Quantifying Micromolar Crystallinity in Pharmaceutical Materials Utilizing 19F Solid-State NMR.

Quantifying low-level components in solid-state analysis presents a significant challenge for most thermal, diffractometric, vibrational, and spectroscopic techniques. In pharmaceutical analysis, identifying and quantifying the physical form of the drug substance in solid dosages is a critical task to ensure the quality of drug products. For example, recrystallization of active pharmaceutical ingredients in amorphous solid dispersions can compromise the stability and bioavailability of drug products. Herein, we have developed and demonstrated fluorine-19 solid-state nuclear magnetic resonance (19F ssNMR) methods and pushed the boundary to quantify minor crystalline contents in amorphous pharmaceuticals. Calibration curves suggest that 19F direct polarization and 1H-19F cross-polarization ssNMR can readily quantify 0.1% w/w crystalline compound I, a commercial fluorinated drug molecule developed by Merck & Co., Inc., Rahway, NJ, U.S.A., in its amorphous formulation. 1H-19F multiple cross-polarization (MultiCP) has been implemented, for the first time, and compared with conventional cross-polarization methods. Most importantly, a relaxation-filtered 19F ssNMR method was utilized to unambiguously identify and quantify as low as 0.04% w/w crystalline components, that is, 6 µmol in a 100 mg tablet at 25% drug loading, by suppressing the signal from the amorphous counterpart. Such a low level of detection offers high confidence and sensitivity to quantify trace amounts of phase change in pharmaceutical amorphous materials in the solid state, which can facilitate formulation development as well as quality control.

Three-Dimensional NMR Spectroscopy of Fluorinated Pharmaceutical Solids under Ultrafast Magic Angle Spinning.

High-resolution solid-state analysis of multicomponent molecular systems, e.g., pharmaceutical formulations, is a great challenge. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy plays a critical role in the characterization of solid dosage forms due to its capabilities of chemical identification, quantification, and structural elucidation at a molecular level. However, the low NMR sensitivity as well as the high spectral complexity and low drug loading of multicomponent products hinder an in-depth investigation of the active pharmaceutical ingredient (API) at the natural isotopic abundance. Herein, we developed two new three-dimensional (3D) ssNMR methods, including 1H-19F-1H and 19F-19F-1H correlations and successfully applied them to characterize a fluorinated drug molecule, aprepitant, and its commercial nanoparticulate formulation EMEND (Merck & Co, Inc., Kenilworth, NJ, USA). These 1H-detection methods utilize the significantly enhanced sensitivity and resolution of 1H and 19F afforded by 60 kHz ultrafast magic angle spinning (MAS) and enable the analysis of milligram samples. The 3D techniques simultaneously provide homonuclear 1H-1H and 19F-19F, and heteronuclear 1H-19F correlations of the crystalline aprepitant without interferences from other pharmaceutical components in the drug product. Moreover, our results demonstrate that 19F is a highly sensitive spin for probing molecular details of fluorinated drug substances in solid formulations, due to its high isotopic abundance, large gyromagnetic ratio, and absence of signal interference from pharmaceutical excipients, as well as for characterizing structural properties of a broad range of fluorine-containing materials.

Combination of Colloidal Silicon Dioxide with Spray-Dried Solid Dispersion to Facilitate Discharge from an Agitated Dryer.

A feasibility evaluation of the addition of fumed silica (SiO2) into an agitated dryer to aid spray-dried solid dispersion intermediate (SDSDi) flow during secondary drying and discharge is described. The quantity of SiO2 to enhance the flow character of SDSDi was assessed by measuring particle size distribution, bulk density, and flow-through-an-orifice. Results indicate that the addition of the SiO2 did not alter the drying kinetics and did not impact the bulk particle size distribution of the SDSDi. While bulk density of SDSDi increased with the addition of SiO2, the flow, and thus the recovery of the SDSDi-SiO2 batch from the secondary dryer, was significantly higher than that for the intermediate alone. Imaging indicated uniform distribution of SiO2 in the bulk powder and coating on intermediate particles. Premixing and co-sieving of the SiO2 with a portion of pre-dry SDSDi promotes the uniform distribution of SiO2 within the bulk powder bed.

