Incompatibility of croscarmellose sodium with alkaline excipients in a tablet formulation.

The objective of the current work was to study an observed incompatibility between croscarmellose sodium and basic excipients in a tablet formulation. Significant dissolution slowdown was observed for alkaline tablet compositions of an acid-labile drug containing croscarmellose sodium (CCS) as a disintegrant. The severity of the dissolution slowdown was directly proportional to both the degree of alkalinity and the level of CCS in the tablet formulation. It is postulated that the ester cross-links in CCS were partially or fully hydrolyzed under basic conditions (pH values >9) forming by-products of increased water solubility. This increase in the level of water-soluble polymer can lead to the formation of a viscous barrier in the tablet upon moisture uptake, thus slowing down its dissolution. The dissolution slowdown was not observed for a similar alkaline tablet preparation containing crospovidone as a disintegrant.

Summary workshop report: Facilitating oral product development and reducing regulatory burden through novel approaches to assess bioavailability/bioequivalence.

This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro-in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen C (max) acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).

Do mitigation strategies reduce global warming potential in the northern U.S. corn belt?

Agricultural management practices that enhance C sequestration, reduce greenhouse gas emission (nitrous oxide [N2O], methane [CH4], and carbon dioxide [CO2]), and promote productivity are needed to mitigate global warming without sacrificing food production. The objectives of the study were to compare productivity, greenhouse gas emission, and change in soil C over time and to assess whether global warming potential and global warming potential per unit biomass produced were reduced through combined mitigation strategies when implemented in the northern U.S. Corn Belt. The systems compared were (i) business as usual (BAU); (ii) maximum C sequestration (MAXC); and (iii) optimum greenhouse gas benefit (OGGB). Biomass production, greenhouse gas flux change in total and organic soil C, and global warming potential were compared among the three systems. Soil organic C accumulated only in the surface 0 to 5 cm. Three-year average emission of N2O and CH was similar among all management systems. When integrated from planting to planting, N2O emission was similar for MAXC and OGGB systems, although only MAXC was fertilized. Overall, the three systems had similar global warming potential based on 4-yr changes in soil organic C, but average rotation biomass was less in the OGGB systems. Global warming potential per dry crop yield was the least for the MAXC system and the most for OGGB system. This suggests management practices designed to reduce global warming potential can be achieved without a loss of productivity. For example, MAXC systems over time may provide sufficient soil C sequestration to offset associated greenhouse gas emission.

Formation of zinc-peptide spherical microparticles during lyophilization from tert-butyl alcohol/water co-solvent system.

PURPOSE: To understand the mechanism of spherical microparticle formation during lyophilizing a tert-Butyl alcohol (TBA)/water solution of a zinc peptide adduct. METHOD: A small peptide, PC-1, as well as zinc PC-1 at (3:2) and (3:1) ratios, were dissolved in 44% (wt.%) of TBA/water, gradually frozen to -50 degrees C over 2 h ("typical freezing step"), annealed at -20 degrees C for 6 h ("annealing step"), and subsequently lyophilized with primary and secondary drying. Zinc peptide (3:1) lyophile was also prepared with quench cooling instead of the typical freezing step, or without the annealing step. Other TBA concentrations, i.e., 25%, 35%, 54% and 65%, were used to make the zinc peptide (3:1) adduct lyophile with the typical freezing and annealing steps. The obtained lyophile was analyzed by Scanning Electron Microscopy (SEM). The zinc peptide solutions in TBA/water were analyzed by Differential Scanning Calorimeter (DSC). The surface tension of the TBA/water co-solvent system was measured by a pendant drop shape method. RESULTS: With typical freezing and annealing steps, the free peptide lyophile showed porous network-like structure that is commonly seen in lyophilized products. However, with increasing the zinc to peptide ratio, uniform particles were gradually evolved. Zinc peptide (3:1) adduct lyophiles obtained from 25%, 35% and 44% TBA exhibit a distinctive morphology of uniform and spherical microparticles with diameters of approximately 3-4 microm, and the spherical zinc peptide particles are more predominant when the TBA level approaches 20%. Adopting quench cooling in the lyophilization cycle leads to irregular shape fine powders, and eliminating the annealing step causes rough particles surface. When TBA concentration increases above 54%, the lyophiles demonstrate primarily irregular shape particles. CONCLUSIONS: A proposed mechanism of spherical particle formation of the 3:1 zinc peptide encompasses the freezing of a TBA/water solution (20-70% TBA) causing the formation of a TBA hydrate phase ("dispersed TBA hydrate"). Decreasing the temperature further causes the formation of a eutectic mixture between TBA hydrate ("eutectic TBA hydrate") and water. Due to its low aqueous solubility, the zinc peptide adduct accumulates in both of the dispersed and eutectic TBA hydrate phases to form a hydrophobic "oil" phase. Since the eutectic TBA hydrate phase is surrounded by ice, a "solid emulsion" forms to lower the interfacial energy, and gives rise to spherical zinc peptide particles upon solvent sublimation. Possibility of liquid-liquid phase separation during freeze-drying was also investigated, and no evidence was found to support this alternative mechanism.

Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: synthesis and biological properties.

Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole.