Quality Control Laboratories Research Articles

Development of Novel Micellar-Enhanced High-Throughput Microwell Spectrofluorimetric Method for Quantification of Lorlatinib: Application to In Vitro Drug Release and Analysis of Urine Samples.

Lorlatinib (LOR) is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor drug. The Food and Drug Administration (FDA) has granted an approval for the use of LOR as a first therapeutic intervention for individuals diagnosed with ALK-positive metastatic and advanced non-small-cell lung cancer (NSCLC). The present study outlines, for the first time, the development and validation of an innovative microwell-based spectrofluorimetric (MW-SFL) method for the quantification of LOR. The proposed method involved the enhancement of the weak native fluorescence of LOR by its micellization into the sodium lauryl sulfate (SLS) micelles. The procedures of the method were conducted in white opaque plates with 96 microwells, and the enhanced fluorescence signals were measured by a fluorescence plate reader at 405 nm after excitation at 310 nm. The measured relative fluorescence intensity (RFI) had a linear relationship with LOR concentrations in the range of 60-1600 ng mL-1. The limit of detection (LOD) and the limit of quantification (LOQ) were found to be 19 and 56 ng mL-1, respectively. The method's accuracy and precision were assessed using a recovery study; the recovery values ranged from 99.98% to 101.40%, accompanied by relative standard deviation (RSD) values of 0.42% to 1.59%. The proposed MW-SFL method combined the advantages of the intrinsically high sensitivity of the spectrofluorimetric measurement and the excellent throughput of the microwell-based approach. The results proved the method is effective in the determination of LOR in its pharmaceutical tablets, tablet dissolution testing, as well as in spiked urine with a high degree of precision and accuracy. The MW-SFL method is notable for its simple procedures and utilization of water as a solvent, as well as minimal quantities of sample solutions. These features align with its ecofriendly approach to green chemistry principles. These advantages gave the proposed MW-SFL method a high potential value for the determination of LOR in clinical and quality control laboratories.

A Diagnostic Tool for Good Chromatographic Practices Applied to HPLC in Pharmaceutical Quality Control

Background: High-performance liquid chromatography is one of the most used analytical techniques in quality control in the pharmaceutical industry. Since it is a complex technique, it needs good practices that can contribute to compliance with regulatory requirements. Objetive: This study aims to establish a diagnostic tool for Good Chromatographic Practices (GCP) for the self-assessment of a Quality Control Laboratory (QCL). Methods: The research was carried out on scientific bases, pharmaceutical legislation, as well as guides published by manufacturers. Results: Seven axes of action were identified: implementation, management, and continuous improvement of GCP in the laboratory; GCP in the installation, operationalization, qualification, and validation processes of the equipment and software; GCP in processes related to data management, including guidelines regarding access, generation, integrity, and traceability; GCP related to the management and use of consumables; GCP related to handling, maintenance, analytical and operational troubleshooting; GCP in the processes of preparation, use, and storage of analytical solutions and reagent solutions; and GCP related to the acquisition and processing of standards, samples, and results. These axes resulted in a diagnostic tool with 124 questions. Conclusion: The application of the GCP diagnostic tool provides the mapping of the routine and procedures related to the execution of the HPLC technique for quality control in the pharmaceutical industry, contributing to meeting regulatory requirements.

Guidelines for Best Practice for Staffing of ART Laboratories and Professional Development of IVF Scientists

