Calorimetric purity method

The basis of any calorimetric purity method is the relationship between the melting depression of a substance and the level of impurities according to van t Hoffs law. The purity is readily calculated from the DSC curve of a single melting event of a few milligrams of the substance, without the need for reference standard of the drug substance and its impurities. 

DSC provides a rapid, accurate and precise method for determining absolute purity. A small amount of sample (milligrams) is required and it is not necessary to use a high-purity standard of the compound for an accurate purity determination. The calorimetric purity method is accepted by the US Pharmacopeia/National Formulary [12] as a reference test method. 

The purity determination of low-molecular-mass organic crystalline compounds by DSC (the so-called calorimetric purity method) is a popular technique because it is simple and quick. While this technique is not specific regarding the contaminations in low-molecular-mass crystalline substances, it can give purity estimations with reasonable accuracy in about 1-2 h. Also, there is no need for a highly skilled scientist within a couple of hours, an operator can be trained to carry out the measurements. 

A good example of an application of the van t Hoff calorimetric purity method is the determination of purity of 4,4 -thiobis(3-methyl-6-rm-butylphenol), a commercial antioxidant, with the trade name Santonox R and a molecular mass of 358g/mol. This type of phenolic antioxidant is used to prolong the life of polyolefins exposed to oxygen. Two comparative melting scans of different lots of Santonox R revealed a startling difference in melting behavior as shown in Fig. 2.11 (Bair 1997). 

The calorimetric purity determination is a rather fast and comfortable method, but the above-mentioned limiting assumptions restrict the precision and uncertainty of the results compared with, say, chromatographic methods that are available nowadays. 

Differential scanning calorimetric methods are applied for the determination of heat of fusion, purity, specific heat and activation energy of decompn for undiluted, unmixed samples of TNT, TNB, Tetryl, RDX, HMX and PETN (Ref 28). The differential thermal analysis thermo-... 

Calorimetric methods are infrequently used for routine quality control purposes because of their non-specific nature and relatively slow speed. However, data from calorimetry experiments are commonly presented in applications for new product licenses and in support of patent applications. To ensure the integrity of all calorimetry data, normal procedures for good laboratory practices, standard operating procedures, appropriate calibration methods, and regular instrument servicing are necessary. The use of DSC for the measurement of transition temperatures and sample purity is described in the United States Pharmacopoeia, and standard procedures for DSC analyses are also suggested by the ASTM (100 Barr Harbor Dr., West Conshohocken, Pennsylvania 19428). 

The purity of metallic surfaces may undoubtedly be enhanced by flashing or evaporating the adsorbing metal, but this method is not applicable to the oxide type of catalysts. Differential adsorption heats on various oxide catalysts have been determined with the indirect method by the author and his co-workers. As a rule, the differential heats of adsorption found in this way proved larger than any of the heats of adsorption formerly reported on the basis of calorimetric measurements. 

The-purity of a /i-pentane sample was determined by a calorimetric method by Clarke et al. (20). The results obtained for pure u-pentane and for a synthetic n-penlane-iso-octane mixture are given in the resistance (temperature) versus time curve in Figure 10.11. For purity determination, these data have been converted to the fraction melted after each equilibration period by allowing for the heat necessary to raise the temperature of the solid and liquid and for the amount of heat leak from radiation and conduction. The heat of fusion determined from this work was 2090 calories per mole, which gave a purity of 99.79 mole-% for the n-pentane. 

A comparison between the DSC method (using the Perkin-Elmer DSC-1B instrument) and the premelting method of Johnston and Giauque (51) is shown in Table 10.3 (52). Johnston and Giauque (51) came to the conclusion that the nitric oxide used in their measurements contained less than 10"3 mole-% of eutectic impurities, or the so-called purity is of the order of 99.999%. The authors excluded the possibility of noneutectic impurities. It should be noted that the difference between the two methods is not in thermodynamics but rather in instrumentation and the properties of the methods of measurement. The disadvantage of the calorimetric method is the extremely long measurement time of 2-4 days, which is due to the large sample masses and the necessity for equilibrium to be attained at each temperature. The penalty for a shorter analysis time is, of course, a lower accuracy in purity measurements. 

An alternative method consists in subjecting high-purity nickel metal to chlorination in a calorimetric bomb according to reaction ... 

Krauss and Wamcke used two different calorimetric methods to determine the specific heat of high-purity nickel. The measurements in the temperature range between 180 and 600°C were carried out using a continuous calorimetric technique and between 500 and 1160°C by means of reverse calorimetry . The source of heat in the last method was a Pt-rod of known temperature and heat capacity which was placed into the calorimeter containing a nickel sample. The separation of the determined heat capacity into a lattice-vibration term, a magnetic term and a residual term was briefly discussed in this paper. The reported data were used by this review for fitting of the thermal heat capacity function for nickel crystal. 

In the p-alkoxyphenyl esters of cyclohexanedicarboxylic acid, the series was prepared and thermally examined in which the alkoxy group was varied from methoxy through hexyloxy The thermal properties and analytical results for this series are listed in Table 1. The first two members of the series have only nematic mesophases, while the propoxy through the hexyloxy have both nematic and smectic phases As the length of the alkyl tail increases, so does the complexity of the transitions There are four distinct solid polymorphs in the pentyloxy and three in the hexyloxy compound The hexyloxy also has three smectic phases as well as the nematic These three transitions were identified as smectic by microscopy, however no attempt was made to assign them to a particular class The heats of two of these transitions were too small to measure with any degree of accuracy and only the temperatures were recorded Solid polymorphism, such as encountered in these compounds where the transitions occur at very close temperatures, prevents the application of the differential scanning calorimetric method for determination of purity ... 

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