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...

DNP‐enhanced solid‐state NMR spectroscopy of active pharmaceutical ingredients

“…Advances in NMR technology and methods have also improved the analysis of APIs by solid‐state NMR spectroscopy. For example, fast magic angle spinning (MAS) and/or homonuclear 1 H decoupling (i.e., combined rotation and multiple‐pulse spectroscopy) are now routinely employed to obtain high‐resolution 1 H solid‐state NMR spectra of APIs and organic solids . Solid‐state 1 H chemical shifts are distinct for different polymorphic forms of APIs, and 1 H solid‐state NMR offers much higher sensitivity than 13 C solid‐state NMR.…”

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

“…[10][11][12]14,15 The emerging field of NMR crystallography of organic solids employs experimental solid-state NMR usually in combination with calculation to probe solid-state structures. [16][17][18][19][20] In the context of organic molecules, a particular focus is upon the interactions that govern the adopted intermolecular packing, notably hydrogen bonding and aromatic - effects.…”

Chapter 2. Solid‐State NMR in Drug Discovery and Development

“…225 A 2D 1 H DQ experiment performed with homonuclear 1 H decoupling (also referred to as the DQ-CRAMPS experiment, where CRAMPS is an acronym for combined rotation and multiple pulse sequence) also successfully detected the API form in formulations, with additional specificity available from the DQ dimension. 226 Relaxation time analysis using SSNMR has been shown to be indicative of formulation stability. 227 2D 1 H-13 C CP-HETCOR and 1 H-19 F CP-HETCOR experiments were shown to be capable of demonstrating formation of the desired glass solution in amorphous drug-polymer dispersions.…”