Probing Hydrogen Bonding in Cocrystals and Amorphous Dispersions

Article pubs.acs.org/molecularpharmaceutics

Probing Hydrogen Bonding in Cocrystals and Amorphous Dispersions Using 14N−1H HMQC Solid-State NMR Andrew S. Tatton,† Tran N. Pham,*,‡ Frederick G. Vogt,§ Dinu Iuga,† Andrew J. Edwards,‡ and Steven P. Brown† †

Department of Physics, University of Warwick, Coventry CV4 7AL, United Kingdom GlaxoSmithKline plc, Product Development, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom § GlaxoSmithKline plc, Product Development, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States ‡

S Supporting Information *

ABSTRACT: Cocrystals and amorphous solid dispersions have generated interest in the pharmaceutical industry as an alternative to more established solid delivery forms. The identification of intermolecular hydrogen bonding interactions in a nicotinamide palmitic acid cocrystal and a 50% w/w acetaminophen−polyvinylpyrrolidone solid dispersion are reported using advanced solid-state magic-angle spinning (MAS) NMR methods. The application of a novel 14N−1H HMQC experiment, where coherence transfer is achieved via through-space couplings, is shown to identify specific hydrogen bonding motifs. Additionally, 1H isotropic chemical shifts and 14N electric field gradient (EFG) parameters, both accessible from 14N−1H HMQC experiments, are shown to be sensitive to changes in hydrogen bonding geometry. Numerous indicators of molecular association are accessible from this experiment, including NH cross-peaks occurring from intermolecular hydrogen bonds and changes in proton chemical shifts or electric field gradient parameters. First-principles calculations using the GIPAW approach that yield accurate estimates of isotropic chemical shifts, and EFG parameters were used to assist in assignment. It is envisaged that 14N−1H HMQC solid state NMR experiments could become a valuable screening technique of solid delivery forms in the pharmaceutical industry. KEYWORDS: pharmaceutical cocrystals, amorphous solid dispersions, molecular dispersions, glass solution, nanosuspension, solid-state NMR, 14N−1H HMQC (heteronuclear multiple-quantum correlation), 14N EFG (electric field gradient), GIPAW (gauge-including projector-augmented wave)

■

INTRODUCTION In the design process of an active pharmaceutical ingredient (API), preferred chemical properties do not always coincide with favorable physical properties, such as solubility, bioavailability, and chemical stability. Currently a number of methodologies are available to improve physical properties, the most common of these being salt forms. However, this requires the API to contain an ionizable functional group, consequently limiting the accessible design space. A drug delivery form of more recent interest is the cocrystal,1−4 with the formation of cocrystals having been demonstrated to improve physical properties in a variety of APIs.5−8 A pharmaceutical cocrystal is typically considered to consist of two or more neutral molecular constituents that are solids (at room temperature and pressure) when separated, where one of the constituents is the API, noncovalently bound in a crystal lattice, and most commonly interacting with the cocrystal former via hydrogen bonding.9 A wide range of molecules can be potentially used to form cocrystals with an API, increasing the accessible design space over that attainable using salt forms. Widespread acceptance is © 2013 American Chemical Society

partially limited by a lack of suitable characterization techniques for confirming cocrystal formation. The solvent drop grinding (SDG) method is the most common methodology used for cocrystal discovery; however, SDG does not easily allow the growth of a single crystal required for single crystal X-ray diffraction (SCXRD).10 Additionally, locating the positions of light elements (e.g., 1H), which is an important consideration when determining the presence of hydrogen bonding, is not always accurate when using diffraction methods. Amorphous solid dispersions also offer relative improvements of physical properties such as solubility, which can have an impact upon bioavailability.11−14 Amorphous dispersions typically consist of a drug with poor water solubility in a solid dispersion with a polymeric hydrophilic carrier. Amorphous phases often have improved dissolution relative to the Received: Revised: Accepted: Published: 999

August 14, 2012 November 19, 2012 January 9, 2013 January 9, 2013 dx.doi.org/10.1021/mp300423r | Mol. Pharmaceutics 2013, 10, 999−1007

Molecular Pharmaceutics

Article

Scheme 1

which a theoretical PDF curve is calculated according to the proportion of API and hydrophilic carrier in the dispersion. If the agreement between the calculated PDF curve of the dispersion and the experimental PDF is poor, then this is indicative of a change in interatomic radii, and therefore incorporation of the API with the hydrophilic carrier on a molecular level. Solid-state NMR (SSNMR) is able to probe the molecular configuration, structure, and dynamics and is nondestructive and applicable to amorphous states lacking in long-range order. 1 H chemical shifts in the solid state have been demonstrated to be a sensitive probe of hydrogen bonding.22−29 In previous work, we demonstrated the capability of a novel SSNMR technique, namely, the 14N−1H HMQC30−32 experiment, for probing intermolecular hydrogen bonding motifs between molecules of a guanosine derivative33 and cimetidine, an antiulcer drug.34 In the present work, we apply the 14N−1H HMQC technique to both a cocrystal and an amorphous dispersion. Rotor-synchronized 2-D 14N−1H HMQC experiments achieve indirect detection of 14N lineshapes through direct proton acquisition. Coherence transfer is achieved through heteronuclear dipolar couplings, with rotary resonance recoupling (R3)35 at the n = 2 condition (ν1 = 2νR) applied to reintroduce heteronuclear dipolar couplings.31 Fast MAS frequencies are important as they average out strong proton homonuclear dipolar couplings and lengthen 1H dephasing times. As discussed in refs 36 and 37, specifically it is the 1H

crystalline state. However, owing to the deviation away from the equilibrium state, amorphous forms are considered thermodynamically unstable and can readily convert back to the crystalline state, often under typical pharmaceutical storage conditions.15 Solid dispersions of an amorphous solid with a highly water-soluble polymer can improve physical stability, while also maintaining improved physical properties associated with the amorphous form.16,17 In solid dispersions, the API can exist as a separate amorphous or crystalline phase, or as a glass solution where the degree of contact varies from a full intimate mixture, toward a state consisting of regions of distinct amorphous or crystalline character.14 A glass solution is typically favorable, as it is generally most soluble and the risk of separation into less desirable crystalline phases is diminished.18−20 Differential scanning calorimetry (DSC) and other thermal methods are widely utilized for the characterization of solid amorphous dispersions. However, the potential complexity of dispersions can impair the suitability of thermal methods if applied in a stand-alone fashion.21 Furthermore, while providing access to the bulk properties of the material, detailed structural information is limited from thermal methods. Traditional X-ray diffraction techniques are hindered by a lack of long-range order and are generally only used to ascertain the absence of crystalline material.21 Separate powder X-ray diffraction (PXRD) patterns for the API, hydrophilic carrier and the amorphous dispersion are analyzed using pair distribution function (PDF) methods. PDF curves of individual molecular components are then used as a “reference”, from 1000

