(T1130-03-16) Thermodynamic Phase Diagrams for Predicting Drug-Polymer Miscibility of High Melting Point Drugs with Poly-2-ethyl-tetra-oxazoline for Development of Amorphous Solid Dispersions

Purpose: Amorphous solid dispersions (ASD) have been the most sought-after formulations for the past few years. The development of ASD is a multi-step approach which involves the vital step of selecting a polymer for formulation development. For an ASD, the polymeric carrier is like a ‘governor’ because it dictates the performance of ASD after delivery. Previous reports suggest the use of Hansen-Hildebrand solubility parameters for the selection of polymeric carriers for ASD. However, solubility parameter estimations can fall short of truly predicting the degree of miscibility of the drug in the formulation. To address the same, techniques such as melting point depression (MPD) have been widely used to screen different polymers. The higher the miscibility of the drug, the higher the depression in the melting point (T_m). Apart from the depression in T_m, drug-polymer interactions (c) can be computed as an additional indicator drug-polymer miscibility. For drugs with high T_m there is a requirement of higher processing temperatures. However, reducing the processing temperatures have been the need of the hour. A system exhibiting a higher degree of melting point depression can be used to determine these lower processing temperatures. To investigate the same, the purpose of this study was to screen the potential of poly-2-ethyl-tetra-oxazoline (PETOX) in improving the drug-polymer miscibility of high melting point drugs and potentially reducing the processing temperatures for developing ASD.

Methods: 4 drugs with melting points ≥200°C were selected as model drugs for the study viz. Tolvaptan (TVPTN), carbamazepine (CBZ), theophylline (TPH), and hydrochlorothiazide (HCTZ) (Table 1.). Based on preliminary studies, two grades of PETOX viz. P50 (MW @ 50,000) and P500 (MW @ 500,000) were selected for their study. Nine different ratios of drug:PETOX (1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1) were prepared and then loaded into hermetically sealed pans for differential scanning calorimetry. All the samples were heated at a rate of 5°C/min from 25 to 300°C. Melting point (T_m), heath of enthalpy (ΔH_m), onset (T_o) and offset (T_off) temperatures of melting were recorded. To calculate the miscibility curve, drug-PETOX interaction parameter (cdrug-PETOX) was calculated at room temperature. The entropic (A) and enthalpic (B) constants were determined after establishing the cdrug-PETOX vs. 1/T relationship. Prediction of the solubility curve was performed by extrapolating the T_m of drug in drug-PETOX blend vs. drug in drug-polymer blend. To predict the drug-PETOX miscibility a thermodynamic phase diagram was constructed. A phase diagram consists of a miscibility, solubility, and glass transition (T_g) curve. Glass transition curve was predicted using the Gordon-Taylor equation.

Results: It was observed that the onset of melting for of all the four drugs were observed to decrease in the presence of PETOX. As shown in Fig. 1(a) and (b), there was a stark decrease in the T_o of TVPTN in presence of P50 in comparison to P500. The T_g of PETOX (59.8^oC) can/would possibly aid in improving the solubilization of the drug in the molten polymer. The value for χ_drug-PETOX for P500 and P50 were calculated to be 1.43 and -1.71, respectively. Hence, suggesting that TVPTN was more miscible in P50. Gibb’s free energy plot suggested that all volume fractions of TVPTN were miscible above 180^oC in P50. By plotting c vs. 1/T (R² = 0.89), a linear relationship was observed with the entropic constant (A) of -37.29 JK^-1 and an enthalpic constant (B) of 17640 J (Fig. 2(a) and (b)). From the phase diagram, it was observed that TVPTN was miscible with P50 at temperatures below its melting point. It can be predicted that ~7-10%w/w of amorphous TVPTN can be stabilized in the presence of P50. It was observed that at 170^oC, both the miscibility and solubility curves for TVPTN in P50 coincide with each other, thus indicating that TVPTN is miscible and soluble in P50 at this temperature. Similar observations were made for CBZ, TPH, and HCTZ.

Conclusion: Material-sparing techniques such as melting point depression method for screening are vital in early-stage development due to the limited active pharmaceutical ingredient being available. Selection of formulation design/strategy for these API’s is generally carried out in these nascent stages. In this study, we have explored the feasibility of melting-point depression method to evaluate the ability of PETOX to develop robust amorphous solid dispersions. Based on the results and calculations, it was observed that TVPTN had good miscibility in P50.


Fig. 1. Onset of melting temperatures of TVPTN in the presence of (a) P50 and (b) P500. A linear relationship was observed in the To with increase in polymeric concentration for P50. However, there was a non-significant reduction in melting temperature with P500.


Fig. 2. Interaction parameter of TVPTN with (a) P50 and (b) P500. Based on the regression equations, TVPTN had an interaction parameter with P50 and P500 of -1.71 and 1.43, respectively.


Table. 1. Physiochemical and thermal properties of selected API.