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Dynamic Nuclear Polarization MAS NMR is introduced to characterize model methylcellulose ether compounds at natural isotopic abundance. In particular an approach is provided to determine the position of the methyl ether group within the repeating unit. Specifically, natural abundance 13C-13C correlation experiments are used to characterize model 3-O-methylcellulose and 2,3-O-dimethylcellulose, and identify changes in chemical shifts with respect to native cellulose. We also probe the use of through space connectivity to the closest carbons to the CH3 to identify the substitution site on the cellulose ether. To this end, a series of methylcellulose ethers was prepared by a multistep synthesis approach. Key intermediates in these reactions were 2,6-O-diprotected thexyldimethylsilyl (TDMS) cellulose and 6-O-monoprotected TDMS cellulose methylated under homogeneous conditions. The products had degrees of substitution of 0.99 (3-O-methylcellulose) and 2.03 (2,3-O-dimethylcellulose) with exclusively regioselective substitution. The approaches developed here will allow characterization of the substitution patterns in cellulose ethers.

We investigate the presence of a surface species for the active pharmaceutical ingredient (API) AZD9496 with dynamic nuclear polarization surface enhanced nuclear spectroscopy (DNP SENS). We show that using DNP we can elucidate the presence of an amorphous form of the API at the surface of crystalline particles of the salt form. The amorphous form of the API has distinguishable 13C chemical shifts when compared to the salt form under various acidic conditions. The predominant form in frozen particles of AZD9496 is the salt, and we provide evidence to suggest that the amorphous layer at the surface is mainly made up of the dissociated free form. (c) 2021 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

The structure of crystalline nanoparticles (CNPs) is determined using dynamic nuclear polarization (DNP) enhanced NMR spectroscopy experiments. The CNPs are composed of a crystalline core containing an active pharmaceutical ingredient (compound P), coated with a layer of PEG (DSPE-PEG 5000) located at the crystal surface, in a D2O suspension. Relayed DNP experiments are performed to study 1H-1H spin diffusion and to determine the size of the crystalline core as well as the thickness of the PEG overlayer. This is achieved through selective doping to create a heterogeneous system in which the D2O contains glycerol and organic radicals, which act as polarization sources, and the CNPs are exempt of radical molecules. We observe features that are characteristic of a core-shell system: high and constant DNP enhancement for components located in the surrounding radical solution, short build-up times for the PEG layer, and longer build-up times and time dependent enhancements for compound P. By comparing numerical simulations and experimental data, we propose a structural model for the CNPs with a core-shell organization and a high affinity between the radical and the PEG molecules.

Here, we show how dynamic nuclear polarization (DNP) NMR spectroscopy experiments permit the atomic level structural characterization of loaded and empty lipid nanoparticles (LNPs). The LNPs used here were synthesized by the microfluidic mixing technique and are composed of ionizable cationic lipid (DLin-MC3-DMA), a phospholipid (distearoylphosphatidylcholine, DSPC), cholesterol, and poly(ethylene glycol) (PEG) (dimyristoyl phosphatidyl ethanolamine (DMPE)-PEG 2000), as well as encapsulated cargoes that are either phosphorothioated siRNA (50 or 100%) or mRNA. We show that LNPs form physically stable complexes with bioactive drug siRNA for a period of 94 days. Relayed DNP experiments are performed to study 1H-1H spin diffusion and to determine the spatial location of the various components of the LNP by studying the average enhancement factors as a function of polarization time. We observe a striking feature of LNPs in the presence and in the absence of encapsulating siRNA or mRNA by comparing our experimental results to numerical spin-diffusion modeling. We observe that LNPs form a layered structure, and we detect that DSPC and DMPE-PEG 2000 lipids form a surface rich layer in the presence (or absence) of the cargoes and that the cholesterol and ionizable cationic lipid are embedded in the core. Furthermore, relayed DNP 31P solid-state NMR experiments allow the location of the cargo encapsulated in the LNPs to be determined. On the basis of the results, we propose a new structural model for the LNPs that features a homogeneous core with a tendency for layering of DSPC and DMPE-PEG at the surface.

