Characterisation of indomethacin and nifedipine using variable‐temperature solid‐state NMR

Abstract

We have characterised the stable polymorphic forms of two drug molecules, indomethacin (1) and nifedipine (2) by 13C CPMAS NMR and the resonances have been assigned. The signal for the C-Cl carbon of indomethacin has been studied as a function of applied magnetic field, and the observed bandshapes have been simulated. Variable-temperature 1H relaxation measurements of static samples have revealed a T1rho minimum for indomethacin at 17.8 degrees C. The associated activation energy is 38 kJ mol(-1). The relevant motion is probably an internal rotation and it is suggested that this involves the C-OCH3 group. Since the two drug compounds are potential candidates for formulation in the amorphous state, we have examined quench-cooled melts in detail by variable-temperature 13C and 1H NMR. There is a change in slope for T1H and T1rhoH at the glass transition temperature (Tg) for indomethacin, but this occurs a few degrees below Tg for nifedipine, which is perhaps relevant to the lower real-time stability of the amorphous form for the latter compound. Comparison of relaxation time data for the crystalline and amorphous forms of each compound reveals a greater difference for nifedipine than for indomethacin, which again probably relates to real-time stabilities. Recrystallisation of the two drugs has been followed by proton bandshape measurements at higher temperatures. It is shown that, under the conditions of the experiments, recrystallisation of nifedipine can be detected already at 70 degrees C, whereas this does not occur until 110 degrees C for indomethacin. The effect of crushing the amorphous samples has been studied by 13C NMR; nifedipine recrystallises but indomethacin does not. The results were supported by DSC, powder XRD, FTIR and solution-state NMR measurements.

Role of Thermodynamic, Molecular, and Kinetic Factors in Crystallization from the Amorphous State

“…In a study of molecular mobility in Indomethacin and Nifedipine, using 13 C and 1 H NMR, a change in slope of the measured relaxation times (T 1 and T 1r ) was observed at T g for Indomethacin, and below T g in the case of Nifedipine. 75 Further, the slope for Nifedipine was significantly smaller than for Indomethacin, indicating lower activation energy for molecular motion in amorphous Nifedipine (for the 200-MHz range). The higher mobility and lower activation energy for motion in Nifedipine was correlated with the faster recrystallization kinetics.…”

Structural studies on lithocholyl-N-(2-aminoethyl)amide in the solid state

“…Single crystal X-ray diffraction is an established method in defining solid state structures of molecules [23], but preparation of single crystals suitable for single crystal X-ray crystallography of bile acid derivatives can be a rather difficult task. Structure solution based on theoretical calculations, powder X-ray diffraction (PXRD) methods, and/or solid state (SS) cross polarization (CP) magic angle spinning (MAS) NMR experiments has been demonstrated to be a very promising alternative [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39], opening opportunities for investigation of solid state structures even in cases, where no suitable single crystals for single crystal X-ray crystallography are obtained.…”

Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution 1H Solid-State NMR Spectroscopy

“…24,25 By employing advances in homonuclear 1 H decoupling that deliver high-resolution 1 H spectra, 26,27 the 1 H-1 H DQ CRAMPS technique [28][29][30][31][32] has been applied to the potassium salt of penicillin characterised anhydrous polymorphs (that are labelled ,  and )  crystal structures are available for the  and  forms. 38,39 13 C CP MAS spectra have been reported for the crystalline polymorphs as well as amorphous forms of indomethacin, 13,[40][41][42] while a recent study has presented 1 H- 13 C and 1 H-1 H DQ twodimensional spectra for an indomethacin-polymer dispersion together with a 1 H-1 H DQ MAS spectrum of -indomethacin. 13 Amorphous forms, dispersions as well as co-crystals of indomethacin have and are being extensively studied on account of the poor solubility exhibited by indomethacin and hence its limited bioavailability.…”

“…The observed spectral resonances are assigned by means of GIPAW chemical shift calculations for the full periodic crystal structure (see Table 1) -indomethacin crystallizes in the centrosymmetric triclinic P1 space group with one molecule in the asymmetric unit. Note that the atom numbering system used here is that employed by Basavoju et al; 44 various alternative numbering schemes have been used in the published single-crystal X-ray structure 39 and other reports of solid-state NMR 13 C CP MAS data by Apperley et al, 40 Masuda et al, 41 Guilbaud et al, 42 and Pham et al 13 currents, that lead to  crystmol changes of at least 1 ppm for the 1 H chemical shift (see Table 1) and (e) 53 and host-guest interactions in molecular tweezers [54][55][56] or calixarene complexes. 57 The distance from the particular proton to the centre of the specific aromatic moiety is 2.72 Å (9b) and 3.12 Å (9a) for the C9 CH 2 protons, 2.68 Å for the nearest C11 CH 3 proton and 3.42 Å for the C16 aromatic CH proton.…”