Research Question: To establish recommendations for optimal staffing levels, training, and professional development in assisted reproductive technology (ART) laboratories in Australia and New Zealand. Design: Exploration by Scientists in Reproductive Technology (SIRT) subcommittee representing 10 different ART centers of the time requirements and complexity of ART procedures and to define training and continuing professional development (CPD) requirements. Results: The Staffing Model for ART (smART) “plug and play” calculator was developed by the SIRT subcommittee. Twelve routine procedures were examined IVF, ICSI, ICSI + PGT, ICSI + TESE, FET, FET from PGT, oocyte vitrification, oocyte warming, intrauterine insemination (IUI), semen freeze, TESE with semen freeze, and semen analysis. Based on a cycle with 10 eggs, the average time taken to do each procedure was considered as well as the complexity of the task. Laboratory quality control (QC), other administrative tasks, and leave days are reflected in the calculator. Recommendations for years of experience were determined as a trained scientist (24 months), a senior scientist (5 years), and Scientific Director (10 years). CPD is strongly recommended to improve the skills, knowledge, and ability of scientific staff. Conclusions: The risks in the IVF laboratory primarily associated with lower staffing levels have been reviewed, and the smART calculator is designed to assist clinics to tailor adequate staffing levels for their specific needs. The smART calculator is an invaluable tool for clinics to use going forward. Key Message We have reviewed the risks in the IVF laboratory primarily associated with lower staffing levels, and created the smART calculator designed to assist clinics in being able to tailor adequate staffing levels for their specific needs. We believe the smART calculator will be an invaluable tool moving forward for all ART clinics and accreditors.

Development and Validation of Chemometric Assisted UV Spectroscopic Methods for the Simultaneous Determination of Amitriptyline Hydrochloride and Propranolol Hydrochloride in Marketed Formulation

The present work discusses the development and validation of chemometric assisted UV spectroscopic methods for analyzing two drugs amitriptyline hydrochloride and propranolol hydrochloride in their marketed formulation. The developed methods are two prominent chemometric models namely, principal component regression (PCR) and partial least squares regression (PLS) on which several research articles have been published for their immense contribution in the quantification of multi-component formulations. Linearity of the UV spectroscopic method was in the concentration ranges of 3-15 μg/mL of amitriptyline hydrochloride and 5-45 μg/mL of propranolol hydrochloride. The PCR and PLS chemometric models were established by employing fourteen mixtures as a calibration set and five mixtures as a validation set and were executed in the wavelength range of 240-320 nm with data interval of 5 nm. The statistical parameters obtained from both the methods revealed their validity and hence allows their suitability for analysis in regular quality control laboratories.

Novel Ultra-Fast Liquid Chromatography Method for Simultaneous Quantification of Metformin Hydrochloride and Remogliflozin Etabonate

An advanced formulation having remogliflozin etabonate (REM) and metformin hydrochloride (MET) for the treatment of diabetes was recently approved. However, there hasn't been any information reported on a UFLC technique for simultaneously quantifying both active substances. Therefore, aim of the study was the development of an ultra-fast isocratic liquid chromatography method for quantification of MET and REM in API and dosage form. The reversed phase-UFLC method was developed with a very short run time of only 3 min with no interference due to blank. The compounds were separated using Shimadzu Sim-pack XR ODS (75 mm × 3 mm, 2.2 μ) column with mobile phase consisting of buffer (0.1% phosphoric acid):acetonitrile (30:70). The developed method was validated as per ICH-Q2(R1). The linearity was established in the range of 0.01-125 ppm and 0.01-25 ppm for MET and REM, respectively. The average assay was found 99.4% for MET and 99.1% for REM. The accuracy was observed 98.29-99.49% for MET and 98.39-99.73% for REM. The proposed method is very fast and simple however precise and accurate. This method is very useful for regular quality control laboratory to quantify MET and REM in API and dosages forms.

Verification of the analytical performance of the serum total cholesterol assay on Abbott Architect ci8200

Serum total cholesterol measurement is an essential aspect of preventive healthcare as high levels of cholesterol are linked to various diseases such as atherosclerosis, heart attacks, and strokes. Serum cholesterol measurement is a simple blood test that assesses the levels of cholesterol in the bloodstream. It is an important diagnostic tool that helps healthcare professionals evaluate a patient's risk of developing cardiovascular disease and make decisions regarding treatment and lifestyle changes. Our study aims to verify the analytical performance of the serum total cholesterol assay method using an Abbott kit on the Architect ci8200 automated system in the biochemistry laboratory of the Mohammed VI University Hospital of Oujda. The analytical performance of the kit was verified through flexible scope A by performing a performance study on the Architect ci8200. We evaluated the repeatability, the reproducibility, the imprecision of the measurements and the comparison between two Architect ci8200 automatons. All the results obtained are in conformity with the acceptability criteria recommended by the supplier and the Valtec protocol of the ‘Société Française de Biologie Clinique’ (SFBC), and the study is globally satisfactory. The analytical performance of the Architect ci8200 automated system was satisfactory for a reliable determination of total cholesterol. Verification of methods of dosage in the medical laboratory is crucial to ensure the accuracy, precision, and reliability of laboratory test results. Verification involves confirming that the test method employed is appropriate for the intended use, produces results that are consistent with the claimed performance characteristics, and meets the laboratory's quality control and quality assurance requirements.

