Formation of a Stable Co-Amorphous System for a Brick Dust Molecule by Utilizing Sodium Taurocholate with High Glass Transition Temperature

Abstract

Brick dust molecules are usually poorly soluble in water and lipoidal components, making it difficult to formulate them in dosage forms that provide efficient pharmacological effects. A co-amorphous system is an effective strategy to resolve these issues. However, their glass transition temperatures (Tg) are relatively lower than those of polymeric amorphous solid dispersions, suggesting the instability of the co-amorphous system. This study aimed to formulate a stable co-amorphous system for brick dust molecules by utilizing sodium taurocholate (NaTC) with a higher Tg. A novel neuropeptide Y₅ receptor antagonist (AntiY₅R) and NaTC with Tg of 155 °C were used as the brick dust model and coformer, respectively. Ball milling formed a co-amorphous system for AntiY₅R and NaTC (AntiY₅R-NaTC) at various molar ratios. Deviation from the theoretical Tg value and peak shifts in Fourier-transform infrared spectroscopy indicated intermolecular interactions between AntiY₅R and NaTC. AntiY₅R-NaTC at equal molar ratios resulting in an 8.5-fold increase in AntiY₅R solubility over its crystalline form. The co-amorphous system remained amorphous for 1 month at 25 °C and 40 °C. These results suggest that the co-amorphous system formed by utilizing NaTC as a coformer could stably maintain the amorphous state and enhance the solubility of brick dust molecules.

Keywords: amorphous; co-amorphous; crystallization; dissolution testing; glass transition temperature; intermolecular interaction; sodium taurocholate.

Figure 1

Chemical structures of (a) AntiY₅R and (b) NaTC.

Figure 2

Typical TG/DTA profiles for (a) AntiY₅R and (b) NaTC.

Figure 2

Typical TG/DTA profiles for (a) AntiY₅R and (b) NaTC.

Figure 3

Typical DSC profiles of 1st heating, cooling and 2nd heating cycle for (a) AntiY₅R and (b) NaTC.

Figure 4

Typical DSC profiles of AntiY₅R, NaTC and mixtures of AntiY₅R and NaTC at different molar ratios. Amorphous samples of AntiY₅R and AntiY₅R-NaTC (9:1) to AntiY₅R-NaTC (6:4) were prepared by the rapid cooling of their melted samples with liquid nitrogen. Amorphous samples of NaTC itself and AntiY₅R-NaTC (5:5) to AntiY₅R-NaTC (1:9) were prepared by cooling cycle during DSC measurement. The black arrows indicate the Tgs.

Figure 5

Comparison of Tg between the experimental and theoretical values for co-amorphous systems AntiY₅R-NaTC at different molar ratios. Experimental values were expressed as the mean with standard deviation of three experiments. Keys: ○, the experimental values. Solid line indicates the theoretical values calculated by the Gordon-Taylor equation.

Figure 6

XRPD patterns of AntiY₅R, NaTC and mixtures of AntiY₅R and NaTC at different molar ratios. Typical patterns of XRPD for (a) before ball milling and (b) after 180 min ball milling.

Figure 7

Typical FT-IR spectra of AntiY₅R, NaTC and the co-amorphous systems comprised of AntiY₅R and NaTC from AntiY₅R-NaTC (1:9) to AntiY₅R-NaTC (5:5).

Figure 8

Powder dissolution profiles of crystalline AntiY₅R, AntiY₅R prepared by ball milling method (BM), co-amorphous systems from AntiY₅R-NaTC (5:5) to AntiY₅R-NaTC (1:9) prepared by BM. Results were expressed as the mean with standard deviation of three experiments. Keys: Red, blue and black solid line indicates the dissolution profile of the co-amorphous system, ball-milled AntiY₅R and crystalline AntiY₅R, respectively.