Compatibility and stability tests of risperidone with soft-drinks by isothermal titration microcalorimetry

Isothermal titration microcalorimetry has been applied to investigate the compatibility testing of risperidone oral solution with soft-drinks and the interaction with tea tannin such as (–)-epigallocatechin, (–)-epicatechin, theaflavin and their gallates. In aqueous solution, risperidone was exothermically bound to tea tannin with binding affinity (10³–10⁴ M^–1), small enthalpy and entropy changes reflecting van der Waal’s interaction to form an insoluble complex at 1:1 molar ratio. The heat effect of risperidone titrated into soft-drinks containing tannin was exothermic and proportional to the quantity of the complex. While, no significant heat effect was found for risperidone titrated into a pet-bottled water and an infusion of parched barley without tea tannin. These results were agreed with stability testing of risperidone in some soft-drinks by HPLC method.     

尿素诱导牛血红蛋白变性的微量热和平衡渗析研究

应用恒温微量热技术和平衡渗析技术,对尿素与牛血红蛋白在30℃水溶液中的结合作用及造成牛血红蛋白变性的过程进行了研究,得到了尿素在牛血红蛋白上的平均结合数、二者之间的结合焓及每摩尔尿素与牛血红蛋白结合的焓效应,并根据简单结合模型,计算了它们之间的结合常数、结合自由能.对实验结果的热力学分析表明,尿素是通过直接和间接的两种作用造成牛血红蛋白变性的,它们之间的相互作用分为三个阶段:尿素浓度达到4molL-1之前为第一阶段,主要产生的是尿素与牛血红蛋白的直接结合作用,在弱酸性条件下这种作用较强;尿素浓度为4molL-1到6molL-1之间为第二阶段,主要通过尿素与溶剂水的作用造成牛血红蛋白周围水结构的变化,在尿素浓度达到6molL-1时两种作用的叠加造成牛血红蛋白结构的破坏,暴露出原来处于结构内部的基团;尿素浓度超过6molL-1之后为第三阶段,尿素分子继续与暴露出来的基团进行结合.牛血红蛋白次级结构的维系具有协作性,其结构的破坏不是渐进的,而是一次性全部打开,结构破坏产生的热效应并不太大.     

Potential applications of microcalorimetry for the study of physical processes in pharmaceuticals

In calorimetry, the heat-flow to or from a sample is measured as a function of time (isothermal calorimetry) or temperature (scanning calorimetry). The technique is not dependent on the physical form of the sample and is usually non-destructive (exceptions include temperature-induced irreversible phase transitions and thermal decomposition). The inherent sensitivity of modern instruments allows measurements on the micro-Watt scale. Calorimetry is highly suited to the study of pharmaceutical systems because small sample masses are usually required and the technique is very sensitive to changes induced by, for instance, formulation or processing. It is the purpose of this review to show applications of both isothermal and scanning calorimetry in the field of physical and bio-physical pharmacy. Potential applications include studies of physical stability, excipient compatibility, chemical stability and the study of the potential interactions of and between macromolecules such as lipids, surfactants, and nucleic acids.     

Characterization of microbial activity in soil by use of isothermal microcalorimetry

Isothermal microcalorimetry is now established as a useful technique for the characterization of the microbial activity in soil. A brief summary of publications from this field and of instruments used in such work is presented. Several experimental parameters that can form important sources for systematic errors are discussed and it is suggested that further method work is made in this area. In most isothermal microcalorimetric investigations on the microbial activity in soil, the samples are amended with glucose. It is proposed that cellulose also will be used.     

Denaturation study of bovine serum albumin induced by guanidine chloride or urea by microcalorimetry

The denaturation of bovine serum albumin (BSA) induced by guanidine chloride or urea at different pH values was studied by isothermal microcalorimetry measurements at 30°C. The simple bonding model, which was developed by Privalov, was employed to obtain the apparent bonding constant K, the apparent singular bonding Gibbs bonding energy ΔG and the total Gibbs energy ΔG(a) between the protein and denaturant, from analysis of the calorimetric data. Furthermore, linear extrapolation at the midpoint of transition was employed to determine the apparent denaturation enthalpy ΔH _d. The results showed that for guanidine chloride, the bonding between BSA and guanidine chloride could proceed more easily in an alkaline condition, and the apparent denaturation enthalpy ΔH _d of BSA due to guanidine chloride was 350 kJ·mol⁻¹ at pH 6.97 and 7.05, while it was 275 kJ·mol⁻¹ at pH 9.30, which indicated that BSA was more stabilized in a neutral condition. However, for urea, the bonding between BSA and urea could proceed more easily in an acidic condition, and the apparent denaturation enthalpy ΔHd of BSA due to urea was 295 kJ · mol⁻¹ at pH 6.97, while it was 230 kJ · mol⁻¹ at pH 7.05 and 9.30. The results indicate that the degree of expansion of BSA in the two denaturants is different. __________ Translated from Acta Chimica Sinica, 2008, 66(5) (in Chinese)     

