A Molecular Dynamic Simulation, Structural Analysis, and Ex Vivo Insights into the P-glycoprotein-Mediated Interactions of Dietary Polyphenols with Cyclin-dependent Kinase Inhibitors: A Potential Strategy to Counteract Drug Efflux.

Introduction: P-glycoprotein, an ATP-dependent efflux transporter, plays a crucial role in eliminating cellular toxins and affects the intracellular concentration and bioavailability of CDK 4/6 inhibitors. Moreover, dietary flavonoids are natural bio-enhancers that can effectively inhibit the efflux function of these transporters. Therefore, this study aimed to assess the impact of dietary polyphenols on the inhibition of P-glycoprotein and the subsequent efflux of CDK inhibitors palbociclib and ribociclib.

Development and validation of stability indicating assay method for mitapivat: Identification of novel hydrolytic, photolytic, and oxidative forced degradation products employing quadrupole-time of flight mass spectrometry.

Mitapivat is a novel, first-in-class orally active pyruvate kinase activator approved by the US Food and Drug Administration in 2022 for the treatment of hemolytic anemia. There is no literature available regarding the identification of degradation impurities of mitapivat. The present study deals with the degradation behavior of mitapivat under various stress conditions such as hydrolytic, photolytic, thermal, and oxidative stress.

Computational-Based Polyphenol Therapy for Nonsmall Cell Lung Cancer: Naringin Coamorphous Systems for Solubility and Bioavailability Enhancement.

In this research, we utilized molecular simulations to create co-amorphous materials (CAMs) of ceritinib (CRT) with the objective of improving its solubility and bioavailability. We identified naringin (NRG) as a suitable co-former for CRT CAMs based on binding energy and intermolecular interactions through computational modeling. We used the solvent evaporation method to produce CAMs of CRT and NRG, expecting to enhance both solubility and bioavailability simultaneously.

Identification and characterization of the in-vivo metabolites of the novel soluble epoxide hydrolase inhibitor EC5026 using liquid chromatography quadrupole time of flight mass spectrometry.

EC5026 is a novel soluble epoxide hydrolase inhibitor being developed clinically to treat neuropathic pain and inflammation. In the current study, we employed the LC-ESI-Q-TOF-MS/MS technique to identify four in-vivo phase-I metabolites of EC5026 in rat model, out of which three were found to be novel. The identified metabolites include aliphatic hydroxylation, di-hydroxylation, terminal desaturation, and carboxylation.

Physicochemical interaction of rifampicin and ritonavir-lopinavir solid dispersion: an in-vitro and ex-vivo investigation.

Objective: To investigate the in-situ physicochemical interaction of Rifampicin and Ritonavir - Lopinavir Solid dispersion administered for the treatment of comorbid conditions i.e. Tuberculosis and HIV/AIDS.

Development and validation of LC-MS/MS method for estimating the pharmacokinetics, protein binding, and metabolic stability of soluble epoxide hydrolase inhibitor EC5026.

EC5026 is a soluble epoxide hydrolase (SEH) inhibitor which is being developed clinically (Phase-1) as a first-in-class analgesic for the treatment of pain. In the present study, we report the development and validation of the LC-MS/MS method for the estimation of EC5026 from rat plasma. The developed method is simple, specific, and sensitive for the quantification of EC5026 from rat plasma.

Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib.

Background: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are known to show inhibitory effect on P-glycoprotein.

Objective: Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein mediated efflux of palbociclib and ribociclib.

A computational-based approach to fabricate Ceritinib co-amorphous system using a novel co-former Rutin for bioavailability enhancement.

In this study, we used molecular simulations to design Ceritinib (CRT) co-amorphous materials (CAMs) with concurrent improvement in solubility and bioavailability. Computational modeling enabled us to select the co-former by estimating the binding energy and intermolecular interactions. Rutin (RTH) was selected as a co-former for CRT CAMs using the solvent evaporation method to anticipate simultaneous improvement of solubility and bioavailability.

In vitro, in-vivo, and in-silico investigation of physicochemical interactions between pioglitazone and rifampicin.

There is a possibility of in-situ physicochemical interactions between concomitantly administered drugs. This study aimed to investigate such physicochemical interactions between pioglitazone and rifampicin. Pioglitazone exhibited significantly higher dissolution in the presence of rifampicin, while the dissolution of rifampicin remained unaffected.