Evaluation and Management of Rectal Prolapse.

Rectal prolapse, or procidentia, is a common pathology for the practicing colorectal surgeon. It is associated with lifestyle limiting symptoms for the patient and frequently co-exists with other types of pelvic prolapse making multidisciplinary management key. It is primarily managed with surgical reconstruction. A number of operative approaches exist, and the optimum procedure is varied dependent upon patient characteristics.

Probing the effect of drug loading and humidity on the mechanical properties of solid dispersions with nanoindentation: antiplasticization of a polymer by a drug molecule.

Amorphous solid dispersions of clotrimazole in the polymer Kollidon VA64 were prepared as films in concentrations from 0% to 100% in 10% by weight increments. Nanoindentation was performed on each film at 18% and 49% relative humidity to assess the effect of drug loading and humidity on the mechanical properties of the solid dispersions. Although the addition of clotrimazole to the polymer reduces the glass transition temperature of the system as measured by differential scanning calorimetry, the hardness, reduced elastic modulus, and storage modulus were found to increase to values greater than those of either pure component up to drug loadings of approximately 60% by weight. Further addition of clotrimazole to the system resulted in decreased hardness and moduli with increased drug load. Dynamic vapor sorption of the dispersions shows that the hygroscopicity of the system is reduced as clotrimazole is added to the polymer.

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors.

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.

Industry White Paper: Contemporary Opportunities and Challenges in Characterizing Crystallinity in Amorphous Solid Dispersions.

Members of the IQ Consortium ″Working Group on Characterization on Amorphous Solid Dispersions″ shares here a perspective on the analytical challenges, and limitations of detecting low levels of crystalline drug substance in amorphous solid dispersions (ASDs) and associated drug products. These companies aim to employ highly sensitive commercially available analytical technologies to guide development, support control strategies, and enable registration of quality products. We hope to promote consistency in development and registration approaches and guide the industry in development of "characterization best practices" in the interest of providing high quality products for patients. The first half of this perspective highlights the unique challenges of analytical methodologies to monitor crystalline drug substance in ASDs and their associated drug products. Challenges around use of limit tests, analyte spiking experiments, and method robustness are also underscored. The latter half describes the merits and limitations of the diverse analytical "toolbox" (such as XRPD, NIR and DSC), which can be readily applied during development and, in some cases, considered for potential application and validation in the commercial QC setting when necessary.

Quantifying Pharmaceutical Formulations from Proton Detected Solid-State NMR under Ultrafast Magic Angle Spinning.

Probing form conversions of active pharmaceutical ingredients in solid dosages is critical for understanding the physicochemical stability of drug substances in formulations. The multicomponent and low drug loading nature of drug products often results in challenges to quantify the phase stability, at a low detection limit and with the chemical resolution that differentiate drug molecules and excipients, for routine laboratory techniques. Recent advancement of ultrafast magic angle spinning (UF-MAS) enables proton-detected solid-state nuclear magnetic resonance (ssNMR) techniques to characterize pharmaceutical materials with enhanced resolution and sensitivity. This study demonstrates one of the first documented cases implementing 60 kHz UF-MAS techniques to quantify the minor content of pioglitazone free base (PIO-FB) in a binary system with its hydrochloride salt (PIO-HCl) and a multicomponent formulation with typical excipients. One-dimensional 1H methods can unambiguously differentiate the two forms and exhibit a limit of detection at 1.77% (w/w). Moreover, we extended it to a two-dimensional 1H-1H correlation for minimizing peak overlap and successfully quantifying approximately 2.0% (w/w) PIO-FB in a multicomponent formulation. These results have demonstrated that 1H ssNMR as a novel method to quantify solid dosages at a higher resolution and faster acquisition than conventional 13C techniques.

