Study on degradation kinetics of epalrestat in aqueous solutions and characterization of its major degradation products under stress degradation conditions by UHPLC-PDA-MS/MS

Drug stability is closely related to drug safety and needs to be considered in the process of drug production,package and storage.To investigate the stability of epalrestat,a carboxylic acid derivative,a reversed-phase high-performance liquid chromatography(RP-HPLC)method was developed in this study and applied to analyzing the degradation kinetics of epalrestat in aqueous solutions in various conditions,such as different pH,temperatures,ionic strengths,oxidation and irradiation.The calibration curve was A=1.6×10^5C–1.3×10^3(r=0.999)with the liner range of 0.5–24μg/mL,the intra-day and inter-day precision was less than 2.0%,as was the repeatibility.The average accuracy for different concentrations was more than 98.5%,indicating that perfect recoveries were achieved.Degradation kinetic parameters such as degradation rate constants(k),activation energy(Ea)and shelf life(t0.9)under different conditions were calculated and discussed.The results indicated that the degradation behavior of epalrestat was pH-dependent and the stability of epalrestat decreased with the rised irradiation and ionic strength;however,it was more stable in neutral and alkaline conditions as well as lower temperatures.The results showed that the degradation kinetics of epalrestat followed first-order reaction kinetics.Furthermore,the degradation products of epalrestat under stress conditions were identified by UHPLC-PDA-MS/MS,with seven degradation products being detected and four of them being tentatively identified.

Degradation kinetics of larotaxel and identification of its degradation products in alkaline condition

Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC–MS method was developed and validated for the study of degradation kinetics of larotaxel, which was carried out in aqueous solutions with different pH（1.5, 3.0, 5.0, 6.5, 7.4, 9.0, 10 and 11.0） and temperature（0, 25, 37 and 45 °C）. The linear range was 0.5–25 μg/mL, the intra-and inter-day precisions were less than 7.0%, and accuracy ranged from 97.4–104.5% for each analyte. The observed rate obtained by measuring the remaining intact larotaxel was shown to follow first-order kinetics. The activation energies for degradation were 126.7 and 87.01 k J/mol at pH 1.5 and 11, respectively. Although larotaxel was stable in pH 5, 6.5 and 7.4 buffers at 37 °C for 24 h during our study, increasing or decreasing the pH of the solutions would decrease its stabilities. Moreover, three main degradation products in alkaline condition were separated by HPLC and identified by Q–TOF–MS. The three degradation products were confirmed as 10-deacetyl larotaxel, 7, 8-cyclopropyl baccatin Ⅲ and 10-deacetyl-7, 8-cyclopropyl baccatin Ⅲ.

Efficiency and degradation products elucidation of the photodegradation of mefenpyrdiethyl in water interface using TiO_2 P-25 and Hombikat UV100

The photodegradation of mefenpyrdiethyl （MFD）, an herbicide safener, was investigated in aqueous suspensions by using Degussa P-25 and Hombikat UV100 titanium oxide under simulated sunlight irradiation. The effects of initial concentration of the herbicide, pH, catalysts and hydrogen peroxide doses as well as their combinations were studied and optimized. Accordingly, the kinetic parameters were determined and the effectiveness of the processes was assessed by calculating the rate constants. A pseudo first-order kinetics was observed. Under experimental conditions, the degradation rate constants were strongly influenced using P-25 and no noticeable effect was observed for Hombikat UV100. DFT calculations with B3LYP/6-311＋G（2d,p）//B3LYP/6-31＋G（d,p） level of theory were performed to check whether significant conformational changes occur when the charge state of the MFD substrate changes and whether these changes could play a role in the dependency of photodegradation rate constant on the studied pH. High resolution mass spectrometry （FT-ICR/MS） was implemented to identify the main degradation products.

