DSC purity determination

Other programs which can be used to calculate reaction kinetics from DSC data were formulated by Kauffman and Beech (41) and Rogers and Smith (42). Heuvel and Lind (43) used a computer to correct DSC data for effects due to thermal lag and heat capacity changes, while Sondack (44) developed a simple equation for linearization of data in DSC purity determinations. 

The important parameters during a DSC purity determination are the following ... 

Quantification of amorphous content using DSC Purity determination using DSC... 

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). 

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. ... 

Because of the large number of applications of the techniques of DTA and DSC, the applications described here will be concerned mainly with analytical chemistry problems. In this area, DTA and DSC can be used as a control or a routine tool for comparing similar but not identical materials. As a control technique, it may be used to distinguish between raw materials quickly and easily in those cases in which the treatment of the material must be modified if slight changes in the material are encountered. As a comparison technique, DTA and DSC may be used in some cases to detect materials that yield anomalous results by other tests. Lastly, by suitable calibration of the instruments, these techniques may be used for the quantitative estimation of a substance or mixture of substances, or for purity determinations (see... 

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 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... 

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. 

Figure 10.IV. Flowchart representing the procedure used in purity determination by DSC (II). 

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. 

When using continuous DSC for purity determination, the data must be corrected for instrument lag and F must be corrected for the omitted portion E as shown in Fig. 4.42 for testosterone. Computer programs exist to optimize the fit to a linear curve. Over-correction would give a downward deviation instead of the upward deviation. This purity determination is only applicable if there is solubility of A and B in the melt, but no solubility of B in crystals of A (eutectic system). 

Owing to the finite sensitivity of the DSC apparatus, premelting of the sample may go undetected, affecting the accuracy of the purity determination. The extent of premelting is difficult to quantify and a number of empirical solutions have been proposed to combat this problem. The fractional area can be rewritten in the form... 

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. 

Temperature and enthalpy calibration of DSC curve. Calibration is carried out using the DSC curve determined under the same conditions as in step 2 for high-purity indium (purity >99.99%), and the leading slope of the indium is used to determine the instantaneous sample temperature during melting taking into account the heat-resistance correction and the heat of fusion of indium (28.41 J g ) used to calibrate the enthalpy of the DSC curve (mjcm" ). 

Purity determination of chanicals (quality control) by the location and sharpness of melting points determined by the nse of a DSC. 

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. 

The final equation for the purity determination by DSC as derived by Gray (1966a,b) is... 

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