Effects of Temperature Excursions on Mean Kinetic Temperature and Shelf Life

The international acceptance of the definition of controlled room temperature (CRT) has given additional impetus to the use of mean kinetic temperature (MKT) as a method of quantifying temperatures during transport and storage and consequent possible effects on drug product stability. The present paper explores some of the implications of the MKT concept and considers the effect of temperature excursions on MKT values and hence on stability of drug products.     

Storage Conditions for Stability Testing of Pharmaceuticals in Hot and Humid Regions

ABSTRACT

A review of the methodology for determination of the storage conditions for stability testing according to Schumacher/Grimm is presented in this paper. The purpose is to provide scientific information useful for the definition of storage conditions for stability testing of pharmaceuticals suitable to the region where the product will be dispensed. Special attention is given to stability testing in the new markets located in developing countries with very hot and humid climates. Finally, storage conditions for stability testing in the Brazilian regions were derived and examined comparatively with the guidelines of the world health organization (WHO) and regulatory bodies. The storage conditions were derived from the calculated values of the mean kinetic temperature and the relative humidity (RH). These parameters were estimated from daily values of dry and dew point temperatures of all Brazilian capitals from 1998 to 2002; collected in the morning (9 a.m.), in the afternoon (3 p.m.), and at night (9 p.m.). The Brazilian Center of Weather Forecast and Climatic Studies of the National Institute of Spatial Research (CPTEC/INPE) kindly furnished these data. Significant differences of the mean kinetic temperature (MKT) and relative humidity (RH) for Brazilian regions were observed. These results indicate the existence of a high climatic diversity between the Brazilian regions, making challenging the definition of a single storage condition for the stability testing. Some regions present RH values higher than 80%, giving support to the concerns of the WHO, indicating the necessity of revision of existing guidelines for stability testing mainly for very hot and humid regions.     

Storage conditions for stability testing of pharmaceuticals in hot and humid regions

A review of the methodology for determination of the storage conditions for stability testing according to Schumacher/Grimm is presented in this paper. The purpose is to provide scientific information useful for the definition of storage conditions for stability testing of pharmaceuticals suitable to the region where the product will be dispensed. Special attention is given to stability testing in the new markets located in developing countries with very hot and humid climates. Finally, storage conditions for stability testing in the Brazilian regions were derived and examined comparatively with the guidelines of the world health organization (WHO) and regulatory bodies. The storage conditions were derived from the calculated values of the mean kinetic temperature and the relative humidity (RH). These parameters were estimated from daily values of dry and dew point temperatures of all Brazilian capitals from 1998 to 2002; collected in the morning (9 a.m.), in the afternoon (3 p.m.), and at night (9 p.m.). The Brazilian Center of Weather Forecast and Climatic Studies of the National Institute of Spatial Research (CPTEC/INPE) kindly furnished these data. Significant differences of the mean kinetic temperature (MKT) and relative humidity (RH) for Brazilian regions were observed. These results indicate the existence of a high climatic diversity between the Brazilian regions, making challenging the definition of a single storage condition for the stability testing. Some regions present RH values higher than 80%, giving support to the concerns of the WHO, indicating the necessity of revision of existing guidelines for stability testing mainly for very hot and humid regions.     

Dynamic temperature model and dynamic temperature compensation ofcrystal oscillators

In temperature-compensated crystal oscillators (TCXO), the compensating action is commonly estimated as a function of one variable-environmental temperature, At the same time, experimental data show that TCXO frequency stability is also dependent on the dynamics of the temperature process. The greater the temperature variation, the more pronounced Is the loss of temperature compensation. In this paper, the origins of this phenomenon are analyzed, and a method for reducing its effects is presented. A new approach is suggested according to which the compensating action is formed as a function of two variables: the temperature and the rate of its variation. A theoretical basis for this method is given. A functional model of the devices performing the dynamic temperature compensation is suggested. Experimental investigations of a TCXO with a microprocessor-based dynamic temperature compensation system confirmed the possibility of TCXO frequency stability improvement in nonstationary thermal conditions. In a system using an AT cut resonator and a separate Y-cut thermosensor, the application of dynamic temperature compensation resulted in an order of magnitude improvement as compared to conventional digital temperature compensation procedures. Even with dual-mode SC-cut resonators, the application of dynamic temperature compensation is shown to be useful     

