R. Gary Hollenbeck

Determination of the energy of tablet formation during compression of selected pharmaceutical powders

Abstract A thermodynamic evaluation of bonding in compressed tablets has been achieved providing a quantitative measure of solid paniculate interaction shown to correlate with tablet strength. The evaluation was accomplished through the design and implementation of a unique compression calorimeter capable of accurate and precise determination of the heat released during powder compaction. Concomitant measurement of the work of compaction permitted an energy balance for the tableting process such that the energy difference between powder and tablet could be accurately assessed. The experimentally determined energy differences at maximum compression force (30,000 N) for 4 pure directly compressible materials (Avicel, DiTab, Fast Flo lactose, Starch 1500) indicate that the formation of a tablet is associated with a decrease in energy of the system. This decrease in energy, termed the energy of formation, is related to the dissipation of surface energy associated with bonding. The compression of a particulate system which did not form a strong tablet presented a much smaller energy of formation at maximum compression force (10.6 J for Avicel versus 0.52 J for granular acetaminophen) and thus demonstrates the potential of the compression calorimeter as a device capable of quantitatively determining energetic differences resulting from the compaction process. The tensile strength measurements for each compressible material are also shown to correlate with the energy of formation.

Bioavailability of phenylpropanolamine HC1 from tablet dosage forms containing croscarmellose sodium

Abstract A comparative bioavailability study was utilized to investigate the physiological significance of the in vitro drug-expcipient interaction between croscarmellose sodium NF and weakly basic drugs. Three formulations of lactose-based tablets containing a 25 mg dose of phenylpropanolamine HC1 (PPA), and compressed to comparable hardness, were used: tablet with no disintegrant (CONTROL); tablet with 10% starch (STARCH); tablet with 10% croscarmellose sodium (CROS). Cumulative urinary excretion for 6 healthy subjects in a cross-over study was examined to determine if the drug-excipient interaction resulted in decreased availability. Even though an in vitro dissolution test in distilled water resulted in 40% drug bound for the CROS tablets, no significant differences ( F 2,15 =0.237) in average cumulative amount of drug excreted in the CONTROL, 22.94 mg; STARCH, 22.41 mg; CROS, 22.85 mg.

Physicochemical characteristics of ferric adriamycin complexes

SummaryFerric ions and adriamycin in solution interact to form complexes that can yield colloidal and flocculant mixtures. At high concentrations (Fe3+≥10-4 M, adriamycin ≥10-5 M) an absorption appears at 600 nm, indicating colloid formation, which is directly responsive to concentrations of the reactants. Evidence from dilution experiments by spectral analysis, ultracentrifugation, titration, and filtration indicate that phase transitition that is sensitive to pH and time occurs with iron-adriamycin complexes to yield flocculated drug. We conclude that patients and animals treated with the iron-adriamycin preparations known as ‘quelamycin’ received flocculated iron-adriamycin, which accounts for the toxic and pharmacologic effects reported. It may be useful to utilize colloidal preparations of reactive or irritating drugs to avert acute toxic effects and to produce slower release of active drug.

Interaction of water vapor and compressible sugar

Abstract The interaction of water vapor with Compressible Sugar NF (DiPac) has been characterized by studying the adsorption and desorption behavior of the solid, preconditioned by drying at 70°C in a vacuum oven. An unusual stepwise adsorption isotherm and extensive isothermal desorption hysteresis were evident for this material at 25°C. The temperature dependence of the adsorption process was used as the basis for a complete thermodynamic analysis: partial molal free energies, enthalpies and entropies of adsorption were calculated. Exothermic maxima in the isosteric heats of adsorption profile indicated discrete stages of surface hydration, thereby accounting for the epwise nature of the isotherm. Strong interaction of water in the initial stages of adsorption, reflected by primary and secondary exothermic maxima of −74.0 kJ and −27.5 kJ per mole of water, suggested that this water was not released during isothermal desorption, thereby accounting for the hysteresis.

