International Council For Harmonisation Research Articles

Development and Validation of Fast and Sensitive RP-HPLC Stability-Indicating Method for Quantification of Piroxicam in Bulk Drug.

A simple, rapid, sensitive, and cost-effective green solvent-assisted reverse-phase high-performance liquid chromatographic technique, coupled with a photodiode array detector, was developed and validated for the estimation of piroxicam (PRXM). The chromatographic separation was achieved by using a C-18 (250 × 4.6) mm, 5-μm stationary phase and a mobile phase consisting of methanol and 0.1% ortho-phosphoric acid in water in a ratio of (80:20) v/v at a flow rate of 1ml/min. The detection was carried out at a wavelength of 254nm with a constant injection volume of 10μL throughout the analysis. The calibration curve was observed to be linear over the optimum concentration range of 50-300μgmL-1, with an R2 value of 0.9995. The developed method was validated as per the International Council for Harmonisation (ICH) Q2 (R1) guideline. Various parameters like selectivity/specificity, accuracy/recovery, linearity, precision, detection limit, quantitation limit, robustness and stability of analyte in solution were performed for the method validation. The PRXM was evaluated under stressed conditions, including acidic, basic, oxidative, thermal and photolytic, as per ICH Q1 (R2) guidelines. Significant degradation was observed in acidic and basic degradation conditions. Conversely, the drug substance showed stability when exposed to oxidative, photolytic and thermal degradation conditions.

Simultaneous measurement of duloxetine hydrochloride and avanafil at dual-wavelength using novel ecologically friendly TLC-densitometric method: application to synthetic mixture and spiked human plasma with evaluation of greenness and blueness

The simultaneous assay of duloxetine hydrochloride (DLX) and avanafil (AVN) in their pure forms, synthetic mixtures, and spiked human plasma was achieved using a novel, eco-friendly, sensitive, and specific HPTLC methodology that have been established and validated. Measuring the levels of co-administered antidepressants and sexual stimulants in biological fluids is an important step for individuals with depression and sexual problems. Separation was performed successfully using pre-coated silica gel 60-F254 as a stationary phase and a mobile phase composed of methanol, acetone, and 33% ammonia (8:2:0.05, v/v/v). Compact bands were produced by the optimized mobile phase that was chosen for development (Rf values were 0.23 and 0.75 for DLX and AVN, individually) after dual-wavelength detection for DLX and AVN at 232 and 253 nm, respectively. The results of polynomial regression analysis were exceptional (r = 0.9999 for both medicines) over concentration ranges of 5-800 and 10-800ng/spot for DLX and AVN, respectively. The quantitation limits were 4.69 and 9.53 ng/spot (0.31 and 0.94 µg/mL), whereas the detection limits were 1.55 and 3.15 ng/spot (0.63 and 1.91 µg/mL), for DLX and AVN, respectively. The International Council for Harmonization (ICH) criteria served as the basis for validating the established approach. Moreover, the proposed technique was evaluated in terms of greenness using four contemporary ecological metrics: The Analytical Greenness software (AGREE), the Green Analytical Procedure Index (GAPI), Eco-Scale, and the National Environmental Method Index (NEMI). Additionally, the Blue Applicability Grade Index (BAGI), a newly developed tool for evaluating the practicality (blueness) of procedures, was taken into consideration when evaluating the sustainability levels of the established approach.

Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability.

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.

Stability indicating high performance thin layer chromatography method development and validation for quantitative determination of tetracycline hydrochloride in tetracycline hydrochloride active pharmaceutical ingredient (API) and its dosage forms