dx.doi.org/10.1021/mp300423r | Mol. Pharmaceutics 2013, 10, 999−1007


Article

acetaminophen amorphous dispersion were heated at 110 °C for 24 h prior to acquisition and samples packed in a glovebox to limit water absorption. The sample of the nicotinamide palmitic acid cocrystal was prepared as described in previous work.43 14 N−1H experiments were performed using a Bruker Avance III spectrometer at a 1H Larmor frequency (ν0) of 850 MHz using a Bruker 1.3 mm triple resonance probe, operating in double resonance mode at an MAS frequency of 60 kHz. A recycle delay of 30 s was used for all samples. Rotary resonance recoupling (R3) with an n = 2 resonance condition using an x, −x phase inversion67 of individual block lengths of duration 16.7 μs was employed. (See Figure S1 in the Supporting Information for a pulse sequence diagram.) Using a rotorsynchronized increment of 16.7 μs, the States method was applied to restore sign-discrimination in F1.68 The 1H 90° pulse was of duration 1.3 μs. 14N pulses were of duration 5 μs, for a nutation frequency of 100 kHz for nicotinamide palmitic acid, PVP, and a PVP-acetaminophen dispersion. For nicotinamide and acetaminophen, 14N pulses were of duration 6 and 8 μs, respectively, using a corresponding nutation frequency of 80 kHz and 55 kHz. A four-step nested phase cycle was used to select changes in coherence order Δp = ± 1 (on the first 1H pulse, 2 steps) and Δp = ± 1 (on the final 14N pulse, 2 steps). Magic angle calibration was achieved by optimizing a 23Na Satellite Transition MAS (STMAS)69 experiment for Na2HPO4, where accurate magic angle setting is also required to remove any large first order quadrupolar interactions. 14N chemical shifts are referenced to liquid CH3NO2 at 0 ppm using saturated NH4Cl aqueous solution at −352.9 ppm as a secondary reference. To convert to the equivalent 15N chemical shift scale frequently used in protein NMR, where the reference is liquid ammonia at −50 °C, it is necessary to add 379.5 to the given values.70 1H chemical shifts were externally referenced to adamantane at 1.63 ppm relative to TMS at 0 ppm. First-principles calculations were performed using the academic release of CASTEP71 version 4.3, which implements density-functional theory using a planewave basis set. All calculations presented used a PBE exchange-correlation functional72 and on-the-fly pseudopotentials.73 Initial geometry optimization of protons was performed by starting with the Xray single-crystal structure obtained from the CSD database. For nicotinamide, the CSD refcode is NICOAM01,41 and Z = 4, i.e., there are 60 atoms in the unit cell. The CSD refcode of the nicotinamide-palmitic acid cocrystal is JEMDIP,40 and Z = 2; i.e., there are 130 atoms in the unit cell. The geometry optimization and NMR calculations used a cutoff energy equal to 1100 eV and a k-point spacing of 0.1 × 2π Å−1 with a Monkhurst packing grid.

dephasing time under the action of the applied heteronuclear dipolar recoupling method that is of relevancenote that this is different to the spin−echo dephasing time, T2′.38,39 The example cocrystal chosen for this work is nicotinamide palmitic acid (CSD refcode: JEMDIP40), labeled as compound I in Scheme 1, which consists of two molecular components with well-characterized crystalline phases, namely, nicotinamide (CSD refcode: NICOAM0141), and palmitic acid (CSD refcode: YEFWEM42). A previous work has demonstrated the capability of solid-state NMR for the characterization of cocrystals using 13C, 15N, and 1H solid-state NMR techniques;43−45 however 14N−1H HMQC experiments32 offer the direct probing of hydrogen bonding motifs. A solid amorphous dispersion of acetaminophen (API) and polyvinylpyrrolidone (PVP, a hydrophilic carrier) was chosen to demonstrate the suitability of the 14N−1H HMQC experiment for amorphous dispersion characterization. Solid-state NMR has been demonstrated in previous work as a suitable probe of amorphous dispersions, including an acetaminophen-PVP amorphous dispersion, where the individual components are labeled as compound II in Scheme 1.46 Understanding nitrogen environments in the solid state is an important pharmaceutical development issue as nitrogen often directly participates in hydrogen bonding interactions. To date, nitrogen solid-state NMR studies of pharmaceuticals have primarily focused upon the 15N isotope6,47,48 due to its favorable spin-1/2 properties and higher gyromagnetic ratio, relative to 14N. However, 15N NMR experiments are timeintensive, owing to low natural abundance (0.37%) levels. 14 N NMR methods demonstrated herein potentially offer much shorter experimental times without the requirement for isotopic labeling, as 14N has a much higher natural abundance (99.6%) level. The properties of the spin-1 14N nuclide complicate NMR lineshapes in the solid state relative to nonquadrupolar 15N lineshapes, because the lack of a central transition and typically large quadrupolar coupling constants lead to extremely broad lineshapes on the order of MHz’s that are challenging to directly observe by solid-state NMR.49 However, the quadrupolar interaction provides access to additional structural information through electric field gradient (EFG) parameters that are not accessible to 15N NMR studies. Notably, 14N EFG parameters determined by nuclear quadrupole resonance,50,51 and also recently by wide-line 14N solidstate NMR,52 are observed to be sensitive to hydrogen bonding interactions. This complements the known sensitivity of the 15 N isotropic chemical shift to changes in hydrogen bonding configurations.53−57 In this work, experimental results are presented together with calculations performed using the GIPAW (gauge-including projector-augmented wave) methodology58,59 to calculate isotropic chemical shifts and EFG parameters. In recent years, first-principles calculations of pharmaceutically interesting compounds have become increasingly prominent.34,60−65

