Evaluation of Cholecystokinin (CCK-8) Peptide Thermal Stability for Use as Radiopharmaceutical by Means Isothermal and Nonisothermal Approaches

ABSTRACT

The purpose of this research was to study thethermal stability of cholecystokinin octapeptide (CCK-8) in aqueous solution at pH 12 and ionic strength 0.01M, which were kept as constants, by using isothermal and nonisothermal methods.

The isothermal decomposition of CCK-8 was investigated as a function of temperature (40°C to 70°C). Nonisothermal stability studies were performed using a linear increasing temperature program. Two different nonisothermal studies were carried out at 0.25°K and 0.5°K per hour, and the temperature interval varied from 40°C to 82°C.

The degradation of CCK-8 followed first-order kinetics, obeying the Arrhenius equation in the experimental temperature range. This indicated that the degradation mechanism of CCK-8 could be the equal within the temperature range studied. The nonisothermal approach resulted in activation energy (Ea) and shelf-life (t_90%) values that agree well with those obtained by the isothermal method. The level of uncertainty in the estimates of t_90% and Ea values is determined mainly by the extent of drug degradation and temperature change during the experiment. Therefore, nonisothermal experiments save time, labor and materials (i.e. the amount of drugs necessary to conduct the experiment) compared to the classic isothermal experiments, if they are performed using a suitable experimental design and a precise analytical method.     

Moist-heat sterilization and the chemical stability of heat-labile parenteral solutions

The impact of moist-heat sterilization (autoclaving) on the chemical stability of parenteral solutions was examined using two heat-labile products, clindamycin phosphate and succinylcholine chloride injections, as examples. A nonisothermal kinetic model was used to predict the extent of product degradation during autoclaving. The predicted results were found to be in close agreement with the experimental data. For the same peak temperature, a greater loss of product was shown by using a cycle with a higher F0. On the other hand, a higher peak-temperature cycle resulted in less product degradation for the same F0 value. The benefit of a high-temperature cycle was further illustrated by the fact that less chemical degradation for both products was produced by a 122 degrees C cycle with an F0 of 11 as compared to that which occurred during a 116.5 degrees C cycle with an F0 of 8. Although clindamycin phosphate was found to be highly unstable during a conventional autoclaving process, predicted data indicate that a UHT (Ultra-High Temperature) process may be used to sterilize this product with acceptable degradation.     

Theoretical analysis of the effect of the temperature fluctuation in an isothermal stability study

The effect of the temperature fluctuation in a nominal isothermal stability study is theoretically analyzed using hypothesized temperature-time functions. It is concluded that for symmetrical temperature-time profiles the extent of degradation in the real nonisothermal condition is less than that in the nominal isothermal condition. However, with the temperature fluctuaction obtainable with the current thermoregulated devices, the difference between the two is usually very small and can be neglected except for extremely fast reactions.     

Theoretical analysis of the effect of the temperature fluctuation in an isothermal stability study

Abstract

The effect of the temperature fluctuation in a nominal isothermal stability study is theoretically analyzed using hypothesized temperature-time functions. It is concluded that for symmetrical temperature-time profiles the extent of degradation in the real nonisothermal condition is less than that in the nominal isothermal condition. However, with the temperature fluctuaction obtainable with the current thermoregulated devices, the difference between the two is usually very small and can be neglected except for extremely fast reactions.     

Thermal stability and nonisothermal kinetics of Folnak® degradation process

Aim: The purpose of this article is to investigate the thermal stability and nonisothermal kinetics of Folnak® drug degradation process using different thermoanalytical techniques. Methods: The nonisothermal degradation of Folnak® powder samples was investigated by simultaneous thermogravimetry–differential thermal analysis, in the temperature range from ambient to 810°C. Results: It was found that the degradation proceeds through five reaction stages, which include the dehydration, the melting process of excipients, the decomposition of folic acid, corn starch, and saccharose. The presence of compounds such as excipients increases the thermal stability of the drug and some kind of solid–solid and/or solid–gas interaction occurs. Conclusion: It was concluded that the main degradation stage of Folnak® sample represents the decomposition of folic acid. It was established that the folic acid decomposition cannot be explained by simple reaction order model (n = 1) but with the complex reaction mechanism that includes higher reaction orders (n > 1). The isothermal predictions of the folic acid decomposition at four different temperatures (T_iso = 180°C, 200°C, 220°C, and 260°C) were established. It was concluded that the shapes of conversion curves at lower temperatures (180–200°C) were similar, whereas they became more complex with further temperature increase because of the complexity of the decomposition reaction.     

