Process Impurities Research Articles

Thermodynamic and Kinetic Studies on the Pyrophoricity of Uranium Flakes

The objective of this work was to arrive at quantitative estimates of pyrophoricity of uranium in different geometries. The major source of heat generation was identified to be exothermic chemical reactions of uranium with moist air. Time evolution of temperature was studied for uranium considering 3D conduction and convection heat loss routes using Finite Element Analysis. Auto ignition temperature for uranium flakes was quantified using heat balance equation and was found to be around 500 K. Excess heat generation rates needed to cause auto ignition of uranium flakes at room temperature were also estimated. The major sources of excess heat leading to its ambient ignition could be attributed to friction and other exothermic chemical reactions of process impurities in uranium.

Targeted isolation of extracellular vesicles from cell culture supernatant using immuno-affinity chromatography

Extracellular vesicles (EVs) have emerged as promising therapeutics with broad clinical applications as diagnostic biomarkers and therapeutic drug delivery systems. Yet, these biopharmaceuticals pose a challenge in terms of manufacturing due to their complexity and heterogeneity. Despite advancements in the field, current purification technologies lack scalability and/or selectivity. Affinity chromatography (AC) − coupling unmatched specificity and scalability − could be used to simplify purification processing and generate clinical-grade EVs with higher titers and purity.In the present work, we report the implementation of an immuno-AC resin to capture and purify EVs directly from clarified cellular feedstocks. Firstly, to guide and support marker selection, vesicle phenotype characterization was conducted using single particle interferometric reflectance image sensing (SP-IRIS) coupled with immunofluorescence. CD81 was the marker which shown to be more present and more likely to have the other markers (CD63 and CD9). Thus, anti-CD81 VHH ligand was generated and evaluated towards recombinant CD81 protein and CD81 bearing EV particles using surface plasmon resonance (SPR). Different chromatographic studies with Anti-CD81 ligand immobilized onto agarose beads resin were conducted to optimize the process parameters (residence time, dynamic binding capacity and impurity clearance). At residence time of 2 min, on average 40 % of pure triple tetraspanin-positive EV fraction was recovered. The enrichment in EV particles herein obtained, based on scale-up calculations, it would be possible to produce 1 × 1013 EVs from a 1L cell culture, while meeting impurity requirements in a single-step purification process (impurity removal over 2 log reduction value). A single-step purification process is possible, enabling the successful isolation of homogeneous EVs population, counting with a final HCP titer of 60 ng/mL and 9 ng/mL of dsDNA impurities. EV’s morphological integrity and internalization ability were also demonstrated, showcasing elution’s efficiency under mild conditions.Overall, this work contributes to the development of a novel, highly specific, AC technology using a camelid-derived affinity ligand which, bridging the scalability requirements demanded of large-scale production, could potentiate the advent of EV-based therapies.

Oxidative stress-induced degradation of Brinzolamide: Isolation and in-depth characterization of unique hydroxylamine and oxime degradation products

Since the safety and efficacy of therapeutic products are strongly related to their stability and purity, impurities including the unavoidable degradation products may affect the pharmacological effect. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q3A requires the identification of process impurities and as well as degradation products in any drug substance to assess the inherent stability of the drug. The present work involves an ICH-guided degradation study for the Brinzolamide (BRZ), a topical ophthalmic drug which is generally used to lower the intraocular pressure (IOP) during glaucoma. Under oxidative stress at room temperature for 20 h, four degradation products (namely BRZ-Pk1, BRZ-PK2, BRZ-Pk3, and BRZ-Pk4) are isolated using advanced chromatographic techniques. Upon confirming the masses of the compounds using High-resolution mass spectrometry (HRMS), functional groups are identified with the help of Fourier-transform infrared spectroscopy (FT-IR). Extensive 1-dimensional (1D) and 2-dimensional (2D) Nuclear Magnetic Resonance spectroscopic (NMR) experiments especially 1D nOe, 1H-13C-HSQC and 1H-13C-HMBC unequivocally confirm the structures. Among the four compounds analyzed, three (BRZ-Pk1, BRZ-Pk2, and BRZ-Pk4) are novel, while BRZ-Pk3 was previously reported solely with mass spectrometric data. Nitrogen-based 2D NMR experiments are crucial for determining the oxidation state of hydroxylamine and oxime products within the molecules, and 1D nOe measurements help confirming E/Z isomerism (geometrical isomerism) for BRZ-Pk2 and BRZ-Pk4. All the proposed structures are justified with appropriate analytical data. The proposed mechanisms are expected to help in identifying the possible degradation pathways for similar pharmaceutical candidates.