Degradation of indomethacin in river water under stress and non-stress laboratory conditions:degradation products,long-term evolution and adsorption to sediment

The pharmaceutical compound indomethacin is not totally removed in wastewater treatment plants,whose effluents flow into aquatic environments;concentrations in the 0.1-100 ng/L range are commonly found in surface waters,and its fate is unknown.Here,biological,photochemical and thermal degradation assays were conducted under stress and non-stress conditions to estimate its degradation rate in river water and establish its degradation products over time.The results revealed that direct sunlight irradiation promoted the complete degradation of indomethacin（2 μg/L） in less than 6 hr,but indomethacin was detected over a period of 4 months when water was kept under the natural day-night cycle and the exposure to sunlight was partially limited,as occurs inside a body of water.The biological degradation in water was negligible,while the hydrolysis at pH 7.8 was slow.Residues were monitored by ultra-pressure liquid chromatography/quadrupole time-of-flight/mass spectrometry after solid-phase extraction,and six degradation products were found;their structures were proposed based on the molecular formulae and fragmentation observed in high-resolution tandem mass spectra.4-Chlorobenzoic and 2-acetamido-5-methoxybenzoic acids were the long-term transformation products,persisting for at least 30 weeks in water kept under non-stress conditions.Furthermore,the degradation in the presence of sediment was also monitored over time,with some differences being noted.The adsorption coefficients of indomethacin and degradation products on river sediment were calculated;long-term degradation products did not have significant adsorption to sediment.

Biodegradation of acetanilide herbicides acetochlor and butachlor in soil

The biodegradation of two acetanilide herbicides, acetochlor and butachlor in soil after other environmental organic matters addition were measured during 35 days laboratory incubations. The herbicides were applied to soil alone, soil SDBS (sodium dodecylbenzene sulfonate) mixtures and soil HA (humic acid) mixtures. Herbicide biodegradation kinetics were compared in the different treatment. Biodegradation products of herbicides in soil alone samples were identified by GC/MS at the end of incubation. Addition of SDBS and HA to soil decreased acetochlor biodegradation, but increased butachlor biodegradation. The biodegradation half life of acetochlor and butachlor in soil alone, soil SDBS mixtures and soil HA mixtures were 4.6d, 6.1d and 5.4d and 5.3d, 4.9d and 5.3d respectively. The biodegradation products were hydroxyacetochlor and 2 methyl 6 ethylaniline for acetochlor, and hydroxybutachlor and 2,6 diethylaniline for butachlor.

Development of forced degradation and stability indicating studies of drugs——A review

Forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. It is required to demonstrate specificity of stability indicating methods and also provides an insight into degradation pathways and degradation products of the drug substance and helps in elucidation of the structure of the degradation products. Forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. Thus, this review discusses the current trends in performance of forced degradation studies by providing a strategy for conducting studies on degradation mechanisms and also describes the analytical methods helpful for development of stability indicating method.

Fibrinogen degradation product levels on arrival for trauma patients requiring a transfusion even without head injury

BACKGROUND: There have been few reports on the clinical significance of the fibrinogen degradation product(FDP) level in trauma patients with and without head injury. We retrospectively analyzed trauma patients with or without head injury to investigate the clinical signifi cance of the FDP level.METHODS: From April 2013 to June 2015, a medical chart review was retrospectively performed for all patients with trauma. The exclusion criteria included patients who did not receive a transfusion. The patients were divided into two groups: a FDP>100 group, which included patients who had an FDP level on arrival over 100 ng/m L, and a FDP≤100 group.RESULTS: The ratio of open fractures and the prothrombin ratio in the FDP>100 group were significantly smaller than those observed in the FDP≤100 group. The average age, ratio of blunt injury, Injury Severity Score(ISS), volume of transfusion and mortality ratio in the FDP>100 group were signifi cantly greater than those in the FDP≤100 group. There was a weakly positive correlation between the FDP level and ISS(R=0.35, P=0.002), but it was not associated with the transfusion volume. The results of an analysis excluding patients with head injury showed a similar tendency.CONCLUSION: The FDP levels may be a useful biochemical parameter for the initial evaluation of the severity of trauma and mortality even in blunt traumatized patients without head injury or with stable vital signs.