■

RESULTS AND DISCUSSION Figure 1 presents 2D 14N−1H HMQC spectra of nicotinamide and a nicotinamide palmitic acid cocrystal, both recorded with a τRCPL duration of 666.7 μs. For such a long recoupling duration, both one-bond and longer-range N···H proximities are observed.33,34 Table 1 lists the experimental 14N shifts (the center of gravity of the corresponding 14N line shape) for the observed 14N resonances in Figure 1a,b. Table 1 also lists the experimental 15N isotropic chemical shifts (as extracted from 15 N CP MAS spectra presented in Figure S2 in the SI). Evident differences in the experimental 14N (spin I = 1) shifts and 15N (spin I = 1/2) isotropic chemical shifts are observed. This is

■

EXPERIMENTAL DETAILS A solid amorphous dispersion containing 50% (w/w) of acetaminophen (Sigma-Aldrich, St. Louis, MO) and PVP was prepared as described previously.66 PXRD (see SI, Figure S6) and 13C solid-state NMR analysis (see SI, Figure S8) indicate the presence of amorphous material, and modulated DSC analysis (see SI, Figure S9) confirms that the dispersion exhibits a single glass transition temperature, all of which are consistent with the formation of a molecular dispersion. PVP and a PVP1001



Article

because the 14N shift depends on the combination of two components, the isotropic chemical shift, which is the same as the 15N isotropic chemical shift, and the isotropic second-order quadrupolar shift, which is given as:31,74 Q δiso

⎛ PQ ⎞2 = {−(3/40)⎜ ⎟ [I(I + 1) − 9m(m − 1) − 3] ⎝ ν0 ⎠ /[I 2(2I − 1)2 ]} × 106

(1)

Q δiso = (3/40)(PQ /ν0)2 × 106

(2)

when I = 1 and m = +1 or 0

where PQ is the quadrupolar product that depends on the quadrupolar coupling constant, CQ, and the asymmetry, ηQ: PQ = CQ [1 + ηQ2 ]

(3)

In Figure 1a, the spectrum shows distinct cross peaks for both nitrogen sites in nicotinamide. The strongest correlations are one-bond correlations between the NH2 (N2) nitrogen and the directly attached protons (H2a and H2b). A weaker correlation for pyridine N1 was also observed. From the geometrically optimized crystal structure, for N1, the intramolecular proximities to H3 and H7 and the intermolecular across hydrogen-bond proximity to H2b are all at the same distance of 2.1 Å (see SI, Table S4). Moreover, the calculated chemical shifts for these three 1H nuclei lie within a range of 2 ppm (see SI, Table S1). This is consistent with the inability to resolve separate correlation peaks for N1 in Figure 1a. In Figure 1b, a 2D spectrum of the nicotinamide palmitic acid cocrystal is presented. A clear correlation between a nitrogen of nicotinamide (N1) and the carboxylic acid hydrogen in palmitic acid (H1) is observed and is labeled N1···H1the N1···H1 distance measured from the geometry optimized crystal structure is 1.7 Ǻ (see Table S4 in the SI). The 1H chemical shift of a carboxylic acid moiety is usually observed at a high ppm value;22,75,76 the marked difference in the isotropic 1H chemical shift of H1 in palmitic acid relative to any nicotinamide proton and the absence of nitrogen nuclei in palmitic acid unambiguously show that the NH cross-peak is indicative of an interaction between N1···H1−O2, illustrating molecular association. The observation of a clear N1−H1 correlation peak in the 14N−1H HMQC spectrum constitutes unambiguous evidence for the formation of an intermolecular hydrogen bond in the cocrystal. Additionally, the NH2 protons of the cocrystal are slightly more shielded (lower ppm) compared to that of nicotinamidethe NH2 cross peaks are

Figure 1. 14N−1H HMQC spectra recorded at ν0 = 850 MHz and an MAS frequency of 60 kHz for (a) nicotinamide and (b) a nicotinamide palmitic acid cocrystal using n = 2 rotary resonance recoupling for a τRCPL duration of 666.7 μs for both cases. For nicotinamide, each of the 26 t1 FIDs were recorded with a total of 84 coadded transients, whereas 30 t1 FIDs increments were acquired using 100 coadded transients for nicotinamide palmitic acid, corresponding to total experimental times of 18 h (nicotinamide) and 25 h (cocrystal). The base contour levels are at (a) 35% and (b) 12% of the maximum peak height. (c, d) 14N columns taken through the highlighted area of the spectrum overlaid with lineshapes simulated using the SpinEvolution software.77 Inputted isotropic chemical shift parameters were taken from 15N CP MAS spectra (see SI, Figure S2), with quadrupolar parameters from GIPAW calculations. To give best agreement between the centers of gravity of the experimental and simulated 14 N lineshapes, the CQ values are scaled to 96% in c and to 97% in d of the calculated values. Stated distances are from the geometrically optimized (CASTEP) crystal structures.

Table 1. A Comparison of Experimental and GIPAW Calculated 15N Isotropic Chemical Shifts and 14N Shifts for Nicotinamide and Nicotinamide Palmitic Acid material

site

δ(15N)expa (ppm)

δ(15N)calcb (ppm)

δ(14N)expc (ppm)

δQiso(14N)expc,d (ppm)

PQexpe (MHz)

PQcalcf (MHz)

nicotinamide nicotinamide nicotinamide palmitic acid cocrystal nicotinamide palmitic acid cocrystal

N1 N2 N1 N2

−77.6 −276.6 −86.9 −272.4

−78.3 −274.3 −84.1 −276.7

270 −140 225 −130

348 137 312 142

4.2 2.6 4.0 2.7

4.3 2.7 4.0 2.7

N isotropic chemical shift values were extracted from 15N CP MAS spectra, which are presented in the Supporting Information (Figure S2). bδiso = −(σiso − σref), where σref for 15N was −160.4 ppm. This was calculated from addition of the mean average of the experimental isotropic chemical shifts and the mean average of σiso values from both compounds. cδ(14N)exp is the center of gravity of the 14N peak extracted from 14N−1H HMQC spectra. The associated error with δ(14N)exp and δQiso is ±5 ppm. dδQiso(14N)exp = δ(14N)exp − δ(15N)exp. eIn the above, PQexp is calculated from eq 2 using δQiso(14N) values and has an estimated error of ±0.1 MHz. fCalculated PQ values were found using a scaling factor of 96% (nicotinamide) and 97% (nicotinamide palmitic acid) applied to the calculated CQ valuesee Table S3 and section S_IV in the Supporting Information. a15