Stability and In Vitro Drug Release of Flurbiprofen-Loaded Poly-ε-Caprolactone Nanospheres

The effects of temperature and two different initial pH (2.67 and 7.00) on poly-ε-caprolactone (PεCL) nanospheres loaded with flurbiprofen (FB) (aqueous suspensions) were studied to investigate their influence on the stability and physicochemical characteristics of these drug delivery systems. The drug release behavior was also studied. Release of the associated FB occurred very fast on high dilution in a buffered medium. The stability of the polymeric system depends on the temperature and the initial pH value; it is more degradable with the particles stored at 40°C with an initial pH value of 2.67.     

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.     

Stability and In Vitro Drug Release of Flurbiprofen-Loaded Poly-ε-Caprolactone Nanospheres

The effects of temperature and two different initial pH (2.67 and 7.00) on poly-ε-caprolactone (PεCL) nanospheres loaded with flurbiprofen (FB) (aqueous suspensions) were studied to investigate their influence on the stability and physicochemical characteristics of these drug delivery systems. The drug release behavior was also studied. Release of the associated FB occurred very fast on high dilution in a buffered medium. The stability of the polymeric system depends on the temperature and the initial pH value; it is more degradable with the particles stored at 40°C with an initial pH value of 2.67.     

Evaluation of a Modified ADC-Based Thermometry Bridge

This article presents the modification and testing of an ADC-based thermometry bridge. The instrument under investigation is an Anton Paar MKT 50 Millikelvin Thermometer (developed at the IFE, TU-Graz) based on a precision analog-to-digital converter (ADC). During preliminary testing, it was found that the MKT 50 performs better than its declared uncertainty (1 mK equal to 1 ppm when using a 100 ?? PRT) and is comparable to thermometry resistance ratio bridges typically used in secondary thermometry laboratories (with typical uncertainties from 0.1 mK to 1 mK). The modifications to the original bridge were undertaken by the development team of the MKT 50 at the Graz University of Technology, Austria. Measurements and evaluation of the modified instruments were performed at the MIRS/UL-FE/LMK. For the MKT 50 to be used in thermometry laboratories as a reference unit, measuring parameters of the instrument had to be changed. During the first modification, the upper limit of the instrument range was decreased from 400 ?? to 133 ??, this is a preferred range for standard platinum resistance thermometers (SPRTs). This also meant an increase in the measuring current from 0.5 mA to the more frequently used 1 mA. A modification of the programmable ADC control unit increased the resolution from 24 bit to 27 bit. By adding a switch, the use of an external standard resistor was enabled. After this stage of the modification, the first tests on the instrument were performed. The second stage was aimed at the removal of noise sources. The instrument was prepared in such a way that it only used two input channels, one connected to the SPRT and the other to the standard resistor. Also, the components of the ADC were upgraded to further reduce noise. The elimination of one input channel sped up measurements, making the PC software capable of taking several readings in a shorter time period. All tests were performed in laboratory conditions, where precision AC and DC resistance ratio bridges are typically used. The non-linearity was assessed by the use of an automated resistance bridge calibrator (RBC, Model RBC100), while the noise value was determined both from the standard deviation of RBC measurements as well as from comparison measurements of two standard resistors. All tests were repeated several times to assure confidence in the results. With its lowered range of 133 ?? and an increased resolution of 27 bit, the instrument non-linearity, its value below 2 ???, was comparable to primary resistance ratio bridges such as the ASL F900 or MI 6015T. However, the noise of the instrument remained relatively high at 4 ???. Since the modified MKT-50 is a much faster instrument than AC and DC bridges, averaging was used for true comparison. Measurements done with the modified MKT 50 were also averaged every 15 s (the time a classic resistance ratio bridge takes for one measurement). When measurements with the MKT-50 were averaged, the noise of measurements would be comparable to primary resistance ratio bridges.     

