TGA测定克拉霉素热分解动力学参数

采用热重分析(TGA)测定克拉霉素的热解曲线,用Ozawa法分析热分解过程,用多元线性回归法确定热分解机制函数,建立热降解动力学方程并用等温试验进行了验证.结果 表明,克拉霉素的热分解活化能较高,较为稳定,其热分解机制与自催化简单反应(Cn型)接近,回归系数0.9998597.其热解动力学参数活化能E、反应级数n和指前因子A对数分别为148.1111、1.3750和10.5158,催化常数k对数值为1.4306.所得动力学参数对该药物的稳定性评价及生产中的质量监控提供了理论依据.     

喹诺酮类药物的热稳定性及其热分解非等温动力学研究

目的　研究喹诺酮类药物的热稳定性及热降解,建立动力学方程。方法　用TG-DTG热重仪测定药物的热解曲线，用Achar微分法和Coats-Redfern积分法确定热分解函数。结果　根据TG-DTG热解曲线和红外图谱推断出依诺沙星、诺氟沙星、盐酸芦氟沙星和氧氟沙星等4种喹诺酮类药物的热分解过程并求出其热解动力学参数活化能E、反应级数n和指前因子A及动力学补偿参数。结论　热稳定性为盐酸芦氟沙星>依诺沙星>氧氟沙星>诺氟沙星,它们的热分解过程相同;4种药物胶囊的稳定性均大于各自原药;诺氟沙星、依诺沙星、氧氟沙星的热解机理函数相同，动力学方程为dα/dt=Ae^-E/RT(1-α)²，盐酸芦氟沙星为dα/dt=Ae^-E/RT(1-α)³。     

Structure identification and analysis of the suspected chemical precursor of 2-fluorodeschloroketamine and its decomposition products

In this work, 1-[(2″-fluorophenyl)(methylimino)methyl]cyclopentan-1-ol (2-fluorodeschlorohydroxylimine) was identified as a suspected chemical precursor of 2-fluorodeschloroketamine (2-FDCK) using gas chromatography–mass spectrometry (GC–MS) and gas chromatography-quadrupole/time-of-flight mass spectrometry (GC-Q/TOF-MS) and comparing the data with those of ketamine and its chemical precursor, hydroxylimine. Furthermore, the entire fragmentation pathway of 2-fluorodeschlorohydroxylimine was theorized from the GC–MS spectrum recorded using an electron ionization (EI) source, and the mechanisms and decomposition pathways of 2-fluorodeschlorohydroxylimine were elucidated. In protic solvents, the nitrogen atom in the C═N group of 2-fluorodeschlorohydroxylimine underwent a protonation reaction. Thereafter, the traces of water present in protic solvents promoted the hydrolysis of the protonated imine, and a carbon cation was obtained following the loss of methylamine. The carbon cation could follow the classical decomposition mechanism of imines and yield an α-hydroxyl ketone, which was the major decomposition product, (2′-fluorophenyl)(1″-hydroxycyclopentyl)methanone. The cation could also undergo a loop expansion rearrangement and yield another α-hydroxyl ketone, 2-(2′-fluorophenyl)-2-hydroxycyclohexan-1-one. The structures of the two aforementioned decomposition products were elucidated using several techniques including theoretical calculation, GC–MS, nuclear magnetic resonance (NMR), the prediction and assistance elucidation functions of ACDLabs-Structure Elucidator Suite, and the virtual separation technology of diffusion-ordered spectroscopy. The aforementioned study revealed important information about the chemical precursor of 2-FDCK and its decomposition. Furthermore, a set of methods for the qualitative analysis of 2-fluorodeschlorohydroxylimine were established, which facilitated accurate analysis of 2-fluorodeschlorohydroxylimine samples following decomposition or destruction.     

嘌呤药物的热解过程及其热分解动力学

目的研究嘌呤类药物的热解过程及非等温动力学。方法用红外光谱技术、加速稳定性试验方法和热重仪分析方法测定分解过程,用Ozawa法以及Coast-Redfern法和MKN法处理数据确定热分解函数。结果确定了阿昔洛韦(aciclovir,Acv)、喷昔洛韦(penciclovir,Pcv)热解过程和中间产物,得到热解动力学参数活化能Ea、指前因子A。结论加速稳定性试验与热重法的计算结果一致,喷昔洛韦的热稳定性大于阿昔洛韦;两者热解第一步具有相同的中间产物鸟嘌呤,且动力学方程相同:dα/dt=Ae^-Ea/RT2(1-α)^3/2,均为1.5级反应过程。     

