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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Discerning the stability behaviour of mavacamten availing liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy: In silico toxicity and mutagenicity prediction of degradation products.

The present study aimed to separate, identify, and characterise the degradation products formed when mavacamten is exposed to stress degradation as well as the stability of the drug in various environments and also to understand its degradation chemistry. Prediction of in silico toxicity and mutagenicity was aimed at the observed degradation products. Stress degradation along with stability studies and degradation kinetics were performed on mavacamten, and separation of degradation products was carried out by high-performance liquid chromatography. Tandem mass spectrometry studies were executed to characterise the structures of degradation products using product ion fragments. Orthogonally, nuclear magnetic resonance experiments were conducted to elucidate the structures having ambiguity in characterising them. Deductive Estimation of Risk from Existing Knowledge and Structure Activity Relationship Analysis using Hypotheses software were used to establish in silico toxicity and mutagenic profiles of mavacamten and its degradation products. Two degradation products of mavacamten found in acidic hydrolytic stress conditions were separated, identified, characterised, and proposed as 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione and 1-phenylethanamine. Mavacamten was found to be stable under different pH and gastrointestinal conditions. The degradation kinetics of mavacamten under 1 N acidic condition followed zero-order kinetics, and it was degraded completely within 6 h. In silico toxicity and mutagenicity studies revealed that 1-phenylethanamine can be a skin sensitiser. A high-performance liquid chromatography method was developed for the separation of degradation products of mavacamten and characterised by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance. During the manufacturing and storage of drug product, precautions need to be taken when dealing with acidic solutions as the drug is prone to hydrolysis in acidic conditions. The formation of 1-phenylethanamine under these conditions is to be monitored as it is a skin sensitiser.

LC-HRMS and NMR studies for the characterization of degradation impurities of ubrogepant along with the in silico approaches for the prediction of degradation and toxicity.

Ubrogepant is the first oral calcitonin gene-related peptide (CGRP) receptor antagonist which is used for the acute treatment of migraine in adults. The present study employs liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance spectroscopy (NMR) techniques for the identification and characterization of degradation impurities of ubrogepant. The forced degradation study of ubrogepant was performed as per the International Council for Harmonisation (ICH) Q1A and Q1B guidelines. The in silico degradation profile of ubrogepant was predicted by Zeneth. It was observed that ubrogepant was labile to acidic hydrolysis, basic hydrolysis, and oxidative degradation conditions (H2O2), although it was stable in neutral hydrolysis and photolytic (UV light and visible light) conditions. Eight degradation impurities were formed, which were separated on reversed-phase HPLC with a gradient program on an InertSustain C8 column (4.6 × 250 mm, 5 µm) using 10 mM ammonium formate (pH unadjusted) and acetonitrile as the mobile phase. The structures of all the degradation impurities were characterized using the exact masses obtained from the HRMS/MS. Further, NMR studies were conducted on two major degradation impurities (UB-4 and UB-7). A plausible mechanism was proposed to support the structures of all the degradation impurities of UBR. In silico toxicity and mutagenicity assessment were done by DEREK Nexus, SARAH Nexus, and ProTox-II.

In Silico Tools to Thaw the Complexity of the Data: Revolutionizing Drug Research in Drug Metabolism, Pharmacokinetics and Toxicity Prediction.

In silico tool is the flourishing pathway for Researchers and budding chemists to strain the analytical data in a snapshot. Traditionally, drug research has heavily relied on labor-intensive experiments, often limited by time, cost, and ethical constraints. In silico tools have paved the way for more efficient and cost-effective drug development processes. By employing advanced computational algorithms, these tools can screen large libraries of compounds, identifying potential toxicities and prioritizing safer drug candidates for further investigation. Integrating in silico tools into the drug research pipeline has significantly accelerated the drug discovery process, facilitating early-stage decision-making and reducing the reliance on resource-intensive experimentation. Moreover, these tools can potentially minimize the need for animal testing, promoting the principles of the 3Rs (reduction, refinement, and replacement) in animal research. This paper highlights the immense potential of in silico tools in revolutionizing drug research. By leveraging computational models to predict drug metabolism, pharmacokinetics, and toxicity. Researchers can make informed decisions and prioritize the most promising drug candidates for further investigation. The synchronicity of In silico tools in this article on trending topics is insightful and will play an increasingly integral role in expediting drug development.

Chromatographic separation of tiropramide hydrochloride and its degradation products along with their structural characterization using liquid chromatography quadrupole time-of-flight tandem mass spectrometry and nuclear magnetic resonance.

Tiropramide HCl, a widely used antispasmodic drug, was subjected to various stress conditions (hydrolytic, oxidative, photolytic and thermal) per International Council for Harmonization guidelines in the present work. However, there were no comprehensive degradation studies reported on the drug. Therefore, forced degradation studies of tiropramide HCl were carried out to establish the degradation profile and the storage conditions to maintain its quality attributes during the shelf life and usage. A selective HPLC method was developed to separate the drug and its degradation products (DPs) using Agilent C18 column (250 × 4.6 mm; 5 µm). The mobile phase of 10 mM ammonium formate at pH 3.6 (solvent A) and methanol (solvent B) with gradient elution at a flow rate of 1.00 ml/min was used. Tiropramide was found to be susceptible to acidic and basic hydrolytic exposures as well as oxidative stress conditions in the solution state. This drug was found to be stable under neutral, thermal and photolytic conditions in both solutions and the solid state. Five DPs were detected under different stress conditions. The mass spectrometric fragmentation pattern of tiropramide and its DPs was extensively studied using liquid chromatography quadrupole time-of-flight tandem mass spectrometry for their structural characterization. The position of the oxygen atom in the N-oxide DP was confirmed by NMR studies. The knowledge gained by these studies was used to predict drug degradation profiles, which help analyse any impurities in the dosage form.