Dynamic nuclear polarization (DNP) allows to dramatically enhance the sensitivity of magic angle spinning nuclear magnetic resonance (MAS NMR). DNP experiments usually rely on the detection of low-γ nuclei hyperpolarized from 1H with the use of cross polarization (CP), which assures more efficient signal enhancement. However, CP is usually not quantitative. Here we determine the quantification performance of three different approaches used in MAS NMR, (conventional CP, variable contact time CP, and multiple-contact CP) under DNP conditions, and we show that absolute quantification in MAS DNP NMR is possible, with errors below 10%.

The crystal structure of the Form A polymorph of N-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino) ethoxy] phenyl] cyclopropyl] amino]-2-oxo-pyrazin-1-yl] benzamide (i.e., AZD7624), determined using single-crystal X-ray diffraction (scXRD) at 100 K, contains two molecules in the asymmetric unit (Z' = 2) and has regions of local static disorder. This substance has been in phase IIa drug development trials for the treatment of chronic obstructive pulmonary disease, a disease which affects over 300 million people and contributes to nearly 3 million deaths annually. While attempting to verify the crystal structure using nuclear magnetic resonance crystallography (NMRX), we measured C-13 solid-state NMR (SSNMR) spectra at 295 K that appeared consistent with Z' = 1 rather than Z' = 2. To understand this surprising observation, we used multinuclear SSNMR (H-1, C-13, N-15), gauge-including projector augmented-wave density functional theory (GIPAW DFT) calculations, crystal structure prediction (CSP), and powder XRD (pXRD) to determine the room temperature crystal structure. Due to the large size of AZD7624 (ca. 500 amu, 54 distinct C-13 environments for Z' = 2), static disorder at 100 K, and (as we show) dynamic disorder at ambient temperatures, NMR spectral assignment was a challenge. We introduce a method to enhance confidence in NMR assignments by comparing experimental C-13 isotropic chemical shifts against site-specific DFT-calculated shift distributions established using CSP-generated crystal structures. The assignment and room temperature NMRX structure determination process also included measurements of C-13 shift tensors and the observation of residual dipolar coupling between C-13 and N-14. CSP generated ca. 90 reasonable candidate structures (Z' = 1 and Z' = 2), which when coupled with GIPAW DFT results, room temperature pXRD, and the assigned SSNMR data, establish Z' = 2 at room temperature. We find that the polymorphic Form A of AZD7624 is maintained at room temperature, although dynamic disorder is present on the NMR timescale. Of the CSP-generated structures, 2 are found to be fully consistent with the SSNMR and pXRD data; within this pair, they are found to be structurally very similar (RMSD16 = 0.30 angstrom). We establish that the CSP structure in best agreement with the NMR data possesses the highest degree of structural similarity with the scXRD-determined structure (RMSD16 = 0.17 angstrom), and has the lowest DFT-calculated energy amongst all CSP-generated structures with Z' = 2.

From the assignment of the solid-state (13)C NMR signals in the C4 region, distinct types of crystalline cellulose, cellulose at crystalline surfaces, and disordered cellulose can be identified and quantified. For regenerated cellulose, complete (13)C assignments of the other carbon regions have not previously been attainable, due to signal overlap. In this study, two-dimensional (2D) NMR correlation methods were used to resolve and assign (13)C signals for all carbon atoms in regenerated cellulose. (13)C-enriched bacterial nanocellulose was biosynthesized, dissolved, and coagulated as highly crystalline cellulose II. Specifically, four distinct (13)C signals were observed corresponding to conformationally different anhydroglucose units: two signals assigned to crystalline moieties and two signals assigned to non-crystalline species. The C1, C4 and C6 regions for cellulose II were fully examined by global spectral deconvolution, which yielded qualitative trends of the relative populations of the different cellulose moieties, as a function of wetting and drying treatments.

We are grateful to Matthew Conley and Christophe Coperet from ETH Zurich for providing the mesoporous silica materials. We are grateful to Prof. P. Tordo, Dr. O. Ouari, and Dr. G. Casano (Aix-Marseille Universite, France) for providing the biradicals used in the DNP NMR experiments.; International audience; We show how dynamic nuclear polarization (DNP) NMR can be used in combination with models for polarization dynamics to determine the domain sizes in complex materials. By selectively doping a source component with radicals and leaving the target undoped, we Can measure experimental polarization buildup curves which can be compared with simulations based on heterogeneous distributions of polarization-within the sample. The variation of the integrated DNP enhancement as a function of the polarization time is found to be characteristic of the geometry. We demonstrate the method experimentally on four different systems where we successfully determine domain sizes between 200 and 20 000 nm, specifically in powdered histidine hydrochloride monohydrate) pore lengths of mesoporous silica materials, and two domain sizes in two component polymer film coatings. Additionally, we find that even in the apparently homogeneous frozen solutions used as polarization sources in most DNP experiments, polarization is relayed from protons near the radicals to the bulk of the solution by spin diffusion, which explains the experimentally observed buildup times in these samples.

