The influence of pH, temperature and buffers on the degradation kinetics of cefetamet pivoxil hydrochloride in aqueous solutions

The first-order hydrolysis kinetics of cefetamet pivoxil (CP) were investigated as a function of pH, temperature and buffers. The degradation was followed by HPLC. Buffer catalysis was observed in acetate and phosphate buffers. The pH–rate profiles for hydrolysis of cefetamet pivoxil were obtained at 333, 343, 353 and 363 K. The pH–rate expression was k_pH=k_H⁺a_H⁺+k_H2Ok_OH⁻a_OH⁻, where k_H⁺ and k_OH⁻ are the second-order rate constants (mol⁻¹ l s⁻¹) for hydrogen ion activity and for hydroxyl ion activity respectively, and k_H2O is the pseudo-first-order rate constant (s⁻¹) for spontaneous reaction under the influence of water. The pH–rate profile was characteristically U-shaped. Maximum stability was observed in the pH region from 3 to 5.     

Stability of ricobendazole in aqueous solutions

The chemical stability of ricobendazole (RBZ) was investigated using a stability-indicating high performance liquid chromatographic (HPLC) assay with ultraviolet detection. The degradation kinetics of RBZ in aqueous solution was evaluated as a function of pH, buffer strength and temperature. The oxidation reaction in hydrogen peroxide solution was also studied. Degradation products were analyzed by mass spectroscopy and degradation pathways are proposed. Degradation of RBZ followed pseudo first-order kinetics and Arrhenius behavior over the temperature range 24–55 °C. A V-shaped pH-rate profile over the pH range 2–12 was observed with maximum stability at pH 4.8. The shape of the pH-rate profile was rationalized by catalytic effects of various components in the solution on each RBZ species. At pH 11 the activation energy for hydrolysis was 79.5 kJ/mol, and phosphate catalysis was not observed. Oxidation occurred in hydrogen peroxide solutions and was catalyzed by the presence of copper (Cu²⁺) ions. Ricobendazole amine and albendazole sulfone were identified by MS assay to be the degradation products of hydrolysis and oxidation respectively.     

A comparison of the stability of ertapenem and meropenem in pharmaceutical preparations in solid state

The following first-order rate constants of the degradation of ertapenem in INVANZ and meropenem in MERONEM were determined: (a) in dry air at 363, 373, 378, 383, 388, 393 K; (b) at increased relative air humidity (76.4% RH) at 313, 323, 333 and 343 K; (c) at increased relative air humidity (50.9, 60.5, 66.5, 76.4% RH-ertapenem and 50.9, 66.5, 76.4 and 90.0% RH-meropenem) at 333 K. The dependence ln k(i) = f(RH%) was described by the equations: ln k(i) = (6.63+/-1.22) x 10(-2) x (RH%)-13.36 +/- 1.68 (ertapenem) and ln k(i) = (4.22 +/- 2.98) x 10(-2) x (RH%)-12.14 +/- 2.16 (meropenem). The dependence lnk(i)=f(1/T) was described by equations: ln k(i) =19.4 +/- 2.6-(9230 +/- 800)(1/T) for ertapenem, at 76.4% RH; ln k(i) = 11.5 +/- 4.9-(9880 +/- 1800)(1/T) for ertapenem in dry air; ln k(i) = 14.8 +/- 11.9-(7785 +/- 3905)(1/T) for meropenem, at 76.4% RH; ln k(i) = 37.6 +/- 7.73-(18385 +/- 2930)(1/T) for meropenem in dry air. The thermodynamic parameters E(a), DeltaH( not equal) and DeltaS( not equal) of the degradation of ertapenem and meropenem were calculated. The difference between the influence of temperature on the stability of ertapenem and meropenem was not significant at 76.4% RH. In dry air (363-393 K) this influence was greater in the case of meropenem. The degradation of ertapenem was slower in this temperature range. Humidity was a significant factor affecting the degradation of these antibiotics and it influenced their stability is similar ways.     