Copper-catalyzed synthesis of enantioenriched tetraarylethanes.

Herein we report the asymmetric synthesis of 1,2-dipyridyl-1,2-diarylethanes via an unusual Cu(I)-catalyzed dimerization reaction. Subjection of a variety of enantioenriched substituted 2-pyridyl alcohols to a one-pot protocol generates the desired products in good yields and diastereoselectivities and with ee's up to >99%.

Locoregional recurrence and survival after curative resection of adenocarcinoma of the colon.

BACKGROUND: There is wide variability in reported locoregional recurrence rates after curative resection of adenocarcinoma of the intraperitoneal colon, and there is no universally accepted surgical technique regarding length of the resected specimen or extent of lymphadenectomy. The aim of this study was to determine the disease-free survival, locoregional failure, and perioperative morbidity of patients undergoing curative resection of colon adenocarcinoma. STUDY DESIGN: The records of 316 consecutive patients undergoing curative resection for primary adenocarcinoma of the intraperitoneal colon between 1990 and 1995 were reviewed. Locoregional recurrence was defined as disease at the anastomosis or in the adjacent mesentery, peritoneum, retroperitoneum, or carcinomatosis. The product-limit method (Kaplan-Meier) was used to analyze survival and tumor recurrence. RESULTS: The study population comprised 167 men and 149 women, mean age 70+/-12 years (range 22 to 95 years). Median followup was 63+/-25 months. Five-year disease-free survival was 84% overall. Disease-free survival paralleled tumor stage: stage I, 99% (n = 73); stage II, 87% (n = 151); stage III, 72% (n = 92). The predominant pattern of tumor recurrence was distant failure only. Overall locoregional recurrence (locoregional and locoregional plus distant) at 5 years was 4%. Locoregional recurrence paralleled tumor stage: stage I, 0%; stage II, 2%; stage III, 10%. Of the 12 patients who suffered locoregional recurrence, 9 (75%) had T4 primary tumors, N2 nodal disease, or both. Major and minor complications occurred in 93 patients (29%) including: anastomotic leak or intraabdominal abscess (n = 4, 1%); hemorrhage (n = 8, 3%); cardiac complications (n= 17, 5%); pulmonary embolism (n=4, 10%); death (n=2, 1%). Multivariate analysis (Cox proportional hazards) revealed that the only independent predictor of disease-free survival and locoregional control was tumor stage. CONCLUSION: Longterm survival and locoregional control can be achieved for patients with colon cancer, with low morbidity. In the absence of adjacent organ invasion and N2 nodal disease, locoregional recurrence should be a rare event. Just as for rectal cancer, the technical aspects of colectomy for colon cancer deserve renewed attention.

A cascade approach to cyclic aminonitrones: reaction discovery, mechanism, and scope.

Treatment of omega-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful substrates for further selective elaboration.

Langmuir monolayers of a photoisomerizable macrocycle surfactant.

An amphiphilic photoisomerizable macrocycle has been prepared that forms stable Langmuir monolayers at the air-water interface. The hydrophilic core of the molecule switches between closed and open isomers upon irradiation by the appropriate wavelengths of light. Isotherm measurements, Brewster angle microscope images, and atomic force micrographs (of transferred Langmuir-Blodgett films) suggest a phase transition between a face-on to a tilted edge-on molecular orientation as a function of surface concentration. In the face-on phase, in situ photoisomerization results in a reversible increase in surface pressure due to greater molecular crowding in the open configuration.

Dizinc alkoxides and amides supported by binucleating bis(amidoamine) ligands.

