Heat Conduction Microcalorimetry Research Articles

The use of isothermal heat conduction microcalorimetry to evaluate drug stability in tablets

Isothermal heat conduction microcalorimetry was used to evaluate chemical stability of a solid drug in tablets. A variety of mixtures were compressed to flat faced tablets of 300 mg weight and 10 mm diameter. The content of drug amounted to 10%. Besides drug containing tablets, also placebo tablets as well as the non compressed mixtures were examined by microcalorimetry at 80°C. The excipient Emcompress® exhibited a substantially high exothermic heat flow that was due to a change in crystallinity. For Emcompress® containing tablets this interfering signal resulted in such a way that the calorimetric data did not reflect the drug decomposition with sufficient accuracy. In the case of the other preparations the heat flow of the excipients were low, and the calorimetric data did reflect the drug decomposition. The stability increased with increasing content of CaHPO 4, respectively, with decreasing content of water.

Use of isothermal heat conduction microcalorimetry to evaluate stability and excipient compatibility of a solid drug

Isothermal heat conduction microcalorimetry was used to evaluate chemical stability and excipient compatibility of a solid drug. Calorimetric data were compared with HPLC data in order to determine the origin of the thermal events. For the pure solid drug, heat flow time curves became constantly exothermic after 3–4 days in the temperature range from 60 to 80°C and were due to chemical decomposition. The activation energy calculated by both methods (microcalorimetry and HPLC) was 170±8 kJ/mol (mean±S.D.). A plot of the evolved heat Q versus the amount of degraded drug showed a linear relationship. Binary mixtures and granules led to higher exothermic signals for microcrystalline cellulose (MCC), potato starch and lactose, and indicated lower stability. In the case of MCC and lactose, physical processes were superimposed and made the interpretation of the heat flow data difficult. In the case of the other systems the exothermic heat flow was in the same range as for the pure solid drug. Neither was physicochemical interaction detected, nor was the chemical decomposition accelerated by the excipients. By combining calorimetric and HPLC data the prediction of final shelf-life at room temperature was estimated.

Thermokinetic Studies of Porphyrin Complexation in Non-Aqueous Solutions by Heat Conduction Microcalorimetry

Abstract Porphyrins are known as unique ligands forming some of the most stable complexes with various metal ions. In this work the thermokinetic investigations of complex formation of tetraphenylporphyrins with copper(II) acetate were carried out in two anhydrous organic solvents: acetic acid and DMF at 25C. Measurements were performed in a heat conduction microcalorimeter [7] adapted for non-aqueous solvents. Total heat effects and thermokinetics were determined. The results were discussed together with spectrophotometric data. Taking into account the high stability of metalloporphyrin complexes, the heat of their formation is rather small (in the case of acetic acid ΔQ=32.71.2 kJ mol−1, for DMF ΔQ=26.21.3 kJ mol−1). Such result can suggest that: 1) the stability of complexes is influenced strongly by an entropy factor, 2) the complexation involves breaking of the NH-bond in the porphyrin coordination centre, accompanied by high consumption of energy.

Determination of specific heats using isothermal microcalorimetry

The specific heat capacities (cp) for the brain and muscle equivalent liquids were determined with isothermal heat conduction microcalorimetry (IMC) and differential scanning calorimetry (DSC). IMC was found to afford an accurate technique to measure cp for solid and liquid samples, when an appropriate reference is employed. The accuracy of obtained cp values was estimated to be better than 0.7% with the equivalent liquids. Intercomparison with a conventional isoperibolic calorimeter showed an excellent agreement within the estimated uncertainty of the isoperibolic calorimeter (±3%). Additionally, suitability of different kinds of IMC sample vessels was tested, and the standard electrical calibration procedure of IMC was evaluated through the determination of cp with and without a reference material.

Solid state reactions studied by isothermal microcalorimetry; The solid state oxidation of ascorbic acid