Simultaneous determination of zidovudine and lamivudine in human serum using HPLC with tandem mass spectrometry

A method employing high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS) has been developed and validated for the simultaneous determination of clinically relevant levels of zidovudine (AZT) and lamivudine (3TC) in human serum. The method incorporates a fully automated ultrafiltration sample preparation step that replaces the solid-phase extraction step typically used for HPLC with UV detection. The calibration range of the dual-analyte LC-MS/MS method is 2.5–2500 and 2.5–5000 ng ml⁻¹ for AZT and 3TC, respectively, using 0.25 ml of human serum. The lower limit of quantification was 2.5 ng ml⁻¹ for each analyte, with a chromatographic run time of approximately 6 min. Overall accuracy, expressed as bias, and inter- and intra-assay precision are <±7 and <10% for AZT, and <±5 and <12.1% for 3TC over the full concentration ranges. A cross-validation study demonstrated that the LC-MS/MS method afforded equivalent results to established methods consisting of a radioimmuno-assay for AZT and an HPLC-UV method for 3TC. Moreover, the LC-MS/MS was more sensitive, allowed markedly higher-throughput, and required smaller sample volumes (for 3TC only). The validated method has been used to support post-marketing clinical studies for Combivir™ — a combination tablet containing AZT and 3TC.     

盐酸环丙沙星的热稳定性和热分解反应动力学研究

目的:用热分析法分析盐酸环丙沙星的热分解过程及机制。方法:以Al2O3为参比物,在氮气条件下采用差示扫描量热法、热重法和微分热重法分析样品,根据热重曲线数据计算出其特征热分解反应表观活化能(E)、指前因子(A)、反应级数n和pk值。结果:E=101.18kJ.mol-1、lnA=26.96s-、n=1、pk=7.01,常温下药品贮存期为2年。结论:用热分析法研究盐酸环丙沙星等固体药物的热分解过程方法简便,结果可靠。     

拉米夫定的热分解机理及其动力学

目的测定拉米夫定(lamivudine,LMVD)的热性质,研究LMVD的热分解机理、热分解动力学和LMVD的热稳定性。方法采用热重法(thermogravimetry,TG)和差示扫描量热法(differentialscanning calorimetry,DSC)测定LMVD在氮气氛和空气氛中的热分解过程,测定LMVD及其在热分解过程中不同阶段残留物的红外光谱,运用量子化学GAMESS软件计算LMVD分子的键级,根据不同升温速率下的热重曲线计算得到LMVD第一阶段热分解反应动力学参数,应用Dakin方程推算LMVD在不同使用温度下的预期寿命。结果 LMVD的热分解过程是一个二阶段过程,起始步骤是胞核嘧啶环中的C-N键断裂。在氮气氛中,表观活化能Ea=126.5 kJ.mol-1,指前因子A=2.88×1011min-1,在空气氛中,Ea=133.0 kJ.mol-1,A=1.15×1012min-1。结论 LMVD在常温下具有很好的热稳定性。     

Conversion of coal fly ash into nanozeolite Na-X by applying ultrasound assisted hydrothermal and fusion-hydrothermal alkaline activation

This research is emphasized on the synthesis of micro-mesoporous nanozeolite Na-X from coal fly ash wastes (CFA) by ultrasound assisted hydrothermal and double stage fusion-hydrothermal alkaline activation. The products from CFA zeolitization were studied with respect to their morphology by scanning electron microscopy (SEM), chemical and phase composition by energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD), respectively. Their thermal properties were investigated by thermogravimetry (TG), derivative thermogravimetry (DTG) and differential scanning calorimetry (DSC) and surface characteristics by nitrogen adsorption. The effects of the ultrasound agitation and additives on the zeolitization process were studied. Sonicated CFA Na-X zeolites possess nanocrystalline morphology and mixed micro-mesoporous structures with higher external specific surface area as compared to microcrystalline zeolite Na-X prepared by magnetic stirring. CFA nanozeolites of Na-X type are expected to behave excellent adsorption potential and catalytic activity due to the enlarged surface and fine morphology with uniformly distributed particles of iron oxides transferred from the raw material.     

LC–MS/MS studies of ritonavir and its forced degradation products

Forced degradation of ritonavir (RTV), under the conditions of hydrolysis (acidic, basic and neutral), oxidation, photolysis and thermal stress as prescribed by ICH was studied using LC–MS/MS. Eight degradation products were formed and their separation was accomplished on Waters XTerra^® C₁₈ column (250 mm × 4.6 mm i.d., 5 μm) using water:methanol:acetonitrile as (40:20:40, v/v/v) mobile phase in an isocratic elution mode by LC. The method was extended to LC–MS/MS for characterization of the degradation products and the pathways of decomposition were proposed. No previous reports were found in the literature regarding the characterization of degradation products of ritonavir.     