Simple, quick, cost-effective, and environmentally friendly analytical methods for quality assurance and control roles for different medicines, including Tetrcyclines, are most significantly needed. Also, different thin layer chromatography (TLC)-based methods for tetracycline identification exist, but high performance thin layer chromatography methods based on modern state- of- the art equipment are still nonexistent. Thus, in this study, analytical method development and verification were done by high performance thin layer chromatography (HPTLC) (using an automated equipment model) using glass plates coated with silica gel 60 F254 after treating with 10% Na2EDTA. Validation was carried out according to International Council for Harmonization (ICH) guidelines. A mobile phase formed from ethyl acetate, acetonitrile, methanol, and 1% aqueous ammonia in the composition of 4.4:19.6:10:6 volume to volume ratio (V/V) was used. Rf value, percentage recoveries, linearity ranges, limit of detection (LOD), and limit of quantitation (LOQ) for the developed HPTLC method were 0.28, 100.83–106.25%, 160–560 ng/band (r2 values of 0.9999), 31.9 ng/band, and 96.7 ng/band, respectively. The results of the sample assays conducted using the new method and the United States Pharmacopoeia (USP) high performance liquid chromatography (HPLC) method were 91.59% to 108.3% and 90.83% to 102.85%, respectively. The F test for the aforementioned methods was 2.01, which is smaller than the tabulated F value of 5.05 with 5 degrees of freedom at a 95% confidence range, proving that the newly developed HPTLC and HPLC pharmacopoeial methods can be used interchangeably.The newly developed HPTLC method is easy, economical, specific, accurate, and roboust, thus it can be employed in a range of settings that require quality control and assurance activities of tetracycline hydrochloride (TC-HCl) in bulk and ointment dosage forms.

METHOD DEVELOPMENT AND VALIDATION OF RAPID ISOCRATIC RP-HPLC METHOD FOR SIMULTANEOUS ESTIMATION OF PARACETAMOL, CAFFEINE, AND PROPYPHENAZONE IN PHARMACEUTICAL FORMULATION

Objective: The objective is to develop a novel, rapid, simple, precise, accurate, and reproducible RP-HPLC method for simultaneous estimation of paracetamol, caffeine, and propyphenazone in bulk and a pharmaceutical dosage form. Method: Optimized chromatographic conditions were used for isocratic elution with Shimadzu C18 (4.6×250 mm, 5 μm), methanol, and 20mM phosphate buffer (60:40, v/v, pH 2.5) as mobile phase, flow rate 1.2 mL/min, and UV detector at λ max 272 nm. The method was validated for specificity, precision, linearity, accuracy, robustness, and solution stability as per the International Council for Harmonization (ICH) guidelines. Result: It was discovered that the retention time for paracetamol, caffeine, and propyphenazone was found to be 2.6 min, 3.0 min, and 7.5 min. The method proved to be rapid, simple, linear (R2>0.999), precise {relative standard deviation (RSD<2.0%)}, accurate (recovery 98–102%), sensitive, and robust. Conclusion: The proposed novel isocratic RP-HPLC method was found to be rapid (short run time of 10 min), highly selective, accurate, and sensitive. The method has been successfully applied to the simultaneous analysis of paracetamol, caffeine, and propyphenazone in a pharmaceutical formulation.

Isoquinoline-based intrinsic fluorescence assessment of erythropoiesis-stimulating agent, Roxadustat (FG-4592), in tablets: applications to content uniformity and human plasma evaluation.

In the present study, a first validated and green spectrofluorimetric approach for its assessment and evaluation in different matrices was investigated. After using an excitation wavelength of 345 nm, Roxadustat (ROX) demonstrates a highly native fluorescence at an emission of 410 nm. The influences of experimental factors such as pH, diluting solvents, and different organized media were tested, and the most appropriate solvent choice was ethanol. It was confirmed that there was a linear relationship between the concentration of ROX and the relative fluorescence intensity in the range 60.0-1000.0 ng ml-1, with the limit of detection and limit of quantitation, respectively, being 17.0 and 53.0 ng ml-1. The mean recoveries % [±standard deviation (SD), n =5] for pharmaceutical preparations were 100.11% ± 2.24%, whereas for plasma samples, they were 100.08 ± 1.08% (±SD, n =5). The results obtained after the application of four greenness criteria, Analytical Eco-Scale metric, NEMI, GAPI, and AGREE metric, confirmed its eco-friendliness. In addition, the whiteness meter (RGB12) confirmed its level of sustainability. The International Council for Harmonisation (ICH) criteria were used to verify the developed method through the study in both spiked plasma samples and content uniformity evaluation. An appropriate standard for various applications in industry and quality control laboratories was developed.

