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ArticleJanuary 10, 2014

Dynamic Nuclear Polarization Enhanced NMR Spectroscopy for Pharmaceutical Formulations
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Cite this: J. Am. Chem. Soc. 2014, 136, 6, 2324–2334

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https://doi.org/10.1021/ja4092038

Published January 10, 2014

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Abstract

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Dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy at 9.4 T is demonstrated for the detailed atomic-level characterization of commercial pharmaceutical formulations. To enable DNP experiments without major modifications of the formulations, the gently ground tablets are impregnated with solutions of biradical polarizing agents. The organic liquid used for impregnation (here 1,1,2,2-tetrachloroethane) is chosen so that the active pharmaceutical ingredient (API) is minimally perturbed. DNP enhancements (ε) of between 40 and 90 at 105 K were obtained for the microparticulate API within four different commercial formulations of the over-the-counter antihistamine drug cetirizine dihydrochloride. The different formulations contain between 4.8 and 8.7 wt % API. DNP enables the rapid acquisition with natural isotopic abundances of one- and two-dimensional ¹³C and ¹⁵N solid-state NMR spectra of the formulations while preserving the microstructure of the API particles. Here this allowed immediate identification of the amorphous form of the API in the tablet. API–excipient interactions were observed in high-sensitivity ¹H–¹⁵N correlation spectra, revealing direct contacts between povidone and the API. The API domain sizes within the formulations were determined by measuring the variation of ε as a function of the polarization time and numerically modeling nuclear spin diffusion. Here we measure an API particle radius of 0.3 μm with a single particle model, while modeling with a Weibull distribution of particle sizes suggests most particles possess radii of around 0.07 μm.

Subjects

1 Introduction

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The characterization of the composition and structure of formulated multicomponent materials in general, and of pharmaceutical formulations in particular, is of great industrial importance today, yet in many respects it remains an unsolved analytical challenge. While several methods can be used as indirect probes of the properties of formulations, there are very few direct probes available. On the other hand, today solid-state NMR (together with diffraction methods) is frequently used to probe the solid-state structures of pure active pharmaceutical ingredients (APIs), often in the context of identifying structural polymorphs. (1-5) In this respect, solid-state NMR spectroscopy would appear to be a potentially powerful direct probe of structure for formulations.

In favorable cases, three-dimensional crystal structures can be determined from pure powdered samples by solid-state NMR with the NMR crystallography approach. This is accomplished either by directly measuring internuclear distances/proximities (e.g., ¹H–¹H, ¹H–¹³C, ²⁹Si–²⁹Si, etc.) (6-10) or by comparing trial structures and computed NMR parameters and/or distances with observed parameters and/or internuclear distance constraints. (11-22) A number of other solid-state NMR techniques exploiting quadrupolar or uncommon spin-1/2 nuclei such as ⁷Li, ¹⁴N, ¹⁵N, ¹⁷O, ¹⁹F, ²³Na, ³⁵Cl, etc., have also been demonstrated as probes of structure and dynamics for organic solids. (23-36)

While all of these NMR based techniques have been successfully demonstrated for the characterization of pure crystalline powdered solids, it would be of great interest to extend these techniques to the characterization of APIs in formulations. This could enable solid-state NMR structure determination “in situ”, allowing polymorph screening and identification, quantification of the degree of crystallinity of the API, measurement of domain sizes, and/or the determination of API–excipient interactions. Characterization of these properties is especially important, since they influence the activity/release properties of the formulations, and the overall stability of the API phase. (30, 37-40) However, the characterization of formulated APIs by solid-state NMR is often challenging due to the combination of the intrinsically low sensitivity of NMR, long longitudinal relaxation times, (41, 42) and the low API content of many formulations (typically between 5 and 10 wt %).

Early solid-state NMR studies of formulated pharmaceuticals were performed on aspirin (2-acetoxybenzoic acid) and paracetamol (N-(4-hydroxyphenyl)ethanamide), because of the importance of these drugs, the very high API contents (>30 wt %), and limited number of excipients. (43-45) Byrn and co-workers subsequently demonstrated that natural abundance ¹³C CPMAS NMR spectra of formulated APIs with contents as low as 5 wt % could be acquired in 8–12 h. (37) Subsequent experiments demonstrated that natural abundance ¹³C solid-state NMR can be applied to formulated APIs with contents as low as 0.5 wt %; however, acquisition times are usually long (∼12–24 h). (25, 38, 39, 46) For these reasons, subsequent solid-state NMR studies of formulated APIs have exploited highly receptive nuclei and/or proton detection, (25, 31, 47-50) have been performed on formulations with relatively high API contents (43-46, 51) (>10 wt %), or used model formulations with a limited number of excipients. (39, 40, 46, 51) Studies of formulations containing many excipients and/or low API contents are relatively rare. (31, 37, 47, 52-54)

More importantly, the ¹H and ¹³C solid-state NMR spectra of formulations generally possess many overlapping resonances from the large number of constituents, and multidimensional NMR spectra are generally required to restore spectral resolution and information content. Moreover, multidimensional methods are often essential to probe API–excipient interactions, or any of the other structural features discussed above. In formulations where resolution is high enough to permit ¹H NMR experiments (47) or highly receptive nuclei are present (such as ¹⁹F and ²³Na), multidimensional experiments are possible even at low API loadings. (23, 25, 31, 36) However, the low sensitivity of NMR usually precludes multidimensional acquisitions at natural isotopic abundance for ¹³C and ¹⁵N (to our knowledge, multidimensional ¹³C experiments have only been previously reported for model formulations with high API contents >30 wt %), (27, 48, 49, 51, 53, 55) and thus, low sensitivity is the key barrier to the introduction of in situ NMR structural characterization methods for formulations.

High field dynamic nuclear polarization (DNP) low temperature (∼105 K) magic angle spinning (MAS) experiments have been demonstrated to enhance the sensitivity of high field solid-state NMR experiments by several orders of magnitude. (56, 57) This technique has recently been applied to characterize biological systems (58-65) and materials. (42, 66-75) In such experiments, a polarizing agent, usually a stable exogenous biradical, (76) is homogeneously dispersed within the sample, resulting in a uniform distribution of enhanced polarization. This is obviously not suited to the analysis of microparticulate APIs within formulations. However, it was previously shown that the protons in the bulk of nanometer sized crystallites of polypeptides could be highly polarized through proton spin diffusion when the polarizing agent is restricted only to the surface of the crystals. (77) We have recently generalized this concept to show how very high polarization enhancements can be obtained from ordinary crystalline organic solids impregnated with a radical containing solution, provided proton longitudinal relaxation times are long (>100 s). (42) This technique provides enhanced NMR sensitivity for powdered organic solids while preserving the crystal structures of the solids and the intrinsic spectral resolution. Griffin and co-workers have recently suggested that DNP experiments on amorphous organic solids (such as amorphous APIs) could be performed by including the radical during solidification/deposition of the amorphous APIs. (78)

Here we show that simple impregnation DNP can be applied to obtain large sensitivity enhancements for formulated pharmaceuticals. This enables the rapid acquisition of 1D and 2D ¹H–¹³C and ¹H–¹⁵N solid-state NMR spectra from drug formulations, at natural isotopic abundance, with API contents between 4.8 and 8.7 wt %. We then show that impregnation DNP can be used to determine in situ the distributions of domain sizes of the API in a formulation, something which was not previously possible by NMR for such a complex sample.

2 Experimental Section

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Crystalline cetirizine dihydrochloride (A, [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride) was obtained from Sigma-Aldrich and used without further purification. Polyvinylpyrrolidone (povidone), starch, α-lactose monohydrate, and hydroxypropylmethylcellulose (hypromellose) were purchased from Alfa Aesar and used without further purification. Amorphous A was prepared by dissolving ca. 0.3 g of A in ca. 60 mL of 50:50 acetone:water solution within a 100 mL ceramic crucible. The volatile solvent was then allowed to evaporate overnight, producing a clear amorphous film of A. The four commercial formulations of the drug containing A as the API were purchased over the counter at different pharmacies in the USA and Canada. The commercial formulations (and manufacturers where available) were “Life Brand Extra Strength Aller-Relief” (Pharmascience, Inc.) (F1), “CVS Indoor/Outdoor Allergy Relief” (manufacturer not provided, product of India, distributed by CVS Pharmacy, Inc.) (F2), “Reactine” (Pfizer, Inc.) (F3), and “Walgreens WAL-ZYR All Day Allergy” (distributed by Walgreens, Co.) (F4). SEM images of F1 were acquired with a LEO 1530 Gemini FEG SEM microscope.

For DNP NMR experiments, typically 40–45 mg of gently ground tablet was impregnated with 20–25 μL of a biradical solution of 1,1,2,2-tetrachlroethane (TCE). Amorphous and crystalline A were finely ground by hand with a mortar and pestle to reduce the particle size prior to impregnation. TEKPol (79) and bCTbK (80) nitroxide biradicals were used as polarizing agents with biradical concentrations between 14 and 24 mM. The biradical TCE solution was partially deuterated with TCE-d₂ in order to increase ε (Table 1). (80)

DNP solid-state NMR experiments were performed on a widebore 400 MHz Bruker Avance III spectrometer equipped with a 263 GHz gyrotron, a low temperature cooling cabinet, and a triple resonance 3.2 mm low temperature probe. (81) The sample temperature for DNP experiments was approximately 105 K. The field sweep coil of the main magnetic field was set so that microwave irradiation occurred at the same position as the positive enhancement maximum for 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL). (76, 81) DNP enhancements (ε) were determined by comparing the intensity of spectra acquired with and without microwave irradiation. Additional solid-state NMR experiments were performed on 500 or 700 MHz Bruker Avance III solid-state NMR spectrometers. ¹⁵N chemical shifts were referenced with respect to nitromethane by comparison to the ¹H resonance frequency. (82) CPMAS experiments were performed with a contact pulse on ¹H which was linearly ramped from ν₁ = 66 to 93 kHz and from 58 to 82 kHz for ¹³C and ¹⁵N experiments, respectively. (83, 84)¹³C and ¹⁵N CP spin lock rf field amplitudes of 57 and 42 kHz were used, respectively. The SPINAL-64 heteronuclear decoupling scheme was applied during acquisition with ¹H rf fields of ca. 100 kHz. (85) During t₁ of the dipolar heteronuclear correlation (HETCOR) experiments, eDUMBO-1₂₂ homonuclear ¹H decoupling was applied and proton chemical shifts were corrected by applying a scaling factor of 0.57. (86) Low temperature experiments at 500 MHz were performed with a double resonance 3.2 mm low temperature MAS probe similar to that used for DNP. Room temperature experiments at 700 and 500 MHz employed 3.2 mm triple resonance HXY and 4 mm double resonance HX probes, respectively. Numerical spin diffusion models were constructed with MatLab v7.10 (The MathWorks, Inc.) as previously described. (42) Differing from the previous procedure, no reduction in the proton T₁’s at the surface of the API particles was assumed in the present case due to the small particle size and similarity of the proton T₁’s at the surface and in the core of the API particles. The MatLab code is available in the Supporting Information, or from the authors upon request.

Table 1. Sample Characteristics, Measured DNP Enhancements, and Relaxation Properties

sample name and composition of the impregnating liquid	brand name/retailer	tablet mass (mg)	initial API content^a (wt %)	ε_C CP^b	T_DNP(¹H)^c (s)	¹³C sensitivity^d (s^–1/2)
crystalline cetirizine dihydrochloride A (16 mM TEKPol, TCE-d₂-20%)^e	Sigma-Aldrich	–	100	31	22	74
crystalline cetirizine dihydrochloride A (298 K, no DNP, 16.45 T)	Sigma-Aldrich	–	100	–	24	0.2
polyvinylpyrrolidone (povidone, P) (24 mM TEKPol, TCE-d₂-26%)	–	–	0	10	2.3	39
formulation F1 (24 mM TEKPol, TCE-d₂-26%)	Life	115.1	8.7	64	2.2	21.5
formulation F2 (16 mM TEKPol, TCE-d₂-20%)	CVS	207.2	4.8	90	2.9	7.8
formulation F3 (16 mM TEKPol, TCE-d₂-20%)	Reactine	170.3	5.9	62	4.2	5.5
formulation F4 (16 mM TEKPol, TCE-d₂-20%)	Wal-Zyr	181.2	5.5	40	6.5	3.1
formulation F1 (115 K, no radical solution, 11.7 T)	Life	115.1	8.7	–	6.6	0.6

The listed API dose of 10 mg was used for the calculation.

ε_C CP is the DNP enhancement measured with ¹H–¹³C cross-polarization. It usually matches the proton DNP enhancement (ε_H), since all of the polarization is derived from protons.