The quality of microbiological diagnostics in Poland based onthe results of external laboratory quality control programmes

<br><b>Introduction:</b> The article describes the results of the 29th edition of the Polish NationalExternal Quality Assessment Scheme in Microbiology POLMICRO created by the Centre ofQuality Control in Microbiology (CQCM).</br><br><b>Aim:</b> The aim of the scheme is the evaluation of the reliability of the results of microbiologicaltests performed by Polish medical laboratories, which includes e.g. identification andassessment of antimicrobial susceptibility of bacterial etiological agents of infections,together with the detection of antimicrobial resistance mechanisms.</br><br><b>Materials and methods:</b> The assessment of external quality control programmes organised byCQCM is based on the analysis of the results of participants of the POLMICRO, POLMICRO/MIKOLOGIA and POLMICRO/SSE programmes in a full annual cycle.</br><br><b>Results:</b> In 2022, 96.00% of POLMICRO participants, as well as 99.22% of laboratories participatingin POLMICRO/SSE and all participants of POLMICRO/MIKOLOGIA, obtained positiveresults.</br><br><b>Conclusions:</b> The results of external quality control programmes conducted by CQCM showthat medical laboratories in Poland have been maintaining a high level of microbiologicaldiagnostics.</br>

Development of sugars quantification method using polarimeter couple with UV-Visible quartz cuvette cell

The objective of this study was to develop the method for determination of sugars at low sample volume using UV-Visible quartz cuvette cuvett instead of polarimeter cell. This proposed method could be analysis of sugars with high sample throughput rate and appropriate for analysis of pharmaceutical formulation. This study, the simple determination method by using sample UV-Visible quartz cuvette was developed in order to analyze dextrose, sucrose and lactose. It was found that quartz cuvette was not affected from the sodium light source at wavelength of 589.0 nm and it was possible to adapt for polarimetry technique. The linear calibration curve of dextrose, sucrose and lactose standard solution using polarimeter sample tube were constructed in the concentration ranges of 2.5–15.0 % w/v. Linear regression between the angle of rotation (y) and concentration of each sample (x) were expressed as the equation of y = 1.0941x – 0.1824 (r2= 0.9993), y = 1.3515x –0.1581 (r2= 0.9998) and y= 1.0390x – 0.0162 (r2= 0.9997) for dextrose, sucrose and lactose, respectively. Interestingly, the calibration curve of sugars standard solution using UV-Visible quartz cuvette were shown as y = 0.1050x - 0.1038 (r2= 0.9990), y = 0.1312x – 0.1458 (r2= 0.9989) and y = 0.1072x – 0.0335 (r2= 0.9991) for dextrose, sucrose and lactose, respectively. The detection limits (LOD) of proposed method for determination of dextrose, sucrose and lactose were 0.5, 1.0 and 0.6 % w/v, respectively, while the quantitation limits (LOQ) were 1.6, 3.0 and 1.9 %w/v for anlysis of dextrose, sucrose and lactose, respectively. The interferences study for proposed method from sodium chloride was investigated. It had found that this salt shown none effect for the proposed method. The results acquired the proposed method were compared favorably with those acquired by the reference method at a 95% confidence level with no significant difference (n=10). The developed method had shown accurate, precise, and reproducible. Moreover, this method indicated the possibility of a modified polarimetric method for the quantification of sugars. The method is possible to apply both in simple quality control laboratory and local industrial that involved with pharmaceutical production.