Development of a scalable route to a complex cyclobutane linchpin via a diastereoselective CuI-catalyzed vinylation of a cyclobutanyl aldehyde

A robust and scalable CuI-catalyzed diastereoselective vinylation of an aliphatic aldehyde was developed to enable clinical supply of investigational Mcl-1 inhibitors in our oncology pipeline. Through process design and impurity control, a telescoped process consisting of a benzotriazole salt break and diastereoselective vinylation was developed. This process eliminated the need to perform distillation operations, improved reaction performance and efficiency, and was successfully scaled to >100 kg.

An Improved Synthesis of Teriflunomide and Identification, Synthesis and Characterization of Its Critical Process Impurities

An Improved Synthesis of Teriflunomide and Identification, Synthesis and Characterization of Its Critical Process Impurities

Advanced Processing Techniques and Impurity Management for High-Purity Quartz in Diverse Industrial Applications

Advanced Processing Techniques and Impurity Management for High-Purity Quartz in Diverse Industrial Applications

Chemical radioanalysis of production of positron-emitting radioisotope Gallium-68 via (p,n) and (p,2n) reactions using compact cyclotron for tomography applications

In this study, the proton-induced reactions of 68Zn and 69Ga aimed at generating 68Ga were simulated and modeled using Talys code and neural network software. In the first step, both targets were simulated under different proton energies and at different bombardments times to generate a total of six thousand data. Then, the obtained data from the Talys, including the various cross-sections, contaminations, the main product i.e. 68Ga, and other options were completely saved in the output file. Afterwards, the inputs of the neural network were selected from the output of the Talys by analyzing and considering most of the key features. A total of four inputs, two of which are different energies related to the reaction, the other is the process sequence and the fourth input is the bombardment time, were recognized as suitable inputs and the model was trained differently depending on the type of target. The selected model was a feed-forward neural network with 5 nodes in a middle layer, which was able to estimate the output of Talys code by changing the input parameters with extremely high accuracy. Two different models including the main model for estimating the output of the main sample (product) and the sub-model for estimating process pollution or impurity were trained, and then the trained model was tested on the deduced process data. The implementation results fully demonstrated the high accuracy of the method. The neural network model is much easier to implement than the Talys code, and its execution speed is very high. In addition, it can be used appropriately as a system alternative for optimization and different structures in medical and biological engineering.

Impurity study of tecovirimat

This article delineates the systematic identification, synthesis, and impurity control methods used during the manufacturing process development of tecovirimat, an antiviral drug that treats monkeypox. Critical impurities were synthesized, and their chemical structure was confirmed through NMR analysis, GC, and HPLC mass spectrometry. The results established a thorough approach to identify, address, and control impurities to produce high-quality tecovirimat drug substance in accordance with International Conference on Harmonization (ICH)-compliant standards. This study is the first of its kind to evaluate both process and genotoxic impurities in tecovirimat, demonstrating effective control measures during commercial sample investigations and scaling up to a 60-kg batch size. The findings highlight the importance of critical impurity characterization and control in pharmaceutical development and production to ensure the safety and efficacy of the final product.

The Impurity Removal and Comprehensive Utilization of Phosphogypsum: A Review.

Phosphogypsum (PG), a byproduct during the phosphoric acid production process, also known as the wet process, contains complex and diverse impurities, resulting in low utilization and considerable accumulation. This leads to a massive waste of land resources and a series of environmental pollution problems. Given the current urgent ecological and environmental situation, developing impurity removal processes with low energy consumption and high efficiency, exploring valuable resource recovery, preparing high value-added PG products, and broadening the comprehensive utilization ways of PG are significant strategies to promote the sustainable consumption of PG and sustainable development of the phosphorus chemical industry. This review comprehensively summarizes the advantages and disadvantages of existing PG impurity removal and utilization technologies and probes into the future development direction, which provides references and ideas for subsequent PG research.