T_DNP is the signal build-up rate constant measured with ¹H saturation recovery experiments with ¹³C CPMAS for signal detection and microwave irradiation to drive DNP. The polarization time was varied from 0.5 to 20 s. T₁ is reported for the 298 K experiment rather than T_DNP.

Sensitivity = [SNR × (τ_opt × NS)^−1/2], where SNR is the measured signal-to-noise ratio of the API resonance (or most intense resonance for povidone and pure API) acquired with a polarization delay near to that providing optimal sensitivity (τ_opt = 1.3 × T_DNP) and NS is the number of scans/transients. 80 Hz of exponential line broadening was applied to the spectra of the formulations prior to Fourier transformation. For the spectra of crystalline cetirizine dihydrochloride acquired with DNP at 105 K (at 9.4 T) and acquired at 298 K (at 16.4 T), 20 and 30 Hz of exponential line broadening were applied, respectively.

The percentage of ²H labeled TCE in the radical solution is indicated.

Chart 1. Molecular Structures of the API Cetirizine Dihydrochloride (A) and the Excipients Magnesium Stearate (M), Hydroxypropyl Methylcellulose (Hypromellose, H), Polyvinylpyrrolidone (Povidone, P), and Lactose (L)

3 Results and Discussion

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3.1 DNP Enhanced NMR for Pharmaceutical Formulations

3.1.1 DNP Enhanced Solid-State NMR of Crystalline Cetirizine Dihydrochloride

Prior to discussing results from DNP experiments on the formulated pharmaceutical, we first discuss experiments on crystalline cetirizine dihydrochloride (A, molecular structure depicted in Chart 1) for reference and to illustrate how DNP can improve the characterization of pure pharmaceuticals. The insolubility of crystalline A in solvents compatible with DNP (87) was screened with solution NMR spectroscopy as previously described. (42)A was found to be insoluble in both TCE and 1,4-dibromobutane. TCE was favored for the experiments here, since its lone ¹³C NMR resonance has minimal overlap with the resonances of A and it usually provides higher enhancements. ¹³C CPMAS NMR spectra of crystalline A with and without the addition of TEKPol TCE solution and powder X-ray diffraction patterns of crystalline A at 298 and 110 K suggest that neither the impregnation procedure nor the reduced sample temperature induce phase transitions in crystalline A (Figure S1, Supporting Information).

Figure 1 shows the DNP enhanced natural abundance ¹³C and ¹⁵N CPMAS NMR spectra of samples of crystalline A impregnated with 16 mM TEKPol TCE solution and cooled to ∼105 K. For crystalline A, a ¹³C CPMAS DNP enhancement (ε_C CP) of 31 was obtained with a polarization delay (τ) of 26 s. The proton DNP enhancement (ε_H) of the TCE at the surface of the crystals was about 118, as indicated by ¹H spin echo experiments (Figure S2, Supporting Information). The high spectral resolution and the reduced ε for A as compared to the impregnating liquid are fully consistent with an externally impregnated crystalline organic solid. (42) The large gain in sensitivity enables the rapid acquisition of ¹H–¹³C and ¹H–¹⁵N 1D CPMAS, 2D dipolar HETCOR, and ¹³C–¹³C scalar correlation (refocused INADEQUATE) solid-state NMR spectra at natural isotopic abundance (Figures 1–3 and 5 and Figure S3, Supporting Information). For example, with impregnation DNP, a one-dimensional natural abundance ¹³C CPMAS spectrum of A with a high signal-to-noise ratio (SNR > 400) was acquired in only 2 min (Figure 1A). For comparison, with standard solid-state NMR instrumentation at 298 K, a spectrum with a SNR of ∼23 required about 4.2 h (Figure S4, Supporting Information). This demonstrates the sensitivity enhancement of several orders of magnitude provided by impregnation DNP at 105 K for crystalline solids. (42)

Figure 1. 105 K DNP enhanced natural abundance (A) ¹³C CPMAS spectrum (4 scans, 26 s τ), (B) ¹³C–¹³C refocused INADEQUATE correlation spectrum, and (C) ¹⁵N CPMAS spectrum (8 scans, 26 s τ) of crystalline A impregnated with a 16 mM solution of TEKPol in TCE (with 20% d₂-TCE). The INADEQUATE spectrum enables the assignment of the ¹³C resonances as indicated on the molecular structure drawing (assigned chemical shifts are given in Table S2, Supporting Information). The 2D spectrum was acquired in 14.2 h (32 scans per increment, a 20 s polarization delay between scans, and 80 t₁ increments with a 32 μs t₁ increment). The States-TPPI procedure (88, 89) was employed to achieve quadrature detection in the indirect dimension. Asterisks indicate folded-back sidebands.

It was also possible to rapidly acquire a one-dimensional ¹⁵N CPMAS spectrum of A with a high SNR (∼40) in only 8 min with DNP (Figure 1C). There are only two resonances in the ¹⁵N CPMAS spectrum, with shifts of 59.1 and 46.4 ppm, corresponding to the two in-equivalent nitrogen atoms in the molecule. The observation of a single set of ¹⁵N and ¹³C peaks suggests that there is only one molecule within the asymmetric unit cell (i.e., Z′ = 1). To the best of our knowledge, a crystal structure for A has not been previously reported, nor have any polymorphs of A been identified.

A ¹³C–¹³C refocused INADEQUATE (90) correlation spectrum was acquired in only 14.2 h (Figure 1). 2D ¹H–¹⁵N dipolar HETCOR spectra of A were acquired in only 27 min (Figure 5A and B). Notably, with short contact times (τ_CP), correlations are observed to acidic protons directly bound to the amine nitrogen atoms (with shifts >10 ppm in the ¹H dimension) and correlations to the adjacent −CH₂ protons are visible. At long contact times, additional long-range correlations to the aromatic protons are visible. The complete assignment of the ¹H, ¹³C, and ¹⁵N resonances for A resulting from this analysis is given in Table S2 (Supporting Information).

3.1.2 DNP Enhanced NMR of Pharmaceutical Formulations

We have applied DNP enhanced NMR to four commercially available solid formulations of the over-the-counter antihistamine drug cetirizine dihydrochloride. The formulations contain from 4.8 to 8.7 wt % API (Table 1). All of the formulations contain the excipients polyvinylpyrrolidone (povidone, P), lactose (L), hydroxypropyl methylcellulose (hypromellose, H), magnesium stearate (M), corn starch (S), polyethylene glycol, and titanium dioxide (structures for some excipients are depicted in Chart 1). These are some of the most commonly encountered excipients in formulated pharmaceuticals. (91) In order to prepare samples for DNP, the tablets were gently ground by hand with a mortar and pestle and then impregnated with a small volume of 1,1,2,2-tetrachloroethane (TCE) solution of the nitroxide biradical TEKPol (Table S1, Supporting Information). (79) The impregnation DNP method is well adapted here, since just enough liquid is used so as to impregnate the sample, without creating a suspension, and thus without significantly diluting the sample. (72)

Ideally, the impregnation procedure should not affect the structure (phase, particle size, etc.) of the API within the formulation. However, as discussed below, here we find that the API within the tablets is present as an amorphous form rather than as a crystalline form. For these reasons, an amorphous form of A was also prepared and characterized by DNP and low temperature NMR experiments (vide infra).

While crystalline A is insoluble in TCE, the form of amorphous A prepared here was found to be soluble in TCE (by solution ¹H NMR experiments, Figure S5, Supporting Information). ¹H solution NMR spectra of extracts of F1 and F4 into a large of excess of TCE indicate that up to ca. 60 and 32% of A can be solubilized, respectively (with less than 200 mg of ground tablet being extracted into more than 0.9 mL of TCE, Figure S6, Supporting Information). Impregnation of less than 50 mg of ground tablet with less than 30 μL of TEKPol TCE solution for the DNP experiments should solubilize only a marginal amount of amorphous A. Within the formulations, a substantial fraction of the TCE solution will be absorbed by swelling of the polymeric components such as H and P. We also note that, for the DNP experiments, the ground formulations are impregnated and then quickly (less than 10 min) frozen when placed into the low temperature NMR probe for experiments. Therefore, it is unlikely that the structure of A within the formulation is significantly perturbed by the impregnation procedure. Consistent with this hypothesis, DNP solid-state NMR experiments on impregnated F1 clearly indicate that amorphous A exists in the sample in microparticulate domains that are externally polarized via spin diffusion (vide infra).

From DNP enhanced ¹³C NMR experiments on P and H, it is clear that these two polymer excipients readily swell and absorb the radical solution. It is likely that the other excipients, which are insoluble in TCE, such as L, S, and titanium dioxide, are unaffected by the impregnation. As we illustrate below, penetration of the impregnating solution into the polymer matrix surrounding the API is a highly advantageous feature of the experiments.

3.1.3 DNP Enhanced Solid-State NMR of Pure Excipients and Formulation F1

The DNP enhanced ¹³C CPMAS spectra of the pure excipients and of crystalline A and amorphous A are compared to the spectrum of F1 in Figure 2. The spectra of the pure excipients enable the “background” signals from the various excipients and the signals from A to be assigned within the DNP enhanced ¹³C CPMAS spectrum of F1, as illustrated in Figure 2.

Comparison of the spectra of pure amorphous or crystalline A and F1 clearly demonstrate that A is amorphous within F1 (and all of the other formulations, vide infra). Comparison of room temperature and low temperature ¹³C CPMAS experiments on F1 (and amorphous A) without the impregnating solvent (Figure S7, Supporting Information) make it clear that the broadening of the ¹³C resonances of A does not arise from the impregnation procedure (or possible partial dissolution of A, as discussed above) or from the reduction in sample temperature. Rather, A clearly exists as an amorphous phase within F1. The room temperature powder X-ray diffraction pattern of F1 does not show any reflections associated with crystalline A, also consistent with an amorphous phase of A (Figure S8, Supporting Information). Previous solid-state NMR studies of formulations indicate that crystalline API is present in most formulations; (25, 31, 36, 39, 43-46, 52) however, at least two studies have also observed amorphous API phases within formulated pharmaceuticals. (23, 54) A number of solid-state NMR studies have also been performed on model amorphous API dispersions. (27, 40, 49)

The DNP enhancements ε_C CP can also be measured for the individual components of F1 with resolved/isolated ¹³C resonances, and we find significant variation between A and the different excipients. A had a relatively high ε_C CP of 55 (measured with ν_rot = 12.5 kHz to eliminate spinning sideband overlap), which enables ¹³C NMR signals for A to be detected with high SNR. In F1, L has an ε_C CP of 34 (with a 60 s polarization delay, Figure S9, Supporting Information), P has an ε_C CP of 85, and H/S have an ε_C CP of 3. The enhancements observed for pure H and L are similar to the enhancements observed for those excipients within F1. Pure P and M possess significantly larger ε in F1 than they do in their pure forms. The difference in ε for pure excipients and excipients within F1 likely reflects a change in the morphology (e.g., particulate vs molecularly dispersed) and/or concentration of the excipients. The enhancements will also likely also depend upon the concentration of the radical near the particular excipient within the formulation. The relatively low enhancements for H, S, and L in F1 are advantageous in the present case because the “background” signals from these excipients are suppressed compared to the API signal.

3.1.4 DNP Enhanced Solid-State NMR of Pure Povidone

Povidone (P) is a water-soluble polymer and is a commonly encountered pharmaceutical excipient. We focus here on P, since interactions between the API and P within formulations are hypothesized to stabilize the amorphous API and to modulate API release rates. (27, 49, 53) For P impregnated with a 24 mM solution of TEKPol in TCE, a ε_H of ∼10 was obtained (Figure 2E). The relatively low ε here probably arises from short proton longitudinal relaxation times (T₁ ∼ 2.3 s at 105 K), high proton concentration, and the dilution of the biradical in the swollen polymer. The low temperature DNP enhanced ¹³C CPMAS NMR spectrum is very similar to a previously reported room temperature spectrum. (27, 40)

Figure 2. 105 K DNP enhanced natural abundance ¹³C CPMAS spectra of (A) magnesium stearate (M), (B) hypromellose (H), (C) α-lactose monohydrate (L), (D) starch (S), (E) povidone (P), (F) crystalline cetirizine dihydrochloride (A), (G) amorphous cetirizine dihydrochloride (A), and (H) formulation F1. All solids were ground and impregnated with TCE solutions of TEKPol except for S where spectra were acquired from the pure solid without any DNP enhancement (Table S1, Supporting Information, provides details of sample preparation). The ¹³C CP DNP enhancement (ε_C CP) for the compound, the number of scans, and the polarization delay (τ) are indicated. Asterisks denote spinning sidebands. Spectra are shown with arbitrary vertical scaling.

