Isochronal Conditions—The Key To Maintain the Given Solubility Limit, of a Small Molecule within the Polymer Matrix, at Elevated Pressure

Abstract

In this work, we proposed the method to maintain the desired level of drug’s solubility within the polymer matrix by adjusting conditions to uphold the same molecular dynamics of the system (e.g., temperature for set elevated pressure or vice versa). Namely, we observed, that recrystallization of the drug from the supersaturated drug–polymer system, initiated for the same structural relaxation time of the sample (τ α-1 ) ceases when certain, different than the initial, molecular mobility of the systems is reached (τ α-2 )—regardless of a given combination of temperature and pressure conditions. Based on the presented results, one can conclude that the molecular dynamics seem to control the process of recrystallization of the excess amount of solute from the supersaturated solution (e.g., small molecules dissolved within the polymer). Therefore, it appears that the elevated pressure compensates the effect of solubility enhancement caused by the elevated temperature. Such information not only is of fundamental relevance in science but also, from a much broader perspective, could be potentially very useful considering extrusion-based manufacturing methods.

High-Pressure Dielectric Studies—a Way to Experimentally Determine the Solubility of a Drug in the Polymer Matrix at Low Temperatures

“…As can be seen in panel (a) of Figure 8 , we estimated the T g values of NMS + 20 wt % KVA, NMS + 40 wt % KVA, and NMS + 55 wt % KVA as 314, 332, and 346 K, respectively, from the extrapolation of VFT fit to 100 s. The nearly constant increase in T g (Δ T = 12 K) is consistent with the high-pressure data obtained for another pharmaceutical, flutamide. 37 , 38 This behavior can be explained by the decrease in the molecular mobility resulting from the increased densification of molecular packing of the system as the applied pressure raises. 63 , 64 Observing the constant increase in T g , we decided to vertically displace the compositional dependence of the T g values obtained at ambient pressure to this relationship.…”

“…This approach has been validated as presented in our previous work on flutamide-based ASDs. 37 , 38 The T g values determined after the recrystallization of the excess amount of drug from the NMS + 40 wt % KVA mixture at an elevated pressure (50 MPa) are listed in Table 3 .…”

“…By following the idea that the relaxation time is the key to sustain the desired level of solubility while increasing the pressure, 38 we evaluated our results in this respect. By analyzing the obtained data, it is possible to observe instances where the recrystallization began for the same initial relaxation time: (i) 398 K and 50 MPa and 383 K and 0.1 MPa (τ α = 1.07 μs); see panel (a) of Figure 10 and (ii) 388 K and 50 MPa and 373 K and 0.1 MPa (τ α = 4.92 μs); see panel (b) of Figure 10 .…”

“…This is consistent with the recently published data. 37,38 By following the idea that the relaxation time is the key to sustain the desired level of solubility while increasing the pressure, 38 Figure 11 shows the solubility limit values obtained for the data above (recrystallization performed for the same initial relaxation time). Clearly, the presented result for the NMS + KVA ASD is yet another example, confirming that regardless of the chosen temperature or pressure conditions, there is a way of maintaining the desired level of solubility by sustaining the same initial relaxation time.…”

“…BDS is an experimental technique already applied to determine the solubility limit at ambient pressure. 39 − 43 Moreover, due to the fact that this method has been repeatedly used to test amorphous materials under elevated pressures, 32 , 44 in particular, as it has been recently shown to determine the aforementioned solubility under elevated pressure conditions, 37 , 38 we chose it as the main experimental technique.…”