Solvent-Mediated Polymorphic Transformations in Molten Polymers: The Account of Acetaminophen

Abstract

Solvent-mediated polymorphic transformations (SMPTs) employing nonconventional solvents (polymer melts) is an underexplored research topic that limits the application of polymer-based formulation processes. Acetaminophen (ACM), a widely studied active pharmaceutical ingredient (API), is known to present SMPTs spontaneously (<30 s) in conventional solvents such as ethanol. In situ Raman spectroscopy was employed to monitor the induction time for the SMPT of ACM II to I in polyethylene glycol (PEG) melts of different molecular weights (M_w, 4000, 10 000, 20 000, 35 000 g/mol). The results presented here demonstrate that the induction time for the SMPT of ACM II to I in PEG melts is driven by its diffusivity through the polymer melts. Compared to conventional solvents (i.e., ethanol) the mass transfer (diffusion coefficient, D) in melts is significantly hindered (D_ethanol = 4.84 × 10^-9 m²/s > D_PEGs = 5.32 × 10^-11-8.36 × 10^-14 m²/s). Ultimately, the study proves that the induction time for the SMPT can be tuned by understanding the dispersant's physicochemical properties (i.e., η) and, thus, the D of the solute in the dispersant. This allows one to kinetically access and stabilize metastable forms or delay their transformations under given process conditions.

Keywords: active pharmaceutical ingredients; crystalline solid dispersion; diffusivity; melt; polymorphism; solvent-mediated polymorphic transformation.

Figure 1.

In situ Raman spectroscopy during a heating profile employed in a hot stage to emulate the DSC measurements at a heating rate of 30 °C/min: black solid line (DSC thermogram of 80 wt % ACM II–20 wt % PEG 10 000) as well as blue squares and red triangles (in situ Raman characteristic peaks at 1234 and 1329 cm⁻¹ for ACM I and II, respectively).

Figure 2.

Phase diagram of ACM I (blue) and II (red) in PEG 10000. Green area accounts for the thermodynamic design space in which PEG is molten and ACM II is in the crystalline state. The trend lines correspond to the best possible data fit utilizing mathematical expressions with the best possible fit. Origin (OriginLab Corporation, v. 9.7.0.188) was utilized to solve the nonlinear curve-fitting problems employing the Levenberg–Marquardt algorithm. If the error bars are not observed, they are obstructed by the data points.

Figure 3.

In situ Raman spectra as a function of time (30 min) to monitor the induction time for the SMPT of an 80 wt % ACM II–20 wt % PEG 20 000 heated at 65 °C. The Raman shift for ACM II and I were monitored at 1245 and 1234 cm⁻¹, respectively. Bottom (surface plot from virtual matrix) and top (top view on surface plot from virtual matrix).

Figure 4.

Induction time for the SMPT of ACM II to I as a function of the T for 80 wt % ACM II in 20 wt % PEG 4000 (black circles), PEG 10 000 (orange triangles), PEG 20 000 (blue squares), and PEG 35 000 (red diamonds). The trend lines composed of four data points for each system correspond to the best possible data fits utilizing mathematical expressions with the best possible fit (Table S1 in the Supporting Information). Origin (OriginLab Corporation, v. 9.7.0.188) was utilized to solve the nonlinear curve-fitting problems employing the Levenberg–Marquardt algorithm. The data points at 80 °C for PEG 4000, 10 000, and 20 000 are overlapping each other. If error bars are not observed, they are obstructed by the data points.

Figure 5.

Induction time for the SMPT of ACM II to I as a function of the temperature $(T)$ and viscosity $(\eta )$ of PEG 4000 (black circles), PEG 10 000 (orange triangles), PEG 20 000 (blue squares), and PEG 35 000 (red diamonds). The data points projected on the $XY$ plane show the effect of $T$ on the PEG $\eta$, and the data points on the $YZ$ plane illustrate the effect of the PEG $\eta$ on the induction time for the SMPT of ACM II to I.

Figure 6.

Induction time for the SMPT of ACM II to I as a function of the diffusion coefficient ($D$, m²/s) for ACM II at infinite dilution in ethanol (magenta cross),^, water (green diagonal cross), PEG 4000 (black circles), PEG 10 000 (orange triangles), PEG 20 000 (blue squares), and PEG 35 000 (red diamonds). The induction time for the two highest $D$ values of PEG 4000 are overlapping. The shaded gray area shows a schematic representation of the general trend observed for the induction time as a function of the D values in PEGs. If error bars are not observed, they are obstructed by the data points.