Hydrogen Bonding Interactions in Amorphous Indomethacin and Its Amorphous Solid Dispersions with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl acetate) Studied Using ¹³C Solid-State NMR

Abstract

Hydrogen bonding interactions in amorphous indomethacin and amorphous solid dispersions of indomethacin with poly(vinylpyrrolidone), or PVP, and poly(vinylpyrrolidone-co-vinyl acetate), or PVP/VA, were investigated quantitatively using solid-state NMR spectroscopy. Indomethacin that was (13)C isotopically labeled at the carboxylic acid carbon was used to selectively analyze the carbonyl region of the spectrum. Deconvolution of the carboxylic acid carbon peak revealed that 59% of amorphous indomethacin molecules were hydrogen bonded through carboxylic acid cyclic dimers, 15% were in disordered carboxylic acid chains, 19% were hydrogen bonded through carboxylic acid and amide interactions, and the remaining 7% were free of hydrogen bonds. The standard dimerization enthalpy and entropy of amorphous indomethacin were estimated to be -38 kJ/mol and -91 J/(mol · K), respectively, using polystyrene as the "solvent". Polymers such as PVP and PVP/VA disrupted indomethacin self-interactions and formed hydrogen bonds with the drug. The carboxylic acid dimers were almost completely disrupted with 50% (wt) of PVP or PVP/VA. The fraction of disordered carboxylic acid chains also decreased as the polymer content increased. The solid-state NMR results were compared with molecular dynamics (MD) simulations from the literature. The present work highlights the potential of (13)C solid-state NMR to detect and quantify various hydrogen bonded species in amorphous solid dispersions as well as to serve as an experimental validation of MD simulations.

The Effect of Cooling on the Degree of Crystallinity, Solid-State Properties, and Dissolution Rate of Multi-Component Hot-Melt Extruded Solid Dispersions

“…This was the case for all SD formulations, as shown in Figure 2a. There was no change in the vinyl acetate C=O carbonyl due to weaker hydrogen bonding potential of the vinyl acetate carbonyl as reported by Yuan et al (2015) as shown in Figure 2b [22]. Any P407 peaks within the pure P407 sample were completely absent in the ATR-FTIR spectra of the SD formulations as shown in Figure 2a and Figure 3.…”

“…The hydrogen-bonded O-H stretch of the acid, shown in Figure 4, is overlaid on the C-H sharp stretches, as literature has reported that the free carboxylic acid O-H stretch as a result of hydrogen bonding can exist as dimers [23]. It is also important to note that in the ATR-FTIR reference spectrum of aINM, the two C=O bands at 1714 cm −1 (free C=O of carboxylic acid) and 1690 cm −1 (acid-acid dimer C=O stretch) shifted to 1707 There was no change in the vinyl acetate C=O carbonyl due to weaker hydrogen bonding potential of the vinyl acetate carbonyl as reported by Yuan et al (2015) as shown in Figure 2b [22]. Any P407 peaks within the pure P407 sample were completely absent in the ATR-FTIR spectra of the SD formulations as shown in Figures 2a and 3.…”

“…The amide carbonyl (vC=O) peak at 1673 cm −1 shifted to 1680 cm −1 in all SD formulations due to hydrogen bond interaction with the -OH carboxylic acid of INM, as shown in Figure 5. The intensity of the vinyl acetate carbonyl group is weak and appears at 1745 cm -1 due to the weaker hydrogen bonding potential as reported by Yuan et al (2015) [22]. Pharmaceutical drugs which are usually conjugated compounds have very strong Raman signals, while pharmaceutical excipients tend to have Raman signals which are weak [8].…”

Effects of Molecular Interactions on Miscibility and Mobility of Ibuprofen in Amorphous Solid Dispersions With Various Polymers

“…Experimentally, 13 C CPMAS solid-state NMR studies have shown that extensive dilution of indomethacin (another carboxylic acidecontaining drug) in PST polymers is necessary to convert HB indomethacin dimers to monomers, with approximately 50% of molecules remaining in dimers at a concentration of only 0.2% indomethacin. 60 In further support of the conclusion that IBP-IBP hydrogen bonding persists even at high dilution in PST, radial distribution functions, g(r), between the centers of mass of IBP and the monomeric units in either PVP or PST were generated at 50 wt% polymer concentrations. The results, shown in Figure 6, indicate that at any given distance between 1.5 and 14 Å, the g(r) value for IBP-PVP is higher than that for IBP-PST.…”

Interpolymer Complexation Between Polyox and Carbopol, and Its Effect on Drug Release From Matrix Tablets

“…The possible hydrogen-bonding states in neat Carbopol 907 included a cyclic COOH-to-COOH dimer, COOH-to-carbonyl C¼O, COOH-to-H 2 O, and free unbound COOH. Recently, Yuan et al 35 have assigned different H-bonding states in amorphous indomethacin using 13 C solid-state NMR, aided by comparison to carboxyl chemical shifts in crystalline polymorphs with known H-bonding motifs. They have shown the highest frequency COOH peak in indomethacin to be cyclic H-bonded dimer (179.3 ppm), followed by a COOH chain (176.3 ppm), COOH H-bonded to carbonyl C¼O (172.4 ppm), and free COOH at lowest frequency (170.4 ppm).…”