In-silico Toxicity Assessment and Trace Level Quantification of Veratryl Chloride a Potential Genotoxic Impurity in Ivabradine Hydrochloride using LC-MS/MS

A sensitive and selective liquid chromatography-mass spectrometry (LC-MS/MS) method using multiple reaction monitoring (MRM) mode was developed and validated for trace analysis of 4-(chloromethyl)-1, 2-dimethoxybenzene (Veratryl chloride) a potential genotoxic impurity in Ivabradine hydrochloride (IVB). Chromatographic separation was performed on a Poroshell 120EC C18 (50 × 3.0 mm, 2.7 μm) column using a mixture of 10 mM ammonium formate and acetonitrile in isocratic elution mode at a 0.25 mL/min flow rate. A simple pre-column derivatization with di-ethylamine was employed for the derivatization of the veratryl chloride. The developed LC-MS/MS method was linear and accurate in the 1.5–10.0 ppm concentration range with r2 ˃ 0.999 and percent recoveries greater than 90%. The developed method was precise with RSD (%) of not more than 4.5%. In-silico genotoxicity and carcinogenicity potential of veratryl chloride was assessed using ICH M7 principles found to be positive. The developed method can identify and quantify veratryl chloride in IVB, hence can be applied by quality control labs of pharmaceutical industries for trace quantification.

Smart Multivariate Spectrophotometric Determination of Two Co-Administered Autoimmune Drugs; Sulfasalazine and Pentoxifylline; in Bulk and Spiked Human Plasma.

Sulfasalazine and pentoxifylline are co-prescribed together to treat psoriasis and pemphigus vulgaris. Sulfasalazine is an anti-inflammatory, immunosuppressant, and antibiotic drug, while pentoxifylline is a vasodilator and immunosuppressant. The spectra of the two drugs and plasma suffer from severe overlap. This work aims to simultaneously determine sulfasalazine and pentoxifylline in their binary mixture and spiked human plasma by the assessment of their UV spectral data. Two model updated chemometric methods were established using principal component regression and partial least-squares regression models. The two models were validated in accordance with the U.S. Food and Drug Administration guidelines for bioanalysis and were applied for the determination of both drugs in synthetic mixtures or spiked human plasma. Accuracy and precision were within the accepted limits. In addition, three different assessment methods were used to evaluate the environmental greenness of the proposed models. The two updated models are simple, rapid, sensitive, and precise, and could be easily applied in QC laboratories for determination of sulfasalazine and pentoxifylline, without any preliminary separation steps or interference from plasma matrix. Two updated chemometric models called principlal component regression and partial least-squares regression were established for determination of sulfasalazine and pentoxifylline in spiked human plasma using UV spectrophotometric data.

A Simple UV Spectrophotometric Method Based on Continuous Wavelet Transform and Multivariate Calibration Model for the Concurrent Analysis of Three Water-Soluble Vitamins in Fertility Supplements.

Owing to the presence of overlapping spectra in pharmaceutical components, classical spectrophotometry is hard for concurrent determination. The advance of chemometrics along with UV-Vis spectrophotometry has contributed to solving this problem. In this study, a fast, easy, precise, accurate, low-cost, and eco-friendly spectrophotometric technique was introduced and validated for the simultaneous analysis of vitamin B6, vitamin B12, and vitamin C in fertility supplements for men and women using continuous wavelet transform (CWT) and partial least squares (PLS) techniques without using time-consuming extraction process and organic solvents. In the CWT method, the zero-crossing technique was applied to obtain the optimum points for plotting calibration curves for each component. The validation of both methods was evaluated by analyzing several mixtures with different concentrations. The efficiency of the proposed methods was also surveyed on commercial capsules. Wavelet families, including Symlet (sym2) at 230, Biorthogonal (bior1.3) at 378 nm, and Daubechies (db2) at 261, were considered for vitamins B6, B12, and C, respectively. The linear range was found to be 8-20, 8-20, and 10-25 μg/mL with the coefficient of determination (R2) equal to 0.9982, 0.9978, and 0.9701 for B6, B12, and C, respectively. Low limit of detection (LOD) (<0.09 μg/mL) and limit of quantification (LOQ) <0.9 μg/mL were achieved. The mean recovery values in synthetic mixtures were from 98.38 to 98.89% and from 99.83 to 99.99%, where root-mean-square error (RMSE) of not more than 0.4 and 0.05 using the CWT and PLS methods, respectively. The obtained results from the commercial capsules, applying the suggested techniques, were compared to those yielded by the high-performance liquid chromatography (HPLC) method using the analysis of variance (ANOVA) test. According to the results, there are no significant differences, and they were in good agreement. According to all the mentioned cases, the proposed approaches can replace the time-consuming and costly HPLC method in quality control laboratories. Green spectrophotometry coupling chemometrics methods were proposed. Simultaneous determination of three water-soluble vitamins in fertility supplements was done using these approaches. Rapidity, simplicity, low cost, and accuracy are the benefits of the proposed methods. A HPLC technique was used as a reference method to compare with the chemometrics methods.

