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Stability Data (stability + data)
Selected AbstractsA solid-state approach to enable early development compounds: Selection and animal bioavailability studies of an itraconazole amorphous solid dispersionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2010David Engers Abstract A solid-state approach to enable compounds in preclinical development is used by identifying an amorphous solid dispersion in a simple formulation to increase bioavailability. Itraconazole (ITZ) was chosen as a model crystalline compound displaying poor aqueous solubility and low bioavailability. Solid dispersions were prepared with different polymers (PVP K-12, K29/32, K90; PVP VA S-630; HPMC-P 55; and HPMC-AS HG) at varied concentrations (1:5, 1:2, 2:1, 5:1 by weight) using two preparation methods (evaporation and freeze drying). Physical characterization and stability data were collected to examine recommended storage, handling, and manufacturing conditions. Based on generated data, a 1:2 (w/w) ITZ/HPMC-P dispersion was selected for further characterization, testing, and scale-up. Thermal data and computational analysis suggest that it is a possible solid nanosuspension. The dispersion was successfully scaled using spray drying, with the materials exhibiting similar physical properties as the screening samples. A simple formulation of 1:2 (w/w) ITZ/HPMC-P dispersion in a capsule was compared to crystalline ITZ in a capsule in a dog bioavailability study, with the dispersion being significantly more bioavailable. This study demonstrated the utility of using an amorphous solid form with desirable physical properties to significantly improve bioavailability and provides a viable strategy for evaluating early drug candidates. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3901,3922, 2010 [source] Method for enantiomeric purity of a quinuclidine candidate drug by capillary electrophoresisJOURNAL OF SEPARATION SCIENCE, JSS, Issue 13 2006Tore Ramstad Abstract A chiral procedure based on EKC was developed and validated for determination of the enantiomeric purity of PHA-543613, a drug candidate that was under development for treatment of the cognitive deficits of Alzheimer's disease and schizophrenia. Separation of enantiomers is accomplished via differential, enantiospecific complexation with a single-isomer, precisely sulfated beta-CD and heptakis-6-sulfato-,-CD (HpS-,-CD). Both neutral and sulfated CDs were screened before selecting HpS-,-CD as the chiral selector. The separation is conducted in a 61 cm×50 ,m uncoated fused silica capillary with 25 mM HpS-,-CD in pH 2.50, 25 mM lithium phosphate as the separation buffer with detection at 220 nm. Application of reverse polarity at ,30 kV results in an elution time of about 12 min for PHA-543613 and 13 min for the undesired S -enantiomer. Quantification is versus an authentic reference S -enantiomer as an external standard in combination with an internal standard. The procedure was validated over the range 0.1,2.0% w/w. The detection limit is 0.01,0.02%. The amount of distomer intrinsic to the drug substance is about 0.1% or less. The developed method was used to generate stability data on multiple lots: in one case for up to 3 years. [source] Sequestration of organometallic compounds by natural organic matter. binding of trimethyltin(IV) by fulvic and alginic acidsAPPLIED ORGANOMETALLIC CHEMISTRY, Issue 10 2006Alba Giacalone Abstract The binding capacity of fulvic and alginic acids towards trimethyl tin(IV) cation was quantitatively determined in order to evaluate the sequestering ability of toxic organometallic compounds by natural organic matter. Investigations were performed in the pH range of natural waters (5,8.5) where the carboxylate groups, largely present in both sequestering agents, are the main binding sites. A chemical interaction model, according to which both the protonation of polyelectrolyte ligands and the hydrolysis of the organotin cation in NaCl aqueous solution were considered, was used to define the speciation of the systems under investigation. Measurements performed at different ionic strength values (0.1, 0.25, 0.5 and 0.7 mol L,1, NaCl) allowed us to consider the dependence of stability constants on the ionic strength, and to calculate the formation constants at infinite dilution. Results obtained show the formation of the complex species TMT(L), TMT(L)2 and TMT(L)(OH) for L = fulvic acid and TMT(L) for L = alginic acid, respectively. In order to compare the strength of interaction of these natural poly electrolytes with other analogous synthetic polyelectrolytes, measurements were also carried out on the trimethyltin(IV),polyacrylate (5.1 kDa) system, and in this case the formation of TMT(L), TMT(L)2 and TMT(L)(OH) species was found. Results show the following trend of stability for the species TMT(L) in the systems investigated: TMT,fulvate , TMT,polyacrylate > TMT,alginate. On the basis of the stability data obtained, the lowest concentration of fulvic and alginic acids, able to act as sequestering agents towards triorganotin(IV) cation in the conditions of natural waters, was also calculated. Copyright © 2006 John Wiley & Sons, Ltd. [source] Structural and thermodynamic encoding in the sequence of rat microsomal cytochrome b5,BIOPOLYMERS, Issue 5 2008Juliette T. J. Lecomte Abstract The water-soluble domain of rat microsomal cytochrome b5 is a convenient protein with which to inspect the connection between amino acid sequence and thermodynamic properties. In the absence of its single heme cofactor, cytochrome b5 contains a partially folded stretch of ,30 residues. This region is recognized as prone to disorder by programs that analyze primary structures for such intrinsic features. The cytochrome was subjected to amino acid replacements in the folded core (I12A), in the portion that refolds only when in contact with the heme group (N57P), and in both (F35H/H39A/L46Y). Despite the difficulties associated with measuring thermodynamic quantities for the heme-bound species, it was possible to rationalize the energetic consequences of both types of replacements and test a simple equation relating apoprotein and holoprotein stability. In addition, a phenomenological relationship between the change in Tm (the temperature at the midpoint of the thermal transition) and the change in thermodynamic stability determined by chemical denaturation was observed that could be used to extend the interpretation of incomplete holoprotein stability data. Structural information was obtained by nuclear magnetic resonance spectroscopy toward an atomic-level analysis of the effects. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 428,442, 2008. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] | ||||||||||