A study was made of coating single particles with water-based dispersions under realistic fluid dynamic and well-defined operating conditions. The surfaces of the coated particles were observed with atomic force microscopy (AFM) and scanning electron microscopy (SEM). AFM was used to study the latex particle packing and the colloid particle coalescence at the nanoscale, while SEM was used to study the film at the droplet size level. The influence of temperature, moisture content and spray rate were investigated. The experiments showed a coating layer built up of rings of colloid particles for all cases studied except for high spray rate. A variation in the degree of coalescence between colloid particles with different glass transition temperatures, T-g, was shown in AFM. Cracks in the coating layer were observed when the temperature was lower than T-g. Mechanism evaluation using dimensionless numbers showed that a droplet will spread to the equilibrium angle without splashing; the colloid particles accumulate at the interface between the liquid and the air for all cases studied except air with 90% RH and 20 degrees C and a wet-bulb temperature in the coating layer. The evaluation indicated that no skin forms in any of the cases. A model of the drying of a single droplet was developed to describe the experimental results with rings of colloid particles. The simulation of the shape and height of the dried droplet agrees well with the experimental results. (C) 2010 Elsevier B.V. All rights reserved.

The purpose of the present work was to study the effect of ultrasound extrusion and cutting on the physical stability of a viscous and sticky supercooled melt containing (50/50, w/w, %) citric acid anhydrate and paracetamol. Samples were extrudated at temperatures of 50, 60, and 70 degrees C using power levels of 0, 50, 100, and 150 W. Similarly, extrudates prepared at 60 degrees C were cut at temperatures ranging from 25-60 degrees C with an ultrasound knife in the range 0, 50, and 100 W. The characterization methods used were: high performance liquid chromatography, differential scanning calorimetry, Karl Fischer titration, X-ray powder diffraction, Fourier transform infrared microscopy, optical- and stereomicroscopy. There was no physical difference in extrudates or cut surfaces whether processed with or without ultrasound. During 1-year aging time in dry conditions, all the samples were observed to crystallize slowly and ultrasound processing did not enhance the crystallization. Ultrasound thus holds some promise for processing of viscous and sticky pharmaceuticals, provided the material is physically stable enough to withstand mechanical and thermal stress. Processing of sticky and viscous material would be difficult without ultrasound with the methods currently used in pharmaceutical industry.

Citric acid anhydrate (CAA) and paracetamol (PARA), prepared as crystalline physical mixtures and as amorphous blends, were studied using (13)C solid-state cross polarization magic angle spinning (CPMAS) NMR. Amorphous blends showed significant line broadening from the conformational distribution as compared to the crystalline samples. Also, chemical shift variations were observed between crystalline and amorphous blends, which were attributed to differences in intermolecular interactions. Averaging of proton rotating-frame spin-lattice relaxation times (T(1rho)) probed via different (13)C sites in the amorphous blends confirmed molecular level mixing. For some, initially amorphous, sample compositions the onset of crystallization was evident directly from spectra and from the significantly longer T(1rho) relaxations. Thus, crystallization caused phase separation with properties of the two phases resembling those of pure CAA and PARA, respectively. (13)C spectra of amorphous 50/50 (w/w, %) CAA/PARA recorded from above the glass transition temperature broadened as the temperature increased to a maximum at T approximately T(g) + 33 K. This was the result of a dynamic interference between the line narrowing techniques being applied and the time scale of molecular reorientation in the miscible melt. The derived average correlation time was found to correspond well with previous results from melt rheology. We conclude that the underlying reasons for physical instability (i.e., crystallization from the miscible melt, including molecular interactions and dynamics) of this class of amorphous binary mixtures can be effectively evaluated using NMR spectroscopy.