1002



Article

centered at a 1H frequency of approximately 8.5 and 7.5 ppm in Figure 1a and b, respectively (H2a and H2b)indicating changes in the intermolecular packing of nicotinamide palmitic acid compared to nicotinamide. A comparison of the 1H skyline projections in Figure 1a and b apparently suggests that the resolution in the 1H dimension is better in Figure 1b. However, the observed 1H linewidths for the N2 resonances are comparable, and this apparent resolution improvement instead is likely a consequence of the change in the 1H chemical shifts of the NH2 protons relative to those of the aromatic protons. As noted above, there are significant differences between the 15 N isotropic chemical shift and 14N shift values (see Table 1) that are a consequence of the additional contribution of the isotropic second-order quadrupolar shift in the latter 14N case. GIPAW calculations and 15N CP MAS spectra (see SI, Figure S2) both show that there are only small differences in the isotropic chemical shifts between the cocrystal and nicotinamide for both N1 and N2. Therefore, the differences in the 14N shift for N1 in nicotinamide relative to the cocrystal is attributed to a change in the isotropic second-order quadrupolar shift for N1 (nicotinamide). Previous studies have found that the CQ values for 14N, and consequently δQiso, are sensitive to subtle changes in hydrogen-bonding geometry for NH2R2+ sites (R is H or a bond to C) in amino acids;52 similar observations have been made for other quadrupolar nuclei, such 17O and 35Cl.78−81 The observed change in δQiso is further evidence of a change in the hydrogen bonding configuration and consequently evidence of cocrystal formation detectable using 14N−1H HMQC experiments. Figure 2 shows 14N−1H HMQC spectra recorded for PVP, acetaminophen, and a 50% PVP−acetaminophen amorphous solid dispersion. In Figure 2a, the PVP spectrum presented reveals a strong cross peak between nitrogen Ne of PVP and protons of water owing to the high water content of PVP. A correlation between Ne and the aliphatic protons is also seen here in the proton projection as a shoulder of the water peak at approximately 2 ppm. Confirmation that the shoulder peak does correspond to aliphatic proton chemical shifts can be seen in the 1D proton spectrum (see Figure S5 in the Supporting Information). The 14N−1H HMQC spectrum of acetaminophen in Figure 2b reveals a close-range correlation of N1 to the directly attached H1 proton at a chemical shift of approximately 8 ppm. Figure 2c shows a 14N−1H HMQC spectrum for the solid dispersion. Interestingly, the 14N shift of the N1 resonance has changed from approximately −125 ppm in the acetaminophen spectrum (Figure 2b) to approximately −60 ppm in the solid amorphous dispersion spectrum. Extraction of 15N isotropic chemical shift values from 15N CP MAS experiments (see SI, Figure S3) shows that there is no significant change between the 15N isotropic chemical shift values observed for N1 in acetaminophen and the PVP-acetaminophen dispersion; therefore, the change must be attributed to different contributions from the isotropic second-order quadrupolar shift, as shown in Table 2. The change in the 14N shift is resultant from a change in δQiso for N1 in the solid dispersion relative to acetaminophen, providing evidence of a change in the hydrogen bonding configuration. A previously reported two-dimensional 13C−1H HETCOR82,83 spectrum of the amorphous dispersion has shown that it is not possible to discriminate between the similar 1H isotropic chemical shifts of the CH3 protons (H8) in acetaminophen and those of the aliphatic protons in PVP.46

Figure 2. 14N−1H HMQC spectra recorded at ν0 = 850 MHz and an MAS frequency of 60 kHz of (a) PVP, (b) acetaminophen, and (c) a 50% w/w PVP−acetaminophen dispersion, using n = 2 rotary resonance recoupling for a τRCPL duration of (a) 533.3 μs, (b) 400 μs, and (c) 666.7 μs. The total number of coadded transients were (a) 72, (b) 64, and (c) 100, for a total of (a) 32, (b) 30, and (c) 40 t1 FIDs, corresponding to a total experimental time of (a) 19, (b) 16, and (c) 33 h. The base contour levels are at (a) 22%, (b) 45%, and (c) 33% of the maximum peak height. Intermolecular correlations are denoted in red.

By comparison, when a two-dimensional 13C−1H spectrum is acquired for the individual components, the 1H isotropic chemical shifts of aliphatic PVP protons and H8 protons in acetaminophen are distinguishable. In the amorphous dispersion spectrum in Figure 2c, it is not possible to definitively assign the N1 correlation to the proton resonance at approximately 2 ppm. If the cross-peak contains a contribution from dipolar coupling between N1 and H8 then this must mean that the 1H isotropic chemical shift of H8 is deshielded relative to acetaminophen, as seen when comparing Figure 2b,c. This would indicate a change in the local chemical environment surrounding H8, suggesting a different molecular configuration. Alternatively, if H8 does not participate in NH correlation transfer, then the peak at a 1H isotropic chemical shift of 3 ppm 1003



Article

Table 2. A Comparison of Experimental 15N Isotropic Chemical Shifts and 14N Shifts for PVP, Acetaminophen, and the 50% w/w PVP−Acetaminophen Amorphous Dispersion material PVP acetaminophen 50% amorphous dispersion 50% amorphous dispersion

site

δ(15N) (ppm)

δ(14N)b (ppm)

δQiso(14N)b,c (ppm)

P Qd (MHz)

Ne N1 Ne

−252a −244 −250

−5 −125 0

247 119 250

3.5 2.5 3.5

N1

−244

−60

184

3.1

presented, definitive evidence of intermolecular hydrogen bonding through identification of cross peaks is limited by overlapping proton resonances. However, a comparison of the relevant 1H isotropic chemical shifts and 14N shifts obtained for the individual constituents to those found for an amorphous dispersion clearly identifies different hydrogen bonding configurations, thus establishing molecular association between the constituents. Future studies of amorphous dispersions could include the use of complementary techniques, such as vibrational spectroscopy and PXRD using pair distribution function analysis, in conjunction with 14N−1H HMQC and other 13C-based solid-state NMR techniques, to gain more detailed information about molecular interactions. Owing to a much higher natural abundance, 14N NMR experimental times are significantly shortened relative to comparable 15N NMR experiments, without the requirement for isotopic labeling. Furthermore, access to quadrupolar parameters, which as demonstrated herein are very sensitive to changes in hydrogen bonding geometry, is only possible when utilizing 14N NMR.

