Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product.

The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical model to guide both formulation and process development of a roller-compacted drug product. True density, compression profiling, and frictional properties of the pre-blend powders are used as inputs for the predictive roller compaction model, while flow properties, particle size distribution, and assay uniformity of roller compaction granules are used to select formulation composition and ribbon solid fraction. Using less than 10 g of a model drug compound for material profiling, roller compacted blend in capsule formulations with appropriate excipient ratios were developed at both 1.4% and 14.4% drug loadings. Subsequently, scale-up batches were successfully manufactured based on the roller compaction process parameters obtained from predictive modeling. The measured solid fractions of roller compaction ribbon samples from the scale-up batches were in good agreement with the target solid fraction of the modeling. This approach demonstrated considerable advantages through savings in both materials and number of batches in the development of a roller-compacted drug product, which is of particular value at early development stages when drug substance is often limited and timelines are aggressive.

Understanding the mechanisms of cobalt-catalyzed hydrogenation and dehydrogenation reactions.

Cobalt(II) alkyl complexes of aliphatic PNP pincer ligands have been synthesized and characterized. The cationic cobalt(II) alkyl complex [(PNHP(Cy))Co(CH2SiMe3)]BAr(F)4 (4) (PNHP(Cy) = bis[(2-dicyclohexylphosphino)ethyl]amine) is an active precatalyst for the hydrogenation of olefins and ketones and the acceptorless dehydrogenation of alcohols. To elucidate the possible involvement of the N-H group on the pincer ligand in the catalysis via a metal-ligand cooperative interaction, the reactivities of 4 and [(PNMeP(Cy))Co(CH2SiMe3)]BAr(F)4 (7) were compared. Complex 7 was found to be an active precatalyst for the hydrogenation of olefins. In contrast, no catalytic activity was observed using 7 as a precatalyst for the hydrogenation of acetophenone under mild conditions. For the acceptorless dehydrogenation of 1-phenylethanol, complex 7 displayed similar activity to complex 4, affording acetophenone in high yield. When the acceptorless dehydrogenation of 1-phenylethanol with precatalyst 4 was monitored by NMR spectroscopy, the formation of the cobalt(III) acetylphenyl hydride complex [(PNHP(Cy))Co(III)(κ(2)-O,C-C6H4C(O)CH3)(H)]BAr(F)4 (13) was detected. Isolated complex 13 was found to be an effective catalyst for the acceptorless dehydrogenation of alcohols, implicating 13 as a catalyst resting state during the alcohol dehydrogenation reaction. Complex 13 catalyzed the hydrogenation of styrene but showed no catalytic activity for the room temperature hydrogenation of acetophenone. These results support the involvement of metal-ligand cooperativity in the room temperature hydrogenation of ketones but not the hydrogenation of olefins or the acceptorless dehydrogenation of alcohols. Mechanisms consistent with these observations are presented for the cobalt-catalyzed hydrogenation of olefins and ketones and the acceptorless dehydrogenation of alcohols.

Tetrakis(imino)pyracene complexes exhibiting multielectron redox processes.

The differences in redox behavior of the monofunctional bis(imino)acenaphthene (BIAN) and bifunctional tetrakis(imino)pyracene (TIP) ligands have been explored by treatment of the latter with PI(3), TeI(4), or BI(3). These reactions result in the formation of products involving the transfer of three or four electrons. Accompanying DFT calculations reveal that in each case the extent of electron transfer from each p-block element into the TIP ligand is dependent upon the element-TIP bonding interactions.

An ionic liquid-mediated route to cerium(III) bromide solvates.

A novel synthetic route to a series of cerium bromide solvates is reported. The combination of bulk cerium bromide and the ionic liquid (IL) 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide results in a precursor paste that enhances the solubility of the cerium(III)bromide moiety in a number of donor solvents. Crystallization from these solvents has resulted in the isolation and characterization of CeBr(3)(THF)(4) (2), CeBr(3)(2-Me-THF)(4) (3), and CeBr(3)(MeCN)(5)·MeCN (4). Additionally, 2 is shown to be an efficient precursor for the new species CeBr(3)(py)(4) (5) and CeBr(3)(bipy)(py)(3) (6).

Synthesis, crystal structure, and photoluminescence of homodinuclear lanthanide 4-(dibenzylamino)benzoate complexes.

