Category: Formulation and Quality
Purpose: Preparation of amorphous solids dispersions (ASDs) is a common strategy used to enhance aqueous solubility and bioavailability of poorly water-soluble drugs. During formulation development it is very important to evaluate and predict long term physical stability of ASDs, particularly in supersaturated systems, since these are thermodynamically unstable. The purpose of this study is to compare the different thermodynamic parameters used in stability evaluation and propose a toolbox that can effectively predict long term stability. Six amorphous drugs and three ASDs were studied and parameters such as configurational entropy, relaxation time, fragility and Kauzmann temperature were evaluated. A stability study was also conducted at 30 ºC to investigate correlations between these parameters and the onset of crystallization. Differential Scanning Calorimetry (DSC) was used to determine all parameters abovementioned.
Methods: Nifedipine, warfarin, indomethacin, itraconazole, sulindac and cimetidine were the drugs selected. Amorphous drugs and solid dispersions were prepared by melt-quenching in situ in the DSC (TA instruments, DSC250) and the melting and glass transition properties were measured. Parameters such as enthalpy, entropy and free energy differences between crystalline and amorphous forms were determined using heat capacity data . Solid dispersions of nifedipine with polymers PVP 29/30 and Eudragit EPO were prepared, at different ratios, by melt-quenching of the respective physical mixtures. The kinetic fragility was determined by varying the cooling rate used to melt-quench the samples, between 25 and 2 ºC/min . The molecular mobility below glass transition temperature was also evaluated in the DSC by annealing the samples at 30ºC for 2, 4, 6 and 12 hours and measuring the kinetics of relaxation.
The stability study was conducted at 30ºC, in an oven, with samples prepared by melt-quenching in a hot plate. During the stability study, the onset of crystallization was monitored by DSC and X-ray Powder Diffraction (XRPD) at time points 0, 1, 3, 7, 15, 22, 30, 45 and 60 days. XRPD measurements were performed with in a range of 5-50 º 2ϴ, with a scanning rate of 0.328 º/s and an acquisition time of 100 s/step.
Results: The crystallization tendency was evaluated for compounds with similar glass transition (Tg) and it was found that this parameter is not, per se, indicative of stability. For example, nifedipine (Tg of 45.96 ºC) crystallizes above Tg, during heating, while indomethacin (Tg of 46.38 ºC) does not.
The Kauzmann temperature was determined for the different drugs and solid dispersions and no correlation with melting or glass transition temperature was found. However, nifedipine, the drug with the lowest Kauzmann temperature (TK), was the first drug to crystallize during the stability study. In this case, the storage temperature was 68 ºC above TK. Drugs who have Kauzmann temperatures near or higher than the storage temperature (30 ºC) did not show any signs of crystallization.
The kinetic fragility, which is a measure of molecular mobility, was also determined and it was possible to establish a correlation between stability and fragility (Figure 1). Again, nifedipine showed a higher fragility and, subsequently, molecular mobility and tendency for crystallization.
Regarding the stability study, while nifedipine crystallizes after 3 days, indomethacin starts crystallizing after one and a half months. Warfarin also starts to crystallize towards the end of the study.
The annealing experiments revealed that the type of polymer has an impact on the stabilization of ASD: the variation of relaxation enthalpy of mixtures with Eudragit was significantly higher when compared to the ones with PVP.
Conclusion: The type of studies and thermodynamic evaluation presented here are very useful to assess and predict physical stability in early stages of formulation development. The results showed that the molecular mobility and Kauzmann temperature are a good indicative of physical stability and can be used to rank formulations in terms of physical stability. The employment of the thermodynamic approaches described is very advantageous and convenient as the data can be collected from simple DSC measurements and, at the same time, provide meaningful information about which factors impact the recrystallization behavior of amorphous materials.
 Almeida e Sousa L, Reutzel-Edens SM, Stephenson GA, Taylor LS. Assessment of the Amorphous “Solubility” of a Group of Diverse Drugs Using New Experimental and Theoretical Approaches. Mol. Pharm. 2015;12(2):484-95.
 Chakravarty P, Pandya K, and Nagapudi K. Determination of Fragility in Organic Small Molecular Glass Forming Liquids: Comparison of Calorimetric and Spectroscopic Data and Commentary on Pharmaceutical Importance. Mol. Pharm. 2018; 15(3): 1248-1257.