The DNP enhanced ¹⁵N CPMAS NMR spectrum possesses a single broad resonance centered at 128 ppm (Figure 3). The ¹H chemical shifts observed in the ¹H–¹³C and ¹H–¹⁵N HETCOR spectra of impregnated P (Figure S10C, Supporting Information) are useful for interpreting the ¹H–¹⁵N HETCOR spectra of F1 below. Notably, at a short CP contact time (0.25 ms), all ¹³C nuclei correlate with protons with chemical shifts between 1.0 and 1.7 ppm. With a longer CP contact time (1.5 ms), additional correlations are observed between the solvent carbon nuclei of TCE and the protons of P. These observations are consistent with swelling of the povidone by the solvent and indicate direct incorporation of TCE and TEKPol into P. The ¹H–¹⁵N HETCOR spectrum acquired with a long CP contact time (2.5 ms) primarily shows a correlation between the single nitrogen resonance and a broad proton resonance centered at 1.8 ppm (Figure S10, Supporting Information).

Figure 3. 105 K DNP enhanced natural abundance ¹³C (left column) and ¹⁵N (right column) CPMAS solid-state NMR spectra of (A) crystalline cetirizine dihydrochloride (A), (B) amorphous cetirizine dihydrochloride (A), (C) povidone (P), (D) “LIFE” brand formulation (F1), (E) “CVS” brand formulation (F2), (F) “Reactine” brand formulation (F3), and (G) “Wal-Zyr” brand formulation (F4) impregnated with TCE solutions of TEKPol (Table 1). ¹³C CP DNP enhancements for the API (or povidone) are listed for each spectrum, and the TCE resonance has been truncated to better illustrate low intensity signals. The number of scans and polarization delay (τ) used for each spectrum are indicated in the figure. All spectra were acquired with a sample spinning frequency (ν_rot) of 12500 Hz in order to eliminate sideband overlap. Note that the DNP enhancements were measured in separate experiments with ν_rot = 8000 Hz. Experiments on F1 indicate that ε_C CP with a 12500 Hz spinning rate are ca. 85% of those measured at 8000 Hz. ¹⁵N CPMAS spectra were acquired with contact times between 2.5 and 4.0 ms.

3.1.5 Sensitivity Enhancement by DNP for Pharmaceutical Formulations

One-dimensional DNP enhanced ¹³C and ¹⁵N CPMAS solid-state NMR spectra of the four commercial formulations of cetirizine dihydrochloride (F1–F4, Table 1) are shown in Figure 3. All four formulations are characterized by relatively low API contents (4.8–8.7 wt % of A). The ¹³C and ¹⁵N CPMAS spectra of F1–F4 are broadly similar because all of the formulations contain the same ingredients (Figure 3). Notably, in all four formulations, A is amorphous, as indicated by the broad ¹³C resonances. Since none of the excipients possess aromatic carbons, the aromatic carbon resonances of A are well resolved in the ¹³C CPMAS spectra, and ε_C CP for the API resonances can be easily measured and used for optimizing experimental conditions. The biradical concentration and TCE deuteration levels providing optimal ε for the API were optimized for F1 and F3. Only a small variation of ε with radical concentration and solvent deuteration level was observed (Figure S11, Supporting Information). With these conditions, large ε_C CP values for the API of between 40 and 90 were obtained for the different formulations (measured with ν_rot = 8 kHz). The variation in ε_C CP for A among F1–F4 likely arises from variations in the grain size of A, API proton longitudinal relaxation times, and the excipient concentrations at the API particle surface. High SNR 1D ¹³C CPMAS spectra could be rapidly acquired for F1–F4 because of the large ε and relatively short T_DNP. For example, the DNP enhanced ¹³C CPMAS spectrum of F1 was acquired in only 13 min (256 scans, 3.0 s polarization delay) with a SNR of ∼600 for the API resonance, despite the relatively low API content of 8.7 wt %. A similar sensitivity is obtained for the other formulations (Table 1). F4 possesses the lowest ¹³C NMR sensitivity due to the relatively low ε_C CP of 40 and API content of 5.5 wt %; however, the SNR was ∼145 after 17 min (128 scans, 8.0 s polarization delay) for the API. This suggests that a 1D ¹³C CPMAS spectrum of F4 with SNR > 15 could be acquired in a similar time frame even if the API wt % was reduced to levels as low as 0.5 wt %. This clearly illustrates the tremendous gain in sensitivity afforded by DNP for pharmaceutical formulations which enables the rapid acquisition of 1D and 2D ¹H–¹⁵N CPMAS spectra of F1–F4.

Figure 4. (A) Signal build-ups observed for F1 with a saturation recovery CP pulse sequence with (black) and without (red) microwave irradiation. Curves were fit with stretched exponential functions of the form S(t) = S₀ × [exp(−(t/T₁*)^β)]. The values of T₁* and β are indicated. (B) The measured values of ε_C CP for the API resonance of F1 at 128 ppm as a function of polarization time. The inset shows ε_C CP at short τ. Error bars were calculated by propagation of error using the noise levels of the spectra acquired with and without microwave irradiation as the standard deviation. (C) Measured values of ε_C CP for the povidone resonance of F1 at 41.5 ppm. The average value of ε_C CP for P was 43, and this was assumed to be the enhancement at the surface of the API particles (ε₀). (D) Comparison between experimental and simulated ε of the API as a function of τ using a numerical model of spin diffusion for spherical particles of the indicated radius (see ref 42 for more details). (E) Simulations of the variation of ε for different Weibull distributions of the particle radius. (F) Plots of the Weibull distributions of the particle radius used in part E. Weibull distributions 1, 2 and 3 employed shape parameters (k) of 1.5 and the center of the distributions (λ) was 0.10, 0.15 and 0.20 μm, respectively. For all simulations, the surface enhancement (ε₀) was fixed at 43, the proton longitudinal relaxation time (T₁) of the API was 5.3 s, the T₁ at the surface of the particles was set to 2.3 s to match the T₁ measured for povidone, and the diffusion constant (D) was 1.0 × 10⁵ Å² s^–1.

3.2 DNP Enhanced NMR to Probe the Microstructure of Formulations

The gain in sensitivity provided by the impregnation DNP method described above allows us to envisage NMR approaches to determine some key properties of formulations. Here we show how DNP enhanced NMR enables previously inaccessible measurements of (i) the API domain sizes and (ii) API–excipient interactions between the domains. For these in-depth analyses, we focus on F1, since it has the highest A content which reduces the required spectrometer time. However, the sensitivity is high enough with DNP that it would certainly be possible to perform such experiments for the other formulations with lower A content.

3.2.1 Measuring API Domain Sizes with DNP

In DNP experiments where the radical is homogeneously distributed and the cross effect is the dominant polarization mechanism, ε is usually constant regardless of the polarization delay (τ). However, in our previous study on slowly relaxing externally impregnated crystalline solids, we observed that ε significantly decreases to a plateau value as τ is increased. (42) This occurs because of the slow signal build-up rates associated with weakly enhanced nuclei residing in the core of particulate solids, and the polarization dynamics can be used to estimate domain size distributions for the particles. Here we use this phenomenon to measure the domain sizes of the particles of amorphous A present within the complex superstructure within the formulation F1.

Figure 5. Natural abundance DNP enhanced ¹H–¹⁵N dipolar HETCOR spectra of crystalline A (A and B), amorphous A (C and D), and F1 (E and F). The spectra were acquired with contact times (τ_CP) of 0.5 ms (top spectra) and 3.0 ms (lower spectra) to probe for short- and long-range ¹H–¹⁵N distances, respectively. Key ¹⁵N chemical shifts and ¹H correlations are indicated on the spectra with dashed lines. An expanded view of the correlations is provided for part F. HETCOR spectra of crystalline A were acquired with 4 scans per increment, an 8 s polarization delay, 52 individual t₁ increments, and a 64 μs t₁ increment (27 min each). HETCOR spectra of amorphous A were acquired with (C) 64 or (D) 48 scans per increment, a 5.2 s polarization delay, 64 individual t₁ increments, and a 64 μs t₁ increment (5.2 and 4.4 h, respectively). HETCOR spectra of F1 were acquired with 128 scans (E) or 96 scans (F) per increment, a 3 s polarization delay, 52 individual t₁ increments, and a 64 μs t₁ increment (5.5 and 4.2 h, respectively). During t₁, eDUMBO-1₂₂ homonuclear ¹H dipolar decoupling (86) was applied and proton chemical shifts were corrected by applying a scaling factor of 0.57. The States-TPPI procedure (88, 89) was employed to achieve quadrature detection in the indirect dimension.

Such NMR domain size measurements in complex materials (such as polymer blends) are usually accomplished with ¹H spin diffusion correlation experiments; however, this requires resolution of the different phases (or amorphous/crystalline domains) within the directly or indirectly detected ¹H NMR spectrum. (92) For example, the molecular level association of APIs and excipients can be confirmed with dipolar HETCOR experiments. (27) Carbon-13 detected proton T₁ measurements for excipients and API signals are also useful to place an upper limit on the size of API domains: the observation of distinct T₁’s for the API and excipients proves phase separation, while the observation of a common T₁ usually suggests that the API exists in domains smaller than 100 nm that are well mixed with the excipient(s). (27) Munson and co-workers have previously demonstrated that qualitative measurements of domain (crystallite) sizes in pharmaceutical solids can be obtained by measuring proton T₁’s and/or measuring the ¹³C peak widths to quantify anisotropic bulk magnetic susceptibility (ABMS). (41, 93) However, domain sizes have never been directly measured by NMR for a formulated pharmaceutical compound. The advantage of the DNP based method is that no ¹H chemical shift differences are required; rather, only CP signal build-ups with and without microwaves need to be observed. For these experiments, F1 was packed into a thin wall 3.2 mm zirconia rotor to maximize sensitivity in the experiments without DNP. Poorer microwave transmission through the zirconia rotor (94) leads to the reduced values of ε_C CP for F1 reported in Figure 4.

As shown in Figure 4A and B, similar to previous observations for crystalline solids, we observed stretched exponential signal build-ups and a significant variation in ε_C CP for the aromatic API carbon resonances as a function of τ. This clearly indicates that A exists in distinct particulate domains within F1 and that the API is externally polarized through proton spin diffusion. (42) Using our previously developed numerical model of the diffusion equation, we can simulate the signal build-up rates and variation in ε with τ for different particle size ranges. We assume that the proton longitudinal relaxation time within the amorphous A particles is 5.3 s based upon a measurement of the proton T₁ for amorphous A in F1 in the absence of added radical solution at 110 K (Figure S12, Supporting Information). The enhancement at the surface of the API particles (ε₀) was assumed to be equal to the ε_C CP value measured for the P resonance at 41.5 ppm, which was found to be 43(7) (Figure 4C). This assumption was made because the enhancement for the API is similar (but less than) the enhancement for P at short polarization delays. The enhancement for P does not decrease with the polarization delay (within the uncertainty of the measurements), and DNP experiments on pure impregnated P also indicate that the biradical solution is directly incorporated into the polymer. The spin diffusion constant (D) was assumed to be equal to 1.0 × 10⁵ Å² s^–1, a value typical of fully protonated organic solids. (77) Using these parameters, simulations of ε as a function of τ with uniform radius particles provide the best agreement for 0.3 μm radius particles (Figure 4D).

Single particle simulations were also performed with D values between 1.0 × 10⁵ and 1.0 × 10⁴ Å² s^–1 (typical values for organic solids) (77, 95) to explore the influence of D on the predicted particle size. As expected, if the particle radius is held constant at 0.3 μm, then the calculated values of ε decrease as D decreases (Figure S13A, Supporting Information). On the other hand, for reduced D values of 1.0 × 10⁴ and 5.0 × 10⁴ Å² s^–1, better agreement with experiment is realized for smaller particles with a radius less than 0.3 μm (Figure S13B, Supporting Information). Therefore, if the precise value of D is unknown, the DNP based particle size measurements will in principle provide an upper limit on the particle size if a large diffusion constant of 1.0 × 10⁵ Å² s^–1 is assumed in the model.

For simulations with (traditional) Weibull distributions (96) of particle radii, we find the agreement is best with an equivalent distribution having a maximum around 0.07 μm (Figure 4E). Note that both the single particle model and Weibull distribution models predict that the majority of particles have radii less than 0.3 μm. We attempted to confirm the DNP solid-state NMR based API domain size measurements with scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) mapping of chlorine within F1; however, the measurements were too insensitive because of the low Cl content of F1. SEM images of ground F1 indicate the presence of particles smaller than 1 μm in diameter, which is consistent with the DNP-NMR particle size measurements (Figure S14, Supporting Information). As discussed above, in the present case, the impregnation procedure may slightly reduce the domain size of A due to the partial solubility of amorphous A in TCE. For formulations with crystalline API, this should not be an issue.

