Thermal analysis study of antihypertensive drug doxazosin mesilate

2.1 Materials

Doxazosin mesilate, raw material and Doxacor tablets were provided from the Minapharm Pharmaceuticals and Chemical Industries, Cairo, Egypt. The purity of doxazosin mesilate was found to be 99.80% according to the British pharmacopoeia, BP 2011.

2.2 Methods

Thermal analysis studies were made by using simultaneous TGA–DTA thermal analyzer apparatus (Shimadzu DTG-60H). The experiments were performed between ambient and 800 °C. The temperature program had a heating rate of 10 °C/min. Dry nitrogen at a low rate of 30 ml/min was used as the purge gas. α-Al₂O₃ was used as the reference material.

DSC curves were measured on Shimadzu DSC-50 cell. Approximately 2 mg of samples was massed out and placed in a sealed aluminum pan. An empty aluminum pan was used as a reference. The purity determination was performed using a heating rate of 10 °C/min in the temperature range of 25–400 °C in nitrogen atmosphere with a flow rate of 30 ml/min. DSC equipment was preliminary calibrated with a standard of indium.

3.1 Thermal analysis behavior of doxazosin mesilate

Fig. 2 indicates that the thermal decomposition of doxazosin mesilate occurs in three consecutive steps. The first step shows the loss of 28.31% in the temperature range of 240–365 °C due to the elimination of the substituent groups dimethoxy and methanesulfonate groups, the second step shows the loss of 24.78% in the temperature range of 365–457 °C due to the elimination of the C₈H₇O₂ molecule, the third step shows the loss of 46.54% in the temperature range of 457–800 °C due to the elimination of C₁₃H₁₂N₅O group and the complete decomposition of the compound.

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Figure 2

TGA, DTG and DTA curves of doxazosin mesilate.

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The DTA curve in Fig. 2 shows that the doxazosin mesilate has an endothermic peak and three exothermic peaks. The endothermic reaction peak which is not accompanied by weight loss occurs at 273 °C. This reaction may be attributed to the melting of the compound. Three exothermic peaks; an exothermic peak with its maximum at 325 °C may be attributed to the loss of dimethoxy and methanesulfonate groups, an exothermic peak at 455 °C as a shoulder may be attributed to loss of C₈H₇O₂ molecule and strong exothermic peak at 488 °C which may be attributed to loss of C₁₃H₁₂N₅O and complete decomposition of the compound.

3.2 Determination of purity of doxazosin mesilate

An important concern of analytical chemistry is the determination of purity of organic compounds. Most techniques that are currently being employed in instrumental analysis involve the analysis of a given sample in comparison with a standard sample. Advances in analytical instrumentation require an extremely high degree of purity warranty for standard samples, the determination of purity is thus important not only for laboratory use, but also for a broad spectrum of applications in which the quality warranty of reagent and drugs is vitally important. There is an increasing need for more accurate determination methods that are easy to use.

Thermal methods are easy to use, can be performed quickly and are effective in measuring unknown impurities. On the other hand, DSC may be a simple and rapid method of estimating the purity of materials. However, its use has been limited to a substance of rather high purity. The minimum purity required for this method is approximately 98%. Therefore, the DSC method is rarely used by itself to warrant purity. For this reason, traditionally chromatographic techniques such as HPLC and GC are used for purity measurement (Mathkar et al., 2009).

The determination of purity is based on the assumption that impurities lower the melting point of a pure substance. The melting transition of a pure, 100% crystalline substance should be infinitely sharp, but impurities or defects in the crystal structure will broaden the melting range and lower the melting point (Hatakeyama and Liu, 1998). In a system which contains impurities, Van^'t Hoff equation approximately holds and allows the purity value to be calculated as follows: $$T_{\text{f}}=T_0-[({\mathit{RT}}_0^{2}X/\mathrm{\Delta }{H}_{\text{f}}).1/F]$$ where T_f is the melting temperature of the sample, T₀ is the melting point of pure substance in Kelvin (K), R is the gas constant, ΔH_f is the heat of fusion, F is the fraction melted and X is the mole fraction of impurities.

Fig. 3 shows the DSC curve for doxazosin mesilate indicating an endothermic reaction with a sharp peak at 275 °C related to the melting point of the drug and another exothermic peak at 325 °C. The sample seems to be suitable for purity determination by the DSC method, the drug was found to be very pure (99.97%). As shown in Table 1 the purity of the drug was compared with that obtained by using the official method (99.80%) confirming low impurity content and also Table 1 showed satisfactory results for the melting point of the used drug by using different methods.

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Figure 3

DSC curves of doxazosin mesilate (a) and doxacor tablets (b).

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3.3 Quality control application of doxazosin mesilate

Thermal analysis is used as an alternative technique for the determination of different quality parameters such as water content and ash content. No significant difference was observed between the obtained results when compared with the reported method as shown in Table 2.

3.4 Thermal analysis application of doxacor tablets

TGA, DTG and DTA of doxacor tablets curves were presented in Fig. 4. The DTA of doxacor tablets indicates the melting of doxazosin mesilate at 212 °C. It was observed that the drug melting event occurs with mass loss; the onset and the end set temperatures of the DTA curve of the doxacor tablets were shifted to lower temperatures than that of the DTA curve of doxazosin mesilate. In fact a similar effect was observed for other drug excipients mixtures and was attributed to drug dissolution in the melted excipients (Cides et al., 2006).

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Figure 4

TGA, DTG and DTA curves of doxacor tablets.

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Fig. 5 shows the DTA curves of these excipients and doxacor tablets. The excipients can produce a different environment in which the behavior of the drug is modified but they are still compatible with the drug. Based on the results of DTA curves, majority of the excipients such as Mg stearate, povidone and microcrystalline cellulose were found to be compatible with the drug.

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Figure 5

DTA curves of doxacor tablets (a), microcrystalline cellulose (b), magnesium stearate (c) and povidone (d).

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DSC curve of doxacor tablets (Fig. 3) shows a sharp endothermic peak at 208.22 °C corresponding to the melting point of doxazosin mesilate. By comparing the melting point values of the pure drug shown in Table 1 with those obtained for doxazosin mesilate in doxacor tablets we found that the melting point values of the pure drug are higher than those in tablets due to the presence of excipients.