Rapid, practical and predictive excipient compatibility screening using isothermal microcalorimetry

Conditions for conducting excipient compatibility studies via isothermal microcalorimetry were explored using model reactions. The resulting recommended procedure for rapid and practical screening consisted of using binary mixtures (100 mg of each component), the addition of 20% (w/w) water, and monitoring the mixture at 50°C for 3 days using an isothermal microcalorimeter. The correlation between calorimetric excipient compatibility results and formulation stability was investigated for two developmental drugs. A comparison of calorimetric results to actual formulation stability suggested that it was possible to predict relative stability within functional classes. However, caution should be exercised in such predictions, because apparent reaction enthalpies were found to vary three-fold among excipients in the same functional class. Based on these observations, a two-step procedure is suggested for efficient development of stable formulations. First, excipient compatibility screening should be conducted using a rapid calorimetric technique. The calorimetric results are then used to evaluate relative risk of incompatibility for each excipient within a particular functional class. The calorimetric data and the functional requirements of the dosage form are then integrated in developing a limited number of model formulations that are likely to succeed from both a performance and a stability perspective. The second step of the process is to conduct traditional HPLC-based accelerated stability studies on the limited number of model formulations.     

Solid-state reactions from isothermal heat conduction microcalorimetry theoretical approach and evaluation via simulated data

Several recent publications from this laboratory have reported developments in the capacity to calculate thermodynamic and kinetic parameters, such as rate constant, enthalpy, order of reaction, from isothermal micro-calorimetric data. To date these developments have all been associated with the calculation of the desired parameters from solution phase reactions. This paper furthers these developments to a theoretical consideration of solid-state reactions and the calculation of the values for the rate coefficient, k, the fitting parameters m and n, the total number of joules released over the lifetime of reaction, Q, and hence either the specific enthalpy or the molar enthalpy of reaction, H. This revised version was published online in July 2006 with corrections to the Cover Date.     

Use of isothermal microcalorimetry for prediction of oxidative stability of several amino acids

Isothermal microcalorimetry has been applied as a method for predicting (in)stability of ascorbic acid and several amino acids that undergo oxidative degradation in aqueous media. The fast and simple method involved the addition of different amounts of hydrogen peroxide. The appearance of the heat flow curves gave a clear general indication of how stability was influenced. The accuracy of the microcalorimetric result was investigated by comparing it with an HPLC assay and a good agreement between the results of both methods was demonstrated. It was also established that susceptibility to oxidative degradation decreases in the following order: cysteine, methionine, ascorbic acid, tyrosine and tryptophan.     

Use of isothermal microcalorimetry in pharmaceutical preformulation studies

Excipient compatibility of a new chemical entity was assessed using an isothermal microcalorimeter. Mixtures of an active pharmaceutical ingredient with a primary amine group and excipients were prepared in a 1:1 ratio and compatibility monitored by exposing to 50, 60 and 70°C in presence of 200 mL of water. The new chemical entity, a primary amine, reacted with reducing sugars such as lactose and resulted in a brown discoloration. This reaction is the Maillard type condensation reaction between amines and reducing sugars. The rate of reaction was dependent on the temperature with rapid degradation at higher temperatures. No other incompatibility was apparent between the primary amine and other excipients This revised version was published online in July 2006 with corrections to the Cover Date.     

Quantitation of amorphicity by microcalorimetry

The amorphous state of solids is characterized by a higher chemical and physical reactivity and a hygroscopic behaviour. Furthermore processing of amorphous powders is often difficult, because of the instability. Fast crystallizations, precipitations and milling favour the formation of the amorphous state. Galenical processes like granulation, drying, lyophilization, mixing, may also induce amorphous regions in the drug products.X-ray diffraction techniques can be used for the determination of the amorphicity of drug raw materials or drug products. Unfortunately, 10% is the detection limit, which in normal cases can be attained. Amorphous substances undergo an exothermic crystallization at temperatures above the glass transition point. Water which is a plasticizer decreases the temperature of the glass transition point, allowing the crystallization to occur at lower temperatures. The crystallization energy is measure of by microcalorimetry.Examples show the influence of the choice of the experimental conditions, especially the influence of the amorphicity on the kinetic of the reaction. Critical steps are discussed for three different drug substances. Limits of detection in the magnitude of 1 % are possible using microcalorimetry.     

