DSC measures the change in energy that occurs as a sample is heated at a constant rate [271].
The principle involves heating two ovens to the same temperature at the same rate with one oven containing the sample to be tested in a sealed pan and the other containing an empty pan, serving as reference. Changes in the sample such as melting will result in consumption of energy and the process is classified as an endothermic event. Energy release will occur if a change such as crystallisation takes place and this process is called an exothermic event.
121 | P a g e
Since the reference pan remains constant, a thermogram displaying thermodynamic changes of a sample is produced indicating release or uptake of energy [271, 272].
The DSC thermogram of NVP revealed a single sharp symmetrical melting endotherm at 250
°C with a ΔH =504.5376 J/g and is depicted in Figure 4.4, indicating that NVP is not a hydrate or solvate. This value of the melting point was within the previously reported range of 244 - 250 °C [11, 270].
Figure 4.4. DSC thermogram of NVP generated at a heating rate of 10 °C/min.
The thermogram for DCP was broad and asymmetrical and revealed the presence of an endotherm at a temperature of 199.50 °C with a ΔH = 497.1446 and is shown in Figure 4.5.
The endotherm may be attributed to the loss of a water of crystallisation [273].
122 | P a g e
Figure 4.5. DSC thermogram of DCP generated at a heating rate of 10 °C/min.
The DSC thermogram of Mg stearate showed a broad and asymmetrical melting endotherm at 120.00 °C with a ΔH = 76.7026 J/g and is shown in Figure 4.6. The melting endotherm was in close agreement with the reported melting range of 110-120 °C and can be attributed to the fusion of Mg stearate [217, 274].
123 | P a g e
Figure 4.6. DSC thermogram of Mg stearate generated at a heating rate of 10 °C/min.
The DSC thermogram of SDL depicted in Figure 4.7 reveals the presence of a broad and symmetrical endothermic peak at 148.50 °C with a ΔH = 137.5859 J/g and can be attributed to dehydration of the lactose. The thermogram also revealed the presence of a broad asymmetrical endothermic peaks at 224.17 °C (ΔH = 129.1749 J/g) and at 234.17 °C (ΔH = 19.9389 J/g) which may be attributed to the heats of fusion of the α- and β forms of –lactose present in the SDL sample [275-277].
124 | P a g e
Figure 4.7. DSC thermogram of SuperTab® SDL generated at a heating rate of 10 °C/min.
The thermograms for colloidal silicon dioxide, talc, Eudragit® RS PO, Methocel® K4M, Avicel® PH102 and Carbopol® 71G NF did not show any significant enthalpy changes in the temperature ranges as can be observed in Figures 4.8a – 4.8f.
125 | P a g e
Figure 4.8a. DSC thermogram of colloidal silicon dioxide generated at a heating rate of 10°C/min.
Figure 4.8b. DSC thermogram of Avicel® PH102 generated at a heating rate of 10 °C/min.
126 | P a g e
Figure 4.8c. DSC thermogram of Eudragit® RSPO generated at a heating rate of 10 °C/min.
Figure 4.8d. DSC thermogram of Carbopol® 71G NF generated at a heating rate of 10
°C/min.
127 | P a g e
Figure 4.8e. DSC thermogram of Methocel® K4M generated at a heating rate of 10 °C/min.
Figure 4.8f. DSC thermogram of talc generated at a heating rate of 10 °C/min.
128 | P a g e
The DSC thermogram of a 1:1 binary mixture of NVP and Avicel® PH102 revealed the presence of a single sharp and symmetrical endothermic peak at a temperature of 254.00 °C as shown in Figure 4.9 and which is slightly higher than the melting point of NVP. The 4°C increase in the melting point of NVP may be attributed to a shielding effect usually associated with microcrystalline cellulose [278].
Figure 4.9. DSC thermogram of a 1:1 binary mixture of Avicel® PH102 and NVP generated at a heating rate of 10 °C/min.
The DSC thermograms of 1:1 binary mixtures of NVP and the excipients under investigation exhibited a reduction in the melting point of NVP and the excipients when compared to the values observed for the individual compounds as shown in Figures 4.10-4.14.
The thermograms of the binary mixture of NVP and Mg stearate showed a sharp symmetrical melting endotherm of 245 °C for NVP and 112.17 °C for magnesium stearate as shown in Figure 4.10.
129 | P a g e
Figure 4.10. DSC thermogram of a 1:1 binary mixture of NVP and Mg stearate generated at a heating rate of 10 °C/min.
The thermogram of a 1:1 binary mixture of NVP and Methocel® K4M yielded a symmetrical peak with a broad base as shown in Figure 4.11, which could be an indication of a change from a crystalline phase to an amorphous phase that may also have an implication for the stability of NVP in HPMC containing dosage forms [278]. The melting endotherm of NVP also decreased to 243.5 °C.
130 | P a g e
Figure 4.11. DSC thermogram of a 1:1 binary mixture of Methocel® K4M and NVP generated at a heating rate of 10 °C/min.
The DSC thermogram of a 1:1 binary mixture of NVP and DCP showed a decreased sharp and symmetrical melting endotherm of NVP of 245.67 and a broad symmetrical melting endotherm of 193.33 °C for DCP as shown in Figure 4.12.
131 | P a g e
Figure 4.12. DSC thermogram of a 1:1 binary mixture of NVP and DCP generated at a heating rate of 10 °C/min.
The DSC thermogram of a 1:1 binary mixture of NVP and SuperTab® SDL showed a sharp symmetrical melting endotherm of 240 °C for NVP as shown in Figure 4.13, with almost complete disappearance of endothermic peaks attributed to heats of fusion of the α- and β- forms of lactose at 219.33 °C and 230 °C. The reduced peak heights may be an artefact of the quantities of materials used to conduct DSC.
Figure 4.13. DSC thermogram of a 1:1 binary mixture of NVP and SDL generated at a heating rate of 10 °C/min.
The DSC thermogram of a 1:1 binary mixture of NVP and talc showed a sharp and symmetrical endothermic peak of 245.67 °C for NVP as shown in Figure 4.14.
132 | P a g e
Figure 4.14. DSC thermogram of a 1:1 binary mixture of NVP and talc generated at a heating rate of 10 °C/min.
The decrease in the peak height of the endotherms of NVP and the excipients may be a consequence of the low mass of samples used as this is known to affect the intensity of peaks when using DSC [278].
The dilution effect of excipients on the response generated from an API is a shortcoming of using DSC as a definitive tool to study any possible drug-excipient interactions. However, significant changes in the melting point of an API are indicative of any potential interactions that may warrant further investigation using additional and more specific analytical techniques. The reduced melting point of NVP that was observed in the presence of excipients indicates that it is unlikely that any significant interactions would occur as the shifts in the melting points were < 10 °C. However there is evidence of a potential for a decrease in the thermal stability of NVP [279] and similar studies have shown that Mg stearate [280], MCC, HPMC and silicon dioxide [281] can decrease the thermal stability of an API. Although DSC analysis is used as a preliminary screening tool for compatibility evaluation it does not preclude the need for long term stability studies on manufactured
133 | P a g e
dosage forms in order to be able to draw meaningful conclusions in respect of the long term stability of products.