LC-HRMS and NMR studies for characterization of forced degradation impurities of ponatinib, a tyrosine kinase inhibitor, insights into in-silico degradation and toxicity profiles.

The degradation profile of ponatinib was established during the present study by exposing it to various stress conditions. In-silico degradation pattern of ponatinib was outlined by using Zeneth software. Five degradation impurities were formed during the stress testing of ponatinib. High performance liquid chromatographic method was developed to separate these degradation impurities which includes ammonium acetate of pH 4.75 (A) and methanol (B) as mobile phase in gradient elution mode and Waters Reliant C18 (4.6 × 250 mm, 5 µm) column as stationary phase. Optimised flow rate, injection volume and detection wavelength of the HPLC method were 1.0 mL/min, 10 µL and 254 nm, respectively. Chemical structures of degradation impurities were proposed by high resolution mass spectrometry further, major degradation products were isolated, enriched and investigated thoroughly with the aid of nuclear magnetic resonance spectroscopy studies. The degradation impurities were identified as 4-aminophthalaldehyde (DP 1), 4-((4-methylpiperazin-1-yl)methyl)- 3-(trifluoromethyl) benzenamine (DP 2), 3-(2-(imidazo[1,2-b]pyridazin-3-yl)acetyl)- 4-methylbenzoic acid (DP 3), 3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)- 4-methylbenzoic acid (DP 4) and N-oxide impurity (DP 5) which are new and were not reported in the literature till date. Additionally, toxicity and mutagenicity profiles of ponatinib and its degradation impurities were predicted in-silico by using DEREK and SARAH software. This whole study gives meaningful insights about chemical stability of ponatinib which is useful in its drug development lifecycle.

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.

Identification and characterization of urapidil stress degradation products by LC-Q-TOF-MS and NMR: Toxicity prediction of degradation products.

Urapidil, an antihypertensive drug is subjected to various stress conditions (acidic, basic, neutral, oxidative and photolytic) as per ICH guidelines. A stability indicating HPLC method was developed using InertSustain C8 (250 × 4.6 mm; 5 µm) column and 10 mM ammonium formate (pH 3.5) with gradient elution at a flow rate of 1 mL/min to separate all the DPs. The drug was susceptible to acidic and basic hydrolysis, oxidative and photolytic stress conditions in the solution phase and stable in neutral solution phase and photolytic solid state conditions. A total of five DPs were detected under different stress conditions including DP4 which was previously reported in the literature. An extensive fragmentation pattern of drug and DPs were established using LC-Q-TOF-MS which aided the characterization of DPs. The ambiguity in the position of N-oxide formation in DP5 was confirmed by NMR studies. In silico toxicity of the drug and its DPs were also evaluated. The plausible mechanism of DPs formation was explained.

Stress degradation study on entrectinib and characterization of its degradation products using HRMS and NMR.

Entrectinib is a potent inhibitor of receptor tyrosine kinases and anaplastic lymphoma kinase. It is designated as an orphan drug. There exists no report of comprehensive degradation profiling of the drug in the literature. Therefore, the present study focused on establishment of its stress degradation chemistry under hydrolytic (acidic, alkaline, neutral), oxidative (H2O2), photolytic and thermal conditions. For the purpose, the stressed solutions were subjected to HPLC studies on a C8 column by employing a gradient elution method, in which acetonitrile and 10 mM ammonium acetate were used as the mobile phase components. The results showed that entrectinib was labile to alkaline, H2O2, and photoneutral conditions in the solution state. The drug proved to be stable under acidic, solid-state photolytic, and thermal conditions. A total of sixteen degradation products were formed, which were characterized with the help of high resolution mass spectrometry, and in one case additional help was taken of 1D and -2D NMR data. The knowledge of the structures of the degradation products helped in establishment of degradation pathway of the drug and the involved mechanisms. Also, the toxicity profile of the drug and its degradation products was predicted using ADMET Predictor™ software, which indicated mutagenic potential of atleast five degradation products.

Stability behaviour of antiretroviral drugs and their combinations. 4: Characterization of degradation products of tenofovir alafenamide fumarate and comparison of its degradation and stability behaviour with tenofovir disoproxil fumarate.

In this study, stress degradation behaviour of tenofovir alafenamide fumarate (TAF), a novel prodrug of tenofovir, was investigated and compared with currently used prodrug congener, tenofovir disoproxil fumarate (TDF), whose intrinsic stability was reported by us earlier [14]. Also, pH stability and gastrointestinal stability studies were conducted on both the drugs. High performance liquid chromatography (HPLC) analysis of stressed samples of TAF revealed formation of six degradation products (DPs) against twelve characterized earlier in the case of TDF (RSC Adv. 5(2015) 96117-96129). Like TDF, characterization of DPs of TAF was done by using sophisticated hyphenated liquid chromatography-high resolution mass spectrometry (LC-HRMS) and multistage mass spectrometry (MSn) tools. pH-stability studies between pH 1.2-10 revealed greater stability of TAF, except in acidic conditions, where TAF was degraded extensively. Investigation of gastrointestinal stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and fed state simulated gastric fluid (FeSSGF) suggested that TAF must be administered in fed state, as the drug was practically stable in FeSSGF as compared to extensive loss at acidic pH and in SGF.