Thermal events

Mixing Cell Calorimetry (MCC) The MCC provides information regarding the instantaneous temperature rise resulting from the mixing of two compounds. Together, DSC and MCC provide a reliable overview of the thermal events that may occur in the process. 

A 100 Degree Rule was often used in the past throughout the chemical industry to assess whether an accident would occur. According to this rule, if the operating temperature of a process is 100 "C away from the nearest detectable exotherm observed in DSC (Differential Scanning Calorimetry) experiment the operation will not experience this thermal event. In such a case no more detailed information on hazards need be searched for. The 100°C degree rule is, however, often far from the safety margin The use of this rule was the reason of many accidents. 

The only thermal event in the differential thermal analysis curve of (/))-penicillamine is the melting endotherm at 185 °C. Either polymorph of (z>)-penicillamine gives the same endotherm [2]. 

Differential thermal analysis (DTA) is the monitoring of the difference in temperature between a sample and a reference as a function of temperature [42], Differences in temperature between the sample and reference are observed when changes occur that require a finite heat of reaction. If AH is positive (endothermic reaction), the temperature of the sample will lag behind that of the reference. If the AH is negative (exothermic reaction), the temperature of the sample will exceed that of the reference. Differential thermal analysis is not normally used for quantitative work instead it is used to deduce temperatures associated with thermal events. 

Solid state characterization studies of the previously mentioned polymorphic systems [26-34] all utilize IR as a means to differentiate the various crystal modifications. In some cases, the observation of variations in IR absorption intensities has led to conclusions regarding intramolecular hydrogen bonding [26]. For other systems, fairly complete IR spectral band assignment has allowed for determination of structure for the polymorphic system. In one study [29], DSC-IR was used to identify the polymorphs and determine simultaneously the correlation between thermal events and structural changes. 

Although it is possible to use DTA as a quantitative tool, such applications are not trivial. For this reason, DTA has historically been mostly used in a quantitative sense as a means to determine the temperatures at which thermal events takes place. Owing to the experimental conditions used for its measure-... 

It was recognized quite some time ago that DTA analysis could be used to deduce the compatibility between a drug substance and its excipients in a formulation. The effect of lubricants on performance was as problematic then as it is now, and DTA proved to be a powerful method in the evaluation of possible incompatibilities. Jacobson and Reier used DTA to study the interaction between various penicillins and stearic acid [17]. For instance, the addition of 5% stearic acid to sodium oxacillin monohydrate completely obliterated the thermal events associated with the antibiotic. Since that time, many workers employed DTA analysis in the study of drug-excipient interactions, although the DTA method has been largely replaced by differential scanning calorimetry technology. 

In many respects, differential scanning calorimetry (DSC) is similar to the DTA method, and analogous information about the same range of thermal events can be obtained. However, DSC is far easier to use routinely on a quantitative basis, and for this reason it has become the most widely used method of thermal analysis. The relevance of the DSC technique as a tool for pharmaceutical scientists has been amply documented in numerous reviews [3-6,25-26], and a general chapter on DSC is documented in the U.S. Pharmacopeia [27]. 

In the DSC method, the sample and reference are maintained at the same temperature and the heat flow required to keep the equality in temperature is measured. Hence DSC plots are obtained as the differential rate of heating (in units of watts/second, calories/second, or Joules/second) against temperature. The area under a DSC peak is directly proportional to the heat absorbed or evolved by the thermal event, and integration of these peak areas yields the heat of reaction (in units of calories/second gram or Joules/second gram). 

Table 11.2 Thermal events. (From Introduction to Thermal Analysis, M. E. Brown, Chapman Hall)...

Carrington, A. K., Sahagian, M. E., Goff, H. D., Stanley, D. W. Ice crystallization temperatures of sugar/polyasaccharide solutions and their relationship to thermal events during warming. Cryo-Letters, 15, p. 235-244, 1994... 

The calibration of DTA systems is dependent on the use of appropriate reference materials, rather than on the application of electrical heating methods. The temperature calibration is normally accomplished with the thermogram being obtained at the heating rate normally used for analysis [20], and the temperatures known for the thermal events used to set temperatures for the empirically observed features. Recommended reference materials that span melting ranges of pharmaceutical interest include benzoic acid (melting point 122.4°C), indium (156.4°C), and tin (231.9°C). 

In the DTA measurement, an exothermic reaction is plotted as a positive thermal event, while an endothermic reaction is usually displayed as a negative event. Unfortunately, the use of power-compensation DSC results in endothermic reactions being displayed as positive events, a situation which is counter to IUPAC recommendations [38]. When the heat-flux method is used to detect the thermal phenomena, the signs of the DSC events concur with those obtained using DTA, and also agree with the IUPAC recommendations. 

TG analysis also represents a powerful adjunct to DTA or DSC analysis, since a combination of either method with a TG determination can be used in the assignment of observed thermal events. Desolvation processes or decomposition reactions must be accompanied by weight changes, and can be thusly identified by a TG weight loss over the same temperature range. On the other hand, solid-liquid or solid-solid phase transformations are not accompanied by any loss of sample mass and would not register in a TG thermogram. 

TG is a powerful adjunct to DSC studies, and are routinely obtained during evaluations of the thermal behavior of a drug substance or excipient component of a formulation. Since TG analysis is restricted to studies involving either a gain or a loss in sample mass (such as desolvation decomposition reactions), it can be used to clearly distinguish thermal events not involving loss of mass (such as phase transitions). 

MDSC is particularly useful for the study of reversible (related to the heat capacity) thermal reactions, and is less useful for non-reversing (kinetically controlled) reactions. Examples of reversible thermal events include glass transitions, heat capacity, melting, and enantiotropic phase transitions. Examples of non-reversible events include vaporization,... 

Based on DSC and TGA experiments in combination with XRD examination and comparison with thermal events observed by other authors [173,174,178,183] who also investigated the thermal behavior of Mg(BH )j we proposed the following scheme of phase transformations taking place during milling and subsequent thermal experiments [175] ... 

Surprisingly, when the cathode material, LiCo02, was in the presence of these thermally stable salts, Lilm and LiMe, much higher reactivity was detected than that in the presence of LiPFe, as indicated by the total absence of any combustion suppression on SHR that had been observed with LiPFe. DSC results of LiCoOz in the presence of Lilm- or LiBeti-based electrolytes confirmed the above observation, which showed the onset thermal decomposition of LiCo02 to be at 280 °C, whereas in LiPFe-based electrolytes the same thermal event was much suppressed in terms of heat evolution as the concentration of LiPFe increased. In other words, the presence of Lilm and LiBeti did not introduce any increase in the thermal stability of the electrode, while LiPFe, although believed to be thermally unstable, efficiently suppressed the thermal decomposition of the cathode. 

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