New Stability Indicating HPLC Method for Related Substances in Dapagliflozin

The requirements established by the International Council for Harmonization (ICH) for the measurement of dapagliflozin from tablets were satisfied by the development and successful implementation of an reversed-phase high performance liquid chromatography (RP-HPLC) technique that is characterized by its speed, precision, and accuracy. In order to separate the samples, an isocratic mode was used on a Princeton C18 column that was operating at a flow rate of 1-mL per minute. The phase was composed of acetonitrile and 0.1% triethylamine in a volume-to-volume ratio of 50:50, with a pH of 5.0 and a detection wavelength of 224 nm. 5.163 minutes was the retention time that was determined to be best under the circumstances of the chromatographic analysis. Based on the correlation value of 0.999, it can be concluded that the procedure adhered to Beer-Lambert’s law within the measurement range of 10 to 70 μg/mL. The findings not only verified the claim that was made on the label, but they also validated the mean percent drug concentration that was specified for the commercial tablet formulation, which was 100.57%. Following the completion of an investigation, it was discovered that the approaches that were proposed have sufficient proportions of precision measurements, robustness, accuracy, range, and linearity. As part of the technique for stress testing, a number of criteria were evaluated and evaluated overall. The elements that were considered to be among these were light, humidity, temperature, oxidation, and pH (acid/base).

An Ecologically Sound RP-HPLC Method for Estimating Citicoline using AQbD with Degradation Studies

Background: Citicoline is widely used for neurological complications. This research work was carried out using reverse-phase high-performance liquid chromatography (RP-HPLC) employing green analytical chemistry principles. Materials and Methods: The method was completely developed with ethanol:water (20:80 v/v) as the mobile phase, 0.1% orthophosphoric acid was used to adjust the pH to 3.5, and an Inertsil ODS 3 (250 x 4.6 mm, 5 μm) column as the stationary phase, the flow rate was set at 1-mL/min. The column temperature was maintained at 35ºC, and an injection volume of 10 μL was used for detection at a wavelength of 250 nm. Results and Discussion: The peak was eluted with isocratic elution with a retention time of 3.996 minutes. The linear concentration range for this method was 10 to 50 μg/mL, and the correlation coefficient R2 was 0.999. The forced degradation studies have shown that 3.5% w/w degraded in acid, 1.35% w/w in alkali, and 0.2% w/w in oxidation. The products formed during degradation were characterized using gas chromatography-mass spectrometry (GC-MS). Conclusion: The International Council for Harmonisation (ICH) guidelines were followed in the development and validation of the method optimized by the use of central composite design, and the method’s greenness was assessed through the use of AGREE, AES, GAPI, and AMGS, among other green assessment tools.

Incorporation of eggshell waste in the preparation of carbon quantum dot nanoprobes for the determination of COVID-19 antiviral drug; molnupiravir

New carbon quantum dots (CQDs) with multi-doped elements from eggshell biomass waste have been employed as a direct, fast, green, and selective probe for the fluorometric determination of molnupiravir, a COVID-19 antiviral drug. For the first time, the eggshell@CQDs were prepared through a simple, single-step microwave heating process that only took 90 s. Upon excitation at λex 340 nm, the resulting CQDs exhibited a maximum bluish fluorescence emission at λem 408 nm. Molnupiravir was found to quench the native fluorescence of the prepared CQDs in a quantitative manner, based on a static mechanism by forming a non-emissive complex. The spectrofluorometric method designed for molnupiravir detection was validated per the International Council for Harmonization (ICH) requirements. The proposed fluorescent probe showed good linearity for molnupiravir detection over a range of 2.5–70 µg/mL, with percent recoveries ranging from 99.53 % to 101.79 % and %RSD (relative standard deviation) less than 1 %. The eggshell@CQDs were successfully employed to determine molnupiravir levels in marketed hard capsules, yielding good percent recoveries and repeatability. The developed approach was found to be greener than the published HPLC/UV approach, as assessed by the analytical eco-scale, green analytical procedure index (GAPI), and analytical greenness metric approach (AGREE). Furthermore, this approach highlights the potential of synthesizing CQDs from natural biomass, specifically low-value biomass waste such as eggshells.

