Investigation of Potential Amorphisation and Co-Amorphisation Behaviour of the Benzene Di-Carboxylic Acids upon Cryo-Milling

Abstract

Multi-component formulations offer a way to modulate the physico-chemical properties of drug molecules and thereby enhance their efficacy as medicines compared to using only the raw drug, with mechano-chemical synthesis being an increasingly popular way to create these novel materials in a research setting. However, to date studies have focussed on employing pharmaceutically acceptable components, which has led to the literature featuring chemically diverse pairings of drug and excipient. Here we investigate the outcome of cryo-milling and co-cryo-milling of a series of three simple geometrical isomers of benzene di-carboxylic acid with a view to developing a chemically simple model system to investigate areas including cryo-milling, co-cryo-milling, co-amorphous formulation, etc. All three single-component materials exhibit differing behaviour upon cryo-milling and subsequent storage, as do the two-component mixtures. The surprisingly differing behaviours of these chemically similar species upon cryo-milling and co-cryo-milling suggest that molecular chemistry may not be the dominant influence on the outcome of mechano-chemical syntheses, and that other properties should be explored to develop a predictive model for the outcomes of these types of reactions.

Keywords: ATR-FTIR; DSC; XRPD; amorphous; co-amorphous; cryo-milling; formulation; mechanochemistry.

Figure 1

Chemical structures of terephthalic acid (TPA), isophthalic acid (IPA) and phthalic acid (PA).

Figure 2

Differential Scanning Calorimetry (DSC) data for: (a) TPA; (b) IPA; and (c) PA. Exothermic up.

Figure 3

X-ray powder diffraction (XRPD) data for: (a) TPA; (b) IPA; and (c) PA, before and after cryo-milling and after storage at 43% relative humidity (RH) and room temperature for three weeks.

Figure 4

Attenuated Total Reflectance Infra-Red (ATR-FTIR) spectra for: TPA; IPA; and PA, as-received and after cryo-milling.

Figure 5

DSC data for co-cryo-milled combinations of (a) TPA, (b) IPA and (c) PA, with reference traces for the cryo-milled individual components at zero days also shown in red for reference. Exothermic up.

Figure 6

XRPD data for co-cryo-milled combinations of (a) TPA, (b) IPA and (c) PA as labelled. Red lines indicate the peak positions of the most intense peaks of the reference materials (freshly cryo-milled individual components) which are labelled “ref” and shown in red.

Figure 7

XRPD data for co-cryo-milled TPA/IPA, along with the predicted XRPD traces for the various TPA polymorphs.