A constraint programming-based iterated greedy algorithm for the open shop with sequence-dependent processing times and makespan minimization

In this paper, a novel variant of the open shop scheduling problem where the jobs have sequence-dependent processing times is addressed. The performance measure considered is the minimization of the length of the schedule (makespan). This problem arises in several real-life settings and, particularly, our work is inspired in scheduling samples in a quality control laboratory where a series of tests have to be performed in different equipment – being irrelevant the order in which these tests are performed –, and the time required to perform the tests depends on the previous sample tested. For this problem, we compare the results of a Mixed-Integer Linear Programming (MILP) model with those from a Constraint Programming (CP) model specifically proposed for the problem, showing that the latter yields better results. Given the NP-hard nature of the problem, in order to obtain good – but not necessarily optimal – solutions within reasonable computational effort, we propose a matheuristic consisting of an Iterated Greedy Algorithm hybridized with a reconstruction phase based in executing the CP model with a partial solution. The results of the computational experiments carried out on 160 instances based on established datasets show the ability of the matheuristic to solve large-sized instances, in contrast with exact (i.e. MILP and CP) models. Our proposal outperforms the most efficient approximate procedures from related problems that have been adapted to the problem under consideration. A subsequent statistical analysis is carried out to prove the statistical significance of these results.

Sustainable eco-friendly ratio-based spectrophotometric and HPTLC-densitometric methods for simultaneous analysis of co-formulated anti-migraine drugs with overlapped spectra

Considering the green chemistry perspective and improving the environmental impact of quality control labs; two direct techniques with less hazardous solvents, less waste production and less energy consumption were developed for simultaneous analysis of Aspirin and Metoclopramide in bulk powder and pharmaceutical formulation. The ratio between the two drugs in their co-formulated preparation is very challenging; (90: 1, Aspirin: Metoclopramide). The first technique is spectrophotometry using simple mathematical operations; ratio difference and derivative ratio–zero crossing. The second technique is high-performance thin-layer chromatography (HPTLC) -densitometry which used a mobile phase consisting of cyclo-hexane: methanol: methylene chloride in a ratio of (1:4:1, v/v/v). The greenest solvents which give acceptable resolution were chosen. Following the International Conference on Harmonization (ICH) guidelines, the methods were found to be accurate, precise, and selective. Those methods were statistically compared to the reported spectrophotometric method and the results proved that there is no significant difference in accuracy and precision. Furthermore, the developed methods were assessed using the Analytical Eco-scale, Green Analytical Procedure Index (GAPI) and the Analytical Greenness calculator (AGREE), which gave a full image about their greenness profile. The spectrophotometry was found to be an excellent green technique compared to HPTLC with was considered an acceptable green one. The developed HPTLC-densitometric method was used for the first time for the analysis of this binary mixture. The two proposed spectrophotometric methos have advantages over the published methods as they used easy manipulation steps and are applied on the market pharmaceutical formulation. Owing to the advantages of the developed techniques; being green, do not require expensive sophisticated equipment or large volume of solvents; they could be used for routine analysis in quality control aspects.

Compliance and regulatory considerations for the implementation of the multi-attribute-method by mass spectrometry in a quality control laboratory

Multi-attribute methods employing mass spectrometry are applied throughout the biopharmaceutical industry for product and process characterization purposes but are not yet widely accepted as a method for batch release and stability testing under the good manufacturing practice (GMP) regime, due to limited experience and level of comfort with the technical, compliance and regulatory aspects of its implementation at quality control (QC) laboratories. This article is the second part of a two-tiered publication aiming at providing guidance for implementation of the multi-attribute method by peptide mapping liquid chromatography mass spectrometry (MAM) in a QC laboratory. The first part [1] focuses on technical considerations, while this second part provides considerations related to GMP compliance and regulatory aspects. This publication has been prepared by a group of industry experts representing 14 globally acting major biotechnology companies under the umbrella of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Manufacturing & Quality Expert Group (MQEG).