Developing generic templates to shape the future for conducting integrated research platform trials

BackgroundInterventional clinical studies conducted in the regulated drug research environment are designed using International Council for Harmonisation (ICH) regulatory guidance documents: ICH E6 (R2) Good Clinical Practice—scientific guideline, first published in 2002 and last updated in 2016. This document provides an international ethical and scientific quality standard for designing and conducting trials that involve the participation of human subjects. Recently, there has been heightened awareness of the importance of integrated research platform trials (IRPs) designed to evaluate multiple therapies simultaneously. The use of a single master protocol as a key source document to fulfill trial conduct obligations has resulted in a re-examination of the templates used to fulfill the dynamic regulatory and modern drug development environment challenges.MethodsRegulatory medical writing, biostatistical, and other members of EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) developed the suite of templates for IRPs over a 3.5-year period. Stakeholders contributing expertise included academic hospitals, pharmaceutical companies, non-governmental organizations, patient representative groups, and small and medium-sized enterprises (SMEs).ResultsThe suite of templates for IRPs based on TransCelerate’s Common Protocol Template (CPT) and statistical analysis plan (SAP) should help authors navigate relevant guidelines as they create study design content relevant for today’s IRP studies. It offers practical suggestions for adaptive platform designs which offer flexible features such as dropping treatments for futility or adding new treatments to be tested during a trial. The EU-PEARL suite of templates for IRPs comprises a preface, followed by the actual resource. The preface clarifies the intended use and underlying principles that inform resource utility. The preface lists references contributing to the development of the resource. The resource includes TransCelerate CPT guidance text, and EU-PEARL-derived guidance text, distinguished from one another using shading. Rationale comments are used throughout for clarification purposes. In addition, a user-friendly, functional, and informative Platform Trials Best Practices tool to support the setup, design, planning, implementation, and conduct of complex and innovative trials to support multi-sourced/multi-company platform trials is also provided. Together, the EU-PEARL suite of templates and the Platform Trials Best Practices tool constitute the reference user manual.ConclusionsThis publication is intended to enhance the use, understanding, and dissemination of the EU-PEARL suite of templates for designing IRPs. The reference user manual and the associated website (http://www.eu-pearl) should facilitate the designing of IRP trials.

Validation of spectrophotometric and colorimetric methods for determination of efavirenz in various biological matrices: Application to the development of dissolvable microneedle-based efavirenz complex inclusion for vaginal delivery

One of the antiretroviral treatments (ART) used to treat Human Immunodeficiency Virus (HIV) disease is efavirenz (EFV). EFV itself has bioavailability issues during oral therapy due to its poor solubility. When injected, administration issues arise. Hence, creating medication delivery methods was crucial to creating EFV delivery. HIV therapy benefits from the vaginal medication delivery system's ease of use, higher bioavailability, and quick systemic absorption in the surface folds. In this study, an inclusion complex (IC) was added to the EFV formulation to increase solubility, and dissolving microneedles (DMN) was used for delivery to increase penetration. Here, in support of this formulation creation process, we carried out validation utilizing spectrophotometric and colorimetric techniques. The amount of EFV was determined by validating ethanol and artificial vaginal fluid (AVF) using UV–Vis spectrophotometry. Vaginal tissue and plasma were also validated using colorimetric with the β-naphthol reagent. The International Council for Harmonization (ICH) and US Food and Drug Administration (FDA) requirements were adhered to in verifying the creation of analytical procedures. The outcomes demonstrated a linear correlation value of ≥0.9998. The LLOQ levels were 0.99 g/mL, 0.97 g/mL, 0.66 g/mL, 0.74 g/mL, and 0.74 g/mL in ethanol, AVF, porcine vaginal tissue, rat vaginal tissue, and vaginal plasma, respectively. The developed precision and accuracy were confirmed. The approach was successfully used to determine the amount of EFV in inclusion complex integration and DMN platform. The outcomes demonstrated high IC-EFV incorporation release and penetration profiles, permeation and high drug retention andex vivokinetics in the vagina and enhanced bioavailability fromin vivostudy pharmacokinetic profiles of DMN-IC-EFV.

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.