Three new binuclear lanthanide complexes of general formula [Ln(2)(L)(6)(H(2)O)(4)] (Ln = Tb (1), Eu (2), and Gd (3)) supported by the novel aromatic carboxylate ligand 4-(dibenzylamino)benzoic acid (HL) have been synthesized. Complexes 1 and 2 were structurally characterized by single-crystal X-ray diffraction. Both 1 and 2 crystallize in the triclinic space group P(1), and their molecular structures consist of homodinuclear species that are bridged by two oxygen atoms from two carboxylate ligands via different coordination modes. The discrete bridged dimer of 1 is centrosymmetric and features 8-coordinate terbium atoms, each of which adopts a distorted square-antiprismatic geometry. Both coordination spheres comprise two eta(2)-chelating benzoates, two mu-eta(1):eta(1)-carboxylate interactions from the bridging benzoates, and two water molecules. By contrast, in complex 2, the Eu(3+) ion coordination environment is best described as a distorted tricapped-trigonal prism, each europium ion being coordinated to three eta(2)-chelating benzoate ligands and two water molecules. One of the eta(2)-carboxylate ligands is involved in a further interaction with an adjacent metal, thus rendering the overall binding mode bridging tridentate, mu-eta(2):eta(1). Scrutiny of the packing diagrams for 1 and 2 revealed the existence of a one-dimensional molecular array that is held together by intermolecular hydrogen-bonding interactions. The Tb(3+) complex 1 exhibits high green luminescence efficiency in the solid state with a quantum yield of 82%. On the other hand, poor luminescence efficiency has been noted for the Eu(3+)-4-(dibenzylamino)benzoate complex.

Synthesis and reactivity of tetrakis(imino)pyracene (TIP) ligands; bifunctional analogues of the BIAN ligand class.

The first two examples of a new class of bifunctional BIAN-type ligand have been prepared, and the reactions of one such ligand with CuBr(2) and BCl(3) have been explored.

Structure Determination and Characterization of a Family of Primary Alcohol Solvates.

We report the preparation and structural characterization of a family of primary alcohol solvates of a small-molecule hydrochloride salt. The structures of the solvates are probed by powder and single crystal X-ray diffraction, and the compounds were additionally characterized by polarized light microscopy, thermogravimetric analysis, and dynamic scanning calorimetry. A comparison of the lattices of each compound is also provided. The results demonstrate the existence of a common solvating channel and highlight the importance of understanding the form landscape early in the development process.

Metallopolymer formation using the (1R,2R)-N,N'-bis(pyridylmethylene)cyclohexane-1,2-diamine (BPID) ligand class.

The BPID ligand class is exploited as a scaffold for polymeric materials. Reaction of excess K or KH with the 2-pyridyl-BPID ligand results in the formation of a novel THF-bridged 1-D metallopolymer while the analogous reaction with the 4-pyridyl derivative results in a pyridyl-bridged 2-D metallopolymer.

Synthesis, crystal structure and photophysical properties of lanthanide coordination polymers of 4-[4-(9H-carbazol-9-yl)butoxy]benzoate: the effect of bidentate nitrogen donors on luminescence.

A new aromatic carboxylate ligand, 4-[4-(9H-carbazol-9-yl)butoxy]benzoic acid (HL), has been synthesized by the replacement of the hydroxyl hydrogen of 4-hydroxy benzoic acid with a 9-butyl-9H-carbazole moiety. The anion derived from HL has been used for the support of a series of lanthanide coordination compounds [Ln = Eu (1), Gd (2) and Tb (3)]. The new lanthanide complexes have been characterized by a variety of spectroscopic techniques. Complex 3 was structurally authenticated by single-crystal X-ray diffraction and found to exist as a solvent-free 1D coordination polymer with the formula [Tb(L)(3)](n). The structural data reveal that the terbium atoms in compound 3 reside in an octahedral ligand environment that is somewhat unusual for a lanthanide. It is interesting to note that each carboxylate group exhibits only a bridging-bidentate mode, with a complete lack of more complex connectivities that are commonly observed for extended lanthanide-containing solid-state structures. Examination of the packing diagram for revealed the existence of two-dimensional molecular arrays held together by means of CH-π interactions. Aromatic carboxylates of the lanthanides are known to exhibit highly efficient luminescence, thus offering the promise of applicability as optical devices. However, due to difficulties that arise on account of their polymeric nature, their practical application is somewhat limited. Accordingly, synthetic routes to discrete molecular species are highly desirable. For this purpose, a series of ternary lanthanide complexes was designed, synthesized and characterized, namely [Eu(L)(3)(phen)] (4), [Eu(L)(3)(tmphen)] (5), [Tb(L)(3)(phen)] (6) and [Tb(L)(3)(tmphen)] (7) (phen = 1,10-phenanthroline and tmphen = 3,4,7,8-tetramethyl-1,10-phenanthroline). The photophysical properties of the foregoing complexes in the solid state at room temperature have been investigated. The quantum yields of the ternary complexes 4 (9.65%), 5 (21.00%), 6 (14.07%) and 7 (32.42%), were found to be significantly enhanced in the presence of bidentate nitrogen donors when compared with those of the corresponding binary compounds 1 (0.11%) and 3 (1.45%). Presumably this is due to effective energy transfer from the ancillary ligands.

Ionic liquid mediated routes to polydentate oxygen-donor adducts of cerium(III) bromide.

The preparation of a series of CeBr(3) molecular adducts supported by the polydentate oxygen donor ligands diglyme, dimethoxyethane and tetraglyme is reported. The new complexes are characterized structurally by X-ray diffraction and optically by photoluminescence studies.