Isolation and characterization of a degradation product in leflunomide and a validated selective stability-indicating HPLC-UV method for their quantification

Leflunomide （LLM） is subjected to forced degradation under conditions of hydrolysis, oxidation, dry heat, and photolysis as recommended by International Conference on Harmonization guideline Q1A（R2）. In total, four degradation products （I-IV） were formed under different conditions. Products I, II and IV were formed in alkaline hydrolytic, acidic hydrolytic and alkaline photolytic conditions. LLM and all degradation products were optimally resolved by gradient elution over a C18 column. The major degradation product （IV） formed in hydrolytic alkaline conditions was isolated through column chromatography. Based on its IH NMR, IR and mass spectral data, it was characterized as a British Pharmacopoeial impurity B. The HPLC method was found to be linear, accurate, precise, sensitive, specific, rugged and robust for quantification of LLM as well as product IV. Finally, the method was applied to stability testing of the commercially available LLM tablets.

Voltammetric Behavior of Degradation Product and Determination of Cefdinir

The electrochemical behavior of the degradation product of cefdinir（CDR） was studied in a 0.05 mol/L NaOH solution by means of linear sweep voltammetry（LSV） and cyclic voltammetry（CV）. The results indicate that the C=N bond in the oxime group was reduced. Moreover, a saturated adsorption amount of 1.32× 10^-10 mol/cm2 at Hg electrode was obtained. The adsorption coefficient β was 1.56× 10^5 L/mol. Gibbs standard energy of adsorption AGO at 25 ℃ was -29.63 kJ/mol and the number of electrons transferred n was 2. A method for the determination of CDR was proposed by differential pulse voltammetry（DPV）. The reduction peak currents of the CDR＇s degradation product were found to be linear in a concentration range of 4.0×10^-7--4.0×10^- 6 mol/L and that of 4.0× 10^-8-4.0× 10^-7 mol/L, respectively. The detection limit was found to be 3.0× 10^-8 mol/L under the optimized conditions. The applica- bility of this approach was illustrated by the determination of CDR in capsules. In addition, the mechanism about the degradation of CDR in 0.2 mol/L NaOH was discussed by UV spectrophotometry.

Characteristics and Degradation Mechanism of Fomesafen

High performance liquid chromatography(HPLC) was used to determine the degradation efficiency of bacteria 2 strain(B2 S) under different conditions, the optimum cultivation conditions for fomesafen degradation bacterium B2 S were as the followings: temperature 35℃; inoculation quantity 5%; p H 5.0; glucose content 0.5% and fomesafen concentration 10 mg · L-1. Under optimal conditions, B2 S degraded fomesafen within 72 h of fomesafen application, with a degradation rate of nearly 100%. High performance liquid chromatography-mass spectrometry(HPLC-MS) was used to analyze fomesafen degradation into microbial products. A more thorough understanding of microbial fomesafen degradation mechanisms was discussed. The pathway of fomesafen degradation by B2 S was also inferred herein.

Clinical association between coagulation indicators and bone metastasis in patients with gastric cancer

BACKGROUND Bones are one of the most common target organs for cancer metastasis.Early evaluation of bone metastasis(BM)status is clinically significant.Cancer patients often experience a hypercoagulable state.AIM To evaluate the correlation between coagulation indicators and the burden of BM in gastric cancer(GC).METHODS We conducted a single-center retrospective study and enrolled 454 patients.Clinical information including routine blood examination and coagulation markers were collected before any treatment.Patients were grouped according to the status of BM.Receiver operating characteristic curves were used to assess diagnostic performance and determine the optimal cutoff values of the above indicators.Cutoff values,sensitivity and specificity were based on the maximum Youden index.Univariate and multivariate logistic regression analyses were used to evaluate the relationships between biomarkers and BM.RESULTS Of the 454 enrolled patients,191 patients were diagnosed with BM.The receiver operating characteristic curve analysis suggested that prothrombin time(PT)Wang X et al.Coagulation indicators predict bone metastasis WJGO https://www.wjgnet.com 1254 July 15,2023 Volume 15 Issue 7[cutoff:13.25;sensitivity:0.651;specificity:0.709;area under receiver operating characteristic curve(AUC)=0.738],activated partial thromboplastin time(aPTT)(cutoff:35.15;sensitivity:0.640;specificity:0.640;AUC=0.678)and fibrin degradation products(FDP)(cutoff:2.75;sensitivity:0.668;specificity:0.801;AUC=0.768)act as novel predictors for BM.Based on multivariate logistic regression analysis,the results showed the independent correlation between PT[odds ratio(OR):3.16;95%confidence interval(CI):1.612-6.194;P=0.001],aPTT(OR:2.234;95%CI:1.157-4.313;P=0.017)and FDP(OR:3.17;95%CI:1.637-6.139;P=0.001)and BM in patients with GC.Moreover,age,carcinoembryonic antigen,erythrocyte and globulin were found to be significantly associated with BM.CONCLUSION Coagulation markers,namely PT,aPTT and FDP,might be potential predictors for screening BM in patients with GC.

