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Nucleosides bearing a branched ribose have significant promise as therapeutic agents and biotechnological and biochemical tools. Thus, synthetic entry into a new class of these analogues, 2'-C-difluoromethylribonucleosides, is described.

The effect of position isomerism on the co-crystals formation and physicochemical properties was evaluated. Piracetam was used as the model compound. Six position isomers, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxybenzoic acid (DHBA), were used as the co-crystal formers. Co-crystals were prepared on a 1:1 molar ratio by crystallization from acetonitrile. The solid-state properties of co-crystals were characterized using X-ray powder diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR). All co-crystal formers formed co-crystal with piracetam except 2,6-DHBA. This failure was possibly due to steric hindrance of two bulk hydroxyl groups and preference of intra-molecular hydrogen bonding formation between hydroxyl group and carboxylic acid group. The XRD patterns of resulting co-crystal indicated that they are highly crystalline and different than parental compounds. Based on the single crystal data, P_23DHBA is orthorhombic while P_24DHBA, P_34DHBA, and P_35DHB belong to monoclinlic system. The hydrogen bonding network patterns of the co-crystals are also different. DSC data showed that the melting temperatures of resulting co-crystals are all lower than that of the starting materials. The melting point rank order of the co-crystals is: P_24DHBA > P_34DHBA > P_23DHBA > P_25DHBA > P_35DHBA. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:246–254, 2010 [ABSTRACT FROM AUTHOR]

The aim of this study was to relate the tableting performance assessed by an instrumented tableting machine to the mechanical properties measured by nanoindentation. Three different polymorphic forms of sulfathiazole were prepared by recrystallization, and the density and X-ray powder diffraction patterns were measured and compared with theoretical density and simulated powder patterns, respectively. Tablets were prepared using a series of applied pressures, and the results were subjected to energy analysis, three dimensional (3D) modeling, and the traditional Heckel analysis. With these approaches, form I was found to be consistently the most brittle material, but the subtle differences between forms II and III were only revealed by 3D modeling. The rank order of the crushing force was found to be I ≌ II < III. From nanoindentation, form III was found to be much harder than forms I and II, and III also had a much higher Young's modulus. The energy calculations of the nanoindentation curves showed that form III was distinct from forms I and II, which is consistent with the presence of slip planes that are only present in form III. However, in this system, there was little correspondence between the macroscopic and microscopic measurements, and thus particle–particle interactions may to be of paramount importance. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:2111–2124, 2007 [ABSTRACT FROM AUTHOR]

AbstractPurpose??To study the effect of processing conditions on the physical state of mannitol during various stages of the lyophilization cycle of a protein formulation.Materials and Methods??Mannitol and trehalose were used as the bulking agent and lyoprotectant, respectively. The physical state of mannitol during various stages of freeze-drying cycle, in the absence and presence of a model protein, was characterized using low temperature X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC).Results??Mannitol did not crystallize even when the solution for lyophilization was cooled to ?45?C at a slow cooling rate of 1?C/min. Annealing facilitated mannitol crystallization, and in the absence of the protein, a mixture of ?-mannitol and mannitol hemihydrate was obtained at both low (?18?C) and high (?8?C) annealing temperatures. However, in the presence of protein, the high annealing temperature promoted ?-mannitol crystallization and inhibited formation of mannitol hemihydrate, while the low annealing temperature facilitated the formation of mannitol hemihydrate. Interestingly, the hemihydrate in the frozen solution was retained in the final lyophile, even when the primary and secondary drying temperatures were as high as ?5 and 65?C, respectively.Conclusions??The presence of protein as well as the processing conditions (annealing temperature and time, primary and secondary drying temperatures) influenced the physical form of mannitol in the final lyophile. The protein promoted formation of ?-mannitol while inhibiting the formation of mannitol hemihydrate. Since the physical form of mannitol was greatly influenced by the presence of protein, it will be prudent to conduct the preliminary lyophilization cycle development studies in the presence of the protein. If mannitol hemihydrate is formed during annealing, its dehydration may require high secondary drying temperature. [ABSTRACT FROM AUTHOR]