A comprehensive review of sources of nitrosamine contamination of pharmaceutical substances and products.

N-nitrosamines are carcinogenic impurities most commonly found in groundwater, treated water, foods, beverages and consumer products. The recent discovery of N-nitrosamines in pharmaceutical products and subsequent recalls pose a significant health risk to patients. Initial investigation by the regulatory agency identified Active Pharmaceutical Ingredients (API) as a source of contamination.

Raloxifene HCl - quercetin co-amorphous system: preparation, characterization, and investigation of its behavior in phosphate buffer.

Purpose: Raloxifene HCl (RLX), a practically insoluble drug used in the treatment of osteoporosis in post-menopausal women; was modified at its molecular level to enhance its solubility using co-amorphous technology.

Methods: In this study, RLX was co-amorphized with Quercetin (QCT; a nutraceutical flavonoid) using solvent evaporation (SE), quench cooling (QC), and ball milling (BM) techniques. The prepared co-amorphous systems (CAMs) were characterized using XRD, DSC, and FT-IR.

Considerations for the selection of co-formers in the preparation of co-amorphous formulations.

Co-amorphous drug delivery systems are evolving as a credible alternative to amorphous solid dispersions technology. In Co-amorphous systems (CAMs), a drug is stabilized in amorphous form using small molecular weight compounds called as co-formers. A wide variety of small molecular weight co-formers have been leveraged in the preparation of CAMs.

Dronedarone HCl-Quercetin Co-Amorphous System: Characterization and RP-HPLC Method Development for Simultaneous Estimation.

Background: Dronedarone HCl (DRN) is an anti-arrhythmic drug indicated for atrial fibrillation. DRN has a low solubility of 2 µg/mL and 4% bioavailability, thus it is formulated as a co-amorphous system to enhance its solubility by using quercetin (QCT) as a co-former. A sensitive, accurate, and economic method for the simultaneous quantification of DRN and QCT in formulation is not found in the literature.

Overview of Extensively Employed Polymeric Carriers in Solid Dispersion Technology.

Solid dispersion is the preferred technology to prepare efficacious forms of BCS class-II/IV APIs. To prepare solid dispersions, there exist a wide variety of polymeric carriers with interesting physicochemical and thermochemical characteristics available at the disposal of a formulation scientist. Since the advent of the solid dispersion technology in the early 1960s, there have been more than 5000 scientific papers published in the subject area.

Naringin nano-ethosomal novel sunscreen creams: Development and performance evaluation.

Long term exposure of skin to UV rays produces detrimental effects such as premature skin-ageing and skin cancer. Although, zinc oxide (ZnO) and titanium dioxide (TiO) are good sunscreen agents, they do not provide highly efficient UV radiation protection and antioxidant and anti-aging effects. The present study was aimed at developing and characterizing ethosomes loaded with naringin and then to incorporate them into sunscreen creams containing nano-ZnO and -TiO to achieve adequate skin penetration and skin retention so as to scavenge the free radicals by virtue of naringin's antioxidant property.

The Significance of Utilizing In Vitro Transfer Model and Media Selection to Study the Dissolution Performance of Weak Ionizable Bases: Investigation Using Saquinavir as a Model Drug.

This study investigated the dissolution behavior of BCS class II ionizable weak base Saquinavir and its mesylate salt in the multi-compartment transfer setup employing different composition of dissolution media. The dissolution behavior of Saquinavir was studied by using a two-compartment transfer model representing the transfer of drug from the stomach (donor compartment) to the upper intestine (acceptor compartment). Various buffers like phosphate, bicarbonate, FaSSIF, and FeSSIF were employed.

Investigation of drug-polymer miscibility, biorelevant dissolution, and bioavailability improvement of Dolutegravir-polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer solid dispersions.

The aim of the current study was to prepare the efficacious amorphous solid dispersion of poorly water-soluble compound, Dolutegravir. After theoretical and experimental determination of drug-polymer miscibility, polyvinyl caprolactam-polyvinyl acetate-polyethylne glycol graft copolymer was chosen as a polymer. The solid dispersions of Dolutegravir were prepared by quench cooling and solvent evaporation method.