Several new dizinc complexes that are supported by dianionic bis(amidoamine) ligands are reported. Reaction of N,N'-bis(2-dimethylaminoethyl)dibenzofuran-4,6-diamine ((Me)LH(2)) with 2 equiv of EtZn(O(i)Pr) forms the dizinc bis(alkoxide) (Me)LZn2(O(i)Pr)2 (1), which was isolated in 76% yield. Similarly, (Me)LH2 reacts cleanly with EtZn(OPh) and EtZn(OCHPh2) to form (Me)LZn2(OPh)2 (2) and (Me)LZn2(OCHPh2)2 (3), respectively. The solid-state structures of 1 and 2 feature puckered [Zn2(mu-OR)2]2+ cores, with short intermetal separations (2.81-2.88 Angstroms). Overall, the molecules have approximate (noncrystallographic) C2v symmetry. The use of the more-hindered (i)Pr-substituted ligand N,N'-bis(2-diisopropylaminoethyl)dibenzofuran-4,6-diamine (i(Pr)LH2) to prepare zinc alkoxides gave similar results. Thus, reaction of i(Pr)LH2 with 2 equiv of EtZn(OPh), EtZn(OMe), EtZn(OCHPh2), and EtZn(OCH2Ph) forms i(Pr)LZn2(OPh)2 (4), i(Pr)LZn2(OMe)2 (5), i(Pr)LZn2(OCHPh2)2 (6), and i(Pr)LZn2(OCH2Ph)2 (7), respectively (isolated yields 48-63%). At 70 degrees C, C6D6 solutions of 6 undergo beta-hydride transfer with 2 equiv of benzaldehyde to form 7 and benzophenone in quantitative yield (according to 1H NMR spectroscopy). Benzene solutions of 1 react with 1 equiv of trimethylsilyl trifluoromethanesulfonate (Me3SiOTf) to form (Me)LZn2(O(i)Pr)(OTf) (8) in 70% isolated yield. In the solid state, 8 features a bridging alkoxide donor as well as a 1,3-bridging triflate group. The previously reported dinuclear organozinc species (Me)LZn2Ph2 (9) reacts with 1 equiv of tert-butylamine to form the protonolysis product (Me)LZn2(Ph)(NH(t)Bu) (10) in 66% isolated yield. The solid-state structure of 10 (two independent molecules) reveals a somewhat asymmetric [Zn2(mu-Ph)(mu-NH(t)Bu)]2+ core with short Zn-Zn separations [2.6761(5) and 2.6518(5) Angstroms]. In CD2Cl2 solution, the Ph bridge of 10 undergoes rapid reversible cleavage. Cleavage of this bridging interaction followed by rotation about the Zn-Ph bond and re-formation of the bridging interaction results in exchange of the inequivalent ortho (and meta) protons of the phenyl ligand. Variable-temperature 1H NMR spectroscopic data indicate that this exchange occurs with DeltaG = 12.7(1) kcal.mol(-1) (-27 degrees C). At 75 degrees C, toluene solutions of (Me)LH2 react with 2 equiv of EtZnNH(t)Bu to form the dizinc bis(amido) product (Me)LZn2(NH(t)Bu)2 (11) in 46% isolated yield. The solid-state structure of 11 (two independent molecules) features a puckered and fairly symmetric [Zn2(mu-NH(t)Bu)2]2+ core with short intermetal separations [2.775(1), 2.760(1) Angstroms].

Hydrogen oxidation and production using nickel-based molecular catalysts with positioned proton relays.