Comparative pharmacokinetic and relative bioavailability study of coated and uncoated azithromycin powder for suspension in healthy Bangladeshi male volunteers

Azithromycin (AZT; CAS 83905-01-5) is an efficient antibiotic and is widely prescribed in Bangladesh. The taste of uncoated AZT suspension is bitter. Although several taste masked oral suspensions of AZT are available in Bangladesh, information regarding the bioavailability of these formulations in Bangladeshi population is unavailable. The purpose of this study was to compare the relative bioavailability and other pharmacokinetic properties of two oral formulation of AZT (200 mg/5 ml) suspensions, the uncoated reference product and coated test product (Tridosil 200 mg/5 ml) and to evaluate whether these formulations meet the FDA criteria to assume bioequivalence in Bangladeshi male volunteers. A randomized, single-dose, two-way cross-over, open-label pharmacokinetic study was conducted in 24 healthy male volunteers after administration of a single dose of 500 mg AZT suspension under fasting condition following a washout period of three weeks. Blood samples were collected in different time intervals and analyzed for serum AZT concentration using a validated LC/MS/MS method. The pharmacokinetic parameters were determined by the non-compartmental method. From serum data, the obtained values for test and reference products were 383.21 +/- 11.59 and 432.28 +/- 7.22 ng/ ml for Cmax; 5677.47 +/- 1229.53 and 6144.56 +/- 1098.70 h x ng/ml for AUC(0-120); and 6085.29 +/- 1267.53 and 6694.15 +/- 1222.50 h x ng/ml for AUC(0-infinity), respectively. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for Cmax and AUMC(0-infinity). The 90% confidence intervals of the test formulation/reference mean ratios of the Intransformed Cmax, AUC(0-120) and AUC(0-infinity) mean values were found to be 87.89% to 89.36%, 87.96% to 95.71% and 86.77% to 94.29% respectively. In this single-dose study of AZT, it was found that the test formulation met the regulatory criteria for bioequivalence to the reference suspension formulation.     

头孢地嗪钠的热分解机理及动力学

目的测定头孢地嗪钠（CDZ）的热性质,研究CDZ的热分解机理、热分解动力学和CDZ的热稳定性。方法采用热重法（TG）和差示扫描量热法（DSC）测定CDZ在氮气氛和空气氛中的热分解过程,测定CDZ及其在热分解过程中不同阶段残存物的红外光谱,运用量子化学GAMESS软件计算CDZ分子的键级,根据不同升温速率下的热重曲线计算CDZ热分解反应的动力学参数,采用Dakin方程计算CDZ在各种温度下的预期寿命。结果CDZ的热分解过程是多阶段过程。在氮气氛中热分解表观活化能Ea=173．9kJ·mol^-1,指前因子A=1．175×10^17min^-1;在空气氛中热分解表观活化能Ea=172.3kJ·mol^-1,指前因子A=2．692×10^17min^-1。结论CDZ在常温下有很好的热稳定性。     

Thermal behavior and stability of biodegradable spray-dried microparticles containing triamcinolone

Thermal analysis has been widely used for obtaining information about drug-polymer interactions and for pre-formulation studies of pharmaceutical dosage forms. In this work, biodegradable microparticles of poly (d,L-lactide-co-glycolide) (PLGA) containing triamcinolone (TR) in various drug:polymer ratios were produced by spray drying. The main purpose of this study was to study the effect of the spray-drying process not only on the drug-polymer interactions but also on the stability of microparticles using differential scanning calorimetry (DSC), thermogravimetry (TG) and derivative thermogravimetry (DTG), X-ray analysis (XRD), and infrared spectroscopy (IR). The evaluation of drug-polymer interactions and the pre-formulation studies were assessed using the DSC, TG and DTG, and IR. The quantitative analysis of drugs entrapped in PLGA microparticles was performed by the HPLC method. The results showed high levels of drug-loading efficiency for all used drug:polymer ratio, and the polymorph used for preparing the microparticles was the form B. The DSC and TG/DTG profiles for drug-loaded microparticles were very similar to those for the physical mixtures of the components. Therefore, a correlation between drug content and the structural and thermal properties of drug-loaded PLGA microparticles was established. These data indicate that the spray-drying technique does not affect the physico-chemical stability of the microparticle components. These results are in agreement with the IR analysis demonstrating that no significant chemical interaction occurs between TR and PLGA in both physical mixtures and microparticles. The results of the X-ray analysis are in agreement with the thermal analysis data showing that the amorphous form of TR prevails over a small fraction of crystalline phase of the drug also present in the TR-loaded microparticles. From the pre-formulation studies, we have found that the spray-drying methodology is an efficient process for obtaining TR-loaded PLGA microparticles.     

