different. DP-4 is chemically, (1a-methyl-6-oxo-3-phenoxy-1,1a,6,6a-tetrahydroindeno [1,2-b] aziridine-6a-carbonyl) glycine. In silico toxicity study was conducted using Dereck software to gain the best knowledge of the drug and its degradation products towards carcinogenicity, mutagenicity, teratogenicity, and skin sensitivity. A further study using molecular docking confirmed the potential interaction of DPs with proteins responsible for toxicity. DP-4 shows a toxicity alert due to the presence of aziridine moiety.

Structural characterization of novel hydrolytic and oxidative degradation products of acalabrutinib by LC-Q-TOF-MS, H/D exchange and NMR.

The drug substance, acalabrutinib was subjected to hydrolytic (acid, base and neutral) and oxidative stress degradation as per ICH recommendations. Degradation products (DPs) generated from the drug substance were separated on a Shimadzu Shim-pak C-8 column utilizing a mobile phase composed of methanol: acetonitrile (90:10 v/v) and ammonium acetate buffer (10 mM, pH 3.80) in a gradient elution mode. Acalabrutinib was found to be labile under acid, basic, neutral and oxidative conditions. A total of eighteen DPs of drug substance were formed in hydrolytic (fourteen DPs) and oxidative degradation conditions (four DPs). All the DPs were characterized by comparing the LC-Q-TOF mass spectrometric fragmentation pathway of the drug substance with DPs. Further, hydrogen/deuterium (H/D) exchange studies were also carried out on the DPs to confirm the presence of labile hydrogens in their structures. Four DPs (H-12, O-2, O-3 and O-4) were isolated for chemical structural elucidation by NMR. Probable mechanisms involved in degradation of acalabrutinib were also postulated.