Fixed dose combinations of anti-tubercular, antimalarial and antiretroviral medicines on the Indian market: critical analysis of ubiquity, sales and regulatory status.

Objective: To assess the proportion and sales of unapproved Fixed Dose Combinations (FDCs) of anti-tubercular, antimalarial and antiretroviral medicines available on the Indian market.

Methods: Available FDCs of anti-tubercular, antimalarial and antiretrovirals were screened against the Central Drugs Standard Control Organization (CDSCO) database of approved FDCs. The FDC sales information in the given categories was obtained from AIOCD AWACS PharmaTrac, a market database.

The relevance of co-amorphous formulations to develop supersaturated dosage forms: In-vitro, and ex-vivo investigation of Ritonavir-Lopinavir co-amorphous materials.

Ritonavir and Lopinavir have previously been demonstrated to decrease the maximum solubility advantage and flux in the presence of each other. The present study investigated the ability of Ritonavir and Lopinavir co-amorphous materials to generate a supersaturated state. Further, it explored the precipitation and flux behavior of co-amorphous materials.

Recent advances in co-amorphous drug formulations.

Co-amorphous drug delivery systems have recently gained considerable interest in the pharmaceutical field because of their potential to improve oral bioavailability of poorly water-soluble drugs through drug dissolution enhancement as a result of the amorphous nature of the material. A co-amorphous system is characterized by the use of only low molecular weight components that are mixed into a homogeneous single-phase co-amorphous blend. The use of only low molecular weight co-formers makes this approach very attractive, as the amount of amorphous stabilizer can be significantly reduced compared with other amorphous stabilization techniques.

Simultaneous improvement of solubility and permeability by fabricating binary glassy materials of Talinolol with Naringin: Solid state characterization, in-vivo in-situ evaluation.

The aim of the current study was to prepare binary amorphous forms of Talinolol (TLN) by using Naringin (NRG) as a stabilizing agent. The secondary objective of this study was to study the effect of P-gp inhibitor NRG on the P-gp probe drug TLN. The binary amorphous samples were prepared by quench cooling technique in the molar ratios TLN:NRG (1:1), TLN:NRG (1:2), TLN:NRG (2:1).

Fabrication, solid state characterization and bioavailability assessment of stable binary amorphous phases of Ritonavir with Quercetin.

In the current study, Quercetin (QRT) was characterized for thermodynamic and kinetic parameters and found as an excellent glass former. QRT was paired with Ritonavir (RTV) (BCS class-IV antiretroviral) to form stable amorphous form and pharmacologically relevant combination. Binary amorphous forms of RTV and QRT in molar ratios 1:1, 1:2 and 2:1 were prepared by solvent evaporation technique and characterized by XRPD, DSC and FTIR.

Development and validation of reversed-phase high-performance liquid chromatography method for estimation of rizatriptan benzoate in oral strip formulations.

Aim: A simple, accurate, precise, and reproducible reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of rizatriptan benzoate in oral strip formulations.

Methodology: Separation was achieved under optimized chromatographic condition on a Hiper C18 column (250 mm × 4.6 mm, 5 m) using Shimadzu HPLC.

Preparation and characterization of co-amorphous Ritonavir-Indomethacin systems by solvent evaporation technique: improved dissolution behavior and physical stability without evidence of intermolecular interactions.

The aim of this study was to stabilize the amorphous form of Ritonavir (RTV) a BCS class-II drug with known amorphous stabilizing small molecule Indomethacin (IND) by co-amorphous technology. The co-amorphous samples were prepared by solvent evaporation technique in the molar ratios RTV:IND (2:1), RTV:IND (1:1), RTV:IND (1:2) and their amorphous nature was confirmed by XRPD, DSC and FT-IR. Physical stability studies were carried out at temp 25°C and 40°C for maximum up to 90 days under dry conditions.

Development and validation of RP-HPLC method with ultraviolet detection for estimation of montelukast in rabbit plasma: Application to preclinical pharmacokinetics.

Objective: To develop a liquid-liquid extraction based reverse phase liquid chromatography method for estimation of montelukast in rabbit plasma.

Methods: Chromatographic separation was carried out using Phenomenex Luna C18 column (250 mm × 4.6 mm × 5 μm) with mobile phase composed of ammonium acetate buffer (20 Mm), pH 5.