Abstract This paper reports a new method for the analysis of isothermal calorimetric data, for reactions in the solid state. As an illustration for this method of analysis, the solid state oxidation of L-ascorbic acid (vitamin C) has been studied. The investigation considers the role that water plays in the solid state oxidation of ascorbic acid and hence poses questions of the generality of water in solid state reactions. Isothermal heat conduction microcalorimetry (e.g., TAM, Thermometric, Sweden) has, for some time, been proposed as a general and rapid analytical technique that allows the calculation of the kinetic and thermodynamic parameters of chemical reactions. A new method for the determination of the kinetic and thermodynamic parameters from calorimetric data allows the quantitative study of reactions without preconceptions of the reaction mechanism and quantities of material reacting. This allows the quantitative study of reactions, especially reactions in the solid state, which, because of the inherently complex nature of reaction, are very difficult to analyse by any other means. From the analysis of the calorimetric data for the solid state oxidation of ascorbic acid at 298.15 K, we have determined that the reaction has a change in enthalpy of −195 ±10 kJ mol−1 with an associated rate constant of 4.1 × 10−6 s−1. The study was carried out as a function of the quantity of water, between dry (i.e. under ambient conditions) to 200μl, added to 0.5 g ascorbic acid. The dry sample of ascorbic acid was used directly from the container, no special attention was paid to prevent atmospheric moisture entering the sample before loading the sample. Between these water quantities the kinetic and thermodynamic parameters remained the same, indicating that the reaction mechanism was unchanging throughout the range studied.

Determination of Thermodynamic and Kinetic Parameters from Isothermal Heat Conduction Microcalorimetry: Applications to Long-Term-Reaction Studies

The application of heat conduction isothermal microcalorimetry has been proposed for some time as a rapid and general technique for the determination of both thermodynamic and kinetic parameters of chemical reactions. These applications have been suggested as being of particular relevance to solid-state reactions and, industrially important, to the prediction of long-term stability and of compatibility data for pharmaceutical materials. However, there has yet to be the development of a general procedure that does not require additional noncalorimetric data and that is free of assumptions, which can be used to determine the thermodynamic and kinetic parameters for a reaction, from calorimetric data. It is the purpose of this paper to describe such a general approach which does not depend upon knowledge of initial concentrations (quantity), enthalpy, or any predetermined reaction order. Equations have been developed whch incorporate calorimetrically accessible data (a, the power, and q, the heat output) and which also include the rate constant, k, the change in enthalpy of the reaction, AH, and the order of reaction. A second procedure is also described which depends only on the analysis of the calorimetric signal and which involves no formal chemical kinetic based equations. The methods described allow estimation of, for example, the annual extent of degradation of a solid compound. The methods developed have been tested through examination of both calculated and experimental data. The experimental work examined very slow reactions (lifetime of years) of known order (there are little reliable enthalpy data available for slow reactions) and involved calorimetric observation of these reactions for up to 50 h. In all cases, the method yielded the appropriate, Le., conforms to literature data, rate constant, reaction order, and, where available, reaction enthalpy. Some situations in which this microcalorimetric approach and subsequent data analysis will be of utility are discussed.

Applications of isothermal microcalorimetry in the pharmaceutical sciences

Abstract Isothermal heat conduction microcalorimetry is a technique which can be used to study very many physical and chemical processes. The experimental yield can potentially give information on thermodynamics of the process, kinetics (mechanism) and analysis. It is argued that with careful experimental design, and experienced data interpretation this technique is an extremely valuable tool for pharmaceutical scientists. The existing literature is discussed in terms of microbiological investigations, tissue culture studies, physical pharmacy (including immersion, adsorption, crystal properties, dissolution and targeting), and chemical stability studies.

Assessment of the degree of disorder in crystalline solids by isothermal microcalorimetry

The use of isothermal heat-conduction microcalorimetry for assessment of degree of the disorder within crystalline material has been evaluated. Single entities, physical mixtures with varying contents of 100% amorphous lactose and 100% crystalline α-lactose monohydrate, and samples of spray dried lactose with varying degrees of disorder were analysed at 25°C. The technique monitors the heat flow from the crystallisation of the amorphous content of the powder, when the powder is exposed to a humid environment. The heat calculated from the heat flow curve by integration revealed good linearity. The technique was able to detect at least 2% disorder in a crystalline sample. Comparisons with X-ray analysis and DSC showed good agreement above 10% disorder. At lower degrees of disorder only microcalorimetry was able to measure the disorder with high accuracy.

Use of Microcalorimetry in the Field of Pharmaceutical Sciences. I. Measurement of Drug Dissolution from Solid Dosage Forms.

A microcalorimetric method for measurement of the dissolution rate of sodium chloride was presented. The method applied the deconvolution theory to heat conduction microcalorimetry. When a calorimetric curve for the heat of dilution was regarded as the response for a unit impulse input (heat conduction profile), a calorimetric curve for the heat of solution was considered to be the convolution of dissolution profile and heat conduction profile. Thus, the dissolution profile was calculated from the calorimetric curves for the heat of dilution and for the heat of solution by a numerical deconvolution. Dissolution rate determined by the calorimetric method coincided well with that obtained by a titration method.

Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies VII. Oxidation of ascorbic acid in aqueous solution

Heat-conduction microcalorimetry at 25.0°C has been evaluated as a method of predicting the stability of a drug undergoing complex degradation in aqueous solution. The oxidation of ascorbic acid was used as a model reaction. The influence on the microcalorimetric response of various amounts of ascorbic acid, oxygen and hydrogen ion in the solution, and of the addition of a metal complex binder or an antioxidant was investigated. In general, the appearance of the heat flow curves and the calculation of the heat evolved gave a clear indication of how the stability was influenced. The accuracy of the microcalorimetric response was investigated by comparing it with an HPLC assay technique. A linear relationship between the cumulative heat and the amount oxidized was obtained. The slope, described as the apparent enthalpy change, was 224 kj/mol. It is concluded that microcalorimetry can be used as a simple stability indication technique, at normal storage temperatures, for a complex degradation reaction. However, for reactions that include an antioxidant (sodium metabisulfite), which in itself undergoes a continuous major chemical reaction, the appearance of the heat flow curves cannot be related to the stability of the ascorbic acid.

Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies. VI. Continuous monitoring of the interaction of water vapour with powders and powder mixtures at various relative humidities

The water vapour uptake by microcrystalline cellulose (MCC) and a powder mixture composed of roller-dried β-lactose (which consisted of 22% anhydrous α-lactose, 9% α-lactose monohydrate and 69% anhydrous β-lactose) and MCC was continuously monitored at 100% relative humidity (RH) using isothermal heat-conduction microcalorimetry at 25.0°C. For the powder mixture, three phases of water vapour uptake were distinguished i.e., firstly the absorption of water by MCC, secondly the incorporation of water of hydration into the original anhydrous α-lactose fraction and finally incorporation of water into anhydrous α-lactose that had been obtained by mutarotation from the β-lactose fraction. The combination of the cumulative heat values for the single materials were comparable to the mixture of the two i.e., the processes were additive and the powders did not interact. However, for mixtures that had been stored for a long time at 94% RH and later monitored at 100% RH, an unknown process was indicated by the heat flow curve. Continuous measurements were also performed at 75, SI and 94% RH. The interpretation of the heat flow curves for the mixtures was not as straightforward at the lowest humidities investigated as at 100% RH, but the water vapour was absorbed by the MCC first, in these cases also. At both 100 and 94% RH, the incorporation rate of water in roller-dried β-lactose alone was shown to be more rapid than in the mixture with MCC. At 75 and 81% RH, the difference in the extent of the incorporation process was small after 14 days exposure.

Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies. V. A new approach for continuous measurements in abundant water vapour

A technique which allows continuous microcalorimetric measurement in abundant water vapour at 100% relative humidity (RH) has been designed and evaluated at 25.0°C. The incorporation of water of hydration in various types of anhydrous lactose powder was studied. In some experiments, lactose samples were prestored at humidities ranging from 58 to 94% RH and thereafter characterized with the new technique at 100% RH. The incorporation process is the main contributor of heat. The heat contributions from other sources in the sample vessel were also investigated. Heats of adsorption and vaporization were negligible, since they cancelled each other out. However, the heat from the incorporation process was somewhat reduced by the heat of mutarotation from β- to α-lactose and possibly also by the heat from a minute amount of dissolution of the lactose. The enthalpy change for the bonding of water of hydration to roller-dried β-lactose was calculated as approx. 16 kJ/mol at 25°C.

Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies. IV. The influence of microcrystalline cellulose on the hydration rate of anhydrous lactose

Abstract Microcalorimetry at 25.0° C, differential scanning calorimetry (DSC) and water uptake measurements were used to monitor the influence of water vapour on a 50/50 mixture of microcrystalline cellulose (MCC) and anhydrous lactose (26% α- and 74% β-lactose), and on MCC alone, after storage at various relative humidities for different lengths of time. It was shown that MCC protects anhydrous lactose when surrounded by abundant water vapour by slowing down the rate of hydration. In a limited amount of water vapour, it was shown that MCC can redistribute its absorbed water through the vapour phase. This extends the duration of incorporation of hydrate water in anhydrous lactose over that seen when anhydrous lactose is alone. In the evaluation of the microcalorimetric technique it was shown that if a process is in progression before the first microcalorimetric measurement in a series, important information can be lost and the result may be difficult to interpret. However, together with other analytical techniques, the microcalorimetric result can give a valuable indication of how the process has proceeded.

Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies. III. Crystallographic changes due to water vapour uptake in anhydrous lactose powder

Microcalorimetry at 25.0°C was used to investigate the incorporation of hydrate water in roller-dried anhydrous lactose that consisted of 31% α- and 69% ß-lactose. Differential scanning calorimetry and water vapour uptake measurements were also performed. The samples were stored for various lengths of time in the range 33–94% relative humidity (RH) at ambient temperatures, before measurement. The anhydrous α-lactose can accommodate a water molecule to become α-lactose monohydrate. ß-Lactose can only exist as the anhydrous form, but it can mutarotate to α-lactose and subsequently incorporate water, as shown by others. It was only at the highest humidity investigated (94% RH) that the mutarotation became an extensive process, although it was shown that the mutarotation did proceed at humidities lower than 94% RH and that it started before all the original anhydrous α-lactose had been converted to the monohydrate form. With the microcalorimetric technique, it was possible to monitor the incorporation of water after 1 day of storage at 58% RH. Furthermore, after 112 days of storage at 94% RH, it was still possible to detect a process, although the standard DSC instrument could not discriminate a change in the heat of dehydration level. It was concluded that, using microcalorimetry, a sensitive characterization of the incorporation of water in the lactose structure was possible and that microcalorimetry can be useful in solid state stability work.

The microcalorimetric approach to human sperm physiology

Heat conduction microcalorimetry has been adopted to evaluate overall basal metabolism in human spermatozoa. Heat output has also been measured in the presence of some metabolic inhibitors in an attempt to relate it to different cellular energetic pathways. Owing to the presence in spermatozoa of mechanochemical events of motility, microcalorimetric data have also been compared with those derived from cell motility analysis. When basally evoked heat was recorded in a rotating batch calorimeter, a mean value of 127.7 mcal h −1 per 10 8 spermatozoa was obtained, which was greatly different from that measured in a static calorimeter. On this basis, the adoption of microcalorimetric instruments in (human) sperm heat production studies is critically analysed. Dose-response experiments showed that metabolic poisons, azide, fluoride and rotenone, induced both heat output and motility reduction. Our first data indicate that, given appropriate experimental conditions, batch calorimetry could represent a promising, powerful tool in the still largely obscure, challenging field of human male gamete physio(patho)logy.

Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies (II) Methods to evaluate the microcalorimetric response

In this study, a well-known reaction, the hydrolysis of acetylsalicylic acid in aqueous solutions between pH 1.9 and 7.5 at 40.0 and 50.0°C, has been investigated by a microcalorimetric technique. The heat flow produced from the reaction was monitored as a function of time, and the degradation rate constant was then calculated from the slope. The precision was evaluated by repeated measurements at 40.0 and 50.0°C, respectively. The obtained rate constant-pH profile had the same general appearance as has been reported earlier for other temperatures. At 40.0°C and in the pH region of maximum stability the value of the rate constant showed low precision, because of a small heat flow change. As alternatives, the heat flow-time curves were evaluated by other methods to characterize stability. The heat flow value for a defined time (2, 4, and 12 h) and the quantity of heat evolved during a defined time interval (2–4, 1–7, and 0–11.5 h) were used. These pH profiles had the same shape, position of the minimum and plateau, as the rate constant-pH profile, except for heat flow at 12 h at 50.0°C. The two alternatives, the heat flow at 4 h and the quantity of heat at 2–4 h, also gave improved precision and the experimental time was shortened. Thermodynamic data for the transition state were calculated for two pH values. The resulting data were found to agree with the literature. The entropy of activation has a negative value, which indicates that the activated complex has a more organized structure than do the reactants.

Heat conduction microcalorimetry of overall metabolism in rabbit alveolar macrophages in monolayers and in suspensions

A technique has been developed for studying the overall metabolism in small numbers of cells in monolayers and in suspensions by measuring the heat exchange rate with a thermopile heat-conduction microcalorimeter. The system was tested with alveolar macrophages from rabbits, and heat flux-time curves could be monitored from numbers of cells as low as 0.05 · 10 6. The metabolic activity was found to be unchanged or to decrease very slowly over a period of 20 h. In a conventional cell medium, without the addition of serum, a mean heat flux value of 19.4 (S.D. 3.2) pW · cell −1 (37°C, pH = 7,4) was obtained for alveolar macrophages in monolayers. The corresponding value for cells in the same medium, with addition fo 20% homologous rabbit serum, was 27.0 (S.D. 2.0). We suggeest that this calorimetric method can be used as a short-term cytotoxic test for measuring potentially toxic agents in our environments: this test can involve alveolar macrophages of either animal or human origin. In such an assay, the cells should be used in monolayers, and suspensions should be avoided. We found that when alveolar macrophages were used in suspension, the metabolic activity, measured as heat flux, was dependent on cell concentration, even at values as low as 0.2 · 10 6 cells per ml.

