A High Energy X-ray Diffraction Study of Amorphous Indomethacin

Abstract

Amorphous pharmaceuticals often possess a wide range of molecular conformations and bonding arrangements. The x-ray pair distribution function (PDF) method is a powerful technique for the characterization of variations in both intra-molecular and inter-molecular packing arrangements. Here, the x-ray PDF of amorphous Indomethacin is shown to be particularly sensitive to the preferred orientations of the chlorobenzyl ring found in isomers in the crystalline state. In some cases, the chlorobenzyl ring has no preferred torsional angle in the amorphous form, while in others evidence of distinct isomer orientations are observed. Amorphous samples with no preferred torsion angles of the chlorobenzyl ring are found to favor enhanced inter-molecular hydrogen bonding, and this is reflected in the intensity of the first sharp diffraction peak. These significant variations in structure rule out amorphous Indomethacin as a possible standard for x-ray PDF measurements. At high humidity, time resolved PDF's for >40 h reveal water molecules forming hydrogen bonds with Indomethacin molecules. A simple linear hydrogen bond model indicates that water molecules in the wet amorphous form have similar hydrogen bond strengths to those found between Indomethacin dimers or chains in the dry amorphous form.

Keywords: Glass; NMR spectroscopy; Pair distribution function; Structure; X-ray powder diffraction.

Figure 1.

Three isomers for Indomethacin present in the α and γ forms.

Figure 2.

Solid state ¹H→¹³C CP MAS (ω_r = 20 kHz) NMR spectra of natural abundance Indomethacin polymorphs and their melt-quenched amorphous solids. (a) Crystalline γ-Indomethacin, (b) melt-quenched amorphous Indomethacin from crystalline γ-Indomethacin precursor; (c) melt-quenched amorphous Indomethacin from crystalline α-Indomethacin precursor, and (d) crystalline α-Indomethacin.

Figure 3.

Solid state MAS NMR spectra of crystalline α polymorph (top) and melt quenched (bottom) chlorobenzyl-d₄-Indomethacin (CIL, 98%). (a) ¹H–¹³C CP MAS (ω_r = 20 kHz) NMR spectra and (b) ²H MAS (ω_r = 5 kHz) NMR spectra.

Figure 4.

The measured x-ray intensities of amorphous Indomethacin. (a) dry Indomethacin (circles) normalized to the x-ray form factor (solid blue line) offset by +20. Wet minus dry amorphous Indomethacin, after >40 h exposure to 80% RH (circles), normalized to the molecular form factor of water (blue solid line, see text) (b) five independent measurements of the total x-ray structure factor for amorphous Indomethacin (see table 1).

Figure 5.

Five independently measured differential atomic pair-distribution functions D(r) for dry amorphous Indomethacin (a) and (b), compared to those calculated for the Z, E and α3 isomers (c) and (d), offset for clarity.

Figure 6.

Changes in the measured differential electronic pair-distribution function ΔD_e(r) exposed to 80% RH at room temperature relative to dry amorphous Indomethacin at time=0. The insert shows the changes in height of the peak at r = 4.4 Å as a function of time with the uptake of water.

Figure 7.

The measured differential electronic pair-distribution function ΔD_e(r) of cryoground amorphous Indomethacin after exposure to 80% RH at room temperature for ~40 h, compared to a linear 2.8 Å inter-molecular hydrogen bond model between a water molecule and an Indomethacin Z isomer molecule.