Design of experiments and white analytical chemistry-driven green and sensitive spectrofluorimetric estimation of pregabalin in its pharmaceutical dosage forms and spiked human plasma

BackgroundPregabalin (PGB) is a medication with anticonvulsant, analgesic and anxiolytic properties, employed in the treatment of epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal syndrome and generalized anxiety disorder. Several spectrofluorimetric techniques have been documented for the determination of PGB in pharmaceutical dosage forms. However, these published methods typically involve the use of expensive and toxic organic solvents and reagents, as well as high reaction temperatures for PGB analysis. These components pose risks to aquatic life and the environment, making them less environmentally friendly and user-friendly. A recent advancement in analytical chemistry has introduced a white analytical approach, providing an economical, eco-friendly and user-friendly method for the development of analytical procedures.ObjectivesTherefore, a green and sensitive spectrofluorimetric determination of PGB, guided by white analytical chemistry principles, has been conducted utilizing distilled water as an environmentally friendly solvent.MethodsThe establishment of the spectrofluorimetric method involved employing the design of experiments approach to ensure a robust, precise and accurate estimation of PGB. Response surface analysis and optimization of critical procedural variables and responses were carried out using the central composite design. The validation of the developed method adhered to the guidelines outlined in ICH (International Council for Harmonization) Q2 (R1) and M10.ResultsThe established spectrofluorimetric method was utilized to determine the PGB content in commercially available formulations and human plasma samples spiked with PGB. The obtained results were in accordance with the labeled claim of PGB in the formulations. The recovery of PGB in the spiked human plasma samples ranged from 85 to 90% of the spiked amount.ConclusionsThe greenness profiles of the published and suggested spectrofluorimetric methods for PGB estimation were evaluated and compared using the AGREE calculator, GAPI software and ESA tool. The suggested method demonstrated sensitivity, robustness, environmental friendliness and user-friendliness.

A Selective Gas Chromatography–Tandem Mass Spectrometry Method for Quantitation of Ethylene and Diethylene Glycol in Paediatric Syrups

Ethylene Glycol (EG) and diethylene Glycol (DEG) are two contaminants known to cause various human health problems. These glycols might be present in drug syrups that are based on glycerol, sorbitol, or polyethylene glycol. In late 2022, several batches of cough, antipyretics, and antihistamine syrups were reported to contain toxic levels of EG and DEG in multiple countries; this incident concerned the World Health Organization (WHO). From an analytical perspective, several methods of glycols analysis in pharmaceuticals have been reported in the literature, with the majority being dedicated to raw material analysis. This study aims to develop a selective method capable of evaluating a wide range of paediatric syrups in order to assess the safety of commercially available paediatric syrups currently distributed in the local market. This research introduces a method for determining glycols utilizing gas chromatography-tandem mass spectrometry (GC–MS/MS), which offers significantly higher selectivity than conventional single quadrupole gas chromatography-mass spectrometry (GC–MS). The developed method meets the current International Council for Harmonisation (ICH) guidelines for validation. The absence of any interfering peaks in both the unspiked sample of promethazine syrup and the reference standard solutions proved the method's selectivity. Furthermore, 2,2,2-trichloroethanol was used as an internal standard, and a new GC–MS/MS method was developed to analyze it. The calibration curves for EG and DEG were linear within the selected concentration range of 1–10 μg/mL. The detection limit for both EG and DEG was 400 ng/mL, while the quantification limit was 1 μg/mL. Recovery values for both EG and DEG met the accuracy acceptance criterion. Thus, the developed method proved to be efficient and accurate for determining EG and DEG levels in suspected contaminated syrups.