A calorimetric and equilibrium investigation of the hydrolysis of lactose

The thermodynamics of the hydrolysis of lactose to glucose and galactose have been investigated using both high pressure liquid chromatography and heat-conduction microcalorimetry. The reaction was carried out over the temperature range 282-316 K and in 0.1 M sodium acetate buffer at a pH of 5.65 using the enzyme beta-galactosidase to catalyze the reaction. For the process lactose(aq) + H2O(liq) = glucose(aq) + galactose(aq), delta G0 = -8.72 +/- 0.20 kJ.mol-1, K0 = 34 +/- 3, delta H0 = 0.44 +/- 0.11 kJ.mol-1, delta S0 = 30.7 +/- 0.8 J.mol-1.K-1, and delta Cop = 9 +/- 20 J.mol-1.K-1 at 298.15 K. The standard state is the hypothetical ideal solution of unit molality. Thermochemical cycle calculations using enthalpies of combustion and solution, entropies, solubilities, activity coefficients, and apparent molar heat capacities have also been performed. These calculations indicate large discrepancies which are attributable primarily to errors in literature data on the enthalpies of combustion and/or third law entropies of the crystalline forms of the substrates.

Thermodynamics of isomerization reactions involving sugar phosphates.

Thermodynamics of isomerization reactions involving sugar phosphates have been studied using heat-conduction microcalorimetry. For the process glucose 6-phosphate2-(aqueous) = fructose 6-phosphate2- (aqueous), K = 0.285 +/- 0.004, delta Go = 3.11 +/- 0.04 kJ.mol-1, delta Ho = 11.7 +/- 0.2 kJ.mol-1, and delta Cop = 44 +/- 11 J.mol-1.K-1 at 298.15 K. For the process mannose 6-phosphate2- (aqueous) = fructose 6-phosphate2- (aqueous), K = 0.99 +/- 0.05, delta Go = 0.025 +/- 0.13 kJ.mol-1, delta Ho = 8.46 +/- 0.2 kJ.mol-1, and delta Cop = 38 +/- 25 J.mol-1.K-1 at 298.15 K. The standard state is the hypothetical ideal solution of unit molality. An approximate result (-14 +/- 5 kJ.mol-1) was obtained for the enthalpy of isomerization of ribulose 5-phosphate (aqueous) to ribose 5-phosphate (aqueous). The data from the literature on isomerization reactions involving sugar phosphates have been summarized, adjusted to a common reference state, and examined for trends and relationships to each other and to other thermodynamic measurements. Estimates are made for thermochemical parameters to predict the state of equilibrium of the several isomerizations considered herein.

Kinetics and Thermodynamics of Chemical Reactions in Li / SOCl2 Cells

The kinetics of the heat producing processes in undischarged and partially discharged cells under open‐ and closed‐circuit conditions have been measured by heat conduction microcalorimetry. The cells studied, Honeywell Type G2666 reserve cells, were activated as needed, and the rates of open‐ and closed‐circuit heat output were determined as a function of time since activation, temperature, and state of discharge. The results of the open‐circuit measurements on whole cells are described by an equation of the form where is the rate of heat output, is the heat produced per unit of reaction, and are empirical constants, and is the time since activation. Both and are found to be functions of temperature. Heat producing processes occur at both the anode and cathode under open‐circuit, undischarged conditions, but the processes at the carbon cathode produce only a few percent of the total heat. The state of discharge has only a small effect on the open‐circuit rate of heat production. Withdrawing current from cells greatly increases the rate of heat output from noncurrent producing reactions. At short times after activation (i.e., <200h) and at high temperatures, the heat produced by nonfaradaic processes can be several times as large as the heat produced by external current being drawn from the cell. At short times after activation, the excess heat is probably due to corrosion of Li, and, at long times after activation, the excess heat is probably due to the reaction of a long‐lived intermediate in the cell electrolyte. A thermodynamic analysis of the cell gives values of and values of , where and are the enthalpy and entropy changes for the cell reaction occurring at the electrodes.