3.2.2 Probing API–Excipient Interactions with DNP Enhanced Solid-State NMR

For all formulations, both the ¹³C and ¹⁵N resonances of the API are much broader than those observed for the corresponding DNP enhanced spectra of crystalline A (Figure 3). The observed chemical shifts and breadths of the observed resonances are similar to those observed for pure amorphous A, consistent with an amorphous phase of A within the formulations. The DNP enhanced ¹⁵N CPMAS spectra of F1–F4 possess two separated broad features with shifts centered around ca. 58 and 44 ppm. Additional broad ¹⁵N sites with shifts between 54 and 51 ppm are also clearly visible for F1–F4 and amorphous A.

Natural abundance 2D ¹H–¹⁵N HETCOR spectra of crystalline and amorphous A and F1 are shown in Figure 5. 2D ¹H–¹⁵N HETCOR NMR spectra were acquired for F1, since it had the highest API wt %, although sensitivity is high enough that 2D ¹⁵N NMR spectra could also be acquired for the other formulations. The ¹H–¹⁵N HETCOR spectrum of F1 acquired with a 3.0 ms contact time shown in Figure 5F indicates the presence of a ¹⁵N chemical shift for A centered at 51.5 ppm. This ¹⁵N chemical shift was not observed in the ¹⁵N CPMAS spectra of crystalline A, but a similar chemical shift is observed in spectra of amorphous A. Within F1, the site at 51.5 ppm correlates to ¹H nuclei with chemical shifts of 1.7 ppm (and other aliphatic protons with shifts >2.0 ppm). Importantly, this correlation is not observed in the HETCOR spectra of amorphous A alone. ¹H–¹³C and ¹H–¹⁵N HETCOR spectra of P show that the ¹H nuclei of P possess shifts between 1.0 and 1.8 ppm (Figure S10, Supporting Information), while all the ¹H nuclei in both amorphous and crystalline A possess chemical shifts greater than 2.7 ppm. Therefore, the ¹H–¹⁵N correlation at 1.7 and 51.5 ppm indicates that a small amount of A is in contact with P (likely through dispersive forces and/or hydrogen bonding interactions). (30, 37-40) As discussed above, amorphous A exists within small sub-μm domains within F1. The ¹⁵N resonance at 51.5 ppm likely corresponds to molecules of A at the surface of the amorphous API particles which interact with P. ¹H–¹³C HETCOR spectra of F1 do not unambiguously show correlations between the povidone carbon nuclei and the protons of A (Figure S3, Supporting Information) because these key correlations are obscured in the crowded ¹H and ¹³C spectra. This demonstrates one of the advantages of ¹⁵N solid-state NMR for the analysis of pharmaceutical formulations. Finally, we note that as discussed above solution ¹H NMR spectra of extracts of F4 in an excess of TCE show signals from A (Figures S6 and S15, Supporting Information). However, in the solution ¹H NMR spectrum, the peaks of A and P are both significantly broadened, suggesting that the A observed in solution is associated with P, consistent with the hypotheses above regarding A–P intermolecular interactions.

4 Conclusions

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In summary, impregnation DNP enables the expedient acquisition of 1D and 2D natural abundance ¹⁵N and ¹³C solid-state NMR spectra of pure organic solids and formulated APIs. This overcomes the sensitivity limitation for formulations with low API contents. The impregnation method is extremely simple, and the only requirement is the identification of a solvent that does not dissolve the API and is compatible with DNP. In the present case, the amorphous API was found to be slightly soluble within the impregnating solution but not to the extent that it prevented the study. With state of the art polarizing agents, (79) sensitivity enhancements of 2 orders of magnitude were obtained for the commercial formulations examined here. The ability to rapidly acquire both ¹³C and ¹⁵N multidimensional CPMAS NMR spectra should aid NMR crystallography studies of bulk solids in situ and provide novel structural insight into formulated pharmaceuticals. In this instance, we immediately identified that the API was present in an amorphous form, and by analyzing the variation in DNP enhancement with polarization delay, it was possible to straightforwardly determine the distribution of API particle sizes present within the complex superstructure of the formulated samples. Furthermore, using high-sensitivity ¹H–¹⁵N correlation NMR spectra, we were able to indentify characteristic ¹⁵N resonances corresponding to API molecules interacting with the excipient. Measuring domain sizes in situ and API–excipient interactions are some of the most challenging parameters to measure by conventional means.

Since DNP enhancements can vary between different components, these experiments do not provide easy access to quantitative measures of composition. In cases where multiple phases of the API are present (e.g., multiple polymorphs, crystalline vs amorphous, molecular vs aggregated, etc.), we expect that quantification of the API phase by NMR is best performed with conventional 1D ¹³C CPMAS NMR spectra. However, with DNP enhanced solid-state NMR, it should be possible to rapidly identify API polymorphs in formulations (including trace amounts of secondary phases), perform in situ NMR crystallography, and/or study the aging of formulations, etc. In particular, the method is well suited for the characterization of APIs with long proton longitudinal relaxation times, (42) something that is extremely challenging for conventional NMR experiments.

Supporting Information

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Details on sample preparations, additional 1D and 2D NMR spectra, SEM images, and MatLab code for the numerical calculations. This material is available free of charge via the Internet at http://pubs.acs.org.

ja4092038_si_001.pdf (12.86 MB)

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Author Information

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Corresponding Author
- Lyndon Emsley - Centre de RMN à Trés Hauts Champs, Institut de Sciences Analytiques, Université de Lyon (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France
Authors
- Aaron J. Rossini - Centre de RMN à Trés Hauts Champs, Institut de Sciences Analytiques, Université de Lyon (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France
- Cory M. Widdifield - Centre de RMN à Trés Hauts Champs, Institut de Sciences Analytiques, Université de Lyon (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France
- Alexandre Zagdoun - Centre de RMN à Trés Hauts Champs, Institut de Sciences Analytiques, Université de Lyon (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France
- Moreno Lelli - Centre de RMN à Trés Hauts Champs, Institut de Sciences Analytiques, Université de Lyon (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France
- Martin Schwarzwälder - Department of Chemistry, Laboratory of Inorganic Chemistry, ETH Zürich, CH-8093 Zürich, Switzerland
- Christophe Copéret - Department of Chemistry, Laboratory of Inorganic Chemistry, ETH Zürich, CH-8093 Zürich, Switzerland
- Anne Lesage - Centre de RMN à Trés Hauts Champs, Institut de Sciences Analytiques, Université de Lyon (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France
Notes
The authors declare no competing financial interest.

Acknowledgment

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We are grateful to Dr. Fabien Aussenac for his assistance with all of the DNP solid-state NMR experiments. We would like to thank Drs. Werner Maas, Alain Belguise, Melanie Rosay, and Bruker for providing access to the DNP solid-state NMR spectrometer. Dr. David Gajan is thanked for assistance with some DNP experiments. We thank the EMEZ center and Dr. F. Krumeich for acquiring SEM images. A.J.R. acknowledges support from a EU Marie-Curie IIF Fellowship (PIIF-GA-2010-274574). C.M.W. acknowledges the Natural Sciences and Engineering Research Council (NSERC) of Canada for a postdoctoral fellowship. Financial support is acknowledged from the Agence Nationale de la Recherche grant ANR-2010-BLAN-0806-01, EQUIPEX contract ANR-10-EQPX-47-01, SNF project number 200021_134775/1, ERC Advanced Grant No. 320860, and the ETH Zürich. We thank Prof. Paul Tordo, Dr. Olivier Ouari and Dr. Gilles Casano (Aix-Marseille Université) for supplying the TEKPol and bCTbK biradicals.