Degradation of camptothecin-20(S)-glycinate ester prodrug under physiological conditions

We have compared the strikingly different decomposition pathways for camptothecin-20(S)-acetate -acetate and camptothecin-20(S)-glycinate in phosphate buffered saline, human plasma and blood. The aliphatic ester analog camptothecin-20(S)-acetate demonstrated excellent stability in the above fluids for many hours with minimal hydrolysis, while the camptothecin-20(S)-glycinate analog (differing solely by the presence of an amino group) underwent rapid and essentially complete decomposition. Reversed-phase high performance liquid chromatography (RP-HPLC) with electrospray ionization–mass spectral (ESI–MS) detection was then used to correlate structural information for camptothecin-20(S)-glycinate decomposition products. ESI–MS detection indicated the ring-opened carboxylate form of camptothecin and the ring-opened degradation product co-elute near the solvent front, while the latest eluting decomposition product was the closed-ring lactone form of camptothecin. A novel decomposition product with intermediate retention time displayed an identical mass-to-charge ratio as camptothecin-20(S)-glycinate ester but a strikingly different fragmentation pattern. The LC–ESI–MS evidence of a novel camptothecin prodrug degradation pathway is provided in this report.     

A method for quantitating the intracellular metabolism of AZT amino acid phosphoramidate pronucleotides by capillary high-performance liquid chromatography-electrospray ionization mass spectrometry

A methodology has been developed for the analysis of the intracellular metabolism of 3'-azido-3'-deoxythymidine (AZT) amino acid phosphoramidates utilizing reverse-phase high-performance liquid chromatography interfaced with negative ion electrospray ionization mass spectrometry (LC/ESI(-) -MS). The presented work demonstrates the potential of capillary LC/MS and LC/MS/MS to identify and quantitate the cellular uptake and metabolism of nucleoside phosphoramidate. Significant intracellular amounts of D- and L-phenylalanine methyl ester or D- and L-tryptophan methyl ester AZT phosphoramidates were observed for human T-lymphoblastoid leukemia (CEM) cells incubated for 2 and 4 h with the prodrugs. AZT-MP was the primary metabolite observed for human T-lymphoblastoid leukemia (CEM) cells. In this paper, the details of using LC/MS to analyze AZT amino acid phosphoramidates in biological samples are discussed. LC/MS is an efficient method for analyzing multiple samples containing several analytes in a short period of time. The method also provides high selectivity and sensitivity, and requires minimal sample preparation. This approach should be broadly applicable for the analysis of the intracellular metabolism of nucleoside prodrugs and pronucleotides.     

Compatibility study between ketoprofen and pharmaceutical excipients used in solid dosage forms

Thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC) techniques were used for assessing the compatibility between ketoprofen (KT) and several excipients as: corn starch, microcrystalline cellulose (PH 101 and PH 102), colloidal silicon dioxide, lactose (monohydrate and anhydre), polyvinylpyrrolidone K30, magnesium stearate and talc, commonly used in the pharmaceutical form.In order to investigate the possible interactions between the components, the thermal curves of KT and each selected excipients were compared with those of their 1:1 (w/w) physical mixtures.For KT, the DSC curves have shown a sharp endothermic peak at 96.8 °C which corresponds to the melting process (literature value: 94-97 °C), respectively the TG curves demonstrated a simple stage of mass loss in the temperature range of 235-400 °C.FT-IR spectroscopy and X-ray powder diffraction (XRPD) were used as complementary techniques to adequately implement and assist in interpretation of the DSC results.On the basis of thermal results, a possible interaction was found between the KT with polyvinylpyrrolidone K30 and magnesium stearate, which could influence the stability of the KT in the binary mixtures. These possible incompatibilities were confirmed by FT-IR and X-ray analysis.     