Assessing the environmental and overall performance of gas chromatographic analyses. Development of a comprehensive evaluation framework and application to routine chiral analyses of fragrances as a case study

Enantioselective gas chromatography is used in fragrance quality control laboratories to authenticate the origin of raw materials and detect possible frauds or adulterations of perfumes. These laboratories must contend with increasing attention to environmental sustainability, quality standards that require accurate and reliable measurements, and practical considerations such as productivity, costs, and simplicity of methods. Quantitative tools enabling a global evaluation of all these aspects are therefore required. In the first part of the study, a GC-MS method for the chiral recognition of a set of odorants was developed and speeded up. The improvement in environmental footprint associated with fast GC was then quantitatively evaluated using AGREE. This tool allowed a rapid comparison of environmental impacts between different analytical methods, but, despite a very different energy consumption, showed few differences in the final score of the developed methods. Therefore, a multi-criteria approach based on the RGB model, for the first time specifically dedicated to GC analytical methods, was developed. It accurately accounts for the contribution of GC and the need to limit the consumption of energy and toxic solvents while maintaining analytical performance and adequate laboratory productivity. The template can be adapted to analyses with a different scope by changing the analytical performance criteria and the reference threshold of the method. The global assessment of the methods developed showed that fast GC improves the greenness and the productivity of a laboratory, and lowers costs while maintaining adequate analytical performance making the approach not only green but also sustainable.

Experimental test of a building thermal system for preventive maintenance based on thermoeconomic analysis

An analysis of the sectorial structure of energy consumption shows that residential and tertiary sector buildings are the third-highest consumers, responsible for 29.5% of a city’s final energy consumption. The Building Quality Control Laboratory of the Basque Government aims to promote quality, innovation, and sustainability in buildings. To accomplish this goal, it has constructed an experimental facility with different energy generation technologies and a very versatile control system for testing different energy systems and operation modes. In this study, we tested a facility for supplying domestic hot water and heating for a multi-family house by means of a condensing boiler and an aerothermal heat pump (together with the corresponding control). This installation could reproduce the thermal demands required to be satisfied by the generation equipment through a programmed operation of the installation based on real demands. Additionally, this installation was analyzed using thermoeconomics (TE) to solve problems unable to be solved using traditional energy analyses based on the First Law of Thermodynamics. These problems include: (1) Determining the costs of the products of the installation based on physical criteria, (2) detecting the places where losses actually occur, evaluating their costs, and proposing cost-effective improvements, and (3) diagnosing issues in the installation. As a result, this paper suggests a solution to the preventive maintenance problems confronting the technical maintenance personnel for thermal installations in buildings by applying TE knowledge and using real data collected from sensors.

Analytical Methods for the Identification and Quantitative Determination of Wool and Fine Animal Fibers: A Review

The identification and quantitative determination of wool and fine animal fibers are of great interest in the textile field because of the significant price differences between them and common impurities in raw and processed textiles. Since animal fibers have remarkable similarities in their chemical and physical characteristics, specific identification methods have been studied and proposed following advances in analytical technologies. The identification methods of wool and fine animal fibers are reviewed in this paper, and the results of relevant studies are listed and summarized, starting from classical microscopy methods, which are still used today not only in small to medium enterprises but also in large industries, research studies and quality control laboratories. Particular attention has been paid to image analysis, Nir spectroscopy and proteomics, which constitute the most promising technologies of quality control in the manufacturing and trading of luxury textiles and can find application in forensic science and archeology.