a

The stated 15N isotropic chemical shift for Ne is the average of the peaks in the 15N CP MAS spectrum (see SI, Figure S3). bδ(14N), the experimental 14N shift, is the center of gravity of the 14N peak extracted from 14N−1H HMQC spectra. The associated error in δ(14N) and consequently δQiso(14N) is ±5 ppm. cδQiso(14N) = δ (14N) − δ(15N). dPQ is calculated using eq 2, and the associated error is estimated as ±0.1 MHz.

must then be assigned to aliphatic protons in PVP, demonstrating molecular association between acetaminophen and PVP. In Figure 2c, an intramolecular N1−H1 correlation is clearly resolved at a 1H isotropic chemical shift of approximately 10 ppmthis is to be compared to approximately 8 ppm in Figure 2b. The 1H isotropic chemical shift of H1 is thus deshielded in the amorphous dispersion relative to acetaminophen. A weaker, longer range intramolecular correlation between N1 and the aromatic protons is also observed. Longer range correlations to aromatic protons are observed in Figure 2c as a longer recoupling time was applied (667 μs compared to 400 μs for the spectrum in Figure 2b). The spectra in Figure 2 provide numerous observations that confirm molecular association. The changes in 1H isotropic chemical shifts of H1 (and possibly H8) are clear evidence of changes in hydrogen bonding configuration, whereas different 14 N shifts are attributed to a change in the CQ of N1, owing to a different hydrogen bonding environment in the amorphous dispersion.

■

ASSOCIATED CONTENT

S Supporting Information *

(i) Pulse sequence, (ii) additional solid-state NMR and PXRD experimental data, (iii) GIPAW calculated chemical shielding tensors, (iv) GIPAW calculated electric field gradients, (v) NH distances (pdf), (vi) geometry optimized (CASTEP) crystal structure of nicotinamide (pdb), and (vii) geometry optimized (CASTEP) crystal structure of the nicotinamide palmitic acid cocrystal (pdb). This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

■

ACKNOWLEDGMENTS Funding from EPSRC is acknowledged. The UK 850 MHz solid-state NMR Facility used in this research was funded by EPSRC and BBSRC, as well as the University of Warwick including via part funding through Birmingham Science City Advanced Materials Projects 1 and 2 supported by Advantage West Midlands (AWM) and the European Regional Development Fund (ERDF). CASTEP calculations were performed on the University of Warwick Centre for Scientific Computing cluster. We are grateful to Accelrys for providing the Materials Studio Interface. Helpful discussions with Prof. Stephen Wimperis, Dr. Luminita Duma, Dr. Hans Forster, and Dr. Stefan Steuernagel concerning 14N−1H experiments are acknowledged.

CONCLUSIONS It is shown that 14N−1H HMQC solid-state MAS NMR experiments have much potential for the characterization of cocrystals and amorphous dispersions. Clear evidence of hydrogen bonding was observed in a nicotinamide palmitic acid cocrystal via an intramolecular NH cross peak. Furthermore, 14N shifts are a combination of the isotropic chemical shift, which is the same for both nitrogen isotopes, and an additional contribution from the isotropic second-order quadrupolar shift. Importantly, the quadrupolar interaction, and hence the isotropic second-order quadrupolar shift, is very sensitive to changes in the hydrogen bonding interaction. Consequently, the comparison between the 14N shift of a cocrystal and one of its molecular components provides further evidence of changes in hydrogen bonding configurations. This was visible when comparing 14N shifts of nicotinamide relative to nicotinamide palmitic acid, where the isotropic chemical shift was shown to be approximately the same for both materials. Additionally, we have demonstrated that a 14N−1H HMQC spectrum can be recorded for an amorphous dispersion. Identification of hydrogen bonding interactions via 14N−1H HMQC spectra provides evidence of molecular association in amorphous solid dispersions. For the example system

■

REFERENCES

(1) Almarsson, O.; Zaworotko, M. J. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chem. Commun. 2004, 1889−1896. (2) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. Pharmaceutical co-crystals. J. Pharm. Sci. 2006, 95, 499−516. (3) Brittain, H. G. Cocrystal Systems of Pharmaceutical Interest: 2010. Cryst. Growth Des. 2012, 12, 1046−1054.