Identification and structural characterization of potential degradation products of baricitinib using liquid chromatography combined with quadrupole time-of-flight mass spectrometry

AbstractBaricitinib (BRT) is a drug substance with potent anti-inflammatory activity indicated in rheumatoid arthritis, atopic dermatitis, severe alopecia areata and recently for the treatment of Covid-19. Process impurities of the drug during its formulation are quite known, however studies regarding its degradation products (DPs) under stress conditions are limited. In this study, the drug was subjected to forced degradation under various degradation conditions, including acidic hydrolysis, alkaline hydrolysis, oxidative and thermal, to determine its inherent stability. To this purpose, a novel HPLC method was developed for the determination of degradation impurities of BRT. Alkaline hydrolysis test showed a selectivity towards breaking C–C bonds. This resulted to five DPs formed by chain scission reactions occurred at the pyrrolo-pyrimidine group between C6–C10 and C8–C9. Also, the ethylsulfonyl-azetidin-ylidene group was subjected to C–C bond cleavage at C12–C15 and C16–C18. Degradation products were further characterized with the use of liquid chromatography quadrupole time of flight tandem mass spectrometry (LC-Q-TOF-MS/MS).

Identification, Synthesis, Characterization, and Control Strategy Establishment for Process Impurities of Baloxavir Marboxil

Identification, Synthesis, Characterization, and Control Strategy Establishment for Process Impurities of Baloxavir Marboxil

Tri-chromic sustainable tools of derivative/discrete Fourier transform HPLC convoluted peaks: Application on LCZ696, an antihypertensive supramolecular complex, with its in process and degradation impurity analysis

The aim of this manuscript is to discuss the use of chemometrics approaches in handling the response data of HPLC to sustainable analytical chemistry procedure development. This was performed on FDA approved LCZ696, an antihypertensive supramolecular complex of sacubitril (SAC) and valsartan (VAL), with the in process and degradation impurity (BMP). Structure similarity between SAC and its in process and degradation impurity (BMP) makes it difficult for their simultaneous determination and need too much time and solvent consumption for their separation. It was found that convolution of the resulting derivative curves using 8-points sin xi polynomials (discrete Fourier functions) after derivative treatment of the chromatographic response data was beneficial in handling one of the most common chromatographic problems which is overlapping of the chromatographic peaks without complete resolution, thus, reducing time of analysis and solvent consumption. The chemometric data handling succeeded in analyzing LCZ696, with its closely related in process impurity in less than 4.5 min. reaching impurity detection limit of 0.5 % in presence of the parent drug, SAC, while the direct chromatographic measurement showed higher LOD and LOQ of BMP with poor recovery, outside the accepted range 98–102 %, ranging from 80.56 to 104.41. Moreover, the proposed chemometric methodology will be compared with other chromatographic methods in terms of greenness, blueness and whiteness (tri-chromic assessment) using Analytical Eco Scale, AGREE, Blue Applicability Grade Index (BAGI) and the up-to-date Chlortox scale in addition to the white RGB 12 model in order to ascertain the influence of chemometric methods in minimizing the amount of time spent conducting the analysis and reducing solvent, energy and waste consumption.

Eco-Friendly Stability-Indicating HPLC Method for Related Compounds in Pemetrexed Ditromethamine (Antineoplastic Agent) for Injection.