Effect of storage of soil at 4°C on the microbial activity studied by microcalorimetry

The effect of the storage of soils on their microbial activity has been studied using a microcalorimetric method. Soil samples were kept in closed polyethene bags at 4°C during 3–6 months. Results show changes in the slope of the differentP?t curves recorded from the samples stored at 4°C. This fact strongly suggest the existence of changes of the microbial activity of soil as the heat evolution is a direct measurement of the cells metabolic activity. The value of the Peak-time (time in which the microcalorimetric signal reaches the maximum value) is related with the microbial density of soil samples. This parameter was affected by the time of storage increasing with time. The total heat evolutionQ(t), of the soil samples amended with glucose calculated from the area limited by the Power-Time curves, also decreases with the time of storage. The soil that had been stored for 6 months before experiments, showed the lowest valu ofQ(t).     

Utilization of microcalorimetry for an assessment of the potential for a runaway decomposition of cumene hydroperoxide at low temperatures

The exothermic decomposition of cumene hydroperoxide (CHP) in cumene liquid was characterized by isothermal microcalorimetry, involving the thermal activity monitor (TAM). Unlike the exothermic behaviors previously determined from an adiabatic calorimeter, such as the vent sizing package 2 (VSP2), or differential scanning calorimetry (DSC), thermal curves revealed that CHP undergoes an autocatalytic decomposition detectable between 75 and 90°C. Previous studies have shown that the CHP in a temperature range higher than 100°C conformed to an n ^th order reaction rate model. CHP heat of decomposition and autocatalytic kinetics behavior were measured and compared with previous reports, and the methodology and the advantages of using the TAM to obtain an autocatalytic model by curve fitting are reported. With various autocatalytic models, such as the Prout-Tompkins equation and the Avrami-Erofeev rate law, the best curve fit among models was also investigated and proposed.     

Thermal methods and microcalorimetry application in the studies of low energy cements

In the DTA studies of the clinkerization process the values of enthalpy attributed to the particular stages of clinker synthesis were determined and the energy consumption decrease due to the modification of the phase composition was calculated for 400 J/g.The activation of the low energy cement by Ba addition was shown using microcalorimetry and thermal methods.

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Zusammenfassung In einer DTA-Studie des Klinkerbildungsprozesses wurden die Enthalpiewerte der einzelnen Stufen der Klinkersynthese bestimmt. Die ermittelte Abnahme der Energieaufnahme für die Änderung der Phasenzusammensetzung beträgt 400 J/g.Mittels Mikrokalorimetrie und thermischen Methoden konnte die Aktivierung des energetisch niedrig liegenden Zementes durch Zusatz von Ba nachgewiesen werden.

     

Flow microcalorimetry and thermokinetics of liquid mixtures

The identification of the calorimetric curves corresponding to liquid mixtures for different injection flows, given by a flow microcalorimeter, permits to classify in a kinetic way the studied mixtures. For this purpose, it is determined the establishment time constant of the mixture (τ_mix) that allows us to estimate the length occupied by the dissipation (through the parameter λ_mix) and thus to justify the sensitivity variation obtained in different chemical calibrations.     

Development and validation of a HPLC method for the determination of buprenorphine hydrochloride, naloxone hydrochloride and noroxymorphone in a tablet formulation

A simple isocratic reversed-phase high-performance liquid chromatographic method (RP-HPLC) was developed for the simultaneous determination of buprenorphine hydrochloride, naloxone hydrochloride dihydrate and its major impurity, noroxymorphone, in pharmaceutical tablets. The chromatographic separation was achieved with 10 mmol L⁻¹ potassium phosphate buffer adjusted to pH 6.0 with orthophosphoric acid and acetonitrile (17:83, v/v) as mobile phase, a C-18 column, Perfectsil Target ODS3 (150 mm × 4.6 mm i.d., 5 μm) kept at 35 °C and UV detection at 210 nm. The compounds were eluted isocratically at a flow rate of 1.0 mL min⁻¹. The average retention times for naloxone, noroxymorphone and buprenorphine were 2.4, 3.8 and 8.1 min, respectively. The method was validated according to the ICH guidelines. The validation characteristics included accuracy, precision, linearity, range, specificity, limit of quantitation and robustness. The calibration curves were linear (r > 0.996) over the concentration range 0.22-220 μg mL⁻¹ for buprenorphine hydrochloride and 0.1-100 μg mL⁻¹ for naloxone hydrochloride dihydrate and noroxymorphone. The recoveries for all three compounds were above 96%. No spectral or chromatographic interferences from the tablet excipients were found. This method is rapid and simple, does not require any sample preparation and is suitable for routine quality control analyses.     