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Variable-Temperature 17O NMR Studies Allow Quantitative Evaluation of Molecular Dynamics in Organic Solids
Kong, Xianqi; ODell, Luke A.; Terskikh, Victor; Ye, Eric; Wang, Ruiyao; Wu, Gang
Journal of the American Chemical Society (2012), 134 (35), 14609-14617CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
We report a comprehensive variable-temp. solid-state 17O NMR study of three 17O-labeled cryst. sulfonic acids: 2-aminoethane-1-sulfonic acid (taurine, T), 3-aminopropane-1-sulfonic acid (homotaurine, HT), and 4-aminobutane-1-sulfonic acid (ABSA). In the solid state, all three compds. exist as zwitterionic structures, NH3+-R-SO3-, in which the SO3- group is involved in various degrees of O···H-N hydrogen bonding. High-quality 17O NMR spectra have been obtained for all three compds. under both static and magic angle spinning (MAS) conditions at 21.1 T, allowing the complete set of 17O NMR tensor parameters to be measured. Assignment of the obsd. 17O NMR parameters to the correct oxygen sites in the crystal lattice was achieved with the aid of DFT calcns. By modeling the temp. dependence of 17O NMR powder line shapes, we have not only confirmed that the SO3- groups in these compds. undergo a 3-fold rotational jump mechanism but also extd. the corresponding jump rates (102-105 s-1) and the assocd. activation energies (Ea) for this process (Ea = 48 ± 7, 42 ± 3, and 45 ± 1 kJ mol-1 for T, HT, and ABSA, resp.). This is the first time that SO3- rotational dynamics have been directly probed by solid-state 17O NMR. Using the exptl. activation energies for SO3- rotation, we were able to evaluate quant. the total hydrogen bond energy that each SO3- group is involved in within the crystal lattice. The activation energies also correlate with calcd. rotational energy barriers. This work provides a clear illustration of the utility of solid-state 17O NMR in quantifying dynamic processes occurring in org. solids. Similar studies applied to selectively 17O-labeled biomols. would appear to be very feasible.
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Haimovich, A.; Eliav, U.; Goldbourt, A. J. Am. Chem. Soc. 2012, 134, 5647– 5651
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Umino, M.; Higashi, K.; Masu, H.; Limwikrant, W.; Yamamoto, K.; Moribe, K. J. Pharm. Sci. 2013, 102, 2738– 2747
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Lubach, J. W.; Padden, B. E.; Winslow, S. L.; Salsbury, J. S.; Masters, D. B.; Topp, E. M.; Munson, E. J. Anal. Bioanal. Chem. 2004, 378, 1504– 1510
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Solid-state NMR studies of pharmaceutical solids in polymer matrices
Lubach, Joseph W.; Padden, Brian E.; Winslow, Stephanie L.; Salsbury, Jonathon S.; Masters, David B.; Topp, Elizabeth M.; Munson, Eric J.
Analytical and Bioanalytical Chemistry (2004), 378 (6), 1504-1510CODEN: ABCNBP; ISSN:1618-2642. (Springer-Verlag)
Biodegradable drug-delivery systems can be formulated to release drug for hours to years and have been used for the controlled release of medications in animals and humans. An important consideration in developing a drug-delivery matrix is knowledge of the long-term stability of the form of the drug and matrix after formulation and any changes that might occur to the drug throughout the delivery process. Solid-state NMR spectroscopy is an effective technique for studying the state of both the drug and the matrix. Two systems that have been studied using solid-state NMR spectroscopy are presented. The first system studied involved bupivacaine, a local anesthetic compd., which was incorporated into microspheres composed of tristearin and encapsulated using a solid protein matrix. Solid-state 13C NMR spectroscopy was used to investigate the solid forms of bupivacaine in their bulk form or as incorporated into the tristearin/protein matrix. Bupivacaine free base and bupivacaine-HCl have very different solid-state NMR spectra, indicating that the mols. of these compds. pack in different crystal forms. In the tristearin matrix, the drug form could be detd. at levels as low as 1:100 (wt./wt.), and the form of bupivacaine was identified upon loading into the tristearin/protein matrix. In the second case, the possibility of using solid-state 13C NMR spectroscopy to characterize biomols. lyophilized within polymer matrixes is evaluated by studying uniformly 13C-labeled asparagine (Asn) in 1:250 (wt./wt.) formulations with poly(vinyl pyrrolidone) (PVP) and poly(vinyl alc.) (PVA). This work shows the capability of solid-state NMR spectroscopy to study interactions between the amino acid and the polymer matrix for synthetic peptides and peptidomimetics contg. selective 13C labeling at the Asn residue.
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Harris, R. K.; Hodgkinson, P.; Larsson, T.; Muruganantham, A. J. Pharm. Biomed. Anal. 2005, 38, 858– 864
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Quantification of bambuterol hydrochloride in a formulated product using solid-state NMR
Harris, Robin K.; Hodgkinson, Paul; Larsson, Tomas; Muruganantham, Amsaveni
Journal of Pharmaceutical and Biomedical Analysis (2005), 38 (5), 858-864CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
Carbon-13 NMR spectra of the stable polymorphs of solid bambuterol hydrochloride (BHC) and terbutaline sulfate (TBS) are reported and the resonances assigned with the aid of soln.-state spectra. A protocol is presented for quantification of BHC in a formulation in lactose, together with TBS, relative to a ref. peak from magnesium stearate. This protocol compares the intensity of an arom. signal of BHC with that of the main-chain methylene carbons of the stearate. It is shown that the limit of detection (LOD) of BHC in this system under the conditions described is 0.5% with an effective limit of quantification (LOQ) of 1.0%. A calibration plot for the quantification is presented and the various factors affecting the accuracy of the measurements are described. No discernible differences are found in the spectra of phys. mixts. of the components, whole tablets, and crushed or ground tablets.
40
Tobyn, M.; Brown, J.; Dennis, A. B.; Fakes, M.; Gao, Q.; Gamble, J.; Khimyak, Y. Z.; McGeorge, G.; Patel, C.; Sinclair, W.; Timmins, P.; Yin, S. J. Pharm. Sci. 2009, 98, 3456– 3468
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Rossini, A. J.; Zagdoun, A.; Hegner, F. S.; Schwarzwälder, M.; Gajan, D.; Copéret, C.; Lesage, A.; Emsley, L. J. Am. Chem. Soc. 2012, 134, 16899– 16908
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Chang, C. J.; Diaz, L. E.; Morin, F.; Grant, D. M. Magn. Reson. Chem. 1986, 24, 768– 771
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Solid-state carbon-13 NMR study of drugs: aspirin
Chang, Ching Jer; Diaz, Luis E.; Morin, Frederick; Grant, David M.
Magnetic Resonance in Chemistry (1986), 24 (9), 768-71CODEN: MRCHEG; ISSN:0749-1581.
Natural abundance 13C-NMR spectra of different crystal habits of pure aspirin [50-78-2] and several aspirin tablets in the solid state were measured by using the combined techniques of high-power decoupling, cross-polarization and magic angle spinning. Solid-state NMR of aspirin had excellent sensitivity compared with liq.-state NMR, and the C signals were assigned using a modified pulse sequence to detect non-protonated carbons. The solid-state 13C-NMR spectra of 2 cryst. forms of aspirin were identical, suggesting that the origin of their difference is not polymorphic. The solid-state 13C-NMR spectra of several com. aspirin tablets, some of them contg. buffer components, indicated that there were no interactions among the aspirin and the buffer components; only after dissolving the tablets and lyophilization did the 13C-NMR spectra of the dry lyophilized powders show strong interactions between aspirin and the buffer components.
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Diaz, L. E.; Frydman, L.; Olivieri, A. C.; Frydman, B. Anal. Lett. 1987, 20, 1657– 1666
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Solid state NMR of drugs: soluble aspirin
Diaz, Luis E.; Frydman, Lucio; Olivieri, Alejandro C.; Frydman, Benjamin
Analytical Letters (1987), 20 (10), 1657-66CODEN: ANALBP; ISSN:0003-2719.
Natural abundance 13C-NMR spectra of a sol. aspirin and model mixts. of acetylsalicylic acid with buffering components were recorded in the solid state by using the combined techniques of cross polarization, high-power decoupling and magic-angle spinning. The solid-state spectrum of the sol. aspirin tablet showed more resonance than the soln. spectrum. These multiplicities were originated in the buffer mixt. contg. citric and tartaric acid, as well as their salts. Solid-state 13C-NMR therefore provided information that the lost in the soln. spectrum was due to the fast proton exchange between the org. acids and their conjugated salts.
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Jagannathan, N. R. Curr. Sci. 1987, 56, 827– 830
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High-resolution solid-state carbon-13 nuclear magnetic resonance study of acetaminophen: a common analgesic drug
Jagannathan, N. R.
Current Science (1987), 56 (16), 827-30CODEN: CUSCAM; ISSN:0011-3891.
Solid-state 13C-NMR spectra of acetaminophen were obtained by using proton enhancement combined with high-power decoupling and magic angle spinning. The contact time was detd. to obtain a max. signal to noise ratio. The chem. shifts obsd. were assigned to different carbons based on both conventional and nonquaternary suppression NMR spectra. In addn. there were no differences in the solid-state NMR spectra of Crocin and Tylenol tablets (com. brands of acetaminophen), except for the different binder content used in the formulation.
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Kelley, W. P.; Chen, S. J.; Floyd, P. D.; Hu, P.; Kapsi, S. G.; Kord, A. S.; Sun, M. J.; Vogt, F. G. Anal. Chem. 2012, 84, 4357– 4372
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2D Solid-State NMR Analysis of Inclusion in Drug-Cyclodextrin Complexes
Vogt, Frederick G.; Strohmeier, Mark
Molecular Pharmaceutics (2012), 9 (11), 3357-3374CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
The soly. of drug mols. can often be improved through prepn. and delivery of cyclodextrin (CD) inclusion complexes. These drug-oligosaccharide complexes can be prepd. in soln. and converted to the solid state via methods such as lyophilization and spray-drying, or they can be prepd. directly from solids by a variety of methods. The development of drug-CD complexes as solids allows for potential advantages in dosage form design, such as the prepn. of layered formulations, and it also can yield improvements in chem. and phys. stability. 2D solid-state NMR (SSNMR) methods provide a direct way to probe drug-CD interactions in solid complexes through dipolar interactions between nuclei within the drug and CD mols. In this study, 2D heteronuclear and homonuclear correlation SSNMR expts. involving 1H, 13C, 19F, and 31P nuclei are used to demonstrate the inclusion of drug within the CD cavity in a variety of powder samples. To illustrate the general applicability of the SSNMR approach presented, examples are shown for the drugs diflunisal, adefovir dipivoxil, voriconazole, dexamethasone, and prednisolone in complexes with α-CD, β-CD, and sulfobutylether-substituted β-CD. The quant. anal. of included and free drug fractions in a solid drug-CD complex using SSNMR is also demonstrated. On the basis of these results, general approaches to the characterization of these materials using SSNMR are proposed.
