Abstract
Liquid forms of pharmaceuticals (ionic liquids and deep eutectic solvents) offer a number of potential advantages over solid-state drugs; a key question is the role of intermolecular hydrogen bonding interactions in enabling membrane transport. Characterization is challenging since high sample viscosities, typical of liquid pharmaceutical formulations, hamper the use of conventional solution NMR at ambient temperature. Here, we report the application of magic-angle spinning (MAS) NMR spectroscopy to the deep eutectic pharmaceutical, lidocaine ibuprofen. Using variable temperature MAS NMR, the neat system, at a fixed molar ratio, can be studied over a wide range of temperatures, characterized by changing mobility, using a single experimental setup. Specific intermolecular hydrogen bonding interactions are identified by two-dimensional 1H–1H NOESY and ROESY MAS NMR experiments. Hydrogen-bonding dynamics are quantitatively determined by following the chemical exchange process between the labile protons by means of line-width analysis of variable temperature 1H MAS NMR spectra.
Highlights
As the pharmaceutical industry continues to look for novel ways to improve drug design and enhance delivery, ionic liquids (ILs) have become a promising growth area that seeks to overcome some of the limitations that can exist with solid active pharmaceutical ingredients (APIs).[1,2]
APIILs have shown an ability to markedly improve characteristics such as solubility and permeability, as well as exhibiting the potential for more tolerable routes of administration.[3−6] In addition to the formation of fully ionized salts, in 2011, Bica et al demonstrated that hydrogen bonding may drive the “liquefaction” of therapeutics in the form of deep eutectic solvents (DESs), the liquid equivalent of cocrystals.[7]
This study considers the prototype deep eutectic “liquid cocrystal”[7,14] formed between the pain relieving compounds lidocaine and ibuprofen,[8,15] denoted Lid·Ibu (Figure 1a)
Summary
As the pharmaceutical industry continues to look for novel ways to improve drug design and enhance delivery, ionic liquids (ILs) have become a promising growth area that seeks to overcome some of the limitations that can exist with solid active pharmaceutical ingredients (APIs).[1,2] APIILs have shown an ability to markedly improve characteristics such as solubility and permeability, as well as exhibiting the potential for more tolerable routes of administration (transdermal or oral versus injection).[3−6] In addition to the formation of fully ionized salts, in 2011, Bica et al demonstrated that hydrogen bonding may drive the “liquefaction” of therapeutics in the form of deep eutectic solvents (DESs), the liquid equivalent of cocrystals.[7]. The feasibility of CP or INEPT techniques is likely to depend on its position on this continuum, which dictates dephasing times and the strength of residual dipolar couplings, factors that affect the efficiency of magnetization transfer for these two methods This can be clearly seen in the variable temperature 1H−13C refocused INEPT and CP 13C MAS NMR spectra presented in this paper. 1H−13C cross-polarization (CP) and refocused INEPT spectra were acquired at ν0H = 500 MHz and νr = 12.5 kHz MAS frequency; 128 transients were coadded, and a recycle delay of 1.5 s was used. NOESY (ν0H = 850 MHz) spectra were recorded with 4 transients coadded for each of 512 t1 FIDs, using the StatesTPPI21 method to restore sign discrimination in the F1 dimension with a t1 increment of 59 μs and a recycle delay of 3 s, corresponding to an experimental time of 3.5 h. An eight-step phase cycle was used in the ROESY experiment where the two 1H 90° pulses before and after the spin-lock were cycled through phases x −x −x x y −y −y y and x −x x −x y −y y −y and the receiver was cycled through phases x −x −x x y −y −y y
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