It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet-visible (UV-vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D H-H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs.

Ionic liquids are described that contain duplex DNA as the anion and polyether-decorated transition metal complexes based on M(MePEG-bpy)(3)(2+) as the cation (M = Fe, Co; MePEG-bpy = 4,4'-(CH(3)(OCH(2)CH(2))(7)OCO)(2)-2,2'-bipyridine). When the undiluted liquid DNA-or molten salt-is interrogated electrochemically by a microelectrode, the molten salts exhibit cyclic voltammograms due to the physical diffusion (D(PHYS)) of the polyether-transition metal complex. When M = Co(II), the cyclic voltammogram of the melt shows an oxidative wave due to the Co(III/II) couple at E(1/2) = 0.40 V (versus Ag/AgCl) and a D(PHYS) of 6 x 10(-12) cm(2)/s, which is significantly lower than that for Co(MePEG-bpy)(3)(ClO(4))(2) (D(PHYS) = 2.6 x 10(-10) cm(2)/s) due to greater viscosity provoked by the DNA polymer. When a 1:1 mixture is made of the Co(MePEG-bpy)(3).DNA and Fe(MePEG-bpy)(3)(ClO(4))(2) melts, two redox waves are observed. The first is due to the Co(III/II) couple, and the second is a catalytic wave due to oxidation of guanine in DNA by electrogenerated Fe(III) in the undiluted melt. Independent experiments show that the Fe(III) form of the complex selectively oxidizes guanine in duplex DNA. These DNA molten salts constitute a new class of materials whose properties can be controlled by nucleic acid sequence and that can be interrogated in undiluted form on microelectrode arrays.

A principal advantage of magic angle spinning (MAS) NMR spectroscopy lies in its ability to determine molecular structure in a noninvasive and quantitative manner. Accordingly, MAS should be widely applicable to studies of the structure of active pharmaceutical ingredients (API) and formulations. However, the low sensitivity encountered in spectroscopy of natural abundance APIs present at low concentration has limited the success of MAS experiments. Dynamic nuclear polarization (DNP) enhances NMR sensitivity and can be used to circumvent this problem provided that suitable paramagnetic polarizing agent can be incorporated into the system without altering the integrity of solid dosages. Here, we demonstrate that DNP polarizing agents can be added in situ during the preparation of amorphous solid dispersions (ASDs) via spray drying and hot-melt extrusion so that ASDs can be examined during drug development. Specifically, the dependence of DNP enhancement on sample composition, radical concentration, relaxation properties of the API and excipients, types of polarizing agents and proton density, has been thoroughly investigated. Optimal enhancement values are obtained from ASDs containing 1% w/w radical concentration. Both polarizing agents TOTAPOL and AMUPol provided reasonable enhancements. Partial deuteration of the excipient produced 3× higher enhancement values. With these parameters, an ASD containing posaconazole and vinyl acetate yields a 32-fold enhancement which presumably results in a reduction of NMR measurement time by ∼1000. This boost in signal intensity enables the full assignment of the natural abundance pharmaceutical formulation through multidimensional correlation experiments.

Films of neat metal salts with covalently attached oligoether side chains ([Co(bpy(CO(2)MePEG-350)(2))(3)](ClO(4))(2); bpy is 2,2'-bipyridine, and MePEG-350 is methyl-terminated oligomeric ethylene oxide with an average molecular weight of 350 Da) undergo marked changes in physical and electrochemical properties upon contact with CO(2). Electrochemical measurements indicate that the physical diffusion coefficient (D(PHYS)) of the Co(II) species, the observed rate constant for Co(II/I) self-exchange (k(EX)), and the physical diffusion coefficient of the perchlorate counterion (D(ClO4)) increase from 2.4 x 10(-11) to 7.0 x 10(-10) cm(2)/s, 6.8 x 10(5) to 4.5 x 10(6) M(-1) s(-1), and 3.4 x 10(-10) to 4.3 x 10(-9) cm(2)/s, respectively, as CO(2) pressure is increased from 0 to 2000 psi at 23 degrees C. A reduction in activation energy accompanies the enhancement of each of these properties over this pressure range. Increasing CO(2) pressure from ambient to 1000 psi causes the films to swell 13%, and free-volume theory explains the enhanced mass transport properties of the films. The origin of increases in electron-transfer kinetics is considered. Plots of log(k(EX)) versus log(D(PHYS)) and log(k(EX)) versus log(D(ClO4)) are both linear. This suggests that electron self-exchange is controlled by factors that also affect log(D(PHYS)) or log(D(ClO4)). One explanation is based on plasticization of the oligoether side-chain motions by CO(2) that affect ether dipole repolarization and Co complex diffusion rates. A second explanation for the changes in k(EX) is based on control of electron transfer by relaxation of counterions neighbor to the Co complexes, which is measured by D(ClO4). Both explanations represent a kind of solvent dynamics control of k(EX).

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