This paper reports on a technique using ultrasound-assisted equipment to characterise and handle stickiness of viscous amorphous blends of citric acid and paracetamol after melt mixing and during processing. Deformability and stickiness were studied using a specially designed sample measurement compartment. An ultrasound-assisted nozzle and knife for pharmaceutical applications were studied. The application of ultrasound was found to increase the mass flow through a nozzle connected to a pressurized tank. This effect was found to be separate from the increased mass transport resulting from the reduced viscosity as the temperature was increased. Ultrasound was also found to have a favourable influence on cutting through melt extrudates. The stickiness and resistance to deformation of samples were observed to be dependent on the amount of paracetamol in the blend and temperature that was in agreement with the glass transition temperature and viscosity. Other influencing factors, such as time-dependent wetting and surface energetics, are discussed. We conclude that it is possible to characterise stickiness and resistance to deformation of viscous amorphous materials with a specially designed probe test, and the stickiness of amorphous material can be handled during processing with ultrasound-assisted equipment.

The purpose of this study was to characterise physically stable amorphous blends that were sticky (low glass transition temperature) in ambient conditions. The effects of composition, melting time and melting temperature were evaluated with respect to physical and chemical property. Citric acid anhydrate and paracetamol were melt-quenched as binary mixtures and as pure materials. Bulk samples were characterised by differential scanning calorimetry, X-ray powder diffractometry, and Raman and Fourier transform infrared spectroscopy. The composition and the sample exposure to moisture affected significantly the physical stability of samples. The extreme melting conditions, coupled with long exposure to heat and a high melting temperature, lowered the overall crystallisation rate. Paracetamol had a stronger tendency to crystallise from the blends than did citric acid. The 50:50% (w/w) blend was physically stable for at least 27 weeks in dry conditions and was partly crystalline after 4 weeks of storage at a relative humidity of 43%. The result of the physical stability of blends is discussed in terms of hydrogen bonding interaction between paracetamol and citric acid and in relation to degradation products formed in a mixing state.

Water-based copolymer dispersions were prepared using methyl methacrylate (MMA), ethyl acrylate (EA) (MMA/EA = 1:2), and a series of nonionic polymerizable surfactants, i.e., "surfmers" based on poly(ethylene glycol)-(meth)acrylates. The latexes were compared with the behavior of a conventionally stabilized (nonionic nonylphenol ethoxylate, NP100 with 84 ethylene oxide units) dispersion with the same MMA-EA composition (PMMAEA). A number of techniques were employed in order to characterize structure, dynamics, and film formation properties: solution/solid-state NMR, dynamic/static light scattering (DLS/SLS), differential scanning calorimetry (DSC), tensile/shear mode dynamic mechanical thermal analysis (DMTA), and atomic force microscopy (AFM). The surfmers were found to be miscible with the MMA-EA copolymer at room temperature, with 46-85 mol % of the reacted surfmer detected at the particle surfaces, and the remaining part buried in the particle bulk. In contrast, the NP100 surfactant formed a separate interphase between the copolymer particles with no mixing detected at room temperature or at 90 degrees C. For a 4.0% dry weight concentration, NP100 phase separated and further crystallized at room temperature over a period of several months. Composition fluctuations related to a limited blockiness on a length scale above approximately 2 nm were detected for PMMAEA particles, whereas the surfmer particles were found to be homogeneous also below this limit. On a particle-particle level, the dispersions tended to form colloidal crystals unless hindered by a broadened particle size distribution or, in the case of PMMAEA, by the action of NP100. Finally, a surface roughness (Rq) master plot was constructed for data above the glass transition temperature (Tg) from Tg + 11 degrees C to Tg + 57 degrees C and compared with the complex shear modulus over 11 frequency decades. Shift factors from the 2 methods obeyed the same Williams-Landel-Ferry (WLF) temperature dependence, thus connecting the long-time surface flattening process to the rheological behavior of the copolymer.

Polymer domain sizes are related to many of the physical properties of polymers. Here we present a solid-state NMR experiment that is capable of measuring domain sizes in multi-component mixtures. The method combines selective excitation of carbon magnetization to isolate a specific component with proton spin diffusion to report on domain size. We demonstrate the method in the context of controlled release formulations, which represents one of today's challenges in pharmaceutical science. We show that we can measure domain sizes of interest in the different components of industrial pharmaceutical formulations at natural isotopic abundance containing various (modified) cellulose derivatives, such as microcrystalline cellulose matrixes that are film-coated with a mixture of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC). (C) 2015 Published by Elsevier Inc.