Highly efficient electrocatalysts for both hydrogen evolution and hydrogen oxidation have been designed, synthesized, and characterized. The catalysts in their resting states are air-stable, mononuclear nickel(II) complexes containing cyclic diphosphine ligands with nitrogen bases incorporated into the ligand backbone. X-ray diffraction studies have established that the cation of [Ni(P(Ph)(2)N(Ph)(2))(2)(CH(3)CN)](BF(4))(2), 6a, (where P(Ph)(2)N(Ph)(2) is 1,3,5,7-tetraphenyl-1,5-diaza-3,7-diphosphacyclooctane) is a trigonal bipyramid with bonds to four phosphorus atoms of the two bidentate diphosphine ligands and the nitrogen atom of an acetonitrile molecule. Two of the six-membered rings formed by the diphosphine ligands and Ni have boat conformations with an average Ni- - -N distance to the two pendant bases of 3.4 A. The cation of [Ni(P(Cy)(2)N(Bz)(2))(2)](BF(4))(2), 6b, (where Cy = cyclohexyl and Bz = benzyl) is a distorted square planar complex. For 6b, all four six-membered rings formed upon coordination of the diphosphine ligands to the metal are in the boat form. In this case, the average Ni- - -N distance to the pendant base is 3.3 A. Complex 6a is an electrocatalyst for hydrogen production in acidic acetonitrile solutions, and compound 6b is an electrocatalyst for hydrogen oxidation in basic acetonitrile solutions. It is demonstrated that the high catalytic rates observed with these complexes are a result of the positioning of the nitrogen base so that it plays an important role in the formation and cleavage of the H-H bond.

Dititanium complexes of preorganized binucleating bis(amidinates).

Four different dianionic bis(amidinate) ligands ((iPr)L(DBF)(2)(-), (tBu,Et)L(DBF)(2)(-), (iPr)L(Xan)(2)(-), (tBu,Et)L(Xan)(2)(-)) featuring rigid dibenzofuran (DBF) and 9,9-dimethylxanthene (Xan) backbones have been used to prepare several new dititanium complexes. Reaction of the free-base bis(amidines) (LH(2)) with 2 equiv of Ti(NMe(2))(4) forms the hexaamido derivatives (iPr)L(DBF)Ti(2)(NMe(2))(6) (1), (tBu,Et)L(DBF)Ti(2)(NMe(2))(6) (2), (iPr)L(Xan)Ti(2)(NMe(2))(6) (3), and (tBu,Et)L(Xan)Ti(2)(NMe(2))(6) (4) in good yields. Compound 4, which features an unsymmetrically substituted bis(amidinate) ligand, was isolated as an 8:1 mixture of rotational diastereomers with C(2) and C(s)() symmetry, respectively. The two diastereomers interconvert upon heating, and at equilibrium the C(2) isomer is preferred thermodynamically by 0.2 kcal/mol. Compound 3 reacts with excess Me(3)SiCl in toluene to form the mixed amido-chloride derivative (iPr)L(Xan)Ti(2)(NMe(2))(2)Cl(4) (5) in low-moderate yield. Alternatively, 5 is also prepared by reaction of (iPr)L(Xan)H(2) with 2 equiv of Ti(NMe(2))(2)Cl(2) in good yield. Compound 3 reacts with CO(2) to form the red carbamate derivative (iPr)L(Xan)Ti(2)(NMe(2))(4)(O(2)CNMe(2))(2) (6) in moderate yield. Infrared data for 6 indicates bidentate coordination of the carbamate ligands. Metathesis reaction of (iPr)L(Xan)Li(2) with 2 equiv of CpTiCl(3) affords (iPr)L(Xan)Ti(2)Cp(2)Cl(4) (7) in moderate yield. Reduction of 7 with 1% Na amalgam in toluene solution affords the paramagnetic dititanium(III) complex (iPr)L(Xan)Ti(2)Cp(2)Cl(2) (8) in good yield. Structural studies reveal that 8 features two bridging chloride ligands. Reaction of the free-base bis(amidines) with 2 equiv of CpTiMe(3) forms the red sigma-alkyl derivatives (iPr)L(DBF)Ti(2)Cp(2)Me(4) (9), (tBu,Et)L(DBF)Ti(2)Cp(2)Me(4) (10), and (iPr)L(Xan)Ti(2)Cp(2)Me(4) (11) in good yields. Structural data are presented for compounds 4, 5, 8, and 9.