(T1130-07-38) The Influence of the Chiral Coformer Tryptophan on the Physical Stability of Co-amorphous Systems with Indomethacin as Model Drug

Purpose: The purpose of this study was to investigate the influence of the enantiomeric properties of the chiral coformer tryptophan (TRP) on the physical stability of co-amorphous systems with the API indomethacin (IND). In a previous study, these co-amorphous systems with TRP in its various enantiomeric forms were prepared by ball milling (BM) [1]. To investigate the large differences in the physical stability of the IND / TRP racemate (IND/TRPr), the IND / TRP conglomerate (IND/TRPc), IND / L-TRP, and IND / D-TRP, the molecular mobility of these co-amorphous systems was characterized applying the Kohlrausch-William-Watts equation (KWW).

Methods: Crystalline TRPc was prepared by physical mixing of D- and L-TRP at an equimolar ratio. Co-amorphous IND/TRP systems were obtained by BM in a cold room (+ 6 °C) at 30 Hz for 90 min using two stainless steel balls (Ø 12 mm). Samples of each co-amorphous system were stored at 40 °C and 0 % RH for up to 6 m. The solid state properties of the co-amorphous IND/TRP systems were investigated by X-ray powder diffraction (XRPD). Additionally, modulated differential scanning calorimetry (mDSC) was applied to determine their glass transition temperatures (T_g) from the respective reversing heat flow curves. The samples were annealed at T = T_g ­– 20 °C for 0, 1, 2, 4, 8, 16, and 24 h and heated up to temperatures exceeding their T_g to determine the relaxation endotherm from the non-reversing heat flow curve. The KWW equation as modified Weibull function was applied to obtain the relaxation time τ and the stretched exponential parameter β.

Results: XRPD analysis of the various co-amorphous systems revealed the differences in their physical stability. The diffractograms of the samples stored at elevated temperature for 3 m (Figure 1A) and for 6 m (Figure 1B) show an amorphous halo with IND/TRPc, whereas with IND/TRPr recrystallization is observed. In Figure 1B, the recrystallization peaks of IND/L-TRP and IND/D-TRP are highlighted. The relaxation endotherms of each annealing time period were used to obtain the respective relaxation functions and subsequently, curve fitting with the KWW equation was performed. The relaxation functions and the fitted curves are shown in Figure 2. The relaxation time decreased in the order: TRPc > L-TRP > D-TRP > TRPr (Table 1). Based on the assessment of the molecular mobility with the KWW parameters [2], it may be deduced that TRPr as coformer leads to the highest molecular mobility and therefore causes a decrease of the physical stability of the co-amorphous system. In contrast, if TRPc is used as coformer, a low molecular mobility and thus a high physical stability is observed. The stability differences between the investigated co-amorphous systems could also be confirmed by XRPD analysis.

Conclusion: The KWW approach has been shown to be valuable for prediction of the physical stability of co-amorphous systems consisting of an API and a chiral coformer. Although this approach does not allow a direct comparison of different APIs [3], it is a potential tool to evaluate the influence of an enantiomeric coformer on the molecular mobility and thus the physical stability of co-amorphous systems. The reasons for the observed differences in the molecular mobility will be focused on in a future study.

References: [1] K. Holzapfel et al., PBP World Meeting, Rotterdam, The Netherlands, 2022.
[2] P. Karmwar et al., Int. J. Pharm., 417, 94-100, 2011.
[3] K. Graeser et al., Curr. Drug Deliv., 6, 374-383, 2009.


Figure 1: XRPD diffractograms of the ball milled co-amorphous systems stored at elevated temperature (40 °C) for 3 m (A) and for 6 m (B).


Figure 2: Relaxation data of the various IND/TRP co-amorphous systems (means ± SD, n = 3).


Table 1: Relaxation parameters of the co-amorphous IND/TRP systems.