Thermal degradation behavior and kinetic analysis of poly(L-lactide) in nitrogen and air atmosphere

The non-isothermal and isothermal degradation behaviors and kinetics of poly(L-lactide) (PLLA) were studied by using thermogravimetry analysis (TGA) in nitrogen and air atmosphere, respectively. At lower heating rate ((5–10)°C/min), PLLA starts to decompose in air at lower temperature than those in nitrogen atmosphere; however, at higher heating rate ((20–40)°C/min), the starting decomposition temperature in air are similar to those in nitrogen atmosphere, not only showing that PLLA has better thermal stability in nitrogen than in air atmosphere, but also suggesting that the faster heating rate will decrease the decomposition of PLLA in thermal processing. Whether in air or in nitrogen atmosphere, the decomposition of PLLA has only one-stage degradation with a first-order decomposed reaction, suggesting that the molecular chains of PLLA have the similar decomposed kinetics. The average apparent activation energy of nonisothermal thermal degradation (Ē _non) calculated by Ozawa theory are 231.7 kJ·mol⁻¹ in air and 181.6 kJ·mol⁻¹ in nitrogen; while the average apparent activation energy of isothermal degradation (Ē _iso) calculated by Flynn method are 144.0 kJ·mol⁻¹ in air and 129.2 kJ·mol⁻¹ in nitrogen, also suggesting that PLLA is easier to decompose in air than in nitrogen. Moreover, the decomposed products of PLLA are also investigated by using thermogravimetry-differential scanning calorimetry-mass spectrometry (TGDSC-MS). In air atmosphere the volatilization products are more complex than those in nitrogen because the oxidation reaction occurring produces some oxides groups.     

Short- and long-term stability of resonant quartz temperature sensors

A new miniaturized design of the thermosensitive quartz resonator (TSQR) using an NLC cut (yxl/ -31 degrees 30') with a fundamental frequency of 29.3 MHz was created in the Acoustoelectronics Laboratory of ISSPBAS for use in a wide temperature range (4.2 K to 450 K) as highly sensitive quartz temperature sensors (QTS). This paper presents the results of the investigations of the short- and long-term frequency stability of QTS. The short-term frequency stability of QTS was measured for averaging times up to 150 s at three constant temperatures: liquid helium (4.2 K), liquid nitrogen (77 K), and melting ice (0 degrees C). The short-term frequency stability is 6.8 * 10(-9) at 0 degrees C for t = 15 s, which permits a temperature sensitivity of 2 * 10(-4) K. The long-term stability (aging) was investigated at room temperature and at 80 degrees C for 500 days. The aging characteristics at 25 degrees C and 80 degrees C are compared. It was observed that the frequency change does not exceed 5 * 10(-7) after the 25th day of accelerated aging at 80 degrees C. This guarantees a reliable operation of the sensor, without additional calibration, for several years.     

含硅氧烷的聚氨酯弹性体的热稳定性与热降解动力学

以末端基为羟基的聚二甲基硅氧烷(PDMS)与聚四甲基醚二醇(PTMG)为混合软段合成出一系列含硅氧烷的聚氨酯弹性体。用热重分析(TGA)与Ozawa-Flynn的方法研究了聚合物的热稳定性以及热降解动力学,结果表明,PDMS的引入改善了传统聚氨酯弹性体的热稳定性,合成所得聚合物均具有两个不同的热降解阶段,且随着PDMS含量的增加,聚合物的热稳定性逐渐降低。     

Evaluation of the Ignition Temperature in Thermal Explosion Synthesis of TiAl3 by Differential Scanning Calorimetry

Application of the Semenov theory of spontaneous ignition to evaluation of the critical temperature(Tˊc) in thermal explosion (TE) synthesis was conducted with the Ti-75at pct Al binary system using nonisothermal differential scanning calorimetry (DSC) at different heating rates.And the critical temperature for isothermal TEis predicted to be 728.9℃ by the multiple linear regression of T′c evaluated according to Semenov theory ,which is close to the range of 740-745℃ obtained from the isothermal DSC observation.This result proves that Semenov theory of spontaneous ignition is also feasible for TE synthesis in binary metallic systems like Ti-75 at.pct Al system.     

