Distinguishing Anhydrous and Hydrous Forms of an Active Pharmaceutical Ingredient in a Tablet Formulation Using Solid‐State NMR Spectroscopy

Abstract

The phenomena of polymorphism and pseudopolymorphism (the formation of hydrates/solvates) and their influence on the chemical and physical properties of molecular crystals are well known.[1] This is especially true for pharmaceutical compounds, where polymorphic or pseudopolymorphic changes in active pharmaceutical ingredients (APIs) can have significant effects on bioavailability.[2] Identification and characterization of (pseudo-)polymorphs is therefore essential during all stages of the development and manufacture of pharmaceuticals; of key importance is the form adopted in a tablet formulation in which the API is combined with a mixture of filler compounds (excipients).13 C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR spectroscopy has proven itself as a powerful workhorse experiment for this purpose; [3][4][5] however, very little use has been made of 1 H solid-state NMR spectroscopy due to the large anisotropic broadening that results from extensive dipolar-coupled proton networks. However, advances such as fast MAS and improved homonuclear decoupling techniques have led to increased resolution for organic compounds. [6] In particular, 1 H double-quantum (DQ) MAS NMR spectroscopy [6][7][8] has become a powerful approach, providing valuable information about, for example, a molecular tweezer host-guest complex, [9] intramolecular hydrogen-bonding in a biological molecule, [10] water and hydroxy-group environments in polyoxoniobate materials, [11] and surface organometallic species.[12] More recently, the 1 H DQ CRAMPS (combined rotation and multiple-pulse spectroscopy) technique [13][14][15] has been shown to dramatically increase resolution, thus allowing well-resolved spectra to be obtained for model compounds. [13][14][15][16] Herein, we show how the presence of a specific pseudopolymorph of an API containing about 20 carbon atoms is identified in a tablet formulation using 1 H DQ CRAMPS NMR spectroscopy. This is demonstrated for an API currently under development, using only 30 mg of sample, and with no need for special preparation (that is, isotopic labeling). We present high-resolution 2D NMR spectra recorded in under two hours, a time equivalent to that needed for a high-quality 1D 13 C CP MAS spectrum. 1 H DQ CRAMPS NMR spectra, recorded using the pulse sequence in reference [15], of pure anhydrous and monohydrate forms of the API are shown in Figure 1 a and 1 b, respectively. For the monohydrate form, broader signals indicate a slightly less crystalline sample. X-ray single-crystal structure analyses reveal different intermolecular hydrogen- Figure 1. 600 MHz 1 H DQ CRAMPS NMR spectra together with skyline projections of a) the anhydrous and b) the monohydrate form of the API under consideration. The pair of DQ signals in both spectra corresponding to the intramolecular proximity of hydrogen-bonded protons with high-ppm resonance signals to the same nearby proton are highlighted. Each spectrum was recorded in 105 min. Base contours are shown at 11 % of maximum intensity. All axe...

Rapid Analysis of Organic Compounds by Proton‐Detected Heteronuclear Correlation NMR Spectroscopy with 40 kHz Magic‐Angle Spinning

“…For these reasons, CRAMPS-based proton-detected HETCOR spectra of natural-abundance samples have not been demonstrated, to the best of our knowledge. Meanwhile, the proton homonuclear spectra correlating abundant protons (e.g., 2 h on 30-mg samples, recycle delay 2 s) [26] are comparable in sensitivity to the HETCOR spectra correlating protons with rare heteronuclei ( 13 C and 15 N), which have the benefit of very large chemical shift ranges. We expect the fast-MAS HETCOR experiments to have adequate resolution for molecules up to 500 Da, for which experiments can be conducted in 3 h given a favorable proton T 1 .…”

“…[12] As an alternative to fast-MAS HETCOR, proton doublequantum homonuclear correlation spectroscopy has recently been used to distinguish anhydrous and hydrous forms of a certain drug ingredient. [26] However, the CRAMPS technique (combined rotation and multiple-pulse spectroscopy) used there to narrow the proton linewidths also compromises signal-to-noise ratio as a result of the large receiver bandwidth and low probe quality factor. Moreover, CRAMPS experiments are difficult to calibrate and often show sub- .…”

Practical aspects of Lee–Goldburg based CRAMPS techniques for high-resolution 1H NMR spectroscopy in solids: Implementation and applications

“…In addition, 1 H windowless multiple-pulse schemes may help between the DQ excitation and reconversion steps, while windowed 1 H acquisition schemes in obtaining a highly resolved DQ 1 H indirect dimension. This has already been successfully applied for moderate spinning speeds, [27,77,86]. Windowed 1 H acquisition schemes have the advantage of affording highly resolved 1 H spectra in a single dimension, thus opening the possibility to be used during t 2 evolution in other 2D pulse schemes where highresolution 1 H detection may help performing insensitive experiments by applying inverse detection experiments.…”

“…In addition, Polarization Inversion and Spin Exchange at the Magic Angle (PISEMA) are experiments, consisting in a sensitivity enhancement method, which has shown to provide precise measurement of chemical shift and heteronuclear dipolar coupling interactions in strongly coupled 1 H-1 H systems [45]. The use of some of these techniques has been illustrated on small molecules [5,35,[46][47][48][49][50][51][52][53][54][55] biological materials [27,[56][57][58][59][60][61][62][63][64][65][66][67][68] photosynthetic pigments [69], inorganic materials [70], inorganic-organic hybrid materials [33,34,[71][72][73][74] catalysts [75], nanoparticles [76], and pharmaceutical compounds [77].…”

Rapid Analysis of Organic Compounds by Proton‐Detected Heteronuclear Correlation NMR Spectroscopy with 40 kHz Magic‐Angle Spinning

“…As an alternative to fast‐MAS HETCOR, proton double‐quantum homonuclear correlation spectroscopy has recently been used to distinguish anhydrous and hydrous forms of a certain drug ingredient 26. However, the CRAMPS technique (combined rotation and multiple‐pulse spectroscopy) used there to narrow the proton linewidths also compromises signal‐to‐noise ratio as a result of the large receiver bandwidth and low probe quality factor.…”