The equilibrium residence times of the nonionic surfactant nonylphenol ethoxylate (NP100) in a latex dispersion were determined using NMR diffusometry. At 16% w/w particle concentration and 0.12, 0.43 and 0.81% w/w NP100, the residence times of the surfactant were 0.16, 1.02 and 4.73 s in solution (τA) and 0.3, 0.37 and 0.61 s on the surface of the particles (τB), respectively. At even higher particle concentration (>45% w/w), τA and τB were 1.47 and 2.2 s. Calculating the number of collisions that ought to result in adsorbed species, at 16% w/w, only 2, 5 and 2‰ (corresponding to 0.12, 0.43 and 0.81% w/w NP100) resulted in adsorption, whereas at >45% w/w, only 12‰ resulted in adsorption, which suggested that the surfactant was irreversibly adsorbed on the particles. The small increase in collision frequency with increased particle concentration could be a result of a diffusion controlled adsorption, while an energy barrier for desorption controlled the overall exchange dynamics in the dispersion. The slow dynamics in the dispersion was controlled, mainly by the nonylphenol group, which gave NP100 a strong preference to surfaces. In addition, the chain length of the poly(ethylene glycol) (PEG) group changed the solution behavior from being that of a typical surfactant to that of a polymer.

We have studied the low-frequency dynamics of oligomers (n = 1 and n = 2) and polymers (n = 45) of propylene glycol using molecular dynamics (MD) simulations. The polymer structure was built from a reverse Monte Carlo (RMC) simulation of the static structure factors S(Q) obtained for ordinary and deuterated poly(prolylene oxide) from neutron diffraction. The fraction of the different stereo-isomers obtained in this way was checked by performing 13C nuclear magnetic resonance studies on the polymers. The RMC polymer structure was used as a starting structure for MD simulations of the polymer, whereas the shorter-chain oligomers were simulated using random starting structures. The vibrational density of states was calculated from the Fourier transform of the velocity autocorrelation function. Our results indicate that the low-frequency peak below 100 cm−1, generally referred to as the boson peak, is to a large extent due to intermolecular degrees of freedom, the peak position and shape being rather...

Solid-state 13C CP/MAS/DD NMR measurements have been carried out at 300 K on melt-mixed blends of poly(ethylene oxide)/atactic poly(methyl methacrylate) (PEO/a-PMMA) in the concentration range 10/90 to 75/25. Several relaxation times for protons and carbons, i.e. relaxation in the rotating frame (T1ρ(1H) and T1ρ(13C)) and in the laboratory frame (T1(1H) and T1(13C)), have been studied. From the carbon relaxations, we conclude that mixing is intimate enough to cause a reduction in local chain mobility for amorphous PEO. Although intermolecular spin diffusion contributes to the proton relaxations in accordance with homogeneity, T1(1H) and T1ρ(1H) data show signs of incomplete averaging. The proton relaxation behavior indicates the existence of heterogeneous domains with shortest dimensions in the nanometer range, which is further supported by the carbon relaxation decays and equilibrium 13C MAS/DD spectra.

The influence of a poly(styrene-graft-ethylene oxide) (P(S-g-EO)) copolymer on poly(2,6-dimethyl-p-phenylene oxide)/poly(methyl methacrylate) (PPO/PMMA) blends was studied by a number of different techniques in order to characterize the properties of the interphase. Scanning electron microscopy shows that the copolymer reduces the dispersed phase size, and dynamic mechanical spectroscopy (DMS) reveals a new micromechanical transition in the ternary blends. These effects are shown to be caused by a copolymer-rich interphase with a certain volume fraction and with its own characteristic properties. Solid-state nuclear magnetic resonance (NMR) relaxation times indicate that the poly(ethylene oxide) side chains of the copolymer are partially miscible with PMMA in the ternary blends, which suggests that the interphase does not only consist of pure copolymer.