Degradation behaviors of Nabumetone and its metabolite during UV/monochloramine process:Experimental and theoretical study

This study investigated degradation behaviors of a nonsteroidal anti-inflammatory drug Nabumetone(NMT)and its major metabolite 6-methoxy-2-naphthylacetic acid(MNA)in the coupling process of ultraviolet and monochloramine(UV/NH2Cl).The second-order rate constants of the contaminants reacting with reactive radicals(HO·,Cl·,Cl_(2)·-,and CO_(3)·^(-))were determined by laser flash photolysis experiments.HO·and Cl·contributed predominantly with 52.3%and 21.7%for NMT degradation and 60.8%and 22.3%for MNA degradation.The presence of chlorides retarded the degradation of NMT,while promoted the destruction of MNA,which was ascribed to the photosensitization effects of MNA under UV irradiation.Density functional theory(DFT)calculations revealed that radical adduct formation(RAF)was dominant pathway for both HO·and Cl·reacting with the contaminants,and hydrogen atom transfer(HAT)preferred to occur on side chains of NMT and MNA.NMT reacted with NO_(2)·through single electron transfer(SET)with the second-order rate constant calculated to be 5.35×10^(7)(mol/L)^(-1)sec^(-1),and the contribution of NO_(2)·was predicted to be 13.0%of the total rate constant of NMT in pure water,which indicated that NO_(2)·played a nonnegligible role in the degradation of NMT.The acute toxicity and developmental toxicity of NMT were enhanced after UV/NH_(2)Cl treatment,while those of MNA were alleviated.The transformation products of both NMT and MNA exhibited higher mutagenicity than their parent compounds.This study provides a deep understanding of the mechanism of radical degradation of NMT and MNA in the treatment of UV/NH2Cl.

Green and efficient degradation of cefoperazone sodium by Bi_(4)O_(5)Br_(2) leading to the production of non-toxic products:Performance and degradation pathway

Photocatalytic process represents a promising approach to overcome the pollution challenge associated with the antibiotics-containing wastewater.This study provides a green,efficient and novel approach to remove cephalosporins,particularly cefoperazone sodium(CFP).Bi_(4)O_(5)Br_(2) was chosen for the first time to systematically study its degradation for CFP,including the analysis of material structure,degradation performance,the structure and toxicity of the transformation products,etc.The degradation rate results indicated that Bi_(4)O_(5)Br_(2) had an excellent catalytic activity leading to 78%CFP removal compared with the pure BiOBr(38%)within 120 min of visible light irradiation.In addition,the Bi_(4)O_(5)Br_(2) presents high stability and good organic carbon removal efficiency.The effects of the solution p H(3.12-8.75)on catalytic activity revealed that CFP was mainly photocatalyzed under acidic conditions and hydrolyzed under alkaline conditions.Combined with active species and degradation product identification,the photocatalytic degradation pathways of CFP by Bi_(4)O_(5)Br_(2) was proposed,including hydrolysis,oxidation,reduction and decarboxylation.Most importantly,the identified products were all hydrolysis rather than oxidation byproducts transformed from the intermediate ofβ-lactam bond cleavage in CFP molecule,quite different from the mostly previous studies.Furthermore,the final products were demonstrated to be less toxic through the toxicity analysis.Overall,this study illustrates the detailed mechanism of CFP degradation by Bi_(4)O_(5)Br_(2) and confirms Bi_(4)O_(5)Br_(2) to be a promising material for the photodegradation of CFP.