Synthesis and coordination compounds of a bis(imino)acenaphthene (BIAN)-supported N-heterocyclic carbene.

The bis(imino)acenaphthene-supported N-heterocyclic carbene IPr(BIAN) has been prepared by deprotonation of the precursor imidazolium chloride. Treatment of IPr(BIAN) imidazolium chloride with Ag(2)O afforded the silver complex [IPr(BIAN)]AgCl which can be converted into the corresponding gold complex [IPr(BIAN)]AuCl by reaction with (tht)AuCl (tht = tetrahydrothiophene). The iridium complex [IPr(BIAN)]Ir(COD)Cl was prepared by reaction of the imidazolium chloride with KO(t)Bu and [Ir(COD)Cl](2) and subsequently converted to the carbonyl complex [IPr(BIAN)]Ir(CO)(2)Cl by exposure to an atmosphere of CO. All new compounds were characterized by single-crystal X-ray diffraction, multinuclear NMR, MS and HRMS data.

Synthesis and crystal structures of lanthanide 4-benzyloxy benzoates: influence of electron-withdrawing and electron-donating groups on luminescent properties.

Three new 4-benzyloxy benzoic acid derivatives [4-benzyloxy benzoic acid = HL1; 3-methoxy-4-benzyloxy benzoic acid = HL2; 3-nitro-4-benzyloxy benzoic acid = HL3] have been employed as ligands for the support of six lanthanide coordination compounds [Tb(3+) = 1-3; Eu(3+) = 4-6] with the aim of testing the influence of electron releasing (-OMe) or electron withdrawing (-NO(2)) substituents on the photophysical properties. The new complexes have been characterized by a variety of spectroscopic techniques and two of the Tb(3+) complexes [1 and 2] have been structurally authenticated by single-crystal X-ray diffraction. Compounds 1 and 2 crystallize in the monoclinic space group P21/n. The molecular structure of 1 consists of homodinuclear species that are bridged by two oxygen atoms from two benzoate ligands [corrected].In the case of 1, the carboxylate ligands coordinate to the central Tb(3+) ion in bidentate chelating and bidentate bridging modes. By contrast, the X-ray structure of 2 reveals that each Tb3+ ion is connected to two neighboring ions by four methoxy substituted benzoates via the carboxylate groups in bridging mode to form an infinite one-dimensional coordination polymer [corrected]. Examination of the packing diagrams for 1 and 2 revealed the presence of a one-dimensional molecular array that is held together by intermolecular hydrogen-bonding interactions. The incorporation of an electron-releasing substituent on position 3 of 4-benzyloxy benzoic acid increases the electron density of the ligand and consequently improves the photoluminescence of the Tb(3+) complexes. On the other hand, the presence of an electron-withdrawing group at this position dramatically decreases the overall sensitization efficiency of the Tb(3+)-centered luminescence due to dissipation of the excitation energy by means of a pi*-n transition of the NO(2) substituent along with the participation of the ILCT bands. The weaker photoluminescence of the Eu(3+) complexes is attributable to the poor match of the triplet energy levels of the 4-benzyloxy benzoic acid derivatives with that of the emitting level of the central metal ion.

Facile syntheses of thiophene-substituted 1,4-diazabutadiene (alpha-diimine) ligands and their conversion to phosphenium triiodide salts.

Four novel N-aryl-2-thienyl substituted 1,4-diazabutadiene (alpha-diimine) ligands 5-8 have been prepared by cyanide ion-catalyzed intermolecular coupling of the appropriate aromatic aldimines. A ligand featuring a phenyl spacer moiety between a thiophene carbon atom and each imino nitrogen atom (12) has been prepared by a similar synthetic route. Ligands 5-8 and 12 were characterized on the basis of 1H and 13C NMR, IR and MS-CI spectroscopy. Upon treatment with PI3 in CH2Cl2 solution, ligands 5-8 undergo redox reactions to furnish the triiodide salts of the corresponding phosphenium cations 13-16 which were characterized by 1H, 13C and 31P NMR, and MS-CI spectroscopy. The phosphenium triiodide salt 15, and ligands 5-7 and 12 were also structurally authenticated.

Boron di- and tri-cations.

Previous work on boron di- and tri-cations is reviewed. The structural chemistry of representative examples of these classes of compound has been probed by determination of the single-crystal X-ray structures of [(4-Mepy)4B]Br3 and [py3BH]Br2. The electronic structures of the polycations [(py)3BH]2+, [(py)3BBr]2+, [(4-Mepy)3BH]2+, [(4-Mepy)4B]3+, [(Me3P)3BH]2+ and [(Me3P)4B]3+ have been examined by DFT methods. The atomic charges on these cations were evaluated by Mulliken, natural population analysis (NPA), Hirschfeld and Voronoi deformation density (VDD) methods.