The local polymer chain mobility of low molecular weight poly(ethylene oxide) (PEO) complexed with Ba(ClO 4 ) 2 has been investigated with 13 C NMR techniques over the temperature range 297-463 K. The carbon line width and the rotating frame spin-lattice relaxation rate provide information of segmental motion in the mid-kilohertz region, as shown by their temperature dependencies'with clear minima at ∼327 K. The laboratory frame spin-lattice relaxation rate minimum is observed at ∼378 K, consistent with the progressive changes in correlation times of motion above the glass transition temperature. When comparing the present relaxation data for PEO-Ba(ClO 4 ) 2 with those from the literature for PEO, we find that salt complexation dramatically slows down the segmental motions in the amorphous phase

13 C CPMAS NMR results from melt-mixed blends of undoped poly(3-octylthiophene) (POT) and poly(phenylene oxide) (PPO) are reported. The behavior of proton spin-lattice relaxation times in the rotating frame (T 1ρ (H)) and laboratory frame (T 1 (H)) indicate that the blends are immiscible. Alkyl side-chain 13 C spin-lattice relaxation times (T 1 (C)) increase considerably in blends of POT concentrations lower than ∼30%, reflecting an increased molecular flexibility for POT

The aim of this study was to investigate the rheological properties, molecular mobility and crystallization tendency of pure citric acid and paracetamol or blends of them. Amorphous samples were produced by ethanol-evaporation or by melt-quenching. Enthalpy recovery, glass fragility and heat capacity were determined by differential scanning calorimetry (DSC). Other physical characterization methods were rheology and the crystallization tendency using X-ray powder diffraction (XRPD) and DSC. All the samples behaved as Newtonian liquids and they were fragile glasses. The 50/50 (w/w, %) blend had good physical stability upon consecutive shearing regardless of the preparation method. All the samples were stable for at least one year in dry conditions at −20 °C. The melt-produced blends containing 25% or 50% paracetamol were stable at least two years in dry ambient conditions. The good physical stability at ambient temperature cannot be explained by molecular mobility because molecular mobility of the model material is less than 100 s in ambient conditions. Thus other factors, such as the thermodynamic and crystallization driving forces or formation of degradation products, must determine the physical stability of the blends. The composition and processing method have an impact on the physical stability of the sample.

The equilibrium residence times of the nonionic surfactant nonylphenol ethoxylate (NP100) in a latex dispersion were determined using NMR diffusometry. At 16% w/w particle concentration and 0.12, 0.43 and 0.81% w/w NP100, the residence times of the surfactant were 0.16, 1.02 and 4.73 s in solution (tau(A)) and 0.3, 0.37 and 0.61 s on the surface of the particles (tau(B)), respectively. At even higher particle concentration (45% w/w), tau(A) and tau(B) were 1.47 and 2.2 s. Calculating the number of collisions that ought to result in adsorbed species, at 16% w/w, only 2, 5 and 2 per thousand (corresponding to 0.12, 0.43 and 0.81% w/w NP100) resulted in adsorption, whereas at45% w/w, only 12 per thousand resulted in adsorption, which suggested that the surfactant was irreversibly adsorbed on the particles. The small increase in collision frequency with increased particle concentration could be a result of a diffusion controlled adsorption, while an energy barrier for desorption controlled the overall exchange dynamics in the dispersion. The slow dynamics in the dispersion was controlled, mainly by the nonylphenol group, which gave NP100 a strong preference to surfaces. In addition, the chain length of the poly(ethylene glycol) (PEG) group changed the solution behavior from being that of a typical surfactant to that of a polymer.

State-of-the-art work in the field of NMR crystallography for molecular systems at natural abundance has recently focused on the accurate measurement of 1H chemical shift values. We will show how when coupled with crystal structure prediction (CSP) methods, this protocol is well-suited for solving the crystal structures of small to medium sized organic molecules, including cocaine and the de-novo structure determination of AZD8329.[1,2] As complementary 1D and 2D NMR experiments are needed for the 1H assignment process, other information, such as isotropic 13C chemical shift values (δiso) are measured. Unfortunately, 13C chemical shifts are not generally useful for structure determination. Additional NMR parameters that are sensitive to structure would ensure that the structure determination procedure is robust, and would provide more accurate refinements when studying larger or more challenging systems. Here, we measure 13C chemical shift tensors for a variety of prototypical organic pharmaceuticals and use density functional theory computations under the gauge-including projector augmented-wave (GIPAW) formalism to probe whether these parameters may be discriminatory for unit cell determinations and structure determination (notably when added to the CSP + 1H chemical shifts protocol).