Establishment of inherent stability of pramipexole and development of validated stability indicating LC-UV and LC-MS method

Pramipexole belongs to a class of nonergot dopamine agonist recently approved for the treatment of early and advanced Parkinson＇s disease.A validated specific stability indicating reversed-phase liquid chromatographic method has been developed for the quantitative determination of pramipexole in bulk as well as in pharmaceutical dosage forms in the presence of degradation products.Forced degradation studies were performed by exposition of drug to hydrolytic（acidic and basic）,oxidative and photolytic stress conditions,as defined under ICH guideline Q1A（R2）.Significant degradation was observed under hydrolytic,oxidative and photolytic conditions and the degradation products formed were identified by LC-MS.

Degradation of metoprolol by UV/sulfite as an advanced oxidation or reduction process:The significant role of oxygen

The degradation of metoprolol(MTP)by the UV/sulfite with oxygen as an advanced reduction process(ARP)and that without oxygen as an advanced oxidation process(AOP)was comparatively studied herein.The degradation of MTP by both processes followed the first-order rate law with comparable reaction rate constants of 1.50×10^(-3)sec^(−1)and 1.20×10^(-3)sec^(−1),respectively.Scavenging experiments demonstrated that both e^(−)_(aq)and H·played a crucial role in MTP degradation by the UV/sulfite as an ARP,while SO_(4)^(·−)was the dominant oxidant in the UV/sulfite AOP.The degradation kinetics of MTP by the UV/sulfite as an ARP and AOP shared a similar pH dependence with a minimum rate obtained around pH 8.The results could be well explained by the pH impacts on the MTP speciation and sulfite species.Totally six transformation products(TPs)were identified from MTP degradation by the UV/sulfite ARP,and two additional ones were detected in the UV/sulfite AOP.The benzene ring and ether groups of MTP were proposed as the major reactive sites for both processes based on molecular orbital calculations by density functional theory(DFT).The similar degradation products of MTP by the UV/sulfite process as an ARP and AOP indicated that e^(−)_(aq)/H·and SO_(4)^(·−)might share similar reaction mechanisms,primarily including hydroxylation,dealkylation,and H abstraction.The toxicity of MTP solution treated by the UV/sulfite AOP was calculated to be higher than that in the ARP by the Ecological Struc-ture Activity Relationships(ECOSAR)software,due to the accumulation of TPs with higher toxicity.

Determination and stress studies on YK-1101,a potential histone deacetylase,by HPLC-UV and HPLC-TOF/MS methods

YK- 1101, with its structure as S-（（E）-4-（（7S, 10S,Z）-4-ethylidene-7-isopropyl-2,5,8,12- tetraoxo -9-oxa- 16-thia-3,6,13,18-tetraazabicyclo[ 13.2.1 ]octadeca- 1 （17）, 15（ 18）-dien- 10-yl）but-3-en- 1 -y l） ethanethioate, is synthesized as a potential histone deacetylase inhibitor. Its quality and stability under various stress conditions are not fully understood. In this study, a high performance liquid chromatographic （HPLC） method was established and validated for the analysis of YK-1101 bulk drug samples. The chromatographic separation was performed on a C18 column with acetonitrile and water as mobile phase in a gradient elution. Based on the established method, the stability studies of YK-1101 under various stress conditions were carried out. YK-1101 was shown to undergo degradation under basic and acidic stress conditions, while it was stable under oxidative, photolytic and thermal conditions. In addition~ a time of flight mass spectrometer （TOF/MS） was coupled to HPLC for the characterization of major degradation products produced under basic and acidic stress conditions. Their degradation pathways were also discussed.

Prolonged prothrombin time at admission predicts poor clinical outcome in COVID-19 patients