Validated specific HPLC method for determination of zidovudine during stability studies

The objective of the current study was to develop a validated stability-indicating assay method (SIAM) for zidovudine (3′-azido-3′-deoxythymidine) after subjecting it to forced decomposition under hydrolysis, oxidation, photolysis and thermal stress conditions. The drug decomposed under hydrolytic stress upon refluxing, and also on exposure to light. It was stable to oxidation and thermal stress. The same major decomposition product could be seen in all the decomposed solutions, which was identified as thymine through comparison with the standard. Separation of drug from major and minor degradation products was successfully achieved on a C-18 column utilising water–methanol in the ratio of 77:23. The detection wavelength was 265 nm. The method was validated and response was found to be linear in the drug concentration range of 25–500 μg ml⁻¹. The mean values (±R.S.D.) of slope and correlation coefficient were 21,859 (±0.213) and 0.9995 (±0.00578), respectively. The R.S.D. values for intra- and inter-day precision were <0.9 and <1.6%, respectively. The method was established to have sufficient intermediate precision as similar separation was achieved on another instrument handled by a different operator. The recovery of the drug from a mixture of degraded samples ranged between 100.6 and 100.9%. PDA peak purity test confirmed the specificity of the method. The method was also successful in analysis of drug in marketed tablets subjected to stability testing under accelerated conditions of temperature, humidity, and to thermal and photolytic stress.     

Thermoanalytical studies of sodium salt of carboxymethylcellulose (CMC-Na) and pectin

The influence of physical and chemical properties of electrolytes on thermal degradation of CMC-Na and pectiny salt were studied. A differential thermal analysis showed that thermal decomposition of CMC-Na and pectin salt proceeds in three stages. The heat of conversion of the studied systems was shown to increase according to the concentration of the applied electrolytes. Significant changes in the structure of CMC-Na at pH = 3.0 were shown by IR analysis. Confirmation of transition of the above system to the acidic form were obtained by DTA and TG curves.     

Quantitative determination of zidovudine diaryl phosphate triester pro-drugs in rat plasma by high-performance liquid chromatography–electrospray ionization tandem mass spectrometry

A rapid, simple, and sensitive high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI–MS/MS) method was developed and validated for quantitative analysis of 3′-azido-3′-deoxythymidine (zidovudine, AZT) diaryl phosphate triester pro-drugs, in rat plasma using 2′,3′-dideoxy-2′3′-didehydrothymidine (d4T) as internal standard (IS). The analytes were extracted from rat plasma with methanol after protein precipitation. The compounds were separated by HPLC with gradient elution (on a Shim-pack VP-ODS C₁₈ analytical column using a mobile phase of methanol/10 mM ammonium acetate). All the analytes were detected in positive ion mode using multiple reaction monitoring (MRM). The method was validated and the specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries and stability were determined. LLOQs were 10 ng mL⁻¹ for M1, M2, M3, M4, and M5, respectively. Correlation coefficient (r) values for the linear range of 10–10,000 ng mL⁻¹ were greater than 0.999 for all the analytes. The intra-day and inter-day precision and accuracy were higher than 7.13%. The relative and absolute recovery was above 72% and no matrix effects were observed for all the analytes. This validated method provides a modern, rapid, and robust procedure for the pharmacokinetic studies of the pro-drugs after intravenous administration to rats. Some important results of AZT diaryl phosphate triester pro-drugs concerning chemical effect on pharmacokinetic performance are also studied.     

头孢呋辛钠的热稳定性及其热分解动力学研究

目的:研究头孢呋辛钠的热稳定性。方法:采用热重分析法和差式扫描量热法测定头孢呋辛钠在氮气和空气中的热分解曲线,借助经典的非等温速率方程Kissinger和Ozawa-Flynn-Wall方法计算该药物的热分解动力学参数。结果:2种方法计算头孢呋辛钠在空气中的热分解动力学参数分别为:表观活化能139.2、139.3kJ.mol-1,指前因子(ln值)18.64、18.66s-1;在氮气中上述参数分别为106.8、108.5kJ.mol-1,14.64、14.85s-1。2种计算方法结果无显著性差异。结论:头孢呋辛钠具有很高的活化能,热稳定性好,在氮气中更稳定。     

Physico-chemical solid-state characterization of omeprazole sodium: Thermal,spectroscopic and crystallinity studies

The physical characterization of active pharmaceutical substances is crucial to the successful development of the final drug product. The different solid forms and variations in the degree of crystallinity can lead to significantly different physical and chemical properties, including color, morphology, stability, dissolution and bioavailability. In the case of omeprazole sodium (OMS), its chemical structures contain a specific number of water molecules (hydrate). The behavior of pharmaceutical hydrates has become the object of increasing attention over the past decade, primarily due to the potential impact of hydrates on the development process and dosage form performance. The present study was designed to characterize and evaluate the crystallinity of omeprazole sodium, dehydrated omeprazole sodium (DOMS) and omeprazole free base (OM) using a variety of techniques including thermal analysis (thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC)), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD). Furthermore, an NMR spectroscopy study was also carried out to clarify the conformation and crystal structure.