56
Maly, T.; Debelouchina, G. T.; Bajaj, V. S.; Hu, K. N.; Joo, C. G.; Mak-Jurkauskas, M. L.; Sirigiri, J. R.; van der Wel, P. C. A.; Herzfeld, J.; Temkin, R. J.; Griffin, R. G. J. Chem. Phys. 2008, 128, 052211
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Ni, Q. Z.; Daviso, E.; Can, T. V.; Markhasin, E.; Jawla, S. K.; Swager, T. M.; Temkin, R. J.; Herzfeld, J.; Griffin, R. G. Acc. Chem. Res. 2013, 48, 1933– 1941
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Mak-Jurkauskas, M. L.; Bajaj, V. S.; Hornstein, M. K.; Belenky, M.; Griffin, R. G.; Herzfeld, J. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 883– 888
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Takahashi, H.; Ayala, I.; Bardet, M.; De Paepe, G.; Simorre, J. P.; Hediger, S. J. Am. Chem. Soc. 2013, 135, 5105– 5110
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Wang, T.; Park, Y. B.; Caporini, M. A.; Rosay, M.; Zhong, L. H.; Cosgrove, D. J.; Hong, M. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 16444– 16449
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Lesage, A.; Lelli, M.; Gajan, D.; Caporini, M. A.; Vitzthum, V.; Mieville, P.; Alauzun, J.; Roussey, A.; Thieuleux, C.; Mehdi, A.; Bodenhausen, G.; Copéret, C.; Emsley, L. J. Am. Chem. Soc. 2010, 132, 15459– 15461
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Lelli, M.; Gajan, D.; Lesage, A.; Caporini, M. A.; Vitzthum, V.; Mieville, P.; Heroguel, F.; Rascon, F.; Roussey, A.; Thieuleux, C.; Boualleg, M.; Veyre, L.; Bodenhausen, G.; Copéret, C.; Emsley, L. J. Am. Chem. Soc. 2011, 133, 2104– 2107
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Lafon, O.; Rosay, M.; Aussenac, F.; Lu, X.; Trebosc, J.; Cristini, O.; Kinowski, C.; Touati, N.; Vezin, H.; Amoureux, J. P. Angew. Chem., Int. Ed. 2011, 50, 8367– 8370
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Rossini, A. J.; Zagdoun, A.; Lelli, M.; Canivet, J.; Aguado, S.; Ouari, O.; Tordo, P.; Rosay, M.; Maas, W. E.; Copéret, C.; Farrusseng, D.; Emsley, L.; Lesage, A. Angew. Chem., Int. Ed. 2012, 51, 123– 127
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Zagdoun, A.; Casano, G.; Ouari, O.; Lapadula, G.; Rossini, A. J.; Lelli, M.; Baffert, M.; Gajan, D.; Veyre, L.; Maas, W. E.; Rosay, M.; Weber, R. T.; Thieuleux, C.; Copéret, C.; Lesage, A.; Tordo, P.; Emsley, L. J. Am. Chem. Soc. 2012, 134, 2284– 2291
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Takahashi, H.; Lee, D.; Dubois, L.; Bardet, M.; Hediger, S.; De Paëpe, G. Angew. Chem., Int. Ed. 2012, 124, 11936– 11939
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Rossini, A. J.; Zagdoun, A.; Lelli, M.; Lesage, A.; Copéret, C.; Emsley, L. Acc. Chem. Res. 2013, 46, 1942– 1951
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Blanc, F.; Sperrin, L.; Jefferson, D. A.; Pawsey, S.; Rosay, M.; Grey, C. P. J. Am. Chem. Soc. 2013, 135, 2975– 2978
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Lafon, O.; Thankamony, A. S. L.; Kobayashi, T.; Carnevale, D.; Vitzthum, V.; Slowing, I. I.; Kandel, K.; Vezin, H.; Amoureux, J. P.; Bodenhausen, G.; Pruski, M. J. Phys. Chem. C 2013, 117, 1375– 1382
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Blanc, F.; Chong, S. Y.; McDonald, T. O.; Adams, D. J.; Pawsey, S.; Caporini, M. A.; Cooper, A. I. J. Am. Chem. Soc. 2013, 135, 15290– 15293
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Song, C. S.; Hu, K. N.; Joo, C. G.; Swager, T. M.; Griffin, R. G. J. Am. Chem. Soc. 2006, 128, 11385– 11390
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TOTAPOL: A Biradical Polarizing Agent for Dynamic Nuclear Polarization Experiments in Aqueous Media
Song, Changsik; Hu, Kan-Nian; Joo, Chan-Gyu; Swager, Timothy M.; Griffin, Robert G.
Journal of the American Chemical Society (2006), 128 (35), 11385-11390CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
In a previous publication, the authors described the use of biradicals, in that case two TEMPO mols. tethered by an ethylene glycol chain of variable length, as polarizing agents for microwave driven dynamic nuclear polarization (DNP) expts. The use of biradicals in place of monomeric paramagnetic centers such as TEMPO yields enhancements that are a factor of approx. 4 larger (ε ∼ 175 at 5 T and 90 K) and concurrently the concn. of the polarizing agent is a factor of 4 smaller (10 mM electron spins), reducing the residual electron nuclear dipole broadening. In this paper the authors describe the synthesis and characterization by EPR and DNP/NMR of an improved polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL (I)). Under the same exptl. conditions and using 2.5 mm magic angle rotors, this new biradical yields larger enhancements (ε ∼ 290) at lower concns. (6 mM electron spins) and has the addnl. important property that it is compatible with expts. in aq. media, including salt solns. commonly used in the study of proteins and nucleic acids.
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van der Wel, P. C. A.; Hu, K. N.; Lewandowski, J.; Griffin, R. G. J. Am. Chem. Soc. 2006, 128, 10840– 10846
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Ong, T. C.; Mak-Jurkauskas, M. L.; Walish, J. J.; Michaelis, V. K.; Corzilius, B.; Smith, A. A.; Clausen, A. M.; Cheetham, J. C.; Swager, T. M.; Griffin, R. G. J. Phys. Chem. B 2013, 117, 3040– 3046
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Zagdoun, A.; Casano, G.; Ouari, O.; Schwarzwälder, M.; Rossini, A. J.; Aussenac, F.; M., Y.; G., J.; Copéret, C.; Lesage, A.; Tordo, P.; Emsley, L. J. Am. Chem. Soc. 2013, 135, 12790– 12797
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Zagdoun, A.; Casano, G.; Ouari, O.; Lapadula, G.; Rossini, A. J.; Lelli, M.; Baffert, M.; Gajan, D.; Veyre, L.; Maas, W. E.; Rosay, M.; Weber, R. T.; Thieuleux, C.; Copéret, C.; Lesage, A.; Tordo, P.; Emsley, L. J. Am. Chem. Soc. 2012, 134, 2284– 2291
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Rosay, M.; Tometich, L.; Pawsey, S.; Bader, R.; Schauwecker, R.; Blank, M.; Borchard, P. M.; Cauffman, S. R.; Felch, K. L.; Weber, R. T.; Temkin, R. J.; Griffin, R. G.; Maas, W. E. Phys. Chem. Chem. Phys. 2010, 12, 5850– 5860
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Harris, R. K.; Becker, E. D.; De Menezes, S. M. C.; Goodfellow, R.; Granger, P. Pure Appl. Chem. 2001, 73, 1795– 1818
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NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC recommendations 2001)
Harris, Robin K.; Becker, Edwin D.; Cabral De Menezes, Sonia M.; Goodfellow, Robin; Granger, Pierre
Pure and Applied Chemistry (2001), 73 (11), 1795-1818CODEN: PACHAS; ISSN:0033-4545. (International Union of Pure and Applied Chemistry)
A review. A unified scale is recommended for reporting the NMR chem. shifts of all nuclei relative to the 1H resonance of tetramethylsilane (TMS). The unified scale is designed to provide a precise ratio, Ξ, of the resonance frequency of a given nuclide to that of the primary ref., the 1H resonance of TMS in dil. soln. (vol. fraction, φ < 1%) in CHCl3. Referencing procedures are discussed, including matters of practical application of the unified scale. Special attention is paid to recommended ref. samples, and values of Ξ for secondary refs. on the unified scale are listed, many of which are the results of new measurements. Some earlier recommendations relating to the reporting of chem. shifts are endorsed. The chem. shift, δ, is redefined to avoid previous ambiguities but to leave practical usage unchanged. Relations between the unified scale and recently published recommendations for referencing in aq. solns. (for specific use in biochem. work) are discussed, as well as the special effects of working in the solid state with magic-angle spinning. In all, nine new recommendations relating to chem. shifts are made. Standardized nuclear spin data are also presented in tabular form for the stable (and some unstable) isotopes of all elements with nonzero quantum nos. The information given includes quantum nos., isotopic abundances, magnetic moments, magnetogyric ratios and receptivities, together with quadrupole moments and line-width factors where appropriate.
83
Metz, G.; Wu, X.; Smith, S. J. Magn. Reson., Ser. A 1994, 110, 219– 227
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Ramped-amplitude cross polarization in magic-angle-spinning NMR
Metz, Guenther; Wu, Xiaoling; Smith, Steven O.
Journal of Magnetic Resonance, Series A (1994), 110 (2), 219-27CODEN: JMRAE2; ISSN:1064-1858.
The Hartmann-Hahn matching profile in CP-MASNMR shows a strong mismatch dependence if the MAS frequency is on the order of the dipolar couplings in the sample. Under these conditions, the profile breaks down into narrow matching bands sepd. by the spinning speed, and it becomes difficult to establish and maintain an efficient matching condition. Variable-amplitude CP (VACP), as introduced previously (Peersen et al., J. Magn. Reson. A 104, 334, 1993), was proven to be effective for restoring flat profiles at high spinning speeds. Here, a refined implementation of VACP using a ramped-amplitude cross-polarization sequence (RAMP-CP) is described. The order of the amplitude modulation is of importance for the cross-polarization process. The new pulse sequence with a linear amplitude ramp is not only easier to set up but also improves the performance of the variable-amplitude expt. in that it produces flat profiles over a wider range of matching conditions even with short total contact times. An increase in signal intensity is obtained compared to both conventional CP and the originally proposed VACP sequence.
84
Peersen, O.; Wu, X.; Kustanovich, I.; Smith, S. J. Magn. Reson., Ser. A 1993, 104, 334– 339
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Variable-amplitude cross-polarization MAS NMR
Peersen, Olve B.; Wu, Xiaoling; Kustanovich, Irina; Smith, Steven O.
Journal of Magnetic Resonance, Series A (1993), 104 (3), 334-9CODEN: JMRAE2; ISSN:1064-1858.
The variable-amplitude cross polarization method in solid state CP-MAS NMR spectrometry is described. The control the oscillary behavior in high speed cross polarization is described. The procedure was illustrated the 13C magic-angle-spinning NMR spectra of an amino acid mixt.
85
Fung, B. M.; Khitrin, A. K.; Ermolaev, K. J. Magn. Reson. 2000, 142, 97– 101
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An Improved Broadband Decoupling Sequence for Liquid Crystals and Solids
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Cite this: J. Am. Chem. Soc. 2014, 136, 6, 2324–2334

