Relationship between diffusivity of water molecules inside hydrating tablets and their drug release behavior elucidated by magnetic resonance imaging

We reported previously that sustained release matrix tablets showed zero-order drug release without being affected by pH change. To understand drug release mechanisms more fully, we monitored the swelling and erosion of hydrating tablets using magnetic resonance imaging (MRI). Three different types of tablets comprised of polyion complex-forming materials and a hydroxypropyl methylcellulose (HPMC) were used. Proton density- and diffusion-weighted images of the hydrating tablets were acquired at intervals. Furthermore, apparent self-diffusion coefficient maps were generated from diffusion-weighted imaging to evaluate the state of hydrating tablets. Our findings indicated that water penetration into polyion complex tablets was faster than that into HPMC matrix tablets. In polyion complex tablets, water molecules were dispersed homogeneously and their diffusivity was relatively high, whereas in HPMC matrix tablets, water molecule movement was tightly restricted within the gel. An optimal tablet formulation determined in a previous study had water molecule penetration and diffusivity properties that appeared intermediate to those of polyion complex and HPMC matrix tablets; water molecules were capable of penetrating throughout the tablets and relatively high diffusivity was similar to that in the polyion complex tablet, whereas like the HPMC matrix tablet, it was well swollen. This study succeeded in characterizing the tablet hydration process. MRI provides profound insight into the state of water molecules in hydrating tablets; thus, it is a useful tool for understanding drug release mechanisms at a molecular level.     

Novel method for constructing a large-scale design space in lubrication process by using bayesian estimation based on the reliability of a scale-up rule

A reliable large-scale design space was constructed by integrating the reliability of a scale-up rule into the Bayesian estimation without enforcing a large-scale design of experiments (DoE). A small-scale DoE was conducted using various Froude numbers (X(1)) and blending times (X(2)) in the lubricant blending process for theophylline tablets. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y(1)), tablet hardness (Y(2)), and dissolution rate (Y(3)) on a small scale were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. A constant Froude number was applied as a scale-up rule. Experiments were conducted at four different small scales with the same Froude number and blending time in order to determine the discrepancies in the response variables between the scales so as to indicate the reliability of the scale-up rule. Three experiments under an optimal condition and two experiments under other conditions were performed on a large scale. The response surfaces on the small scale were corrected to those on the large scale by Bayesian estimation using the large-scale results and the reliability of the scale-up rule. Large-scale experiments performed under three additional sets of conditions showed that the corrected design space was more reliable than the small-scale design space even when there was some discrepancy in the pharmaceutical quality between the manufacturing scales. This approach is useful for setting up a design space in pharmaceutical development when a DoE cannot be performed at a commercial large manufacturing scale.     

A modified Ortega method to evaluate the activation energies of solid state reactions

The application of the average linear integral isoconversional method developed by Ortega for evaluating the activation energies of solid state reactions may be hindered by experimental noise and the uncertainties associated with selecting appropriate reaction segments. This paper suggests a procedure, called the modified Ortega method, which can avoid or minimize these hindrances. By applying the modified Ortega method to the kinetic analyses of both simulated and experimental data, a more consistent dependence of the activation energy on the extent of reaction conversion was found with those calculated from the modified Vyazovkin method and the Friedman method.     

Reactions of Sterically Protected 1-Halo- and 1-Pseudohalo-2-Phosphaethenyl-Lithiums

Abstract

Phosphorus analogs of alkylidenecarbenoid, Ar-P=C(X)Li, where X equals halogen or pseudohalogen atom, such as C1, Br, or SPh, have been generated by use of the 2,4,6-tri-t-butylphenyl group (abbreviated to Ar in the Scheme) as a protecting group for low coordinated organophosphorus compounds. The reaction with methyl iodide and with some aldehydes or ketones, at low temperature, gave the corresponding alkylation products^[l]. The reaction with copper salts gave 1,4-diphosphabutadiene (1) or 1,4-diphosphabutatriene (2), depending upon the substituent X^[2,3], as well as reaction conditions, such as reaction tenlperature and time, solvent, presence or absence of oxygen. Upon warming the phosphaethenyllithiun1s, thus generated, the chloro derivative of E-configuration gave a phosphaalkyne (3) via [1,2]-aromatic migration^[4], whereas the bromo derivative of Z-configuration gave a l-phospha-3,4-dihydronaphthalene derivative (4), that is a formal C-H insertion product of a phosphinidenecarbene intermediate^[5].     

Real-time quantification of Staphylococcusaureus in liquid medium using infrared thermography

We previously showed that infrared thermography (IRT) could be used to quantify viable Escherichiacoli, a representative gram-negative bacterium, in liquid growth media. Here, we evaluated the ability of IRT to enumerate a viable representative gram-positive organism, Staphylococcusaureus. We found that the energy content (EC) of the media was strongly positively correlated (r = 0.999) to measured viable counts of S.aureus ranging from 85 colony-forming units (CFU)/ml to ∼4 × 10⁸ CFU/ml. The EC of S.aureus was ∼2-fold higher than that of E.coli at comparable cell concentrations suggesting that IRT may be used to distinguish genera.     

Semiempirical Pm3 Quantum Mechanics Calculations of Carbohydrate Crystals

ABSTRACT

Miniature crystal models of six small carbohydrates were examined using the PM3 semiempirical quantum mechanics method. The minicrystal structures, consisting of 27 sugar residues, were optimized by the combined procedure of partial optimization and reconstruction of the model, while maintaining the original crystal symmetries. All of the minicrystals were successfully optimized without exhibiting a great increase in an energy at any reconstruction step. Some minicrystals showed a prolonged behavior of optimization cycles. A major source of structure change appeared to arise from hydroxyl group rotations wherein the largest movements mostly occurred in an early optimization stage. No significant deformations in geometry of either residues or hydrogen bonds were observed in the final minicrystal structures. The thermodynamic values calculated for the optimized minicrystals were in reasonably good agreement with the literature data. The present study indicated that the PM3 semiempirical method successfully predicted the basic features of intermolecular hydrogen bonding involved in a condensed system.     

Synthesis and radical polymerization of styrene‐based monomer having a five‐membered cyclic carbonate structure

A styrene‐based monomer having a five‐membered cyclic carbonate structure, 4‐vinylbenzyl 2,5‐dioxoran‐3‐ylmethyl ether (VBCE), was prepared by lithium bromide‐catalyzed addition of carbon dioxide to 4‐vinylbenxyl glycidyl ether (VBGE). Radical polymerization of the obtained VBCE was carried out using 2,2′‐azobisisobutyronitrile as an initiator. PolyVBCE with number‐averaged molecular weight higher than 13,800 was obtained by a solution polymerization in N,N‐dimethylformamide, N,N‐dimethylacetamide, dimethyl sulfoxide, and methyl ethyl ketone. The glass transition temperature and 5 wt % decomposition temperature of the polyVBCE were determined to be 52 and 305 °C by differential scanning calorimetry and thermal gravimetry analysis, respectively. It was confirmed that a polymer consisting of the same VBCE repeating unit can be also obtained via chemical modification of polyVBGE, that is, a lithium‐bromide‐catalyzed addition of carbon dioxide to a polyVBGE prepared from a radical polymerization of VBGE. Further copolymerization of VBCE with styrene gave the corresponding copolymer in a high yield. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Accurate position detection of targets in noise image

Targets at various positions in a noise image were detected by the optical matched filtering technique. In this case the thermoplastic optical recorder was used as a matched filter recorder. High accuracy of position detection was obtained, i.e. the position error was 2% or less.