1004



Article

Pulse Spectroscopy. J. Chem. Soc., Faraday Trans. I. 1988, 84, 3649− 3672. (23) Harris, R. K.; Ghi, P. Y.; Hammond, R. B.; Ma, C. Y.; Roberts, K. J. Refinement of hydrogen atomic position in a hydrogen bond using a combination of solid-state NMR and computation. Chem. Commun. 2003, 2834−2835. (24) Yates, J. R.; Pham, T. N.; Pickard, C. J.; Mauri, F.; Amado, A. M.; Gil, A. M.; Brown, S. P. An investigation of weak CH···O hydrogen bonds in maltose anomers by a combination of calculation and experimental solid-state NMR spectroscopy. J. Am. Chem. Soc. 2005, 127, 10216−10220. (25) Schmidt, J.; Hoffmann, A.; Spiess, H. W.; Sebastiani, D. Bulk Chemical Shifts in Hydrogen-Bonded Systems from First-Principles Calculations and Solid-State-NMR. J. Phys. Chem. B. 2006, 110, 23204−23210. (26) Griffin, J. M.; Martin, D. R.; Brown, S. P. Distinguishing anhydrous and hydrous forms of an active pharmaceutical ingredient in a tablet formulation using solid-state NMR spectroscopy. Angew. Chem., Int. Ed. Engl. 2007, 46, 8036−8038. (27) Sharif, S.; Schagen, D.; Toney, M. D.; Limbach, H. H. Coupling of functional hydrogen bonds in pyridoxal-5′-phosphate-enzyme model systems observed by solid-state NMR spectroscopy. J. Am. Chem. Soc. 2007, 129, 4440−4455. (28) Uldry, A. C.; Griffin, J. M.; Yates, J. R.; Perez-Torralba, M.; Maria, M. D. S.; Webber, A. L.; Beaumont, M. L. L.; Samoson, A.; Claramunt, R. M.; Pickard, C. J.; Brown, S. P. Quantifying weak hydrogen bonding in uracil and 4-cyano-4′-ethynylbiphenyl: A combined computational and experimental investigation of NMR chemical shifts in the solid state. J. Am. Chem. Soc. 2008, 130, 945− 954. (29) Brown, S. P. Applications of high-resolution 1H solid-state NMR. Solid State Nucl. Magn. Reson. 2012, 41, 1−27. (30) Cavadini, S.; Antonijevic, S.; Lupulescu, A.; Bodenhausen, G. Indirect detection of nitrogen-14 in solids via protons by nuclear magnetic resonance spectroscopy. J. Magn. Reson. 2006, 182, 168−172. (31) Gan, Z. H.; Amoureux, J. P.; Trebosc, J. Proton-detected 14N MAS NMR using homonuclear decoupled rotary resonance. Chem. Phys. Lett. 2007, 435, 163−169. (32) Cavadini, S. Indirect detection of nitrogen-14 in solid-state NMR spectroscopy. Prog. Nucl. Magn. Reson. Spectrosc. 2010, 56, 46− 77. (33) Webber, A. L.; Masiero, S.; Pieraccini, S.; Burley, J. C.; Tatton, A. S.; Iuga, D.; Pham, T. N.; Spada, G. P.; Brown, S. P. Identifying Guanosine Self Assembly at Natural Isotopic Abundance by HighResolution 1H and 13C Solid-State NMR Spectroscopy. J. Am. Chem. Soc. 2011, 133, 19777−19795. (34) Tatton, A. S.; Pham, T. N.; Vogt, F. G.; Iuga, D.; Edwards, A. J.; Brown, S. P. Probing intermolecular interactions and nitrogen protonation in pharmaceuticals by novel 15N-edited and 2D 14N-1H solid-state NMR. CrystEngComm 2012, 14, 2654−2659. (35) Levitt, M. H.; Oas, T. G.; Griffin, R. G. Rotary Resonance Recoupling in Heteronuclear Spin Pair Systems. Isr. J. Chem. 1988, 28, 271−282. (36) Nishiyama, Y.; Endo, Y.; Nemoto, T.; Utsumi, H.; Yamauchi, K.; Hioka, K.; Asakura, T. Very fast magic angle spinning 1H-14N 2D solidstate NMR: Sub-micro-liter sample data collection in a few minutes. J. Magn. Reson. 2011, 208, 44−48. (37) Tatton, A. S.; Bradley, J. P.; Iuga, D.; Brown, S. P. 14N−1H Heteronuclear Multiple-Quantum Correlation Magic-Angle Spinning NMR Spectroscopy of Organic Solids. Z. Phys. Chem. 2012, 226, 1187−1203. (38) Lesage, A.; Bardet, M.; Emsley, L. Through-Bond Carbon− Carbon Connectivities in Disordered Solids by NMR. J. Am. Chem. Soc. 1999, 121, 10987−10993. (39) Zorin, V. E.; Brown, S. P.; Hodgkinson, P. Origins of linewidth in 1H magic-angle spinning NMR. J. Chem. Phys. 2006, 125, 144508: 1−13.

(4) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Kumar Thaper, R.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Polymorphs, Salts, and Cocrystals: What’s in a Name? Cryst. Growth Des. 2012, 12, 2147− 2152. (5) Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, O. Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J. Am. Chem. Soc. 2003, 125, 8456−8457. (6) Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek, A.; Trask, A. V. Solid-state acid-base interactions in complexes of heterocyclic bases with dicarboxylic acids: Crystallography, hydrogen bond analysis, and 15N NMR spectroscopy. J. Am. Chem. Soc. 2006, 128, 8199−8210. (7) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm. Res. 2006, 23, 1888−1897. (8) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Physical stability enhancement of theophylline via cocrystallization. Int. J. Pharmaceutics 2006, 320, 114−123. (9) Bernstein, J.; Etter, M. C.; Leiserowitz, L. The Role of Hydrogen Bonding in Molecular Assemblies. In In Structure Correlation; WileyVCH, Verlag GmbH: Munchen, Germany, 2008; pp 431−507. (10) Friscic, T.; Trask, A. V.; Jones, W.; Motherwell, W. D. S. Screening for inclusion compounds and systematic construction of three-component solids by liquid-assisted grinding. Angew. Chem., Int. Ed. Engl. 2006, 45, 7546−7550. (11) Torrado, S.; Torrado, S.; Torrado, J. J.; Cadorniga, R. Preparation, dissolution and characterization of albendazole solid dispersions. Int. J. Pharmaceutics 1996, 140, 247−250. (12) Serajuddin, A. T. M. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 1999, 88, 1058−1066. (13) Desai, J.; Alexander, K.; Riga, A. Characterization of polymeric dispersions of dimenhydrinate in ethyl cellulose for controlled release. Int. J. Pharmaceutics 2006, 308, 115−123. (14) Janssens, S.; Van den Mooter, G. Review: physical chemistry of solid dispersions. J. Pharm. Pharmacol. 2009, 61, 1571−1586. (15) Bhugra, C.; Pikal, M. J. Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state. J. Pharm. Sci. 2008, 97, 1329−1349. (16) Konno, H.; Taylor, L. S. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J. Pharm. Sci. 2006, 95, 2692−2705. (17) Newman, A.; Knipp, G.; Zografi, G. Assessing the performance of amorphous solid dispersions. J. Pharm. Sci. 2012, 101, 1355−1377. (18) Chiou, W. L.; Riegelma, S. Pharmaceutical Applications of Solid Dispersion Systems. J. Pharm. Sci. 1971, 60, 1281−1302. (19) Rumondor, A. C. F.; Marsac, P. J.; Stanford, L. A.; Taylor, L. S. Phase Behavior of Poly(vinylpyrrolidone) Containing Amorphous Solid Dispersions in the Presence of Moisture. Mol. Pharmaceutics 2009, 6, 1492−1505. (20) Rumondor, A. C. F.; Taylor, L. S. Effect of Polymer Hygroscopicity on the Phase Behavior of Amorphous Solid Dispersions in the Presence of Moisture. Mol. Pharmaceutics 2010, 7, 477−490. (21) Newman, A.; Engers, D.; Bates, S.; Ivanisevic, I.; Kelly, R. C.; Zografi, G. Characterization of Amorphous API:Polymer Mixtures Using X-Ray Powder Diffraction. J. Pharm. Sci. 2008, 97, 4840−4856. (22) Harris, R. K.; Jackson, P.; Merwin, L. H.; Say, B. J.; Hagele, G. Perspectives in High-Resolution Solid-State Nuclear MagneticResonance, with Emphasis on Combined Rotation and Multiple1005