Temperature-programmed high-performance liquid chromatography coupled to isotope ratio mass spectrometry

The utility of liquid chromatography coupled to the isotope ratio mass spectrometry technique (LC-IRMS) has already been established through a variety of successful applications. However, the analytical constraint related to the use of aqueous mobile phases limits the LC separation mechanism. We report here a new strategy for high-precision (13)C isotopic analyses based on temperature-programmed LC-IRMS using aqueous mobile phases. Under these conditions, the isotopic precision and accuracy were studied. On one hand, experiments were carried out with phenolic acids using isothermal LC conditions at high temperature (170 degrees C); on the other hand, several experiments were performed by ramping the temperature, as conventionally used in a gas chromatography-based method with hydrosoluble fatty acids and pulses of CO 2 reference gas. In isothermal conditions at 170 degrees C, despite the increase of the CO 2 background, p-coumaric acid and its glucuronide conjugate gave reliable isotopic ratios compared to flow injection analysis-isotopic ratio mass spectrometry (FIA-IRMS) analyses (isotopic precision and accuracy are lower than 0.3 per thousand). On the opposite, for its sulfate conjugate, the isotopic accuracy is affected by its coelution with p-coumaric acid. Not surprisingly, this study also demonstrates that at high temperature (170 degrees C), a compound eluting with long residence time (i.e., ferulic acid) is degraded, affecting thus the delta (13)C (drift of 3 per thousand) and the peak area (compared to FIA-IRMS analysis at room temperature). Quantitation is also reported in isothermal conditions for p-coumaric acid in the range of 10-400 ng/mL and with benzoic acid as an internal standard. For temperature gradient LC-IRMS, in the area of the LC gradient (set up at 20 degrees C/min), the drift of the background observed produces a nonlinearity of SD (delta (13)C) approximately 0.01 per thousand/mV. To circumvent this drift, which impacts severely the precision and accuracy, an alternative approach, i.e., eluting the compound on the plateau of temperature studied was reported here. Other experiments with temperature-programmed LC-IRMS experiments are also reported with the presence of methanol in the injected solution to mimic residual solvent originating from the sample preparation or to slightly increase the solubility of the targeted compound for high-precision measurement.     

Factors affecting stability of z-ligustilide in the volatile oil of radix angelicae sinensis and ligusticum chuanxiong and its stability prediction

The purpose of this investigation is to obtain a suitable vehicle for Z-ligustilide in the volatile oil of Radix Angelicae Sinensis and Ligusticum Chuanxiong in which it is stable enough for the application in pharmaceutics, to investigate its degradation laws, and to predict its shelf-life at 25 degrees C. Factors including temperature, light, pH value, co-solvents and antioxidants can all influence the stability of Z-ligustilide, thereinto antioxidants could markedly improve its stability in aqueous solution by almost 35%. The suitable vehicle for Z-ligustilide contains 1.5% tween-80, 0.3% Vitamin C, and 20% propylene glycol (PG). Furthermore, the degradation rates of Z-ligustilide were found to conform to a rate equation following Weibull probability distribution within a range of degradation ratio, and the equation could be expressed as follow: ln ln (1/1-alpha) = ln k + m ln t. Where alpha is degradation ratio; t is time; m and k are constants relating to the degradation rate. The degradation rate will get greater as the increasing of parameter k. According to the degradation law obtained from the equation, the drug shelf-life (10% of active ingredient degraded, T90) in this vehicle was predicted to be more than 1.77 years at 25 degrees C through Arrehenius equation and accelerating experiments.The present investigation was undertaken to propose a kinetic treatment that may be applicable to any type of degradation of the active ingredient of pharmaceutical formulation, and also could provide a good foundation for the new drug development of Z-ligustilide, especially for injection formulation.     

Urokinase: Stability Studies in Solution and Lyophilized Formulations

Abstract

Urokinase - a serine protease - is used clinically as a thrombolytic agent to dissolve blood clots. Low molecular weight Urokinase (33,000 dalton) isolated from human kidney cells using tissue culture techniques was used in the stability studies. Quantitative determination of Urokinase was accomplished by either amidolytic or fibrinolytic activity assay methods. The degradation of Urokinase in solution at 55 °C follows pseudo-first order kinetics at several pH values. The pH range for maximum stability has been determined to be about 6 to 7.