A rapid technique to evaluate the oxidative stability of a model drug

The objective of the current study was to investigate the oxidative induction time (OIT) as a measurement of the stability of an oxygen-sensitive model drug. The OIT was determined by differential scanning calorimetry and represents the time required for oxidative decomposition to occur at a given temperature. Samples were heated to a specific temperature under a nitrogen blanket then held isothermal while exposed to oxygen. The experiment proceeded until oxidative degradation of the sample was apparent from the real-time heat flow graphs. Variables investigated in this study included different lots and suppliers of a model drug as well as the addition of antioxidants. Results demonstrated that the stability of the drug was dependent on the supplier. All antioxidants investigated in this study improved oxygen stability of the model compound, as evidenced by a longer OIT. Butylated hydroxyanisole (BHA) was found to better stabilize the drug than butylated hydroxytoluene at equivalent concentrations. The combination of ascorbic acid and BHA provided the greatest protection against oxidation of the model compound. The results of this study demonstrate the usefulness of OIT to investigate the oxygen stability of pharmaceutical compounds.     

A Rapid Technique to Evaluate the Oxidative Stability of a Model Drug

ABSTRACT

The objective of the current study was to investigate the oxidative induction time (OIT) as a measurement of the stability of an oxygen-sensitive model drug. The OIT was determined by differential scanning calorimetry and represents the time required for oxidative decomposition to occur at a given temperature. Samples were heated to a specific temperature under a nitrogen blanket then held isothermal while exposed to oxygen. The experiment proceeded until oxidative degradation of the sample was apparent from the real-time heat flow graphs. Variables investigated in this study included different lots and suppliers of a model drug as well as the addition of antioxidants. Results demonstrated that the stability of the drug was dependent on the supplier. All antioxidants investigated in this study improved oxygen stability of the model compound, as evidenced by a longer OIT. Butylated hydroxyanisole (BHA) was found to better stabilize the drug than butylated hydroxytoluene at equivalent concentrations. The combination of ascorbic acid and BHA provided the greatest protection against oxidation of the model compound. The results of this study demonstrate the usefulness of OIT to investigate the oxygen stability of pharmaceutical compounds.     

Effects of calcination temperature on the drug delivery behaviour of Ibuprofen from hydroxyapatite powders

The effects of heat treatment time and temperature on the delivery behaviour of Ibuprofen from hydroxyapatite particles were investigated in this study. The drug release was seen to follow Fickian diffusion for the initial period of release for all heat treatment conditions. The gradient of Fickian release increased with (1) increasing crystallite size, attributed to the decreasing amount of boundary area, and (2) with decreasing surface area, due to the reduction in porosity and hence tortuosity within the apatite particles. This study has shown that altering the heat treatment conditions used to calcine hydroxyapatite may alter its drug delivery abilities, whereby calcination temperature was noted to influence the drug release behaviour to a greater extent than calcination time.     

Observation and control of temperature instabilities in a four-valve pulse tube refrigerator

The use of a pulse tube cryocooler in an application requires temperature stability at the cold end. In our four-valve pulse tube refrigerator we have observed long-term temperature instabilities lasting some days and short-term instabilities lasting some hours or even minutes. Investigations have shown that the latter anomaly is caused by the dc-flow. The negative influence on the stability is due to an additional mass flow (dc-flow) to the cold end of the pulse tube, which results in a parasitic heat input.In this paper we present an actively controlled dc-flow suppression device, which uses a temperature gradient in the regenerator as a control parameter. This device enables us to eliminate the temperature instabilities.     