Article

(40) Amai, M.; Kamijo, M.; Nagase, H.; Ogawa, N.; Endo, T.; Ueda, H. Crystal Structure of a 1:1 Complex of Palmitic acid and Nicotinamide. Anal. Sci. 2006, 22, x121−x122. (41) Miwa, Y.; Mizuno, T.; Tsuchida, K.; Taga, T.; Iwata, Y. Experimental charge density and electrostatic potential in nicotinamide. Acta Crystallogr., Sect. B 1999, 55, 78−84. (42) Moreno, E.; Cordobilla, R.; Calvet, T.; Lahoz, F. J.; Balana, A. I. The C form of n-hexadecanoic acid. Acta Crystallogr., Sect. C 2006, 62, O129−O131. (43) Vogt, F. G.; Clawson, J. S.; Strohmeier, M.; Edwards, A. J.; Pham, T. N.; Watson, S. A. Solid-State NMR Analysis of Organic Cocrystals and Complexes. Cryst. Growth Des. 2009, 9, 921−937. (44) Khan, M.; Enkelmann, V.; Brunklaus, G. Crystal Engineering of Pharmaceutical Co-crystals: Application of Methyl Paraben as Molecular Hook. J. Am. Chem. Soc. 2010, 132, 5254−5263. (45) Khan, M.; Enkelmann, V.; Brunklaus, G. Heterosynthon mediated tailored synthesis of pharmaceutical complexes: a solidstate NMR approach. CrystEngComm 2011, 13, 3213−3223. (46) Pham, T. N.; Watson, S. A.; Edwards, A. J.; Chavda, M.; Clawson, J. S.; Strohmeier, M.; Vogt, F. G. Analysis of Amorphous Solid Dispersions Using 2D Solid-State NMR and 1H T1 Relaxation Measurements. Mol. Pharmaceutics 2010, 7, 1667−1691. (47) Bauer, M.; Harris, R. K.; Rao, R. C.; Apperley, D. C.; Rodger, C. A. NMR study of desmotropy in Irbesartan, a tetrazole-containing pharmaceutical compound. J. Chem. Soc., Perkin Trans. 2 1998, 475− 482. (48) Smith, E. D. L.; Hammond, R. B.; Jones, M. J.; Roberts, K. J.; Mitchell, J. B. O.; Price, S. L.; Harris, R. K.; Apperley, D. C.; Cherryman, J. C.; Docherty, R. The Determination of the Crystal Structure of Anhydrous Theophylline by X-ray Powder Diffraction with a Systematic Search Algorithm, Lattice Energy Calculations, and 13 C and 15N Solid-State NMR: A Question of Polymorphism in a Given Unit Cell. J. Phys. Chem. B 2001, 105, 5818−5826. (49) O’Dell, L. A. Direct detection of nitrogen-14 in solid-state NMR spectroscopy. Prog. Nucl. Magn. Reson. Spectrosc. 2011, 59, 295−318. (50) Rubenacker, G. V.; Brown, T. L. Nitrogen-14 nuclear quadrupole resonance spectra of coordinated pyridine. An extended evaluation of the coordinated nitrogen model. Inorg. Chem. 1980, 19, 392−398. (51) Seliger, J.; Ž agar, V. 14N NQR Study of Polymorphism and Hydrogen Bonding in Molecular Complex Isonicotinamide−Oxalic Acid (2:1). J. Phys. Chem. A. 2010, 114, 12083−12087. (52) O’Dell, L. A.; Schurko, R. W. Static solid-state 14N NMR and computational studies of nitrogen EFG tensors in some crystalline amino acids. Phys. Chem. Chem. Phys. 2009, 11, 7069−7077. (53) Naito, A.; Tuzi, S.; Saitô, H. A High-resolution 15N Solid-state NMR Study of Collagen and Related Polypeptides. Eur. J. Biochem. 1994, 224, 729−734. (54) Facelli, J. C. Nitrogen-15 chemical shift in the pyridine− methanol complex. Chem. Phys. Lett. 2000, 322, 91−96. (55) Lorente, P.; Shenderovich, I. G.; Golubev, N. S.; Denisov, G. S.; Buntkowsky, G.; Limbach, H.-H. 1H/15N NMR chemical shielding, dipolar 15N,2H coupling and hydrogen bond geometry correlations in a novel series of hydrogen-bonded acid−base complexes of collidine with carboxylic acids. Magn. Reson. Chem. 2001, 39, S18−S29. (56) Schilf, W.; Kamieński, B.; Dziembowska, T. Intramolecular hydrogen bond investigations in Schiff bases derivatives of 2-hydroxy1-naphthaldehyde and 2-hydroxy-1-acetonaphthone in CDCl3 solution and in the solid state by NMR methods. J. Mol. Struct. 2002, 602−603, 41−47. (57) Sharif, S.; Schagen, D.; Toney, M. D.; Limbach, H.-H. Coupling of Functional Hydrogen Bonds in Pyridoxal-5′-phosphate−Enzyme Model Systems Observed by Solid-State NMR Spectroscopy. J. Am. Chem. Soc. 2007, 129, 4440−4455. (58) Pickard, C. J.; Mauri, F. All-electron magnetic response with pseudopotentials: NMR chemical shifts. Phys. Rev. B 2001, 63, 245101. (59) Yates, J. R.; Pickard, C. J.; Mauri, F. Calculation of NMR chemical shifts for extended systems using ultrasoft pseudopotentials. Phys. Rev. B 2007, 76, 024401.