Green LC-MS/MS method for in-vivo pharmacokinetics of mirabegron-encapsulated nanostructured lipid carriers in rat plasma: Integrating white analytical chemistry and analytical quality by design approach

Mirabegron (MBG) stands as the top choice for managing overactive bladder, yet its limited aqueous solubility and low bioavailability pose significant challenges. To overcome these hurdles, the objective was to develop and characterize nanostructured lipid carriers (NLCs) for mirabegron, facilitating its controlled release for overactive bladder treatment through the Quality by Design (QbD) approach. The literature showcases several analytical techniques for mirabegron quantification in pharmaceutical formulations and biological fluids, yet most employ toxic organic solvents in their mobile phases, posing environmental risks and threats to aquatic life. To address this concern, a green liquid chromatographic-tandem mass spectrometry method was developed for in-vivo pharmacokinetic assessment of mirabegron-loaded NLCs in rat plasma, utilizing safe organic solvents. The method's development embraced the principles of analytical QbD, aiming to curtail organic waste generation during sample analysis. Rigorous validation was conducted in accordance with the International Council for Harmonization (ICH) Q2 (R1) and M10 guidelines. The developed method found application in both in-vitro drug release kinetics and in-vivo pharmacokinetic investigations of mirabegron-loaded NLCs. Its performance was assessed using the principles of green and white analytical chemistry through a comparative study with existing analytical techniques. The proposed method's exceptional sensitivity, robustness, and eco-friendliness in mirabegron estimation were highlighted by the results. In conclusion, this proposed green analytical approach not only provides a reliable means of mirabegron analysis but also aligns with sustainable practices by minimizing environmental impact and promoting the principles of green and white analytical chemistry and analytical quality by design.

Estimands for clinical endpoints in tuberculosis treatment randomized controlled trials: a retrospective application in a completed trial

BackgroundRandomized trials for the treatment of tuberculosis (TB) rely on a composite primary outcome to capture unfavorable treatment responses. However, variability between trials in the outcome definition and estimation methods complicates across-trial comparisons and hinders the advancement of treatment guidelines. The International Council for Harmonization (ICH) provides international regulatory standards for clinical trials. The estimand framework outlined in the recent ICH E9(R1) addendum offers a timely opportunity for randomized trials of TB treatment to adopt broadly standardized outcome definitions and analytic approaches. We previously proposed and defined four estimands for use in this context. Our objective was to evaluate how the use of these estimands and choice of estimation method impacts results and interpretation of a large phase III TB trial.MethodsWe reanalyzed participant-level data from the REMoxTB trial. We applied four estimands and various methods of estimation to assess non-inferiority of both novel 4-month treatment regimens against standard of care.ResultsWith each of the four estimands, we reached the same conclusion as the original trial analysis that the novel regimens were not non-inferior to standard of care. Each estimand and method of estimation gave similar estimates of the treatment effect with fluctuations in variance and differences driven by the methods applied for handling intercurrent events.ConclusionsOur application of estimands defined by the ICH E9 (R1) addendum offers a formalized framework for addressing the primary TB treatment trial objective and can promote uniformity in future trials by limiting heterogeneity in trial outcome definitions. We demonstrated the utility of our proposal using data from the REMoxTB randomized trial. We outlined methods for estimating each estimand and found consistent conclusions across estimands. We recommend future late-phase TB treatment trials to implement some or all of our estimands to promote rigorous outcome definitions and reduce variability between trials.Trial registrationClinicalTrials.gov NCT00864383. Registered on March 2009

Validation of RP-HPLC Method for the Estimation of Timolol Maleate in Fast Dissolving Tablets

A simple, precise and reproducible validation method was develop for Timolol Maleate as per ICH (International Council for Harmonization) guidelines Q2R(1) and subsequently stability indicating method as per ICH guidelines Q1A(R2). Chromatographic evaluation was carried out on C18 column of Agilent (25 cm x 4.6 mm), (i.d. 5 µm.) with a mobile phase consist of Methanol : Water (20:80 v/v). Flowrate was maintained to 0.8ml/min. The stability indicating data revealed that Timolol Maleate was found to be unstable alkaline condition. The validated method was applied various validation parameters like Linearity(calibrationcurve),Precision, Accuracy,Robustness,LOD and LOQ were found to be 0.9μg/ml and 2μg/ml. The validated method can be used for estimation of Timolol Maleate in prepared Fast DissolvingTablets (FDTs) by using Croscar mellose Sodium(CCS) as a superdisintegrant a calculated their optical parameters.

