Cocrystal habit engineering to improve drug dissolution and alter derived powder properties

YesObjectives: Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM:4-ASA cocrystals with different habits in order to investigate the effect on dissolution, and the derived powder properties of flow and compaction. Methods: Cocrystals were prepared in a 1:1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray-drying (habit IV). Key findings: Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr’s compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. Conclusions: Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behavior.Science Foundation Ireland. Grant Number: SFI/12/RC/227

Rank Maximal Matchings -- Structure and Algorithms

Let G = (A U P, E) be a bipartite graph where A denotes a set of agents, P denotes a set of posts and ranks on the edges denote preferences of the agents over posts. A matching M in G is rank-maximal if it matches the maximum number of applicants to their top-rank post, subject to this, the maximum number of applicants to their second rank post and so on. In this paper, we develop a switching graph characterization of rank-maximal matchings, which is a useful tool that encodes all rank-maximal matchings in an instance. The characterization leads to simple and efficient algorithms for several interesting problems. In particular, we give an efficient algorithm to compute the set of rank-maximal pairs in an instance. We show that the problem of counting the number of rank-maximal matchings is #P-Complete and also give an FPRAS for the problem. Finally, we consider the problem of deciding whether a rank-maximal matching is popular among all the rank-maximal matchings in a given instance, and give an efficient algorithm for the problem

Steering cell migration by alternating blebs and actin-rich protrusions

Background High directional persistence is often assumed to enhance the efficiency of chemotactic migration. Yet, cells in vivo usually display meandering trajectories with relatively low directional persistence, and the control and function of directional persistence during cell migration in three-dimensional environments are poorly understood. Results Here, we use mesendoderm progenitors migrating during zebrafish gastrulation as a model system to investigate the control of directional persistence during migration in vivo. We show that progenitor cells alternate persistent run phases with tumble phases that result in cell reorientation. Runs are characterized by the formation of directed actin-rich protrusions and tumbles by enhanced blebbing. Increasing the proportion of actin-rich protrusions or blebs leads to longer or shorter run phases, respectively. Importantly, both reducing and increasing run phases result in larger spatial dispersion of the cells, indicative of reduced migration precision. A physical model quantitatively recapitulating the migratory behavior of mesendoderm progenitors indicates that the ratio of tumbling to run times, and thus the specific degree of directional persistence of migration, are critical for optimizing migration precision. Conclusions Together, our experiments and model provide mechanistic insight into the control of migration directionality for cells moving in three-dimensional environments that combine different protrusion types, whereby the proportion of blebs to actin-rich protrusions determines the directional persistence and precision of movement by regulating the ratio of tumbling to run times

New Changes in Insurance Requirements for Commercial Pesticide Applicator Businesses

On July 1, 2012, the Iowa Legislature passed changes to the Iowa Code that affected the evidence of financial responsibility for commercial pesticide applicator businesses. In order to be issued a license, commercial pesticide applicator licensees (businesses) were required to provide proof of financial responsibility for a minimum amount of $250,000 for property damage and$250,000 for public liability, each separately

Impact of alternative solid state forms and specific surface area of high-dose, hydrophilic active pharmaceutical ingredients on tabletability

YesIn order to investigate the effect of using different solid state forms and specific surface area (TBET) of active pharmaceutical ingredients on tabletability and dissolution performance, the mono- and dihydrated crystalline forms of chlorothiazide sodium and chlorothiazide potassium (CTZK) salts were compared to alternative anhydrous and amorphous forms, as well as to amorphous microparticles of chlorothiazide sodium and potassium which were produced by spray drying and had a large specific surface area. The tablet hardness and tensile strength, porosity, and specific surface area of single-component, convex tablets prepared at different compression pressures were characterized. Results confirmed the complexity of the compressibility mechanisms. In general it may be concluded that factors such as solid-state form (crystalline vs amorphous), type of hydration (presence of interstitial molecules of water, dehydrates), or specific surface area of the material have a direct impact on the tabletability of the powder. It was observed that, for powders of the same solid state form, those with a larger specific surface area compacted well, and better than powders of a lower surface area, even at relatively low compression pressures. Compacts prepared at lower compression pressures from high surface area porous microparticles presented the shortest times to dissolve, when compared with compacts made of equivalent materials, which had to be compressed at higher compression pressures in order to obtain satisfactory compacts. Therefore, materials composed of nanoparticulate microparticles (NPMPs) may be considered as suitable for direct compaction and possibly for inclusion in tablet formulations as bulking agents, APIs, carriers, or binders due to their good compactibility performanceSolid State Pharmaceutical Cluster (SSPC), supported by Science Foundation Ireland under Grant No. 07/SRC/B1158