BACKGROUND Supported by the National Natural Science Foundation of China,No.The prognostic value of coagulation disorder in coronavirus disease 2019(COVID-19)patients should be demonstrated.AIM To investigate the abnormalities of coagulation parameters in the patients with COVID-19 and their prognostic values.METHODS Consecutive patients admitted in the isolation ward of Renmin Hospital of Wuhan University from January 31 to February 5,2020 with confirmed COVID-19 were included.The primary outcomes were death and survival as of March 11.Demographics,vital signs,comorbidities and laboratory tests were collected and compared between those who died and survivors.Logistic regression analysis for prognostic factors was performed.Kaplan-Meier analysis was used to compare the estimated survival rate between patients with prolonged prothrombin time and normal prothrombin time.RESULTS The total number of patients with confirmed COVID-19 who were enrolled was 213.The median age was 62 years,and 95 patients(44.6%)were men.Fifty-one patients were critical(23.9%),79 patients were severe(37.1%)and 83 patients were moderate(39%).As of March 11,2020,99 patients were discharged(46.5%),79 patients(37.1%)stayed in the hospital and 35 patients(16.2%)died.Median time to death was 6(4-8)d,while median hospital stay was 32(22-36)d in survivors(P<0.001).More men(P=0.002)and elderly patients(P<0.001)were found in the group of those who died.The respiration rate at admission was higher in the group of those who died(P<0.001).The incidences of hypertension(P=0.028),cerebrovascular disease(P<0.001),chronic kidney disease(P=0.02)and chronic obstructive pulmonary disease(P<0.001)were higher in the group of those who died.Platelet count was decreased in the group of those who died(P=0.002)whereas prothrombin time(P<0.001),activated partial thromboplastin time(P=0.033),concentration of D-dimer(P<0.001)and fibrin degradation products(P<0.001)were increased in the group of those who died.Prothrombin time[odds ratio(OR):2.19,P=0.004],respiration rate(OR:1.223,P<0.001),age(OR:1.074,P<0.001)and fibrin degradation products concentration(OR:1.02,P=0.014)were predictors of death.The survival rate was significantly lower in patients with prolonge CONCLUSION Prothrombin time,concentration of fibrin degradation products,respiration rate and age were predictive factors for clinical outcomes of COVID-19 patients.

Removal of a type of endocrine disruptors—di-n-butyl phthalate from water by ozonation

Ozonation of synthetic water containing a type of endocrine disruptor-di-n-butyl phthalate （DBP） was examined. Key impact factors such as pH, temperature, ionic strength, ozone dosage and initial DBP concentration were investigated. In addition, the activities of radicals on uncatalysed and catalysed ozonation were studied. The degradation intermediate products were followed and the kinetic of the ozonation were assessed as well. Results revealed that ozonation of DBP followed two mechanisms. Firstly, the reaction rate of direct ozonation was slower at lower pH, temperature, and ionic strength. Secondly, when these factors were increased for indirect radical reaction, higher percentage of DBP was removed with the increase of the initial ozone dosage and the decrease of the initial DBP concentration. In addition, tea-butanol, humic substances and Fe（Ⅱ） affected DBP ozonation through the radical pathway. It was determined that ozonation was restrained by adding tea-butanol for its radical inhibition effect. Furthermore, humic substances enhanced the reaction to some extent, but a slight negative effect would be encountered if the optimum dosage was exceeded. As a matter of fact, Mn（Ⅱ） affected the ozonation by ＂active sites＂ mechanism. In the experiment, three different kinds of intermediate products were produced during ozonation, but the amount of products for each one of them decreased as pH, temperature, ionic strength and initial ozone dosage increased. A kinetic equation of the reaction between ozone and DBP was obtained.

LC-ESI-MS分析两性霉素B降解产物

两性霉素B(amphotericin B)是一种常用的抗真菌抗生素[1],属于多烯大环内酯类化合物,化学性质不稳定,在生产和储存过程中容易发生多种降解反应,产生无活性甚至有毒性的降解物,直接影响产品质量和临床用药的安全,因此,研究该抗生素降解物和降解途径,对防止产品降解、保证产品质量非常必要.……

The environmental prospects of cultured meat in China

To deal with concerns in China about environmental degradation and a growth in population accompanied by increased consumption of livestock products, a meat alternative is required. This study compared the environmental impacts of producing different protein sources for nutrition, including crops, livestock products, and cultured meat. The results showed that cultured meat has the lowest land use per unit of protein and unit of human digestible energy. China＇s crops have the lowest energy use and greenhouse gas（GHG） emissions per unit of energy and protein. The energy use in cultured meat production is slightly higher than that of current pork production in China, whereas GHG emissions are lower. It is concluded that the overall impact of replacing livestock products with cultured meat would be beneficial for China＇s environment and would potentially improve food security because less land is needed to produce the same amount of protein and energy.