Hydrogen Bonding in Amorphous Indomethacin

Abstract

Amorphous Indomethacin has enhanced bioavailability over its crystalline forms, yet amorphous forms can still possess a wide variety of structures. Here, Empirical Potential Structure Refinement (EPSR) has been used to provide accurate molecular models on the structure of five different amorphous Indomethacin samples, that are consistent with their high-energy X-ray diffraction patterns. It is found that the majority of molecules in amorphous Indomethacin are non-bonded or bonded to one neighboring molecule via a single hydrogen bond, in contrast to the doubly bonded dimers found in the crystalline state. The EPSR models further indicate a substantial variation in hydrogen bonding between different amorphous forms, leading to a diversity of chain structures not found in any known crystal structures. The majority of hydrogen bonds are associated with the carboxylic acid group, although a significant number of amide hydrogen bonding interactions are also found in the models. Evidence of some dipole-dipole interactions are also observed in the more structurally ordered models. The results are consistent with a distribution of Z-isomer intramolecular type conformations in the more disordered structures, that distort when stronger intermolecular hydrogen bonding occurs. The findings are supported by ¹H and ²H NMR studies of the hydrogen bond dynamics in amorphous Indomethacin.

Keywords: Monte Carlo simulation; X-ray diffraction; amorphous; indomethacin; pair distribution function.

Figure 1

(Left) Starting conformation of the Indomethacin molecule used in our EPSR models together with labels of the different atom types. (Right) Overlay of Z, E, and α3 isomers to illustrate the choice of the five specified allowed rotations denoted by curved arrows. Carbon atoms are shown as black, nitrogen as blue, oxygen as red, chlorine as green, and hydrogen as white.

Figure 2

The X-ray structure factors of the five amorphous Indomethacin samples reported by Benmore et al. [17]. (Left panel) shows the S(Q) low-Q region encompassing the first sharp diffraction peak. The (right panel) shows the entire measured Q-range (circles) using the formalism Q[S(Q)-1] to emphasize high-Q, together with the EPSR model fits from this study (lines).

Figure 3

(Left) The difference between measured structure factors of amorphous Indomethacin samples (open circles) compared to the same difference between EPSR models (red lines). (Right) EPSR fits (blue lines) to the experimental real space X-ray pair distribution function D(r) (black circles) using the different sized Indomethacin molecules as described in Table 2.

Figure 4

(Left panel) The intermolecular carboxyl acid oxygen donor O2-O1 oxygen acceptor partial pair distribution functions from our EPSR models. The (right panel) shows corresponding running coordination numbers for the amorphous Indomethacin samples.

Figure 5

(Left panel). The intermolecular carboxyl acid oxygen donor O2-O3 amide oxygen acceptor partial pair distribution functions from our EPSR models. The (right panel) shows the corresponding running coordination numbers for the amorphous Indomethacin samples.

Figure 6

(A) ¹H solid-state MAS (ν_r = 20 kHz) NMR spectra of alpha, gamma, and amorphous indomethacin. A selectively acid deuterium-enriched amorphous indomethacin sample was made through ¹H to ²H exchange prior to melt quenching. The ¹H solid-state MAS (ν_r = 20 kHz) NMR spectrum of the (grey) partially acid deuterated amorphous indomethacin sample (d₁-indomethacin) is overlaid with the (black) standard amorphous indomethacin and shows a reduction in ¹H signal due to the partial acid deuteration. Dotted vertical lines are shown at 12.7 and 11.5 ppm and labeled (a) and (c), respectively. These are the approximate ¹H chemical shifts for the acid (COOH) protons in a (a) hydrogen-bonded dicarboxylic acid environment (gamma-indomethacin) and (c) in a weaker hydrogen-bonded carbonyl—carboxylic acid environment. (B) ²H solid-state MAS (ν_r = 5 kHz) NMR spectra (black) and DMFit simulation (Blue) of amorphous d₁-indomethacin (~50% ²H exchanged at the acid site). The best fit ²H quadrupolar tensor gave a coupling constant (C_Q) of 178 kHz with no asymmetry (η = 0) with a ²H chemical shift of 8 ppm and a linewidth of 10 ppm. Above the full 2H spectrum and simulation is a zoomed in plot to more clearly show the center band and the first few satellite transitions (black) and associated simulation fit (blue) of amorphous d₁-indomethacin.

Figure 7

The intramolecular ∠O3-N-Cl angle determined from the EPSR models of the five samples. The angles associated with the three different isomers found in the crystal are denoted on the top axis.

Figure 8

The percent of the number of hydrogen bonds per molecule as a function of chain size for our amorphous Indomethacin samples.

Figure 9

Snapshots of (a) a carboxylic acid dimer found in γ-Indomethacin, (b) a singly hydrogen-bonded molecular pair, and a (c) hydrogen bond between the carboxylic acid and an amide carbonyl found in our EPSR models. Carbon atoms are shown as black, nitrogen as blue, oxygen as red, chlorine as green, and hydrogen as white.