(60) Yates, J. R.; Dobbins, S. E.; Pickard, C. J.; Mauri, F.; Ghi, P. Y.; Harris, R. K. A combined first principles computational and solid-state NMR study of a molecular crystal: flurbiprofen. Phys. Chem. Chem. Phys. 2005, 7, 1402−1407. (61) Mifsud, N.; Elena, B.; Pickard, C. J.; Lesage, A.; Emsley, L. Assigning powders to crystal structures by high-resolution 1H-1H double quantum and 1H-13C J-INEPT solid-state NMR spectroscopy and first principles computation. A case study of penicillin G. Phys. Chem. Chem. Phys. 2006, 8, 3418−3422. (62) Vogt, F. G.; Katrincic, L. M.; Long, S. T.; Mueller, R. L.; Carlton, R. A.; Sun, Y. T.; Johnson, M. N.; Copley, R. C. B.; Light, M. E. Enantiotropically-Related Polymorphs of {4-(4-Chloro-3-Fluorophenyl)-2-[4-(Methyloxy)Phenyl]-1,3-Thiazol-5-yl} Acetic Acid: Crystal Structures and Multinuclear Solid-State NMR. J. Pharm. Sci. 2008, 97, 4756−4782. (63) Salager, E.; Stein, R. S.; Pickard, C. J.; Elena, B.; Emsley, L. Powder NMR crystallography of thymol. Phys. Chem. Chem. Phys. 2009, 11, 2610−2621. (64) Bradley, J. P.; Velaga, S. P.; Antzutkin, O. N.; Brown, S. P. Probing Intermolecular Crystal Packing in γ-Indomethacin by HighResolution 1H Solid-State NMR Spectroscopy. Cryst. Growth Des. 2011, 11, 3463−3471. (65) Bradley, J. P.; Pickard, C. J.; Burley, J. C.; Martin, D. R.; Hughes, L. P.; Cosgrove, S. D.; Brown, S. P. Probing intermolecular hydrogen bonding in sibenadet hydrochloride polymorphs by high-resolution 1H double-quantum solid-state NMR spectroscopy. J. Pharm. Sci. 2012, 101, 1821−1830. (66) de Villiers, M. M.; Wurster, D. E.; Van der Watt, J. G.; Ketkar, A. X-Ray powder diffraction determination of the relative amount of crystalline acetaminophen in solid dispersions with polyvinylpyrrolidone. Int. J. Pharmaceutics 1998, 163, 219−224. (67) Costa, P. R.; Gross, J. D.; Hong, M.; Griffin, R. G. Solid-state NMR measurement of Ψ in peptides: a NCCN 2Q-heteronuclear local field experiment. Chem. Phys. Lett. 1997, 280, 95−103. (68) States, D. J.; Haberkorn, R. A.; Ruben, D. J. A Two-Dimensional Nuclear Overhauser Experiment with Pure Absorption Phase in 4 Quadrants. J. Magn. Reson. 1982, 48, 286−292. (69) Gan, Z. H. Isotropic NMR spectra of half-integer quadrupolar nuclei using satellite transitions and magic-angle spinning. J. Am. Chem. Soc. 2000, 122, 3242−3243. (70) Martin, G. E.; Hadden, C. E. Long-Range 1 H− 15 N Heteronuclear Shift Correlation at Natural Abundance. J. Nat. Prod. 2000, 63, 543−585. (71) Clark, S. J.; Segall, M. D.; Pickard, C. J.; Hasnip, P. J.; Probert, M. J.; Refson, K.; Payne, M. C. First principles methods using CASTEP. Z. Kristallogr. 2005, 220, 567−570. (72) Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized gradient approximation made simple. Phys. Rev. Lett. 1996, 77, 3865−3868. (73) Vanderbilt, D. Soft Self-Consistent Pseudopotentials in a Generalized Eigenvalue Formalism. Phys. Rev. B 1990, 41, 7892−7895. (74) Samoson, A. Satellite transition high-resolution NMR of quadrupolar nuclei in powders. Chem. Phys. Lett. 1985, 119, 29−32. (75) Berglund, B.; Vaughan, R. W. Correlations between proton chemical shift tensors, deuterium quadrupole couplings, and bond distances for hydrogen bonds in solids. J. Chem. Phys. 1980, 73, 2037− 2043. (76) Jeffrey, G. A.; Yeon, Y. The correlation between hydrogen-bond lengths and proton chemical shifts in crystals. Acta Crystallogr., Sect. B 1986, 42, 410−413. (77) Veshtort, M.; Griffin, R. G. SPINEVOLUTION: A powerful tool for the simulation of solid and liquid state NMR experiments. J. Magn. Reson. 2006, 178, 248−282. (78) Gervais, C.; Dupree, R.; Pike, K. J.; Bonhomme, C.; Profeta, M.; Pickard, C. J.; Mauri, F. Combined first-principles computational and experimental multinuclear solid-state NMR investigation of amino acids. J. Phys. Chem. A 2005, 109, 6960−6969. (79) Kwan, I. C. M.; Mo, X.; Wu, G. Probing hydrogen bonding and ion-carbonyl interactions by solid-state 17O NMR spectroscopy: Gribbon and G-quartet. J. Am. Chem. Soc. 2007, 129, 2398−2407. 1006



Article

(80) Chapman, R. P.; Bryce, D. L. A high-field solid-state 35/37Cl NMR and quantum chemical investigation of the chlorine quadrupolar and chemical shift tensors in amino acid hydrochlorides. Phys. Chem. Chem. Phys. 2007, 9, 6219−6230. (81) Hamaed, H.; Pawlowski, J. M.; Cooper, B. F. T.; Fu, R.; Eichhorn, S. H.; Schurko, R. W. Application of Solid-State 35Cl NMR to the Structural Characterization of Hydrochloride Pharmaceuticals and their Polymorphs. J. Am. Chem. Soc. 2008, 130, 11056−11065. (82) de Groot, H. J. M.; van Rossum, B. J.; de Groot, C. P.; Ladizhansky, V.; Vega, S. A method for measuring heteronuclear 1 H-13C distances in high speed MAS NMR. J. Am. Chem. Soc. 2000, 122, 3465−3472. (83) Brown, S. P.; Spiess, H. W. Advanced solid-state NMR methods for the elucidation of structure and dynamics of molecular, macromolecular, and supramolecular systems. Chem. Rev. 2001, 101, 4125−4155.

1007


Probing Hydrogen Bonding in Cocrystals and Amorphous Dispersions

Recommend Documents