A SYSTEMATIC REVIEW: EXPLORATION OF PROCESS ANALYTICAL TECHNOLOGY TECHNIQUES (PAT) AND THEIR MULTIFACETED ADVANTAGES IN INDUSTRIAL PROCESSES

FDA initiated the PAT technology framework in the year of 2004 with the guidelines of “A framework of innovative pharmaceutical development, manufacturing and quality assurance. With that, the International Council for Harmonisation has also initiated continuous process verification to overcome the limitations of traditional methods and improve the understanding of the process and quality of the product throughout the product lifecycle. Since the year of implementation, the advancement of analytical and chemometric tools has evolved to deliver consistent quality products by understanding their process and product performance. However, the pharmaceutical industry was lacking in this technicality and implementation of highly regulated specifications. To this respect, we have stated some of the PAT tools, including NIR, Raman and Terahertz spectroscopy, as they will transfer to the futuristic prospects of analyzing the drug product with non-destructive, improved process understanding, real-time monitoring, and enhanced data integrity. This review article emphasizes the importance of PAT technology with different monitoring processes with their historical background and regulatory framework. Special attention was given to strategies, challenges, opportunities, and the compatibility of PAT tools with data fusion. Further, this will give a high-priority disciplinary scientific topic to Pharma 4.0.

Voltammetric analysis of pholcodine on graphene-modified GNPs/PTs with green assessment

Pholcodine, an anti-tussive medication widely used as an over-the-counter, OTC drug, has recently faced restrictions in several countries. This paper presents a sensitive electrochemical approach for pholcodine detection. The electrochemical method involved fabricating a graphene nanoplatelets electrode, incorporating polythiophene nanospheres polymer to promote electron transfer and increase the activated surface area. Characterization of the fabricated electrode was performed using transmission electron microscopy, ATR-Fourier-transform infrared spectroscopy, X-ray crystallography, X-ray photoelectron spectroscopy, and electrochemical impedance spectroscopy. The electrochemical behavior of pholcodine with the fabricated electrode was investigated using cyclic voltammetry, chronoamperometry, square wave voltammetry (SWV), and differential pulse voltammetry (DPV). The developed electrode led to a linear response for pholcodine ranging from 10 to 45 mg/L with detection limits of 1.41 and 1.51 mg/mL for SWV and DPV, respectively and quantification limits of 4.27 and 4.57 mg/L for SWV and DPV, respectively. The proposed method has accurately recovered pholcodine in spiked serum samples with a recovery percentage ranging from 1.2 to 2.9%. The optimized method is found to be accurate, precise, and robust by applying validation parameters provided by International Council for Harmonization. Two green metrics were computed to assess the method’s greenness, the findings showed that the developed method is environmentally friendly with minimum sample preparation steps.

Integration of a facile sustainable resonance Rayleigh scattering switchable-based system for feasible determination of centrophenoxine, a nootropic and antioxidant agent; application to crude materials and dosage forms

The proposed research adheres to a certain methodology to ensure that the technique used for analyzing the centrophenoxine drug is sustainable and green. It is important to highlight that several tools that have been recently developed were utilized as potential indicators of environmental sustainability and applicability. The present research presents a novel and entirely innovative method utilizing ultrasensitive spectrofluorimetry for the detection of centrophenoxine (CPX) drug. The employed methodology in this study involved the utilization of one-step, one-pot, and direct spectrofluorimetric technique, which was found to be both efficient and environmentally sustainable in the validation and assessment of the drug. Simply, when CPX and erythrosine B reagent were combined in an acidic environment, the highly resonance Rayleigh scattering product was immediately produced. The sensitivity limits were observed to be within the range of 15–47 ng mL−1, whereas the linearity was assessed to be in the range of 50–2000 ng mL−1. The optimal settings for all modifiable parameters of the system were ascertained through an analysis of centrophenoxine-erythrosine B complexes. Moreover, the system demonstrated compliance with International Council for Harmonization (ICH) specifications without encountering any issues. The suggested process was then rated on different recent environmental safety measuring metrics to see how good it was for the environment. Fortunately, the WAC standards that combine ecological and functional elements utilizing the Green/Red/Blue (RGB 12) design also acclaimed the current analytical technique as a white one. Additionally, a new applicability evaluation tool (BAGI) was employed to estimate the practicability of the planned method in the analytical chemistry field.