厄他培南治疗老年社区获得性肺炎的临床疗效和安全性

目的评价厄他培南治疗老年社区获得性肺炎的疗效和安全性。方法 100例老年(≥65岁)社区获得性肺炎患者随机分为2组,每组50例。实验组给予注射用厄他培南1.0 g,1次/d,对照组给予莫西沙星注射液400 mg,1次/d,两组疗程均为7～14 d。观察治疗前后两组的临床疗效。结果实验组治疗有效率为92%,细菌清除率为88.9%;对照组治疗有效率为76%,细菌清除率为69.8%;两组间比较差异有统计学意义(P<0.05)。结论厄他培南治疗老年社区获得性肺炎临床疗效良好,不良反应较少,安全性高。     

苍鹅鼻炎片中的鱼腥草素钠在水溶液中的稳定性考察

摘 要 目的:考察苍鹅鼻炎片中鱼腥草素钠在水溶液中的稳定性。方法: 采用高效液相色谱法,考察时间、温度等因素对水溶液中鱼腥草素钠稳定性的影响情况。结果:苍鹅鼻炎片中的鱼腥草素钠在水溶液中的降解反应为一级动力学模式,片中的鱼腥草素钠在37℃水溶液中t_0.9=27.81 min,t_0.5=182.85 min;在25℃水溶液中t_0.9=58.92 min,t_0.5=387.37 min。结论:苍鹅鼻炎片中鱼腥草素钠在水溶液中不稳定,在37℃水溶液中27.81 min下降10%,在182.85 min降解50%。     

Kinetics of cefamandole nafate degradation in solid phase

The influence of temperature and relative humidity (RH) on the stability of cefamandole (CM) nafate sodium in the solid phase was investigated. Changes in the concentration of cefemandole nafate sodium were recorded using HPLC with UV detection. The method was validated for the following parameters: selectivity, linearity, precision, limit of detection and sensitivity. It showed good linearity (r=0.9996) in the range 0.4 x 10(-4)-5.6 x 10(-4) g ml(-1) using a LiChrospher RP-18 column and as mobile phase acetonitryle-triethylamine (10% v/v, adjusted to pH 2.5 with phosphoric acid (84%) and diluted with water) (35:65). The degradation of CM occurring at 0% RH of the ambient air and at air humidity RH>50% is a first-order reaction relative to substrate concentration. The first-order rate constants (k) were determined for CM degradation in dry air at 373, 383, 388 and 393 K, at air humidity RH=76.4% at 323, 333, 343 and 353 K, and at 353 K at air humidity RH>50%. The kinetic and thermodynamic parameters of the decomposition were calculated.     

“全合一”静脉营养液与胶体溶液配伍的稳定性研究

目的评价“全舍一”静脉营养液（AIO）与白蛋白、羟乙基淀粉2种胶体溶液的配伍稳定性。方法在固定配比的AIO中按比例分别加入临床应用浓度的白蛋白和羟乙基淀粉作为试验溶液，以单纯AIO为对照，3组溶液在室温（25℃）储存24h，考察其外观、渗透压、pH值及脂肪乳粒的粒径大小和分布的变化。结果24h后3组溶液均无乳剂分层或凝集现象，pH值变化在0．05之内。与单纯AIO相比，加入胶体的混合液中脂肪乳粒粒径和分布均无显著改变，渗透压也在输液安全范围内。结论在室温下24h内，固定配比的“全合一”静脉营养液与一定量白蛋白或羟乙基淀粉溶液混合配伍是稳定的，符合静脉用注射乳状液的质量要求。     

Stability of galactose in aqueous solutions

The stability of 5%-30% w/v galactose in sterile water for injection and acetate and phosphate buffers was studied. The concentration of galactose was determined after each sample was diluted to a nominal concentration of 0.5% (w/v); for purposes of data analysis, the concentration as measured in the diluted sample was multiplied by a dilution factor to obtain the true concentration in the sample. The concentrations were determined from the regression line obtained by plotting the peak-height ratios (for various concentrations of galactose and the internal standard cellobiose) versus the galactose concentrations. Triplicate samples were quantitatively analyzed for galactose content by high-performance liquid chromatography. The stability of the samples was then studied in relation to buffer concentration; pH; storage at 25, 45, and 65 degrees C for six weeks, and autoclaving at 121 degrees C for 30 minutes. Galactose degradation increased in relation to its concentration, increasing temperature, and buffer concentration. Galactose solutions in water and phosphate incurred less than 5% degradation on autoclaving; however, the 30% solutions in acetate buffers lost up to 21% of initial content. Yellow discoloration of solutions was associated with autoclaving and prolonged exposure at 65 degrees C and appeared in some solutions that did not exceed the USP XXI limit of 5-hydroxymethylfurfural and related compounds in dextrose injection. The estimated room temperature shelf-life of galactose in sterile water for injection sterilized by 0.45-micron-porosity membrane filtration is four and one-half months. Solutions may also be sterilized by autoclaving at 121 degrees C for 30 minutes; galactose solutions containing pH buffers should not be sterilized by autoclaving.     

