DSC purity method

The DSC method for calculating purity is not universally applicable to all compounds. The material being studied should not undergo decomposition during melting. The DSC curves in Figure 1020 represent cases in which the DSC purity method should not be applied (70). 

Figure 10.20. DSC curves of compounds that should not be studied bv the DSC purity method (2t).

Since procaine hydrochloride melts without decomposition, the DSC method can be used to establish the absolute purity of the material. The DSC purity of the tested sample was found to be 100.14 mole%, and the enthalpy of fusion for this sample was determined to be 31.5 kJ/mole (7.52 Kcal/mole). 

Differential scanning calorimetry (DSC) The method to measure the heat flow to a sample as a function of temperature. It is used to measure, for example, specific heats, glass transition temperatures, melting points, melting profiles, degree of crystallinity, degree of cure, and purity. 

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. 

When a compound is observed to melt without decomposition, DSC analysis can be used to determine the absolute purity [44]. This method can therefore be used to evaluate the absolute purity of a given compound without reference to a standard, with purities being obtained in terms of mole percent. Unfortunately, the method is limited to reasonably pure compounds that melt without decomposition, since the assumptions justifying the methodology fail when the compound purity is below approximately 97 mole%. 

Thermal methods have found extensive use in the past as part of a program of preformulation studies, since carefully planned work can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [2], It should be noted, however, that the use of differential scanning calorimetry (DSC) for such work is less in vogue than it used to be. Nevertheless, in appropriately designed applications, thermal methods of analysis can be used to evaluate compound purity,... 

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). 

Phase diagrams with monotropic transformation or enantiotropic transformation have been discussed. " Quite interesting is the transformation of the racemic compound into a conglomerate since this phenomenon can be used for purification via crystallization, as described for nimodipine. DSC is applied for the establishment of phase diagrams, for the determination of thermodynamic data, for the purity determination, or for the monitoring of industrial resolutions. For the establishment of phase diagrams it is suitable to add spectroscopic or crystallographic methods. ... 

DSC) is a method that measures the difference in energy (heat flux or heat flow) between a reference and a sample. The result of a DSC analysis is a thermogram, a plot of temperature difference versus temperature and represents the enthalpies of various processes occurring in the heated sample, such as solvent loss, crystallization, polymorphism, and chemical reactions. Additionally, DSC is an absolute method and with proper calibration can be used to accurately measure the melting point and purity of the reference material.52,53... 

DSC, melting point DSC methods may be developed to determine crystal purities, and transformation of one polymorph to another during heating. 

In most cases, the purity of a pharmaceutical substance is determined by comparison of the reference standard with the known purity assigned. On the other hand, when no reference standard sample is available, the purity is determined by an absolute method in which the calculated result is based on theory and not by a comparative method. Purity established by analytical methods such as phase-solubility analysis or differential scanning calorimetry (DSC) is known as absolute purity (Figs. 3 and 4). 

The applications of DTA and DSC techniques to organic compounds are quite diverse, as is seen in Figure 7.32. It is difficult to point to one of the applications as the most important, or. for that matter, the most widely used. In the pharmaceutical and organic compound manufacturing industries, purity determination is perhaps the most important application. In other areas, identification only may be of vital interest. Only recently, due to the use of sealed-tube DtA and DSC sample holders, the study of organic reactions has assumed some importance. Information can be obtained from a single run which would normally take hours or days to complete by standard methods. 

The determination of the relative purity of an organic compound by DTA and DSC methods will be discussed in Chapter 10. Most of the analytical methods are based on the DSC technique, although DTA may also be used. 

Sample First Reaction Second Reaction Purity by DSC Method (mole%)... 

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. 

The DSC method for the purity determination of organic compounds has been extensively and critically reviewed by numerous authors. One of the most comprehensive reviews is that by Marti (52) others include those by... 

All the DSC methods of purity determination depend on the applicability of the van t Hoff equation. This restricts the method to systems where the impurity forms a simple eutectic phase diagram with the major component that is, the impurity or impurities are soluble in the melt and the components do not form solid solutions (53). Use of the van t Hoff equation assumes that the solution of impurity in major components above the melting point is an ideal solution in the thermodynamics sense. Also, the method assumes that the solid-liquid system is essentially in true thermodynamic equilibrium during the measurements. Failure to meet any of these conditions will lead to erroneous results. Other possible errors are associated with the instrumentation employed. This involves the use of the smallest possible sample size consistent with homogeneity (50), proper encapsulation to minimize temperature gradients within the sample, and the slowest possible heating rate lo approach equilibrium conditions. It is recommended that the melting... 

The estimation of purity of pharmaceutical compounds is one of the most important aspects of a drug profile (67). Use of the DSC method has significantly decreased thetime necessary for such an analysis. 

Impurities in liquid crystal materials can induce the appearance of a mesophore where none exists in a purer sample, or can inhibit the formation of a mesophore that would be present (68). Small amounts of impurity may broaden and shift the mesophore transition to lower temperatures by several degrees. Hence, the DSC method is useful for the determination of liquid crystal purity. 

A correlation of the purity determined by DSC and by the phase solubility method for several pharmaceutical samples is given in Table 10.6 (69). The correlation between these two methods is quite good. Seven independent determination of the purity of estradiol dipropionate sample gave a standard deviation of 0.04% purity. 

The lower limit of purity determination using the stepwise DSC method is about 95 mole-% without linearization and 92 mole-% with linearization (57). However, the time required is approximately I -2 hours compared to about 30 min for the DSC method. Using only two peaks in the stepwise DSC method, the investigators concluded that this method could be used down to 90 mole-%. Palermo and Chiu (57) do not think that it can be used below this value because the van t Hoff approximation becomes invalid. The two-step method is independent of the heat of fusion and less time-consuming. It was cautioned that other analytical methods should always be used in conjunction with DSC methods, whenever possible. Once the applicability of the method is established, DSC may prove to be the most convenient one to use. 

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