Granular aluminium nanojunction fluxonium qubit

Mesoscopic Josephson junctions, consisting of overlapping superconducting electrodes separated by a nanometre-thin oxide layer, provide a precious source of nonlinearity for superconducting quantum circuits. Here we show that in a fluxonium qubit, the role of the Josephson junction can also be played by a lithographically defined, self-structured granular aluminium nanojunction: a superconductor–insulator–superconductor Josephson junction obtained in a single-layer, zero-angle evaporation. The measured spectrum of the resulting qubit, which we nickname gralmonium, is indistinguishable from that of a standard fluxonium. Remarkably, the lack of a mesoscopic parallel plate capacitor gives rise to an intrinsically large granular aluminium nanojunction charging energy in the range of tens of gigahertz, comparable to its Josephson energy. We measure coherence times in the microsecond range and we observe spontaneous jumps of the value of the Josephson energy on timescales from milliseconds to days, which offers a powerful diagnostics tool for microscopic defects in superconducting materials

Actin cortex architecture regulates cell surface tension

Animal cell shape is largely determined by the cortex, a thin actin network underlying the plasma membrane in which myosin-driven stresses generate contractile tension. Tension gradients result in local contractions and drive cell deformations. Previous cortical tension regulation studies have focused on myosin motors. Here, we show that cortical actin network architecture is equally important. First, we observe that actin cortex thickness and tension are inversely correlated during cell-cycle progression. We then show that the actin filament length regulators CFL1, CAPZB and DIAPH1 regulate mitotic cortex thickness and find that both increasing and decreasing thickness decreases tension in mitosis. This suggests that the mitotic cortex is poised close to a tension maximum. Finally, using a computational model, we identify a physical mechanism by which maximum tension is achieved at intermediate actin filament lengths. Our results indicate that actin network architecture, alongside myosin activity, is key to cell surface tension regulation

Experimental evidence of high pressure decoupling between charge transport and structural dynamics in a protic ionic glass-former

In this paper the relaxation dynamics of ionic glass-former acebutolol hydrochloride (ACB-HCl) is studied as a function of temperature and pressure by using dynamic light scattering and broadband dielectric spectroscopy. These unique experimental data provide the first direct evidence that the decoupling between the charge transport and structural relaxation exists in proton conductors over a wide T-P thermodynamic space, with the time scale of structural relaxation being constant at the liquid-glass transition (τα = 1000 s). We demonstrate that the enhanced proton transport, being a combination of intermolecular H+ hopping between cation and anion as well as tautomerization process within amide moiety of ACB molecule, results in a breakdown of the Stokes-Einstein relation at ambient and elevated pressure with the fractional exponent k being pressure dependent. The dT g /dP coefficient, stretching exponent βKWW and dynamic modulus E a /ΔV # were found to be the same regardless of the relaxation processes studied. This is in contrast to the apparent activation volume parameter that is different when charge transport and structural dynamics are considered. These experimental results together with theoretical considerations create new ideas to design efficient proton conductors for potential electrochemical applications

Manipulation Strategies for the Rank Maximal Matching Problem

We consider manipulation strategies for the rank-maximal matching problem. In the rank-maximal matching problem we are given a bipartite graph $G = (A \cup P, E)$ such that $A$ denotes a set of applicants and $P$ a set of posts. Each applicant $a \in A$ has a preference list over the set of his neighbours in $G$, possibly involving ties. Preference lists are represented by ranks on the edges - an edge $(a,p)$ has rank $i$, denoted as $rank(a,p)=i$, if post $p$ belongs to one of $a$'s $i$-th choices. A rank-maximal matching is one in which the maximum number of applicants is matched to their rank one posts and subject to this condition, the maximum number of applicants is matched to their rank two posts, and so on. A rank-maximal matching can be computed in $O(\min(c \sqrt{n},n) m)$ time, where $n$ denotes the number of applicants, $m$ the number of edges and $c$ the maximum rank of an edge in an optimal solution. A central authority matches applicants to posts. It does so using one of the rank-maximal matchings. Since there may be more than one rank- maximal matching of $G$, we assume that the central authority chooses any one of them randomly. Let $a_1$ be a manipulative applicant, who knows the preference lists of all the other applicants and wants to falsify his preference list so that he has a chance of getting better posts than if he were truthful. In the first problem addressed in this paper the manipulative applicant $a_1$ wants to ensure that he is never matched to any post worse than the most preferred among those of rank greater than one and obtainable when he is truthful. In the second problem the manipulator wants to construct such a preference list that the worst post he can become matched to by the central authority is best possible or in other words, $a_1$ wants to minimize the maximal rank of a post he can become matched to