厄他培南在老年急性单纯性阑尾炎非手术治疗中的疗效观察

目的观察厄他培南在老年急性单纯性阑尾炎非手术治疗中的临床疗效。方法 2014年3月至2016年3月于我院急诊诊断为急性单纯性阑尾炎并拒绝急诊手术的患者(≥65岁)。采用随机对照的方法,研究组(35例)应用厄他培南抗炎治疗,对照组(35例)应用头孢+甲硝唑抗炎治疗。观察两组治疗效果。结果老年急性单纯性阑尾炎非手术治疗有效率为62.9%,治愈率为44.3%。厄他培南组治疗有效率为68.6%(治愈率为28.6%),头孢+甲硝唑组有效率为57.1%(治愈率为25.7%),两组对比差异无统计学意义(P>0.05)。厄他培南组及头孢+甲硝唑组48 h症状改善率分别为60.0%及48.6%,近5 d总有效率分别为68.6%、57.1%,两组比较差异无统计学意义(P>0.05)。结论老年急性单纯性阑尾炎非手术疗效一般,在确诊后建议首选手术治疗。针对老年急性单纯性阑尾炎,厄他培南与传统三代头孢+甲硝唑抗炎方案疗效相近,且具有用药方案简易、过敏率低、耐药率低的优点,更适合急诊用药。如急诊老年急性单纯性阑尾炎患者拒绝或不适合手术,可尝试厄他培南抗炎治疗,在治疗期间需密切观察病情变化,48 h未见好转建议急诊手术。     

Kinetics and Mechanism of Degradation of a Cyclic Hexapeptide (Somatostatin Analogue) in Aqueous Solution

A highly active cyclic hexapeptide analogue of somatostatin, Cyclo(N-Me-L-Ala-L-Tyr-D-Trp-L-Lys-L-Val-L-Phe), L-363,586, was found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The compound is reported to be relatively stable in blood, nasal cavity, and intestinal lumen but undergoes rapid degradation in aqueous solution. The objective of this study was to elucidate the degradation mechanisms based on the kinetic data and the structure of the degradation products. Both pH and temperature had a profound influence on the instability of the peptide in aqueous solution. The data indicated that the peptide was most stable at a pH of about 4.7. The pH-rate profile exhibited specific acid catalysis at a pH less than 3.0 and base catalysis above pH 10.5. The kinetic pK _a was determined to be 9.7. This pK _a could be attributed to the tyrosine residue. The mechanisms of degradation under acidic and alkaline conditions appear to be different. Identification of the fragments obtained using mass spectrometry and amino acid sequencing suggest that the cyclic compound was cleaved to yield a linear fragment, which underwent further cleavage at both peptide linkages alpha to the trypto-phanyl residue. The indole group of that residue is probably the potential nucleophile attacking the adjacent carbonyls. A rate equation for the degradation of the hexapeptide has been proposed.     

Stability of Gonadorelin and Triptorelin in Aqueous Solution

The influence of pH, temperature, various buffer species at different concentrations, and ionic strength on the stability of gonadorelin and triptorelin in aqueous solution has been studied using stability-indicating high-performance liquid chromatographic methods. The degradation behavior of both peptides is similar. The maximum stability of both peptides was shown to be at an approximate pH of 5.0. Acetate has the most favorable effect on stability, while phosphate causes higher degradation. Varying the concentration of acetate buffer does not affect the degradation behavior of the peptides. A higher phosphate concentration in buffer solutions causes higher degradation, however. The ionic strength of buffer solutions has no significant influence on stability. Solutions of gonadorelin and triptorelin, respectively, buffered with acetate (0.1 M, pH 5.0) with 3% (w/v) mannitol as an additive show a predicted t _90% of 9.0 years and 7.7 years at 20°C, respectively.     

