Anthony E. Beezer

Dendrimers as potential drug carriers; encapsulation of acidic hydrophobes within water soluble PAMAM derivatives

This paper describes the synthesis of three neutral water soluble poly(amidoamine) (PAMAM) dendrimer derivatives. The ability of the two larger dendrimers to bind small acidic hydrophobic molecules is reported. Spectroscopic data and pH behaviour suggested that the acidic hydrophobes were forming stable ion pairs with the dendrimers internal, basic tertiary nitrogens. With respect to forming 1:1 and 2:1 substrate/dendrimer complexes, both of the larger dendrimers were equally efficient at binding. All dendrimer/substrate complexes were completely miscible with water in all proportions (i.e. infinitely water soluble). When the bound substrates are drug moieties, then the resulting complexes could be considered as potential drug delivery systems. Flow calorimetry demonstrated that the dendrimers were able to release their hydrophobic guests when in contact with a biological cell.

THE SYNTHESIS OF WATER SOLUBLE DENDRIMERS, AND THEIR APPLICATION AS POSSIBLE DRUG DELIVERY SYSTEMS

The synthesis of two water soluble dendrimers is described. The formation of water soluble inclusion complexes with a variety of small, hydrophobic guest molecules is also described. Moreover, when these guest molecules are drug moieties, then the resulting drug/dendrimer complexes can be considered ideal candidates for use as novel drug delivery systems.

The relationship between particle size and solubility

[where the rate of change of mass dissolved (m) with time (t) is related to the diffusion coefficient (D) through a static layer of liquid of thickness h, and C, is the equilibrium solubility and the amount dissolved at time t (C)l * in that an increase in the surface area of a drug will result in a more rapid dissolution process, particularly under sink conditions (where C a C,). This kinetic observation is clear and unambiguous, however, experimental results also lead to the conclusion that the value of C, can be influenced by a change in particle size. For example, Banker and Rhodes (1979) review studies which have shown

Antimicrobial properties of silver-containing wound dressings: a microcalorimetric study

The studies reported here have been undertaken to assess the potential use of isothermal microcalorimetry in studying the antimicrobial efficacy of wound dressings that contain antimicrobial agents. The microcalorimetric technique allows non-invasive and non-destructive analysis to be performed directly on a test sample, regardless of whether it is homogeneous or heterogeneous in nature. Microcalorimetry is an established procedure that offers quantitative measurements and has the distinct advantage over traditional antimicrobial test methodologies in that calorimetric measurements are made continuously over real-time, thus the dynamic response of microorganisms to an antimicrobial agent is observed in situ. The results described in this paper are for interaction of two silver-containing wound care products AQUACEL Ag Hydrofiber (ConvaTec, Deeside, UK) and Acticoat 7 with SILCRYST (Smith and Nephew Healthcare, UK) with the wound pathogenic organisms Staphylococcus aureus and Pseudomonas aeruginosa. Both dressings are shown, microcalorimetrically, to have the capacity to kill these common wound pathogens within 1-2 h of contact. A dose-response study was conducted with the AQUACEL Ag dressing. Microcalorimetry is shown to be rapid, simple and effective in the study of the antimicrobial properties of gel forming wound dressings.

The effect of the comminution technique on the surface energy of a powder

Abstract Six samples of powdered aspirin were prepared from one crystalline source by use of ball, vibrating ball, hammer and fluid energy mills, either alone or in combination. These were compared with a sample of powdered aspirin obtained from Macarthys. The surface energetics of the classified and milled samples were assessed with a vacuum microbalance and a microcalorimeter, to monitor water adsorption. Thermodynamic parameters and apparent rate constants for adsorption were obtained. Milling was shown to alter surface energetics in a manner related to the perceived energetics of the mill. Powders which were milled by two consecutive processes were found to retain the surface energetics imparted by the first process. Electron micrographs have been used to attempt an explanation of this phenomenon. The wetting process seems to be controlled by the availability of adsorption sites on the powder and the degree of order that is consequently imposed on adsorbed water; the entropy of adsorption is most directly related to wettability.

A kinetic study of the oxidation of L-ascorbic acid (vitamin C) in solution using an isothermal microcalorimeter

Abstract This paper reports the results of a microcalorimetric study of the oxidation of L-ascorbic acid in solution. The study of the oxidation reaction was carried out under varying conditions of pH, oxygen concentration, ascorbic acid concentration, temperature, addition of ethylenediaminetetraacetic acid (EDTA) and addition of a radical scavenger. From these results it is proposed that ascorbic acid is oxidised in solution by molecular oxygen via an ascorbic acid radical, formed from the interaction of ascorbic acid and free metal in solution. The oxidation product, dehydroascorbic acid, then goes on to form other products by hydrolysis. The change in enthalpy associated with the oxidation reaction was determined as − 130.9 kJ mol−1 and the reaction has a first order rate constant, with respect to the oxygen concentration, of 1.8 × 10−4 s−1. The rate of oxidation was found to increase with pH, oxygen concentration of metal in solution.

The Synthesis of Chiral Dendritic Molecules Based on the Repeat Unit L-Glutamic Acid

Abstract The convenient synthesis of a glutamate based dendrimeric molecule is reported. This chiral unsymmetrical dendrimer, contains 15 chiral centres all with identical configurations (L).

The applications of microcalorimetry in the field of physical pharmacy

Abstract The technique of microcalorimetry is introduced, the instrumental output is shown to relate to thermodynamics, kinetics and the concentration of the reactants (analysis). The detection sensitivity of the instrument is discussed, with particular reference to possible application to isothermal stability testing of solid-state reactions in pharmaceuticals, at ambient conditions: this particular aspect is compared directly to the current practice of use of differential scanning calorimetry (DSC) to screen for excipient incompatibilities. It is necessary to raise the temperature of a reaction significantly to observe a response in a DSC that is detectable at ambient conditions in a microcalorimeter, thus the DSC experiment may give false conclusions if the reaction which occurs at elevated temperatures is not chemically identical to the reaction that proceeds under ambient conditions. Microcalorimetry detects all processes that occur in the reaction cell, this can have advantages in, for example, studies of mechanism, but can cause problems with regard to quantification, the experiment must often be designed to limit investigation to a specific process that is of interest. A selective literature review of applications is presented, which covers stability testing, studies of powder wettability (by immersion and adsorption), crystal properties, dissolution of tablets in artificial foodstuffs and aspects of drug targeting. These examples do not cover the full list of applications, but demonstrate that microcalorimetry can be used to investigate any stage of the development, production and use of a dosage form, e.g. powder properties, excipient compatibility, product stability, tablet dissolution, direct in vitro studies of biological response etc.

Pharmaceutical calorimetry: a selective review

Calorimetric investigations of systems of pharmaceutical interest are selectively reviewed. Attention is drawn to the need for more systematic and quantitative investigations of bioactivity, especially of synergic and antagonistic drug combinations. Formulation affects biological response (BR) and hence attention is given in this review to some of the factors that may be of biopharmaceutical importance.

Analysis of drugs by microcalorimetry: Isothermal power-conduction calorimetry and thermometric titrimetry

Microcalorimetric analysis has been the subject of a few reviews in recent years, but these reviews have mainly dealt with the wide-ranging capabilities of calorimetric assay. This review, however, discusses the experimental basis and practical exploitation of the method in the particularly important area of pharmaceuticals. This field of analysis embraces both conventional chemical assays and bioassays which involve living microbial species. The review highlights the design of calorimetric instruments appropriate for study of microbial metabolism and interaction with drug substances. For comprehensiveness, both microcalorimetric and thermometric assay systems are discussed and critically assessed.