Influence of hydrophilic excipients on the interaction of aspirin and water

Abstract Photomicrographic evidence is presented which documents the existence of an apparent hydrophobic field generated by an aspirin crystal which prohibits the condensation of water from a high humidity environment in the vicinity of that crystal at 25C. Water vapor sorption results on aspirin at the same temperature were found to be consistent with those expected for a solid which is not completely wetted by the condensed adsorbate (Type III). Photomicrographic evidence is also presented which shows that when aspirin is combined with certain hydrophilic excipients, condensation in the vicinity of the aspirin crystals is found. In certain cases individual aspirin crystals become immersed in a pool of water when the powder blend is exposed to high humidity. Sodium starch glycolate, croscarmellose sodium, crospovidone, and colloidal silicon dioxide blends were studied. Since the amount and perhaps the state of water associated with aspirin influences hydrolytic degradation, it is suggested that the stability of aspirin formulations may correlate with these observed sorption results.

ABSORPTION AND DISPOSITION OF COLLOIDAL DRUG DELIVERY SYSTEMS. I, HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC (HPLC) ANALYSIS OF A CYCLOSPORIN EMULSION

The amount of cyclosporin A in an oil-in-water emulsion drug delivery system was determined by HPLC. The direct extraction and analysis of an intact emulsion were compared to the analysis of a cracked emulsion and an olive oil solution of the drug. The intra- and interday variability for the intact emulsion was less than 10% from 35 to 150 µg/ml, with recovery of 94%. Comparison of the assay results obtained with the emulsion and the olive oil solution gave a highly correlated regression line with a small intercept and a slope close to unity. Thus, the direct extraction and HPLC analysis of drugs in emulsions may be a viable approach to evaluate drug content

Stability of bioreductive drug delivery systems containing melphalan is influenced by conformational constraint and electronic properties of substituents.

The stability of bioreductive drug delivery systems (TDDS) was monitored at various pH values and in the presence of glutathione (GSH). Results suggest that steric hindrance due to conformational constraint in TDDS led to an increase in stability of TDDS toward nucleophilic degradation under aqueous conditions. The electronic properties of substituents influenced TDDS stability at different pH values and in the presence of GSH.

Dissolution test development for complex veterinary dosage forms: Oral boluses

Fundamental aspects of electrolyte chemistry were used to design an appropriate dissolution medium with the capacity to maintain sink conditions throughout the test. Dissolution of various bolus dosage forms was studied using USP Apparatus II at various stirring speeds. Complete dissolution of each drug in the designed medium was achieved, and there is evidence that such a dissolution test could be discriminating. This review details the development of potentially discriminating in vitro dissolution tests for veterinary boluses using USP Apparatus II and examines the potential role of such testing during product quality assessments, in the evaluation of postapproval manufacturing changes and for the establishment of the generic equivalence of veterinary products.

Dissolution Testing of Sulfa Boluses

h o l l e n be c k @ u p m i n c. co m Raafat Fahmy1, William Marnane1 and Dennis Bensley, Jr.1 , R. Gary Hollenbeck*2 1Division of Manufacturing Technologies, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD 2Associate Professor, Department of Pharmaceutical Sciences, University of Maryland School of Pharmac y and Vice President, University Pharmaceuticals of Maryland, Inc., Baltimore, MD

Dissolution Testing of Tetracycline Boluses

Background ntibiotics such as te t ra cycline may be indicated in animals for the tre at m e nt of bacte ri a l pneumonia or bacte rial ente ritis caused by E. Coli and Salmonella organisms susce p t i b l e to te t ra cyc l i n e.USP 24 (1) includes monog raphs on te t ra cycline and te t ra cycline hyd roc h l o ride dru g s u b s t a n ce as well as seve ral dosage fo rm s, including a monog raph for Te t ra cycline Bo l u s e s. The monog raph for these boluses does not include a dissolution te s t ;h oweve r,a dissolution test is p rovided in the USP that uses water as the medium for te t ra cycline hyd roc h l o ride capsules and tablets. While the general object i ves of this wo rk are a d d ressed in the pre ceding articles on Sulfa and As p i rin bo l u s e s, the inte nt of this study is to demons t rate that existing methods may be appro p ri ate and to consider when water may be suitable as the dissolution medium. Calf Scour Bolus Antibiotic examined in this study (NADA 65-004,Lot# 30DRB manufact u red fo r Du rve t,I n c. ,Blue Sp ri n g s,MO by Ph a rmacia & Upjohn Co m p a ny,Ka l a m a zoo,MI) co ntains 500 mg of te t ra cycline hyd roc h l o ride in a bolus that we i g h s a p p rox i m ately 5.8 g.While the bolus is quite larg e, the amount of the act i ve ingre d i e nt in this dosage fo rm is not that much larger than what is ofte n found in capsules and tablets for human use.