厄他培南对比哌拉西林/他唑巴坦治疗复杂性腹腔感染的成本效果分析

目的：为了解厄他培南与哌拉西林/他唑巴坦治疗复杂性腹腔感染（cIAI）的经济性,为临床合理用药提供参考。方法：构建决策树模型对厄他培南治疗复杂性腹腔感染进行成本效果分析,疾病治疗情况和治疗费用,临床试验中药物的治疗有效性和中国的耐药菌的药物敏感度情况等参数主要来源于相关临床试验和文献。针对参数的不确定性进行敏感性分析。结果：厄他培南与哌拉西林/他唑巴坦相比有效率略高,单次住院厄他培南较哌拉西林/他唑巴坦可节约2566元,多治愈一位cIAI患者可节约卫生费用33966元。敏感性分析显示厄他培南和哌拉西林/他唑巴坦的疗效会对结果产生较大影响,其他因素对结果影响不大,上述结论相对稳健。结论：厄他培南在治疗复杂性腹腔感染与哌拉西林/他唑巴坦相比是成本节约的,即厄他培南治疗复杂性腹腔感染具有经济性。     

体外诱导大肠埃希菌对厄他培南敏感性降低及机制研究

目的 体外诱导获得对厄他培南敏感性降低的大肠埃希菌,并分析可能的产生机制.方法 将厄他培南敏感大肠埃希菌经厄他培南体外诱导后分离突变株;药敏试验测定MIC(无或含PAβN); PFGE检测同源性;SDS-PAGE及Real-time PCR检测外膜蛋白表达;MALDI-TOF/TOF鉴定差异蛋白;并对外膜蛋白基因进行测序.结果 厄他培南处理得到的两个突变株(大肠埃希菌08-1E及大肠埃希菌08-3E)除对厄他培南敏感性显著降低外,对美罗培南、头孢西丁及头孢吡肟等β-内酰胺类药物敏感性也呈现不同程度的降低.PFGE显示突变株与亲本株同源,进一步的研究发现突变株对厄他培南敏感性降低与外排泵无关,而与基因的插入失活等机制引起的外膜蛋白(OmpC、NmpC、LamB、OmpF)缺失或表达降低有关.结论 体外诱导大肠埃希菌对厄他培南敏感性降低与外膜蛋白缺失或表达降低紧密相关.     

Stability kinetics of piperacillin in aqueous solutions

The degradation process of piperacillin in acidic, neutral and alkaline solutions was followed by both high-pressure liquid chromatographic and spectrophotometric assays. Pseudo-first-order rate constants were determined in a variety of buffer solutions. The overall pH-rate profile was determined at 35°C and an ionic strength of 0.5. β-Lactam moiety degradation occurred in acidic media to produce the hydrolysis products. In alkaline solutions, the piperazinyl ring of piperacillin was hydrolyzed about 20 times faster than the β-lactam moiety.     

全胃肠外营养液的稳定性考察

目的：考察全胃肠外营养液（TPN）组方的稳定性,为临床使用提供参考,并希望能引起各环节（生产、复配使用、贮存）对药品稳定性的重视.方法：选择临床常用科室的10份TPN液处方,包括外科、内科系统,在本院静脉用药配置中心的净化环境下,按TPN液标准操作规程配制后,在常温下,采用外观观察法、pH检测法、不溶性微粒检查法考察TPN液在0,4,8,12,16,20,24,30 h各时间点外观、pH、微粒的变化,并进行无菌考察.结果：10份TPN液在各时间点,外观未见明显变化,10组TPN液的pH在不同时间点比较,差异均无统计学意义（P＞0.05）,但不同组TPN液的pH差异有统计学意义（P＜0.05）;TPN配伍后随着放置时间的延长,微粒直径≥10 μm和≥25 μm的微粒数都有所增加,不同组TPN液的微粒数比较,差异无统计学意义（P＞0.05）;配制后无菌考察均合格.结论：建议TPN液在净化环境下配置,其pH在5～6范围内稳定性最好,TPN配制后不溶性微粒会随着放置时间的延长而明显增多,需引起临床注意并及早输注,以保证临床应用安全、合理、有效.     