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Abstract
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Chart 1
Chart 1. Molecular Structures of the API Cetirizine Dihydrochloride (A) and the Excipients Magnesium Stearate (M), Hydroxypropyl Methylcellulose (Hypromellose, H), Polyvinylpyrrolidone (Povidone, P), and Lactose (L)
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Figure 1
Figure 1. 105 K DNP enhanced natural abundance (A) ¹³C CPMAS spectrum (4 scans, 26 s τ), (B) ¹³C–¹³C refocused INADEQUATE correlation spectrum, and (C) ¹⁵N CPMAS spectrum (8 scans, 26 s τ) of crystalline A impregnated with a 16 mM solution of TEKPol in TCE (with 20% d₂-TCE). The INADEQUATE spectrum enables the assignment of the ¹³C resonances as indicated on the molecular structure drawing (assigned chemical shifts are given in Table S2, Supporting Information). The 2D spectrum was acquired in 14.2 h (32 scans per increment, a 20 s polarization delay between scans, and 80 t₁ increments with a 32 μs t₁ increment). The States-TPPI procedure (88, 89) was employed to achieve quadrature detection in the indirect dimension. Asterisks indicate folded-back sidebands.
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Figure 2
Figure 2. 105 K DNP enhanced natural abundance ¹³C CPMAS spectra of (A) magnesium stearate (M), (B) hypromellose (H), (C) α-lactose monohydrate (L), (D) starch (S), (E) povidone (P), (F) crystalline cetirizine dihydrochloride (A), (G) amorphous cetirizine dihydrochloride (A), and (H) formulation F1. All solids were ground and impregnated with TCE solutions of TEKPol except for S where spectra were acquired from the pure solid without any DNP enhancement (Table S1, Supporting Information, provides details of sample preparation). The ¹³C CP DNP enhancement (ε_C CP) for the compound, the number of scans, and the polarization delay (τ) are indicated. Asterisks denote spinning sidebands. Spectra are shown with arbitrary vertical scaling.
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Figure 3
Figure 3. 105 K DNP enhanced natural abundance ¹³C (left column) and ¹⁵N (right column) CPMAS solid-state NMR spectra of (A) crystalline cetirizine dihydrochloride (A), (B) amorphous cetirizine dihydrochloride (A), (C) povidone (P), (D) “LIFE” brand formulation (F1), (E) “CVS” brand formulation (F2), (F) “Reactine” brand formulation (F3), and (G) “Wal-Zyr” brand formulation (F4) impregnated with TCE solutions of TEKPol (Table 1). ¹³C CP DNP enhancements for the API (or povidone) are listed for each spectrum, and the TCE resonance has been truncated to better illustrate low intensity signals. The number of scans and polarization delay (τ) used for each spectrum are indicated in the figure. All spectra were acquired with a sample spinning frequency (ν_rot) of 12500 Hz in order to eliminate sideband overlap. Note that the DNP enhancements were measured in separate experiments with ν_rot = 8000 Hz. Experiments on F1 indicate that ε_C CP with a 12500 Hz spinning rate are ca. 85% of those measured at 8000 Hz. ¹⁵N CPMAS spectra were acquired with contact times between 2.5 and 4.0 ms.
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Figure 4
Figure 4. (A) Signal build-ups observed for F1 with a saturation recovery CP pulse sequence with (black) and without (red) microwave irradiation. Curves were fit with stretched exponential functions of the form S(t) = S₀ × [exp(−(t/T₁*)^β)]. The values of T₁* and β are indicated. (B) The measured values of ε_C CP for the API resonance of F1 at 128 ppm as a function of polarization time. The inset shows ε_C CP at short τ. Error bars were calculated by propagation of error using the noise levels of the spectra acquired with and without microwave irradiation as the standard deviation. (C) Measured values of ε_C CP for the povidone resonance of F1 at 41.5 ppm. The average value of ε_C CP for P was 43, and this was assumed to be the enhancement at the surface of the API particles (ε₀). (D) Comparison between experimental and simulated ε of the API as a function of τ using a numerical model of spin diffusion for spherical particles of the indicated radius (see ref 42 for more details). (E) Simulations of the variation of ε for different Weibull distributions of the particle radius. (F) Plots of the Weibull distributions of the particle radius used in part E. Weibull distributions 1, 2 and 3 employed shape parameters (k) of 1.5 and the center of the distributions (λ) was 0.10, 0.15 and 0.20 μm, respectively. For all simulations, the surface enhancement (ε₀) was fixed at 43, the proton longitudinal relaxation time (T₁) of the API was 5.3 s, the T₁ at the surface of the particles was set to 2.3 s to match the T₁ measured for povidone, and the diffusion constant (D) was 1.0 × 10⁵ Å² s^–1.
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Figure 5
Figure 5. Natural abundance DNP enhanced ¹H–¹⁵N dipolar HETCOR spectra of crystalline A (A and B), amorphous A (C and D), and F1 (E and F). The spectra were acquired with contact times (τ_CP) of 0.5 ms (top spectra) and 3.0 ms (lower spectra) to probe for short- and long-range ¹H–¹⁵N distances, respectively. Key ¹⁵N chemical shifts and ¹H correlations are indicated on the spectra with dashed lines. An expanded view of the correlations is provided for part F. HETCOR spectra of crystalline A were acquired with 4 scans per increment, an 8 s polarization delay, 52 individual t₁ increments, and a 64 μs t₁ increment (27 min each). HETCOR spectra of amorphous A were acquired with (C) 64 or (D) 48 scans per increment, a 5.2 s polarization delay, 64 individual t₁ increments, and a 64 μs t₁ increment (5.2 and 4.4 h, respectively). HETCOR spectra of F1 were acquired with 128 scans (E) or 96 scans (F) per increment, a 3 s polarization delay, 52 individual t₁ increments, and a 64 μs t₁ increment (5.5 and 4.2 h, respectively). During t₁, eDUMBO-1₂₂ homonuclear ¹H dipolar decoupling (86) was applied and proton chemical shifts were corrected by applying a scaling factor of 0.57. The States-TPPI procedure (88, 89) was employed to achieve quadrature detection in the indirect dimension.
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  Solid-state NMR (SSNMR) can provide detailed structural information about amorphous solid dispersions of pharmaceutical small mols. In this study, the ability of SSNMR expts. based on dipolar correlation, spin diffusion, and relaxation measurements to characterize the structure of solid dispersions is explored. Observation of spin diffusion effects using the 2D 1H-13C cross-polarization heteronuclear correlation (CP-HETCOR) expt. is shown to be a useful probe of assocn. between the amorphous drug and polymer that is capable of directly proving glass soln. formation. Dispersions of acetaminophen and indomethacin in different polymers are examd. using this approach, as well as 1H double-quantum correlation expts. to probe addnl. structural features. 1H-19F CP-HETCOR serves a similar role for fluorinated drug mols. such as diflunisal in dispersions, providing a rapid means to prove the formation of a glass soln. Phase sepn. is detected using 13C, 19F, and 23Na-detected 1H T1 expts. in cryst. and amorphous solid dispersions that contain small domains. 1H T1 measurements of amorphous nanosuspensions of trehalose and dextran illustrate the ability of SSNMR to detect domain size effects in dispersions that are not glass solns. via spin diffusion effects. Two previously unreported amorphous solid dispersions involving up to three components and contg. voriconazole and telithromycin are analyzed using these expts. to demonstrate the general applicability of the approach.
28. 28
  O’Dell, L. A.; Schurko, R. W.; Harris, K. J.; Autschbach, J.; Ratcliffe, C. I. J. Am. Chem. Soc. 2011, 133, 527– 546
  There is no corresponding record for this reference.
29. 29
  Bonhomme, C.; Gervais, C.; Folliet, N.; Pourpoint, F.; Diogo, C. C.; Lao, J.; Jallot, E.; Lacroix, J.; Nedelec, J. M.; Iuga, D.; Hanna, J. V.; Smith, M. E.; Xiang, Y.; Du, J. C.; Laurencin, D. J. Am. Chem. Soc. 2012, 134, 12611– 12628
  There is no corresponding record for this reference.
30. 30
  Tatton, A. S.; Pham, T. N.; Vogt, F. G.; Iuga, D.; Edwards, A. J.; Brown, S. P. CrystEngComm 2012, 14, 2654– 2659
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31. 31
  Burgess, K. M. N.; Perras, F. A.; Lebrun, A.; Messner-Henning, E.; Korobkov, I.; Bryce, D. L. J. Pharm. Sci. 2012, 101, 2930– 2940
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32. 32
  Kong, X. Q.; O’Dell, L. A.; Terskikh, V.; Ye, E.; Wang, R. Y.; Wu, G. J. Am. Chem. Soc. 2012, 134, 14609– 14617
  32
  Variable-Temperature 17O NMR Studies Allow Quantitative Evaluation of Molecular Dynamics in Organic Solids
  Kong, Xianqi; ODell, Luke A.; Terskikh, Victor; Ye, Eric; Wang, Ruiyao; Wu, Gang
  Journal of the American Chemical Society (2012), 134 (35), 14609-14617CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  We report a comprehensive variable-temp. solid-state 17O NMR study of three 17O-labeled cryst. sulfonic acids: 2-aminoethane-1-sulfonic acid (taurine, T), 3-aminopropane-1-sulfonic acid (homotaurine, HT), and 4-aminobutane-1-sulfonic acid (ABSA). In the solid state, all three compds. exist as zwitterionic structures, NH3+-R-SO3-, in which the SO3- group is involved in various degrees of O···H-N hydrogen bonding. High-quality 17O NMR spectra have been obtained for all three compds. under both static and magic angle spinning (MAS) conditions at 21.1 T, allowing the complete set of 17O NMR tensor parameters to be measured. Assignment of the obsd. 17O NMR parameters to the correct oxygen sites in the crystal lattice was achieved with the aid of DFT calcns. By modeling the temp. dependence of 17O NMR powder line shapes, we have not only confirmed that the SO3- groups in these compds. undergo a 3-fold rotational jump mechanism but also extd. the corresponding jump rates (102-105 s-1) and the assocd. activation energies (Ea) for this process (Ea = 48 ± 7, 42 ± 3, and 45 ± 1 kJ mol-1 for T, HT, and ABSA, resp.). This is the first time that SO3- rotational dynamics have been directly probed by solid-state 17O NMR. Using the exptl. activation energies for SO3- rotation, we were able to evaluate quant. the total hydrogen bond energy that each SO3- group is involved in within the crystal lattice. The activation energies also correlate with calcd. rotational energy barriers. This work provides a clear illustration of the utility of solid-state 17O NMR in quantifying dynamic processes occurring in org. solids. Similar studies applied to selectively 17O-labeled biomols. would appear to be very feasible.
33. 33
  Haimovich, A.; Eliav, U.; Goldbourt, A. J. Am. Chem. Soc. 2012, 134, 5647– 5651
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34. 34
  Vogt, F. G.; Yin, H.; Forcino, R. G.; Wu, L. Mol. Pharmacol. 2013, 10, 3433– 3446
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35. 35
  Kong, X. Q.; Shan, M.; Terskikh, V.; Hung, I.; Gan, Z. H.; Wu, G. J. Phys. Chem. B 2013, 117, 9643– 9654
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36. 36
  Umino, M.; Higashi, K.; Masu, H.; Limwikrant, W.; Yamamoto, K.; Moribe, K. J. Pharm. Sci. 2013, 102, 2738– 2747
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37. 37
  Saindon, P. J.; Cauchon, N. S.; Sutton, P. A.; Chang, C. J.; Peck, G. E.; Byrn, S. R. Pharm. Res. 1993, 10, 197– 203
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38. 38
  Lubach, J. W.; Padden, B. E.; Winslow, S. L.; Salsbury, J. S.; Masters, D. B.; Topp, E. M.; Munson, E. J. Anal. Bioanal. Chem. 2004, 378, 1504– 1510
  38
  Solid-state NMR studies of pharmaceutical solids in polymer matrices
  Lubach, Joseph W.; Padden, Brian E.; Winslow, Stephanie L.; Salsbury, Jonathon S.; Masters, David B.; Topp, Elizabeth M.; Munson, Eric J.
  Analytical and Bioanalytical Chemistry (2004), 378 (6), 1504-1510CODEN: ABCNBP; ISSN:1618-2642. (Springer-Verlag)
  Biodegradable drug-delivery systems can be formulated to release drug for hours to years and have been used for the controlled release of medications in animals and humans. An important consideration in developing a drug-delivery matrix is knowledge of the long-term stability of the form of the drug and matrix after formulation and any changes that might occur to the drug throughout the delivery process. Solid-state NMR spectroscopy is an effective technique for studying the state of both the drug and the matrix. Two systems that have been studied using solid-state NMR spectroscopy are presented. The first system studied involved bupivacaine, a local anesthetic compd., which was incorporated into microspheres composed of tristearin and encapsulated using a solid protein matrix. Solid-state 13C NMR spectroscopy was used to investigate the solid forms of bupivacaine in their bulk form or as incorporated into the tristearin/protein matrix. Bupivacaine free base and bupivacaine-HCl have very different solid-state NMR spectra, indicating that the mols. of these compds. pack in different crystal forms. In the tristearin matrix, the drug form could be detd. at levels as low as 1:100 (wt./wt.), and the form of bupivacaine was identified upon loading into the tristearin/protein matrix. In the second case, the possibility of using solid-state 13C NMR spectroscopy to characterize biomols. lyophilized within polymer matrixes is evaluated by studying uniformly 13C-labeled asparagine (Asn) in 1:250 (wt./wt.) formulations with poly(vinyl pyrrolidone) (PVP) and poly(vinyl alc.) (PVA). This work shows the capability of solid-state NMR spectroscopy to study interactions between the amino acid and the polymer matrix for synthetic peptides and peptidomimetics contg. selective 13C labeling at the Asn residue.
39. 39
  Harris, R. K.; Hodgkinson, P.; Larsson, T.; Muruganantham, A. J. Pharm. Biomed. Anal. 2005, 38, 858– 864
  39
  Quantification of bambuterol hydrochloride in a formulated product using solid-state NMR
  Harris, Robin K.; Hodgkinson, Paul; Larsson, Tomas; Muruganantham, Amsaveni
  Journal of Pharmaceutical and Biomedical Analysis (2005), 38 (5), 858-864CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
  Carbon-13 NMR spectra of the stable polymorphs of solid bambuterol hydrochloride (BHC) and terbutaline sulfate (TBS) are reported and the resonances assigned with the aid of soln.-state spectra. A protocol is presented for quantification of BHC in a formulation in lactose, together with TBS, relative to a ref. peak from magnesium stearate. This protocol compares the intensity of an arom. signal of BHC with that of the main-chain methylene carbons of the stearate. It is shown that the limit of detection (LOD) of BHC in this system under the conditions described is 0.5% with an effective limit of quantification (LOQ) of 1.0%. A calibration plot for the quantification is presented and the various factors affecting the accuracy of the measurements are described. No discernible differences are found in the spectra of phys. mixts. of the components, whole tablets, and crushed or ground tablets.
40. 40
  Tobyn, M.; Brown, J.; Dennis, A. B.; Fakes, M.; Gao, Q.; Gamble, J.; Khimyak, Y. Z.; McGeorge, G.; Patel, C.; Sinclair, W.; Timmins, P.; Yin, S. J. Pharm. Sci. 2009, 98, 3456– 3468
  There is no corresponding record for this reference.
41. 41
  Lubach, J. W.; Xu, D.; Segmuller, B. E.; Munson, E. J. J. Pharm. Sci. 2007, 96, 777– 787
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42. 42
  Rossini, A. J.; Zagdoun, A.; Hegner, F. S.; Schwarzwälder, M.; Gajan, D.; Copéret, C.; Lesage, A.; Emsley, L. J. Am. Chem. Soc. 2012, 134, 16899– 16908
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43. 43
  Chang, C. J.; Diaz, L. E.; Morin, F.; Grant, D. M. Magn. Reson. Chem. 1986, 24, 768– 771
  43
  Solid-state carbon-13 NMR study of drugs: aspirin
  Chang, Ching Jer; Diaz, Luis E.; Morin, Frederick; Grant, David M.
  Magnetic Resonance in Chemistry (1986), 24 (9), 768-71CODEN: MRCHEG; ISSN:0749-1581.
  Natural abundance 13C-NMR spectra of different crystal habits of pure aspirin [50-78-2] and several aspirin tablets in the solid state were measured by using the combined techniques of high-power decoupling, cross-polarization and magic angle spinning. Solid-state NMR of aspirin had excellent sensitivity compared with liq.-state NMR, and the C signals were assigned using a modified pulse sequence to detect non-protonated carbons. The solid-state 13C-NMR spectra of 2 cryst. forms of aspirin were identical, suggesting that the origin of their difference is not polymorphic. The solid-state 13C-NMR spectra of several com. aspirin tablets, some of them contg. buffer components, indicated that there were no interactions among the aspirin and the buffer components; only after dissolving the tablets and lyophilization did the 13C-NMR spectra of the dry lyophilized powders show strong interactions between aspirin and the buffer components.