Investigation of the Stability of Doxorubicin Hydrochloride Using Factorial Design

Abstract

Using drug concentration remaining at a given time as the criterion, a 2⁴x3 factorial design has been employed to investigate the effects of temperature, light, media (aqueous or organic/aqueous), ionic strength and pH on the stability of doxorubicin hydrochloride. Following the application of first order kinetics, and assuming an additive model, the statistical significance of the factors and their interactions have been determined using analysis of variance (ANOVA) on the dependent variable ln(lnC_o-InC). The results indicate that temperature, pH and media are the major factors responsible for the stability of drug. The two-way interaction between temperature and pH, and the three-way interaction between temperature, light and ionic strength are also significant. It is found that doxorubicin is more stable in non-aqueous media at low temperature and low pH values. A combination of darkness and low ionic strength is also conducive to its stability.     

温度和湿度对聚四氟乙烯多孔驻极体膜压电活性稳定性的影响

研究了具有开放性孔洞的聚四氟乙烯(voided polytetrafluoroethylene,PTFE)多孔膜和PP蜂窝膜(polypropylene cellular)的驻极体行为和压电活性的温度效应。研究结果指出：和PP蜂窝膜驻极体相比．PTFE多孔膜驻极体呈现出突出的电荷储存和压电活性的温度稳定性;研究了这类稳定性的驻极体和材料的结构根源。PTFE多孔薄膜驻板体这种压电活性的温度稳定性主要依赖于这类驻极体材料电荷储存及材料的本征性能(如力学性质等)的温度稳定性。实验结果还说明：PTFE多孔膜突出的压电系数温度稳定性使它大大扩展了以包括PP在内的空间电荷型多孔膜研制的压电功能元器件的耐温要求。本文还讨论了环境因素(如相对湿度)对这类功能膜压电活性的影响,分析了环境湿度对压电活性影响的结构根源。     

半导体激光器恒温控制系统的高精度温度测量研究

 半导体激光器性能受温度影响较大,为了提高其工作稳定性,设计了一个应用于半导体激光器的恒温控制系统.该系统由05 mA恒流源对Pt100温度传感器供电,采用四线制测量方法获得精确的温度信号.应用TLC2652斩波放大器设计前置放大器,并采用差分放大电路对信号进行后续比较放大.使用半导体制冷器(TEC)制冷,实现系统的恒温控制.经实验数据分析可以看出,该恒温系统可有效地工作,温度控制偏差最大为±002 ℃.通过调节相应参数,可自由设定恒温系统的温度值,应用于不同温度控制环境.     

Effects of reinforcement filler and temperature on the stability of β-crystal in glass bead filled polypropylene

The effects of crystallization temperature (T_c), glass bead content and its size on the formation of β-crystal and structural stability of originally formed β-crystal in glass bead filled polypropylene (PP) were examined. The differential scanning calorimetry (DSC) measurements indicated that the amount of β-phase in PP crystals was a function of the crystallization temperature and glass bead content. For a constant crystallization temperature, it was observed that the amount of β-crystal initially increased with increase in glass bead content up to 30 wt.%, and then decreased slightly with further increase in the filler content. From the DSC data, a disorder parameter (S) was derived to define the structural stability of originally formed β-crystals. The structural stability of originally formed β-crystals was enhanced with increase in either the crystallization temperature or the glass bead content. Also, the influence of glass bead size (4–66 μm) on the formation and stability of β-crystals in PP/glass bead blends was studied. Large glass bead particles suppressed the formation and decreased the stability of β-crystals.     

