thin film on top of the substrate
Chapter 4: Prediction of drug-polymer miscibility and solubility using different theoretical approaches using different theoretical approaches
4.3.3 Melting enthalpy approach .1 Theoretical background .1 Theoretical background
4.3.3.2 Solid solubility predicted by the enthalpy approach
The same data sets used in the melting point depression approach was also used for this approach (physical mixtures of fenofibrate and EUDRAGIT® EPO were tested at the heating rate of 1oC/min). The plot of melting enthalpies of model drugs in physical mixtures with EUDRAGIT® EPO against drug ratios is shown in Figure 4.10. Three drug-polymer behaviours were observed for all physical mixtures of model drugs and EUDRAGIT® EPO. According to the theory mentioned above, two breaking points in the regression line are defined as solid solubility of the drug in the polymer and solid solubility of the polymer in the drug. Therefore, solid solubility of model drugs in EUDRAGIT® EPO is circa 20% (w/w) for felodipine, 20% (w/w) for fenofibrate, 30% (w/w) for carbamazepine and 40% (w/w) for fenofibrate.
Figure 4.10: Plot of melting enthalpies of model drugs in physical mixtures against drug ratios (a:
felodipine; b: celecoxib; c: carbamazepine; d: fenofibrate).
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Solid solubility of model drugs in EUDRAGIT® EPO predicted by this approach was still restricted to a high narrow temperature range which is close to the melting points of the crystalline model drugs. This is because the drug-polymer behaviours mentioned in the theory occurred at high temperatures where the equilibrium of the dissolution of model drugs into the polymer can be established rapidly due to their low viscosity at high temperature. Therefore, there may still be deviation from the true drug-polymer solubility at room temperature.
Solid solubility of model drugs in EUDRAGIT® EPO predicted by different theoretical approaches are summarised in Table 4.6. It can be seen that the predicted solid solubility of individual drugs in EUDRAGIT® EPO varies significantly depending on the method applied. For instance, predicted solid solubility of carbamazepine in EUDRAGIT® EPO varies ranging from 15%
to 46% (w/w) by different approaches. Several factors can contribute to the discrepancy of predicted solid solubility. Firstly, the applied approaches are all based on different assumptions and they all have limitations and restrictions, which may be far different from real drug-polymer cases.
Secondly, solubility is a parameter associated with temperature and pressure, and it is reasonable that solid solubility predicted by the solubility parameter method is different form that by melting point depression method since the former is on the basis at room temperature and the latter is applied at the temperature close to melting points of model drugs. Thirdly, predicted solid solubility by theoretical approaches are thermodynamic solubility which is not related to the preparation process, for instance apparent solid solubility of drugs in polymers can vary significantly between prepared by film casting and by spray drying (39). Therefore, the application of theoretical approaches may not be accurate in predict the physical stability of amorphous solid dispersions prepared by different processing methods. standard pressure; c: condition of temperature close to melting points of individual drug, standard pressure.
143 4.4 Conclusions
In this chapter, three commonly used theoretical approaches, including solubility parameter, melting point depression and a enthalpy method, were applied to predict model drugs-EUDRAGIT® EPO miscibility and solubility. Discrepancies of predicted results can be found due to the fact that the applied approaches are based on different assumptions and solid solubility was also predicted at different temperatures. It has been agreed that solid solubility is one of the key factors which plays important impact on physical stability of solid dispersions. However, predicted drug-polymer solubilities by different theoretical approaches vary in a relatively large range, which may indicate these methods are less accurate. More significantly, these theoretical approaches did not take into account the effect of processing method on the drug-polymer solubility. Therefore, in order to predict drug-polymer solubility more accurately, processing related prediction method is required to be established. Accordingly, in the next chapter, a practical method for the prediction of the solubility of drugs in melt extrudates is developed.
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