Enabling honey quality and authenticity with NMR and LC-IRMS based platform

Honey has been known for economically motivated adulteration around the world, because of its high demand and short supply. As consequence increasing honey production using the deliberate addition of sugar syrups while claiming a fictitious origin and diversifying it to increase its value. Generally, honey testing is supervised by a set of guidelines and quality parameters to ensure its quality and authenticity. As per the many regulatory bodies, current honey scams have been challenging to identify with conventional methods, so quality control labs require sophisticated technology. With these paradigm shifts, the aim of the present review is focused on the authenticity of honey through two important cutting-edge methods viz LC-IRMS and NMR. The LC-IRMS aids in the detection of added C3 and C4 sugars. Whereas NMR has provided a potent solution by allowing the classification of botanical varieties and geographical origin along with the quantification of a set of quality parameters in a single experiment.

Application of Box-Behnken Design and Response Surface Methodology for Selecting the Optimum RP-HPLC Conditions for the Simultaneous Determination of Paracetamol and Diclofenac Sodium Along With Three Skeletal Muscle Relaxants in Three Different Pharmaceutical Dosage Forms.

An isocratic HPLC method has been developed and validated for estimating paracetamol and diclofenac sodium simultaneously with three skeletal muscle relaxants, namely, methocarbamol, tizanidine hydrochloride and chlorzoxazone in their pure standard mixtures and in different multi-component dosage forms in a single chromatographic run. HPLC separation was achieved on a C18 Inertsil ODS-3V 5μm column (250 × 4.6mm) using a mobile phase mixture containing acetonitrile and 25mM phosphate buffer (pH7.4 adjusted with NaOH) in the proportion of (39.7:60.3, v/v) pumped at 1.2mL/min flow rate with UV detection at 220nm. An experimental design was used by applying Plackett-Burman design for screening the most critical predictors affecting the chromatographic separation and Box-Behnken design for optimizing the selected predictors and creating the response surface between the selected predictors and the interested responses. ICH recommendations were applied for validating the proposed method with regard to linearity, precision, accuracy, selectivity, limits of detection and quantitation, and robustness. There are many applications for the optimized method that can be applied for routine estimation of the cited drugs in laboratories of quality control and pharmaceutical industries to save money and time and to reduce material waste and effort.

Analytical method development, validation, and out-of-specification investigations for polyethylene glycol

This work was motivated by the United States Pharmacopeia monograph modernization initiative and European directorate for the quality of medicines and healthcare. An out-of-specification (OOS) occurrence prompted OOS investigations for the cGMP (cGMP refers to the Current Good Manufacturing Practice regulations enforced by the FDA) release testing of residual ethylene oxide in polyethylene glycol (PEG) according to the standards detailed within the United States Pharmacopeia/National Formulary (USP-NF) for polyethylene glycol, and the European Pharmacopoeia (Ph. Eur.) for macrogols. During the OOS root cause investigations, we observed a PEG degradant and identified it as methyl formate, which co-elutes with ethylene oxide using the GC (gas chromatography) methods published in current USP-NF and Ph. Eur. for PEGs. To address this, a novel method utilizing static headspace gas chromatography with flame ionization detection (HS-GC-FID) was developed to test various grades of PEGs for the presence of residual ethylene oxide, along with other process related impurities and degradation products. With this new method, ethylene oxide, a known genotoxic impurity and IARC (International Agency for Research on Cancer) Class 1 human carcinogen, can be well resolved from methyl formate, a newly identified and comparatively innocuous degradant derived from PEG. The currently available official compendial methods are unable to separate the specific impurities in PEGs. However, the new GC method presented in this paper has been shown to have a high and unique selectivity, allowing for baseline separations (chromatographic resolutions greater than 1.5) of all related impurities in PEGs, which is a challenging task. Additionally, this method has been found to be stability-indicating based on a forced degradation study. During stress stability study of PEGs involving acid, alkali, heat, light, and oxidation, some other PEG degradants, including formaldehyde, were identified. It is possible that formaldehyde undergoes a disproportionation reaction known as the Cannizzaro reaction, leading to the formation of formic acid and methanol. The formic acid then undergoes an esterification reaction with methanol to produce methyl formate. To the best of our knowledge, this is the first stability-indicating HS-GC-FID method that accomplishes this separation in a single run, and it was successfully validated as per ICH (the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines. Therefore, this method is suitable for the conduct of cGMP batch release and stability testing of PEGs in regulated quality control (QC) laboratories.