An eco-friendly analytical technique was developed with the intention of preserving the environment by using green chemistry principles. Pemetrexed is a folate analogue indicated for the treatment of advanced lung cancer. Development of a green stability-indicating HPLC method for the quantification of pemetrexed ditromethamine (PDT) impurities in Active Pharmaceutical Ingredient (API) and parenteral dosage form. Chromatographic separation was achieved using a Zorbax SB C18 column (150 mm × 4.6 mm i.d., 3.5 µ particle size) with perchlorate buffer (pH 3.0 ± 0.1, 50 mM) as mobile phase A and acetonitrile-perchlorate (90 + 10, v/v) buffer as mobile phase B at a flow rate of 0.8 mL/min with a column temperature of 40°C ± 0.5°C. All analytes were well resolved by gradient elution with a total run time of 75 min. The UV detection wavelength was 230 nm. The RP-HPLC method is capable of resolving all the degradation and process impurities for PDT API and parenteral dosage form. The related compounds method was validated in accordance with International conference on harmonization (ICH) Q2(R1) and United states of Pharmacopoeia (USP) <1225> guidelines, and found to be accurate, specific, precise, linear, robust and stability-indicating. The precision and intermediate results were <5% CV for all the impurities. The accuracy for all the impurities was found to be between 90 and 110%. The linearity of regression co-efficient values for all the impurities were found to be more than 0.999. The proposed related compounds method is found suitable for the determination of process and degradation impurities of commercial formulations, stability samples in QC analysis for PDT API, and drug product. The developed liquid chromatographic method greenness and eco-friendliness were assessed using the green analytical procedure index (GAPI) and the analytical greenness (AGREE) tool, and found to be green. A PDT detoxification procedure was also developed to reduce environmental pollution.

Analytical Methods and Their Significance in Pharmaceutical Process Impurities: A Review

AbstractPotential genotoxic substances in medicines are of rising concern to pharmaceutical and regulatory authorities at detectable levels due to their potential to induce human carcinogenesis. Molecule functional groups may contribute to the genotoxicity of small molecules by converting starting materials and synthetic intermediates into reactive components. It is challenging for the pharmaceutical research and development analytical community to identify these genotoxic chemicals at trace levels without using susceptible and selective analytical methods. The literature currently needs more experimental advice for analyzing some significant contaminants. Analytical methods play a vital role in the pharmaceutical industry for monitoring and controlling impurities in drug products. These methods provide critical information on the final product's quality, purity, and efficacy by identifying unwanted substances such as degradation products, residual solvents, and process contaminants. The significance of analytical methods in pharmaceutical process impurities includes ensuring quality control, regulatory compliance, process optimization, troubleshooting, and batch release. These methods help to ensure that the final product meets the required specifications, complies with regulatory requirements, and provides the safe and effective patient treatment. The study analyses the structural alarms of commonly encountered likely genotoxic contaminants and draught regulations of various regulatory authorities to restrict the number of impurities in medicinal substances and to identify their toxicity.

Highly efficient freezing desalination technology: Parameters optimization and model configuration

Seawater desalination has become an available route to reduce the shortage of freshwater resources. Lower energy consumption and suitable operational conditions make freezing crystallization a green technique in the desalination area. Herein, we coupled the sweating intensification with the freezing crystallization to reach a highly efficient desalination performance. Under the trajectory of the freezing temperature and time: 259.15 K and 150 min, the sweating temperature, heating rate, and sweating time: 272.15 K, 0.5 K/min, and 120 min, the desalination ratio exceeds 70 %. Meanwhile, we established the theoretical models to expound the intrinsic correlations of process variables and target parameters, to visualize the impurity migration. Two kinetic models are proposed to analyze temperature effects on the crystal layer growth, sweating melt flow, and inclusion entrapment. Next, the fractal slice model is proposed to describe the complex microstructure of the crystal pillar. The thermal coefficients are deduced based on the fractal theory, where the larger porosity is against thermal conduction. Finally, we discussed the kinetic and porosity effects on the impurity migration and desalination performance, and established a boundary layer model to correlate the separation efficiency with process kinetic and impurity distribution successfully.

Continuous flow synthesis of β-hydroxyethyl hydrazine in microreactors: process behavior and impurity formation mechanism

The synthesis of β-hydroxyethyl hydrazine (HEH) via the reaction between ethylene oxide (EO) and hydrazine hydrate (N2H4·H2O) suffers from a series of consecutive side reactions, such as ammonolysis and addition of EO.