Nucleosides bearing a branched ribose have significant promise as therapeutic agents and biotechnological and biochemical tools. Here we describe synthetic entry into a new subclass of these analogues, 2′-C-β-difiuoromethylribonucleosides. We constructed the glycosylating agent 4 in three steps from 1,3,5-tri-O-benzoyl-α-D-ribofuranose 1. The key steps included nucleophilic addition of difluoromethyl phenyl sulfone to 2-ketoribose 2 followed by mild and efficient reductive desulfonation. Ribofuranose 4 glycosylated bis(trimethylsilyl)uracil directly, giving difluoromethyluridine 7 efficiently after deprotection. Conversion of 4 to the corresponding ribofuranosyl bromide allowed efficient access to C, A, and G analogues. A related approach starting from methyl D-ribofuranose offered synthetic entry into the diastereomeric manifold, 2′-C-α-difiuoromethylarabino-α-pyrimidine. To incorporate 2′-C-β-difluoromethyluridine into an oligodeoxynucleotide we converted 7 to the bisphosphate and carried out successive ligation reactions using T4 RNA ligase and T4 DNA ligase. Analogous to natural RNA linkages, the resulting oligonucleotide undergoes hydroxide-catalyzed backbone scission at the difluoromethyluridine residue via internal transphosphorylation. [ABSTRACT FROM AUTHOR]

Purpose. The association of hydrophobic, cationic drugs with lung surfactant was determined to assess the pharmacokinetic implications on drug disposition and retention in the lung. Methods. The distribution coefficients, K, were determined at 25 and 37° in normal saline solution buffered at pH 7.4 for a series of structurally related, cationic drugs. Drugs were dispersed into lung surfactant, equilibrated, and then centrifuged to separate the aqueous phase from the surfactant pellet. Drug concentrations in the supernatant and pellet were determined following dilution using spectrophotometric assays. In addition, the apparent acid dissociation constant of quinacrine in the presence and absence of surfactant was determined by measuring the pH-dependent absorption spectra. The effect of stereochemistry on the distribution of drugs into surfactant was examined with (R)- and (S)-propranolol. Results. The mole fraction distribution coefficients for amitriptyline, promethazine, promazine, ethopropazine, imipramine, R-propranolol, and S-propranolol at 25°C were 6,560 ± 500, 28,400 ± 1,500, 12,100 ± 840, 5,480 ± 330, 4,490 ± 250, 8,680 ± 260, 8,190 ± 530, respectively. At 37°C, the distribution coefficients were generally smaller indicating a significant exothermic heat of transfer for these solutes from aqueous solution to the lung surfactant. The pKa of quinacrine was 7.43 ± 0.04 in aqueous solution and was shifted to 7.62 ± 0.06 in the presence of lung surfactant. From this shift, the double layer potential for quinacrine-lung surfactant was estimated to be -0.012 V assuming a dielectric constant equivalent to that of water. Conclusions. Cationic drugs have very favorable distributions from an aqueous solution to the lipid phase of lung surfactant. The transfer process generally has both a large entropic and enthalpic contribution. The latter thermodynamic aspect may be related to the charge interaction between the solute and the negatively charged surfactant. Finally, no significant effect of stereochemistry was evident with the distribution of (R)- and (S)-propranolol. KEY WORDS: lung surfactant; phenothiazines; pKa; partition coefficient; solubilization. [ABSTRACT FROM AUTHOR]

Examines the reactivity of Tetrahymena ribozyme with a DNA substrate containing a 5'-methylene phosphonate monoester. Single-atom substrate modification; Ribozyme cleavage with the methylene phosphonate monoester; Interaction of the ribozyme and 5'-oxygen in the transition state; Catalysis of phosphoryl transfer reactions.

Illustrates a strategy for the synthesis of 2'-C-branched ribonucleoside into oligonucleotides via solid-phase synthesis using phosphoramidite derivatives. Nucleic acids as antisense molecules or biochemical probes; Chemotherapeutic property of the 2'-C-branched ribonucleoside.