Conformation and other biophysical properties of cyclic antimicrobial peptides in aqueous solutions

Abstract: As a step towards understanding the mechanism of the biological activity of cyclic antimicrobial peptides, the biophysical properties and conformations of four membrane‐active cyclic peptide antibiotics, based on gramicidin S (GS), were examined in aqueous environments. These cyclic peptides, GS10 [cyclo(VKLdY P)₂], GS12 [cyclo(VKLKdY PKVKLdY P)], GS14 [cyclo(VKLKVdY PLKVKLdY P)] and [d ‐Lys]⁴GS14 [cyclo(VKLdK VdY PLKVKLdY P)] (d ‐amino acid residues are denoted by d and are underlined) had different ring sizes of 10, 12 and 14 residues, were different in structure and amphipathicity, and covered a broad spectrum of hemolytic and antimicrobial activities. GS10, GS12 and [d ‐Lys]⁴GS14 were shown to be monomeric in buffer systems with ionic strength biological environments. GS14 was also monomeric at low concentrations, but aggregated at concentrations > 50 µm . The affinity of peptides for self‐assembly and interaction with hydrophobic surfaces was related to their free energy of intermolecular interaction. The effects of variations in salt and organic solvent (trifluoroethanol) concentration and temperature on peptide conformation were also examined. Similar to GS, GS10 proved to have a stable and rather rigid conformation in different environments and over a broad range of temperatures, whereas GS12, GS14 and [d ‐Lys]⁴GS14 had more flexible conformations. Despite its conformational similarity to GS10, GS14 had unique physicochemical properties due to its tendency to aggregate at relatively low concentrations. The biophysical data explain the direct relation between structure, amphipathicity and hydrophobicity of the cyclic peptides and their hemolytic activity. However, this relation with the antimicrobial activity of the peptides is of a more complex nature due to the diversity in membrane structures of microorganisms.     

Stability of batanopride hydrochloride in aqueous solutions.

The degradation of batanopride hydrochloride, an investigational antiemetic drug, was studied in aqueous buffer solutions (pH 2-10; ionic strength, 0.5; 56 degrees C) in an attempt to improve drug stability for parenteral administration. Degradation occurs by two different mechanisms depending on the pH of the solution. In acidic media (pH 2-6), the predominant reaction was intramolecular cyclization followed by dehydration to form a 2,3-dimethylbenzofuran. There was no kinetic or analytical (high-performance liquid chromatography) evidence for the formation of an intermediate; therefore, the rate of dehydration must have been very rapid compared with the rate of cyclization. In alkaline media (pH 8-10), the primary route of degradation was cleavage of the C-O alkyl ether bond. In the intermediate pH range (pH 6-8), both reactions contributed to the overall degradation. Both degradation reactions followed apparent first-order kinetics. The pH-rate profile suggests that batanopride hydrochloride attains its optimal stability at pH 4.5-5.5. Citrate buffer was catalytic at pH 3 and 5, and phosphate buffer was catalytic at pH 8. No catalytic effect was observed for the borate buffer at pH 9-10.     

Stability of irinotecan hydrochloride in aqueous solutions.

The stability of irinotecan after reconstitution in several vehicles for i.v. infusion was studied. Irinotecan hydrochloride injection was diluted in phosphate buffer solution (pH 4.0, 6.0, and 7.4), 5% dextrose injection, and 0.9% sodium chloride injection to a final concentration of 20 micrograms/mL. The solutions were stored at 25, 37, and 50 degrees C and assayed at intervals up to 24 hours by high-performance liquid chromatography for the concentration of the lactone form of irinotecan remaining. The effect of temperature and pH on the extent and rate of degradation of irinotecan was determined. The hydrolysis of irinotecan to its carboxylate form was reversible. The rate and extent of hydrolysis increased with increasing pH. The use of a weakly acidic vehicle, such as 5% dextrose injection, for reconstitution of irinotecan may maintain the drug's stability prior to administration.