The stability of Urokinase is very sensitive to the quantity of residual moisture in the lyophilized formulation. Rubber stoppers used as closures for the glass vials were identified as a major source of moisture. The loss of activity from freeze dried formulations was inversely related to the specific activity of tissue culture derived Urokinase. Similar relationship was also observed for the adsorption of Urokinase from 5% dextrose diluent to the surface of polyvinyl chloride large volume parenteral diluent bags. Initial degradation rates (zero order) for freeze dried urokinase formulations with and without the addition of human serum albumin (HSA) as a stabilizer determined at 50, 40 and 30 °C demonstrated that loss of urokinase followed the Arrhenius relationship with an apparent energy of activation (Ea) of 15 kcal per mol. The addition of HSA resulted in an increase in stability by about a factor of four. However, the apparent Ea for the formulations with and without HSA was not significantly different as evident from parallel slopes in the Arrhenius plots.     

Urokinase: Stability Studies in Solution and Lyophilized Formulations

Urokinase - a serine protease - is used clinically as a thrombolytic agent to dissolve blood clots. Low molecular weight Urokinase (33,000 dalton) isolated from human kidney cells using tissue culture techniques was used in the stability studies. Quantitative determination of Urokinase was accomplished by either amidolytic or fibrinolytic activity assay methods. The degradation of Urokinase in solution at 55 °C follows pseudo-first order kinetics at several pH values. The pH range for maximum stability has been determined to be about 6 to 7.

The stability of Urokinase is very sensitive to the quantity of residual moisture in the lyophilized formulation. Rubber stoppers used as closures for the glass vials were identified as a major source of moisture. The loss of activity from freeze dried formulations was inversely related to the specific activity of tissue culture derived Urokinase. Similar relationship was also observed for the adsorption of Urokinase from 5% dextrose diluent to the surface of polyvinyl chloride large volume parenteral diluent bags. Initial degradation rates (zero order) for freeze dried urokinase formulations with and without the addition of human serum albumin (HSA) as a stabilizer determined at 50, 40 and 30 °C demonstrated that loss of urokinase followed the Arrhenius relationship with an apparent energy of activation (Ea) of 15 kcal per mol. The addition of HSA resulted in an increase in stability by about a factor of four. However, the apparent Ea for the formulations with and without HSA was not significantly different as evident from parallel slopes in the Arrhenius plots.     

Elevated temperature stability of carbon-fibre,nickel-matrix composites: morphological and mechanical property degradation

Carbon-fibre, nickel-matrix composites exhibit excellent microstructural stability when the composites are isothermally annealed at temperatures to 1200° C for several hundred hours; morphological degradation of the reinforcing phase takes place at temperatures in excess of 1250° C. The degradation temperature is less than 1200° C when the composites are subjected to thermal cycling or temperature gradients.The mechanical properties of fibres extracted from annealed composites are approximately 40 to 50% less than the corresponding properties of unprocessed stressgraphitized fibres. Substantial mechanical property degradation occurs during the hotforming of nickel-coated fibres into dense shapes. Subsequent re-annealing of the dense composite results in additional fibre damage. Most of this additional degradation occurs within the first few minutes from the start of the anneal; prolonged isothermal annealing does not result in further property degeneration.     

Development of a lyophilized formulation for (R,R)-formoterol (L)-tartrate

(R,R)-formoterol is a beta-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50 degrees C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moisture were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moisture in mannitol formulations were typically below 1%, the degradation rate (50 degrees C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p < 0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50 degrees C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.     

Preparation and properties evaluation of zirconia-based/Al2O3 composites electrolytes for solid oxide fuel cell systems

The compaction behaviour of ultrafine yttria-doped zirconia powders (6–8 nm) without and with alumina additions (0 to 20 wt%) has been studied. From the pore size distribution and using isothermal and nonisothermal techniques, the sintering behaviour of zirconia compacts in the temperature range 800–1500 °C was studied. It was found that alumina additions (up to 10 wt%) enhanced the zirconia compacts' densification process and, above that alumina content, that process was retarded. Alumina additions did not affect the grain grown process in tetragonal zirconia samples. However, this was strongly hindered in the fully stabilized zirconia ones. The results were compared with those obtained in the same experimental conditions on a commercial zirconia powder.     