Valorization of beverage waste as a sugar source for 5-hydroxymethylfurfural production

This study highlights the valorization of beverage waste as a promising sugar-based raw material for 5-hydroxymethylfurfural (5-HMF) production. In this work, both beverage waste purification and 5-HMF production were experimentally demonstrated through the practicality and effectiveness of continuous-flow processes. In the purification process, solid and liquid impurities were wholly eliminated through membrane filtration and a two-stage adsorption process using activated carbon. The purified beverage waste primarily consisted of fructose, glucose, and sucrose, offering a plentiful source of sugar. A mini fixed-bed reactor was employed to thoroughly investigate the impact of various operating variables on continuous 5-HMF production from synthetic beverage waste. The variables considered included residence time, reaction temperature, catalyst type, solvent type, water content, and sugar concentration. The optimization analysis was conducted to achieve both high 5-HMF yield and productivity. The optimal condition, which resulted in the 5-HMF yield of 42.6% and productivity of 3.3e−3 kg5-HMF/kgcat-h, was obtained with a residence time of 15 min, sugar feed concentration of 10 g/L, reaction temperature of 120 °C, and water content of 10 g/L. Dimethyl sulfoxide (DMSO) and Amberlyst 15 were the selected solvent and catalyst, respectively. The feasibility of producing 5-HMF from actual beverage waste was validated under optimal conditions. Furthermore, the stability of the catalyst was demonstrated over 24 h of time-on-stream. The proposed processes offer the potential for continuous purification of beverage waste and the efficient production of 5-HMF.

Multi-Gram Scale Synthesis and Characterization of Mometasone Furoate EP Impurity C

Mometasone furoate is a synthetic corticosteroid used in the treatment of skin inflammatory conditions, hay fever and asthma. The industrial manufacturing routes to mometasone furoate are generally accompanied by the formation of numerous process impurities that need to be detected and quantified, as requested by regulatory authorities. The ready availability of such impurities in the required quantity and purity is therefore essential for toxicological studies, analytical method development and process validation. Herein, we report the multi-gram scale preparation of 21′-chloro-(16′α-methyl-3′,11′,20′-trioxo-pregna-1′,4′-dien-17′-yl)-furan-2-carboxylate (mometasone furoate EP impurity C), one of the known impurities of mometasone furoate. This study also includes the systematic investigation of the final acylation step, as well as the characterization of the difuroate enol ether intermediate and its conversion to the target impurity C.

A modern chromatographic energy-saving approach for the analysis of doxycycline, ambroxol, and its precursor and impurity: Green metric assessment and comparison

The ternary mixture of doxycycline hyclate (DOX), ambroxol hydrochloride (AMB), and ambroxol synthetic precursor and process impurity (IMP) as chemically identified in the British Pharmacopeia as 2-amino-3, 5-dibromobenzaldehyde was examined for the first time using an ultra-performance liquid chromatographic technique. The presented work aimed to develop and validate a green accurate sensitive modern method for determination of this mixture. The obtained UPLC was accomplished by using an UPLC C18 column with mobile phase combination of acetonitrile: water (60:40, v/v) which was flowed at the rate of 0.22 mL per minute. Elution was in an isocratic manner and temperature control set at room temperature. UV was used to identify the effluent, which was injected at a volume of 5.00 µL; 370 nm for DOX and 240 nm for AMB and IMP. In concentration ranges; of (5–150) µg mL−1, linearity of both DOX and AMB was attained and of (0.5–40) µg mL−1, linearity of IMP was attained. Accuracy of this UPLC method was found to be 100.28, 99.66, and 100.36 for DOX, AMB, and IMP, respectively. ICH standards were followed while making the method validation. The existing combined pharmaceutical dosage form was analyzed by the obtained UPLC method for determination of the evaluated drugs successfully and the obtained results expressed as (Recovery % ± SD) were 101.02 ± 1.37 for DOX and 102.22 ± 1.56 for AMB. Also, the statistically significant correlation of our created approach to the reported HPLC method revealed no appreciable differences in terms of accuracy and precision. The developed method’s greenness profile was appraised using many greenness metrics, green assessment comparison between the established columnar method and the published ones was made.

Actual Process Impurity or an Analytical Artifact? A Case Study Involving Conversion of Amide to Nitrile to Uncover the Truth and Mitigate

Actual Process Impurity or an Analytical Artifact? A Case Study Involving Conversion of Amide to Nitrile to Uncover the Truth and Mitigate