Highly stabilized amorphous 3-bis(4-methoxyphenyl)methylene-2-indolinone (TAS-301) in melt-adsorbed products with silicate compounds

3-Bis(4-Methoxyphenyl)methylene-2-indolinone (TAS-301) is a poorly water-soluble drug showing low oral bioavailability in rats and dogs. Previously, we reported that when a physical mixture of TAS-301 and a porous calcium silicate, Florite® RE (FLR), was heated at high temperature (250°C), the drug melted and was adsorbed by the FLR in an amorphous state, and that the preparation (melt-adsorbed product) showed a significantly increased solubility and dissolution rate, and a significantly enhanced oral bioavailability of the drug. The aim of the present study was to elucidate important factors for preparing a melt-adsorbed product showing greater stability of drug in an amorphous state. We examined the effects of the kind of adsorbent, drug/adsorbent ratio, heating conditions, and drug particle size on converting drug crystal into an amorphous state, the stability of amorphous state, and chemical stability of the drug in the melt-adsorbed products under a high temperature and high humidity condition (60°C/80% RH, open). FLR, light anhydrous silicic acid and two types of hydrated silicon dioxides were tested as adsorbents. For the batch method, TAS-301 was converted into an amorphous state by heating TAS-301/adsorbents physical mixtures above the melting point of TAS-301 for more than 2 min. The amorphous state was most stabilized when FLR was used as an adsorbent and drug/FLR ratio was 1:0.5 and more. For the continuous method using the twin screw extruder that enables significantly larger scale manufacturing than batch method, TAS-301 melt-adsorbed products were able to produce when only FLR was used as adsorbent. The heating temperature was needed to be set above the melting point of TAS-301 to convert it into an amorphous state as well as batch method. The amorphous state was stabilized when drug/FLR ratio was 1:2 and more. The micronization of the drug decreased the stability of the amorphous state. These results indicate the importance of optimizing the above factors in the preparation of melt-adsorbed product.     

Consideration on the formulation of benzoyl peroxide at ambient temperature: choice of non-polar solvent and preparation of submicron emulsion gels

The aim of this study performed at ambient temperature was first to determine the solubility of benzoyl peroxide in various solvents with a large range of polarity. All these solvents can be used in the dermatological field. Then, using the most suitable solvent, a new drug vehicle submicron oil-in-water emulsion was formulated. Correlation between dielectric constant (ε) and drug solubility in various solvents and different binary mixtures was verified. An original ternary diagram with surfactant-co-surfactant/oil/water was performed at low temperature to determine the regions of submicron emulsions. A dramatic change in the magnitude of benzoyl peroxide solubility occurred above a dielectric constant value of about 20. The solubility of this drug can be enhanced by the replacement of polar solvent by a vehicle of lower dielectric constant. A stable submicron emulsion gel was made with cremophor EL, glycerol, caprilic-capric triglycerides, and water in the proportion of 20-20/35/25, respectively; 1.5% benzoyl peroxide was also added. This submicron emulsion vehicle consisted of oil droplets, with a mean diameter of approximately 100-150 nm, dispersed in a continuous water phase. These studies confirm the potential of benzoyl peroxide incorporation into submicron emulsion gel and the stability of this formulation.     

A thermal analysis on self-propagating high temperature synthesis in joining technology

This paper addresses the thermal analysis of self-propagating high temperature synthesis (SHS) in joining operations of temperature sensitive materials. A parametric finite element analysis of SHS is conducted, i.e. the influence of reaction rate, ignition temperature and reaction zone thickness on reaction stability and velocity is investigated. Special regard is given to surrounding materials such as amorphous alloys in joining operations. These materials act as heat sinks that conduct energy away from the reaction zone and thus diminish or even extinguish the reaction. In addition to the numerical simulation, analytical relations are developed to introduce criteria for reaction stability. Analytical and numerical results are compared for verification.     

Influence of high temperatures on a fiber-optic probe for temperature measurement

The use of optical fiber in a temperature probe or sensor for optical pyrometry in the 100-1000 °C range is affected by the low thermal stability of classical fibers. We have studied the different sources of perturbations induced by exposure to high temperature. Two specific fibers especially suited for a high-temperature environment were tested and compared. Low (100 °C/min) and very fast (100 °C/s) fiber heating was performed to evaluate its influence on the guided flux and the induced error on temperature measurement. The metallic-coated fiber shows a reproducible temperature error that can be predicted. This important result permits the development of an uncooled fiber probe for temperature monitoring in high-temperature environments such as aerospace engines.