Characterization of low-k dielectric SiCOH films deposited with decamethylcyclopentasiloxane and cyclohexane

Ultra low-k dielectric SiCOH films were deposited with decamethylcyclopentasiloxane (DMCPSO, C10H30O5Si5) and cyclohexane (C6H12) precursors by plasma-enhanced chemical vapor deposition at the deposition temperature between 25 and 200 degrees C and their chemical composition and deposition kinetics were investigated in this work. Low dielectric constants of 1.9-2.4 were obtained due to intrinsic nanoscale pores originating from the relatively large ring structure of DMCPSO and to the relatively large fraction of carbon contents in cyclohexane. Three different deposition regions were identified in the temperature range. Deposition rates increased with temperature below 40 degrees C and decreased as temperature increased to 75 degrees C with apparent activation energies of 56 kJ/mol x K at < 40 degrees C, -26 kJ/mol x K at 40-100 degrees C, respectively. In the temperature region of 40-100 degrees C hydrocarbon deposition and decomposition process compete each other and decomposition becomes dominant, which results in apparent negative activation energy. Deposition rates remain relatively unaffected with further increases of temperature above 100 degrees C. FTIR analysis and deposition kinetic analysis showed that hydrocarbon deposition is the major factor determining chemical composition and deposition rate. The hydrocarbon deposition dominates especially at lower temperatures below 40 degrees C and Si-O fraction increases above 40 degrees C. We believe that dielectric constants of low-k films can be controlled by manipulating the fraction of deposited hydrocarbon through temperature control.     

In vitro degradation of poly-<Emphasis Type="SmallCaps">l</Emphasis>-<Emphasis Type="SmallCaps">d</Emphasis>-lactic acid (PLDLA) pellets and powder used as synthetic alloplasts for bone grafting

The objective of this study was to evaluate the in vitro degradation of pellet and powder forms of a poly-L: -D: -lactic acid material used to produce plates and screws for orthopedic, oral, and maxillofacial applications. Materials and methods In order to produce the powder form the as-received pellets were milled in a cryogenic chamber. Particles size distribution (PSD) histograms were developed for both forms. The materials were then characterized by Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA) before and after immersion in simulated body fluid for 30, 60, and 90 days. Results SEM showed that for both forms material degradation started after 30 days of immersion in SBF and evolved until 90 days. Degradation started at the amorphous zones of the polymer and exposed of deeper crystalline layers. The pellet and powder samples PSD showed polydispersed patterns with mean diameters of 673.98 mum and 259.55 mum. Thermal onset degradation temperatures were 365.64 degrees C and 360.30 degrees C, and of 363.49 degrees C and 359.83 degrees C before immersion and after 90 days in SBF for the pellet and powder forms, respectively. The Tg's of the pellets and the powder were approximately 61.5 degrees C and 66 degrees C, and their respective endothermic peaks were observed at approximately 125 degrees C and 120 degrees C. The specific heat (c) was approximately 8.5 J/g and 6.2 J/g for the pellet and powder material, respectively. Conclusion According to the results obtained, cryogenic milling resulted in particle plastic deformation, and alterations in glass transition temperature, melting temperature, and specific heat of the material.     

Investigation kinetics mechanisms of adsorption malachite green onto activated carbon

Lignite was used to prepare activated carbon (T3K618) by chemical activation with KOH. Pore properties of the activated carbon such as BET surface area, pore volume, pore size distribution, and pore diameter were characterized by t-plot based on N2 adsorption isotherm. BET surface area of activated carbon is determined as 1000 m2/g. Adsorption capacity of malachite green (MG) onto T3K618 activated carbon was investigated in a batch system by considering the effects of various parameters like initial concentration (100, 150 and 200 mg/L) and temperature (25, 40 and 50 degrees C). The adsorption process was relatively fast and equilibrium was reached after about 20 min for 100, 150 mg/L at all adsorption temperature. Equilibrium time for 200 mg/L was determined as 20 min and 40 min at 298, 313 and 323 K, respectively. Simple mass and kinetic models were applied to the experimental data to examine the mechanisms of adsorption and potential rate controlling steps such as external mass transfer, intraparticle diffusion. Pseudo second-order model was found to explain the kinetics of MG adsorption most effectively. It was found that both mass transfer and pore diffusion are important in determining the adsorption rates. The intraparticle diffusion rate constant, external mass transfer coefficient, film and pore diffusion coefficient at various temperatures were evaluated. The activation energy (Ea) was determined as 48.56, 63.16, 67.93 kJ/mol for 100, 150, 200 mg/L, respectively. The Langmiur and Freundlich isotherm were used to describe the adsorption equilibrium studies at different temperatures. Langmiur isotherm shows better fit than Freundlich isotherm in the temperature range studied. The thermodynamic parameters, such as DeltaG degrees, DeltaS and DeltaH degrees were calculated. The thermodynamics of dyes-T3K618 system indicates endothermic process.