44. 44
  Diaz, L. E.; Frydman, L.; Olivieri, A. C.; Frydman, B. Anal. Lett. 1987, 20, 1657– 1666
  44
  Solid state NMR of drugs: soluble aspirin
  Diaz, Luis E.; Frydman, Lucio; Olivieri, Alejandro C.; Frydman, Benjamin
  Analytical Letters (1987), 20 (10), 1657-66CODEN: ANALBP; ISSN:0003-2719.
  Natural abundance 13C-NMR spectra of a sol. aspirin and model mixts. of acetylsalicylic acid with buffering components were recorded in the solid state by using the combined techniques of cross polarization, high-power decoupling and magic-angle spinning. The solid-state spectrum of the sol. aspirin tablet showed more resonance than the soln. spectrum. These multiplicities were originated in the buffer mixt. contg. citric and tartaric acid, as well as their salts. Solid-state 13C-NMR therefore provided information that the lost in the soln. spectrum was due to the fast proton exchange between the org. acids and their conjugated salts.
45. 45
  Jagannathan, N. R. Curr. Sci. 1987, 56, 827– 830
  45
  High-resolution solid-state carbon-13 nuclear magnetic resonance study of acetaminophen: a common analgesic drug
  Jagannathan, N. R.
  Current Science (1987), 56 (16), 827-30CODEN: CUSCAM; ISSN:0011-3891.
  Solid-state 13C-NMR spectra of acetaminophen were obtained by using proton enhancement combined with high-power decoupling and magic angle spinning. The contact time was detd. to obtain a max. signal to noise ratio. The chem. shifts obsd. were assigned to different carbons based on both conventional and nonquaternary suppression NMR spectra. In addn. there were no differences in the solid-state NMR spectra of Crocin and Tylenol tablets (com. brands of acetaminophen), except for the different binder content used in the formulation.
46. 46
  Sanchez, S.; Ziarelli, F.; Viel, S.; Delaurent, C.; Caldarelli, S. J. Pharm. Biomed. Anal. 2008, 47, 683– 687
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47. 47
  Griffin, J. M.; Martin, D. R.; Brown, S. P. Angew. Chem., Int. Ed. 2007, 46, 8036– 8038
  There is no corresponding record for this reference.
48. 48
  Zhou, D. H.; Rienstra, C. M. Angew. Chem., Int. Ed. 2008, 47, 7328– 7331
  There is no corresponding record for this reference.
49. 49
  Tatton, A. S.; Pham, T. N.; Vogt, F. G.; Iuga, D.; Edwards, A. J.; Brown, S. P. Mol. Pharmacol. 2013, 10, 999– 1007
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50. 50
  Zhou, D. H.; Shah, G.; Mullen, C.; Sandoz, D.; Rienstra, C. M. Angew. Chem., Int. Ed. 2009, 48, 1253– 1256
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51. 51
  Nishiyama, Y.; Frey, M. H.; Mukasa, S.; Utsumi, H. J. Magn. Reson. 2010, 202, 135– 139
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52. 52
  Zielinska-Pisklak, M.; Pisklak, D. M.; Wawer, I. J. Pharm. Sci. 2012, 101, 1763– 1772
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53. 53
  Vogt, F. G.; Williams, G. R. Pharm. Res. 2012, 29, 1866– 1881
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54. 54
  Kelley, W. P.; Chen, S. J.; Floyd, P. D.; Hu, P.; Kapsi, S. G.; Kord, A. S.; Sun, M. J.; Vogt, F. G. Anal. Chem. 2012, 84, 4357– 4372
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55. 55
  Vogt, F. G.; Strohmeier, M. Mol. Pharm. 2012, 9, 3357– 3374
  55
  2D Solid-State NMR Analysis of Inclusion in Drug-Cyclodextrin Complexes
  Vogt, Frederick G.; Strohmeier, Mark
  Molecular Pharmaceutics (2012), 9 (11), 3357-3374CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  The soly. of drug mols. can often be improved through prepn. and delivery of cyclodextrin (CD) inclusion complexes. These drug-oligosaccharide complexes can be prepd. in soln. and converted to the solid state via methods such as lyophilization and spray-drying, or they can be prepd. directly from solids by a variety of methods. The development of drug-CD complexes as solids allows for potential advantages in dosage form design, such as the prepn. of layered formulations, and it also can yield improvements in chem. and phys. stability. 2D solid-state NMR (SSNMR) methods provide a direct way to probe drug-CD interactions in solid complexes through dipolar interactions between nuclei within the drug and CD mols. In this study, 2D heteronuclear and homonuclear correlation SSNMR expts. involving 1H, 13C, 19F, and 31P nuclei are used to demonstrate the inclusion of drug within the CD cavity in a variety of powder samples. To illustrate the general applicability of the SSNMR approach presented, examples are shown for the drugs diflunisal, adefovir dipivoxil, voriconazole, dexamethasone, and prednisolone in complexes with α-CD, β-CD, and sulfobutylether-substituted β-CD. The quant. anal. of included and free drug fractions in a solid drug-CD complex using SSNMR is also demonstrated. On the basis of these results, general approaches to the characterization of these materials using SSNMR are proposed.
56. 56
  Maly, T.; Debelouchina, G. T.; Bajaj, V. S.; Hu, K. N.; Joo, C. G.; Mak-Jurkauskas, M. L.; Sirigiri, J. R.; van der Wel, P. C. A.; Herzfeld, J.; Temkin, R. J.; Griffin, R. G. J. Chem. Phys. 2008, 128, 052211
  There is no corresponding record for this reference.
57. 57
  Ni, Q. Z.; Daviso, E.; Can, T. V.; Markhasin, E.; Jawla, S. K.; Swager, T. M.; Temkin, R. J.; Herzfeld, J.; Griffin, R. G. Acc. Chem. Res. 2013, 48, 1933– 1941
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58. 58
  Mak-Jurkauskas, M. L.; Bajaj, V. S.; Hornstein, M. K.; Belenky, M.; Griffin, R. G.; Herzfeld, J. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 883– 888
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59. 59
  Salnikov, E.; Rosay, M.; Pawsey, S.; Ouari, O.; Tordo, P.; Bechinger, B. J. Am. Chem. Soc. 2010, 132, 5940– 5941
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60. 60
  Sergeyev, I. V.; Day, L. A.; Goldbourt, A.; McDermott, A. E. J. Am. Chem. Soc. 2011, 133, 20208– 20217
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61. 61
  Linden, A. H.; Lange, S.; Franks, W. T.; Akbey, U.; Specker, E.; van Rossum, B.-J.; Oschkinat, H. J. Am. Chem. Soc. 2011, 133, 19266– 19269
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62. 62
  Reggie, L.; Lopez, J. J.; Collinson, I.; Glaubitz, C.; Lorch, M. J. Am. Chem. Soc. 2011, 133, 19084– 19086
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63. 63
  Potapov, A.; Yau, W.-M.; Tycko, R. J. Magn. Reson. 2013, 231, 5– 14
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64. 64
  Takahashi, H.; Ayala, I.; Bardet, M.; De Paepe, G.; Simorre, J. P.; Hediger, S. J. Am. Chem. Soc. 2013, 135, 5105– 5110
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65. 65
  Wang, T.; Park, Y. B.; Caporini, M. A.; Rosay, M.; Zhong, L. H.; Cosgrove, D. J.; Hong, M. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 16444– 16449
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66. 66
  Lesage, A.; Lelli, M.; Gajan, D.; Caporini, M. A.; Vitzthum, V.; Mieville, P.; Alauzun, J.; Roussey, A.; Thieuleux, C.; Mehdi, A.; Bodenhausen, G.; Copéret, C.; Emsley, L. J. Am. Chem. Soc. 2010, 132, 15459– 15461
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67. 67
  Lelli, M.; Gajan, D.; Lesage, A.; Caporini, M. A.; Vitzthum, V.; Mieville, P.; Heroguel, F.; Rascon, F.; Roussey, A.; Thieuleux, C.; Boualleg, M.; Veyre, L.; Bodenhausen, G.; Copéret, C.; Emsley, L. J. Am. Chem. Soc. 2011, 133, 2104– 2107
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68. 68
  Lafon, O.; Rosay, M.; Aussenac, F.; Lu, X.; Trebosc, J.; Cristini, O.; Kinowski, C.; Touati, N.; Vezin, H.; Amoureux, J. P. Angew. Chem., Int. Ed. 2011, 50, 8367– 8370
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69. 69
  Rossini, A. J.; Zagdoun, A.; Lelli, M.; Canivet, J.; Aguado, S.; Ouari, O.; Tordo, P.; Rosay, M.; Maas, W. E.; Copéret, C.; Farrusseng, D.; Emsley, L.; Lesage, A. Angew. Chem., Int. Ed. 2012, 51, 123– 127
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70. 70
  Zagdoun, A.; Casano, G.; Ouari, O.; Lapadula, G.; Rossini, A. J.; Lelli, M.; Baffert, M.; Gajan, D.; Veyre, L.; Maas, W. E.; Rosay, M.; Weber, R. T.; Thieuleux, C.; Copéret, C.; Lesage, A.; Tordo, P.; Emsley, L. J. Am. Chem. Soc. 2012, 134, 2284– 2291
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71. 71
  Takahashi, H.; Lee, D.; Dubois, L.; Bardet, M.; Hediger, S.; De Paëpe, G. Angew. Chem., Int. Ed. 2012, 124, 11936– 11939
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72. 72
  Rossini, A. J.; Zagdoun, A.; Lelli, M.; Lesage, A.; Copéret, C.; Emsley, L. Acc. Chem. Res. 2013, 46, 1942– 1951
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73. 73
  Blanc, F.; Sperrin, L.; Jefferson, D. A.; Pawsey, S.; Rosay, M.; Grey, C. P. J. Am. Chem. Soc. 2013, 135, 2975– 2978
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74. 74
  Lafon, O.; Thankamony, A. S. L.; Kobayashi, T.; Carnevale, D.; Vitzthum, V.; Slowing, I. I.; Kandel, K.; Vezin, H.; Amoureux, J. P.; Bodenhausen, G.; Pruski, M. J. Phys. Chem. C 2013, 117, 1375– 1382
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75. 75
  Blanc, F.; Chong, S. Y.; McDonald, T. O.; Adams, D. J.; Pawsey, S.; Caporini, M. A.; Cooper, A. I. J. Am. Chem. Soc. 2013, 135, 15290– 15293
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76. 76
  Song, C. S.; Hu, K. N.; Joo, C. G.; Swager, T. M.; Griffin, R. G. J. Am. Chem. Soc. 2006, 128, 11385– 11390
  76
  TOTAPOL: A Biradical Polarizing Agent for Dynamic Nuclear Polarization Experiments in Aqueous Media
  Song, Changsik; Hu, Kan-Nian; Joo, Chan-Gyu; Swager, Timothy M.; Griffin, Robert G.
  Journal of the American Chemical Society (2006), 128 (35), 11385-11390CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  In a previous publication, the authors described the use of biradicals, in that case two TEMPO mols. tethered by an ethylene glycol chain of variable length, as polarizing agents for microwave driven dynamic nuclear polarization (DNP) expts. The use of biradicals in place of monomeric paramagnetic centers such as TEMPO yields enhancements that are a factor of approx. 4 larger (ε ∼ 175 at 5 T and 90 K) and concurrently the concn. of the polarizing agent is a factor of 4 smaller (10 mM electron spins), reducing the residual electron nuclear dipole broadening. In this paper the authors describe the synthesis and characterization by EPR and DNP/NMR of an improved polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL (I)). Under the same exptl. conditions and using 2.5 mm magic angle rotors, this new biradical yields larger enhancements (ε ∼ 290) at lower concns. (6 mM electron spins) and has the addnl. important property that it is compatible with expts. in aq. media, including salt solns. commonly used in the study of proteins and nucleic acids.
77. 77
  van der Wel, P. C. A.; Hu, K. N.; Lewandowski, J.; Griffin, R. G. J. Am. Chem. Soc. 2006, 128, 10840– 10846
  There is no corresponding record for this reference.
78. 78
  Ong, T. C.; Mak-Jurkauskas, M. L.; Walish, J. J.; Michaelis, V. K.; Corzilius, B.; Smith, A. A.; Clausen, A. M.; Cheetham, J. C.; Swager, T. M.; Griffin, R. G. J. Phys. Chem. B 2013, 117, 3040– 3046
  There is no corresponding record for this reference.
79. 79
  Zagdoun, A.; Casano, G.; Ouari, O.; Schwarzwälder, M.; Rossini, A. J.; Aussenac, F.; M., Y.; G., J.; Copéret, C.; Lesage, A.; Tordo, P.; Emsley, L. J. Am. Chem. Soc. 2013, 135, 12790– 12797
  There is no corresponding record for this reference.
80. 80
  Zagdoun, A.; Casano, G.; Ouari, O.; Lapadula, G.; Rossini, A. J.; Lelli, M.; Baffert, M.; Gajan, D.; Veyre, L.; Maas, W. E.; Rosay, M.; Weber, R. T.; Thieuleux, C.; Copéret, C.; Lesage, A.; Tordo, P.; Emsley, L. J. Am. Chem. Soc. 2012, 134, 2284– 2291
  There is no corresponding record for this reference.
81. 81
  Rosay, M.; Tometich, L.; Pawsey, S.; Bader, R.; Schauwecker, R.; Blank, M.; Borchard, P. M.; Cauffman, S. R.; Felch, K. L.; Weber, R. T.; Temkin, R. J.; Griffin, R. G.; Maas, W. E. Phys. Chem. Chem. Phys. 2010, 12, 5850– 5860
  There is no corresponding record for this reference.
82. 82
  Harris, R. K.; Becker, E. D.; De Menezes, S. M. C.; Goodfellow, R.; Granger, P. Pure Appl. Chem. 2001, 73, 1795– 1818
  82
  NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC recommendations 2001)
  Harris, Robin K.; Becker, Edwin D.; Cabral De Menezes, Sonia M.; Goodfellow, Robin; Granger, Pierre
  Pure and Applied Chemistry (2001), 73 (11), 1795-1818CODEN: PACHAS; ISSN:0033-4545. (International Union of Pure and Applied Chemistry)
  A review. A unified scale is recommended for reporting the NMR chem. shifts of all nuclei relative to the 1H resonance of tetramethylsilane (TMS). The unified scale is designed to provide a precise ratio, Ξ, of the resonance frequency of a given nuclide to that of the primary ref., the 1H resonance of TMS in dil. soln. (vol. fraction, φ < 1%) in CHCl3. Referencing procedures are discussed, including matters of practical application of the unified scale. Special attention is paid to recommended ref. samples, and values of Ξ for secondary refs. on the unified scale are listed, many of which are the results of new measurements. Some earlier recommendations relating to the reporting of chem. shifts are endorsed. The chem. shift, δ, is redefined to avoid previous ambiguities but to leave practical usage unchanged. Relations between the unified scale and recently published recommendations for referencing in aq. solns. (for specific use in biochem. work) are discussed, as well as the special effects of working in the solid state with magic-angle spinning. In all, nine new recommendations relating to chem. shifts are made. Standardized nuclear spin data are also presented in tabular form for the stable (and some unstable) isotopes of all elements with nonzero quantum nos. The information given includes quantum nos., isotopic abundances, magnetic moments, magnetogyric ratios and receptivities, together with quadrupole moments and line-width factors where appropriate.
83. 83
  Metz, G.; Wu, X.; Smith, S. J. Magn. Reson., Ser. A 1994, 110, 219– 227
  83
  Ramped-amplitude cross polarization in magic-angle-spinning NMR
  Metz, Guenther; Wu, Xiaoling; Smith, Steven O.
  Journal of Magnetic Resonance, Series A (1994), 110 (2), 219-27CODEN: JMRAE2; ISSN:1064-1858.
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Supporting Information
Supporting Information
Details on sample preparations, additional 1D and 2D NMR spectra, SEM images, and MatLab code for the numerical calculations. This material is available free of charge via the Internet at http://pubs.acs.org.
- ja4092038_si_001.pdf (12.86 MB)
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Dynamic Nuclear Polarization Enhanced NMR Spectroscopy for Pharmaceutical FormulationsClick to copy article linkArticle link copied!

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Abstract

1 Introduction

2 Experimental Section

Chart 1

3 Results and Discussion

3.1 DNP Enhanced NMR for Pharmaceutical Formulations

3.1.1 DNP Enhanced Solid-State NMR of Crystalline Cetirizine Dihydrochloride

Figure 1

3.1.2 DNP Enhanced NMR of Pharmaceutical Formulations

3.1.3 DNP Enhanced Solid-State NMR of Pure Excipients and Formulation F1

3.1.4 DNP Enhanced Solid-State NMR of Pure Povidone

Figure 2

Figure 3

3.1.5 Sensitivity Enhancement by DNP for Pharmaceutical Formulations

Figure 4

3.2 DNP Enhanced NMR to Probe the Microstructure of Formulations

3.2.1 Measuring API Domain Sizes with DNP

Figure 5

3.2.2 Probing API–Excipient Interactions with DNP Enhanced Solid-State NMR

4 Conclusions

Supporting Information

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Acknowledgment

References

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Abstract

Chart 1

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

References

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Supporting Information

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Dynamic Nuclear Polarization Enhanced NMR Spectroscopy for Pharmaceutical Formulations
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