Use of isothermal microcalorimetry in pharmaceutical preformulation studies,Part II. Amorphous phase quantification in a predominantly crystalline phase

Low amounts of amorphous phase present in predominantly crystalline powders were quantified by using various analytical techniques with an emphasis on the use of Isothermal Perfusion Microcalorimetry. The amorphous phase was plasticized using ethanol vapor and enthalpy of re-crystallization of amorphous phase was used for generation of a calibration curve. Amorphous content as low as 5% was quantified using this technique. Although baseline noise was very low, additional processes occurring during re-crystallization confounded quantification of lower amorphous fractions. This revised version was published online in July 2006 with corrections to the Cover Date.     

Using isothermal microcalorimetry for the prediction and testing of long-term properties of materials and products

The use of isothermal microcalorimetry (MC) as a sensitive monitor for slow reactions is demonstrated in a number of examples. In Example 1 the spontaneous decomposition of a nitrate ester propellant is studied and the absolute degradation rate estimated. Example 2 illustrates how MC can be used for comparing the rate of oxidative ageing at different O₂ concentrations. Synergetic effects between oxygen and moisture in accelerated ageing of nitrile rubber are evaluated from a so-called 4-point test in Example 3. The last example shows a simple MC technique for rapid determination of moisture permeability through a polymeric sealant.     

A microcalorimetry and binding study on interaction of dodecyl trimethylammonium bromide with wigeon hemoglobin

The thermodynamic parameters for the binding of dodecyl trimethylammonium bromide (DTAB) with wigeon hemoglobin (Hb) in aqueous solution at various pH and 27 °C have been measured by equilibrium dialysis and titration microcalorimetry techniques. The Scatchard plots represent unusual features at neutral and alkaline pH and specific binding at acidic pH. This leads us to analyze the binding data by fitting the data to the Hill equation for multiclasses of binding sites. The best fit was obtained with the equation for one class at acidic pH and two classes at neutral and alkaline pH. The thermodynamic analysis of the binding process shows that the strength of binding at neutral pH is more than these at other pH values. This can be related to the more accessible hydrophobic surface area of wigeon hemoglobin at this pH. The endothermic enthalpy data which was measured by microcalorimetry confirms the binding data analysis and represents the more regular and stable structure of wigeon hemoglobin at neutral pH.     

Isothermal microcalorimetry perfusion experiments: A method to verify the relative vapour pressure of organic liquids inside the sample vessel

Perfusion microcalorimetry is frequently applied to expose pharmaceutical solids to specific relative vapour pressures (RVP) of organic liquids or water. The aim was to set up a general procedure to check the performance of a vapour pressure control device used to create a specific RVP. This was achieved by identifying and checking the significant factors in the creation of the RVP inside the reaction vessel. The flow switch valve was tested by volume flow measurements whereas the saturation of the wet line was verified in a calorimetric experiment employing methanol as model solvent. The results of the measurements were used to calculate the RVP inside the reaction vessel. The method developed is suitable to test the vapour pressure control device. It can be applied for any solvent.     

In Vitro Investigation on Interaction of Ranitidine Hydrochloride in the Presence of Cross-Linked Carboxymethyl Cellulose Sodium.

Summary: The adsorbance of ranitidine hydrochloride – drug selective H₂ histamine receptor inhibitor used In the treatment of gastric and duodenal ulcer was investigated in the presence of croscarmellose, a cross- linked polymer of polysaccharide character used as a swelling additive in oral pharmaceutical formulations – capsules, tablets and granules. The evaluation of adsorbance capability was carried out by means of a statistical method in in vitro conditions, taking into account environmental pH, concentration of the investigated drug as well as the properties of the polymer. Obtained results prove that the analyzed active agent is adsorbed on polymer at all the investigated pH ranges and the capability of polymer binding depends on environmental pH. The highest binding capability was revealed in samples with pH of 7.6, (adsorbance capacity k = 0.6958) while the lowest binding capability was observed at pH 1.5 (adsorbance capacity k = 0.0005) in the presence of croscarmellose sodium. Level of adsorption depends on the analyzed drug concentration and adsorption on polymer in increasing concentration and pH environment.