P261 calorimetric investigation of spray dried salbutamol sulphate

184

Posters / European Journal of Pharmaceutical Sciences 2 (1994) 117-194

1>261CALORIMETR~ INVESTIGATION OF SPRAY DRIED SALBUTAMOLSULPHATE

G. Men,eye1, K.M.G.Taylor1, J.M.Ne~onl, M.C.R.Johnson2 1 School~ P ~ a ~ , Un~ersity~ London,WC1N1AX,U,K. 2 Rh~e-Poul~cRotorLtd.,De~nham,RMIO7XS,U.K. Amorphous spray dried salbutamol sulphate havinE a resDirable size range has been investigated as an a l t e r n a t i v e t o microni~ed crystalline druK for dry Dowder inhaler aerosol formulations. . Differential scannin~ calorimetry (DSC) (Perkin Elmer, USA) and isothermal heat-conduction mfcrocalorimetry (2277 Thermal Activity Monitor, Thermometric AB, Sweden) were employed to study the relative physical stability of salbutamol sulphate spray dried from a 20%w/v aqueous solution fed into a Mini E~ehi 190 spray dryer (B~chi, Switzerland) at variable feed solution temperatures (4°C, 21°C and 60°C). All calorimetric determinations were performed in triplicate. VaryinE the temperature of the initial feed solution allowed the production of 100% amorphous material of respirable size i.e. 3-5~Jm with different residual moisture contents. NO major differences were seen in the DSC peaks obtained for 4mE samples run at 10°C/min between 40°C and 275°C. All traces Rave similar re-crystallisation exothermic peaks at 80°C with an associated enthalpy in the ranEe 20-30 J/EHowever, the exothermic peaks obtained with the more sensitive microcalorimeter usinE a miniature humidity chamber technique2at 25oC and 85% relative humidity showed clear differences in the relative physical stabilities, as the time taken for the re-crystallisation peak maximum to occur was 1.93, 5.63 and 6.77 h for samples produced from the different feed solution temperatures respectively. In addition, calculatin~ the total heat flow durin~ this process usin~ lOm~, ZOm~ and 40m~ samples yielded a sDecific enthalpy of re-erystallisation of 25.16 J/R, which corresponds well with the data obtained from the DSC. Ichawla, A. et al (1994) Int. J. Pharm., 108: 233-240 2AnEberR, M. et al (1992) Int. J. Pharm., 81: 153-167.

P262 DRUG PERMEABILITY OF BOVINE ROOF MEMBRANESAND HUMANNAIL PLATESIN VITRO

D. Mertin,8.C. Lippold Departmentof PharmaceutiCalTechnology,Heinrich-Heine-Universit~t, 40225DOsseldort,Germany /n vitro investigations of drug permeation through human nail plates provide important information for the conduct of comprehensive clinical studies. Despite the need of improved drug formulations for the local treatment of onychomycosis not many in vitro studies regarding human nail plate permeability have been published (1). For this reason, an in vitro model for the investigation of drug permeability of keratinous materials was developed. It basically consists of a modified Franz diffusion cell using bovine hoof pads as membrane material. The permeability properties of these membranes are compared to those of the human nail plate. Permeability coefficients of homologous nicotinic acid esters in aqueous solution, ranging from 2.58-10 -7 cm2/s (hexyl nicotinate) to 3.25-10 -7 cm2/s (methyl nicotinate) were determined with the bovine hoof model. In contrast, the partition coefficients octanol/water of these compounds range from 7 (methyl nicotinate) to over 51,000 (octyl nicotinate). This indicates that the bovine hoof membrane behaves like a hydrophilic gel membrane rather than a lipophilic partition membrane. Accordingly, the maximum flux, i.e. the flux obtained after application of saturated solutions, is only dependent on the drug solubility in the donor compartment or the vehicle. This was confirmed by the results of permeability studies with the model compounds acetaminophen and phenacetin which widely differ from each other in terms of water solubility but show similar molecular weights. The results of recent investigations with human nail plates indicate that the latter also may be regarded as hydrophilic gel membranes. The molecular weight of the permeating compounds seems to have a more pronounced influence on the permeability of human nail plates than on that of the bovine hoof membranes. (1) Waiters K.A., Flynn GL.; Int. J. Cosmet. Sci. 5, 231-46 (1983)

P263 EMULSIONSAS CARRIERSFORHEXADECYLPHOSPHOCHOUNE WITHTHEAIM OF DECREASINGTHEHEMOLYTICEFFECSOFTHEINCORPORATEDDRUG T.K. Beck,B.W.MOiler Departmento4Pharmaceuticser~iSiopharmaceutics,Chfis~ian-Albr echts-Unive~'sity,24118Kiel,Germany

Hemolytic side effects may limit the intravenous administration of drugs. As only the drug dissolved in the aqueous dispersion medium is hemolytically active, incorporation of the drug into colloidal carder systems can decrease the hemolytic activity. The hemolysis of the incorporated drug can be determined in in vitro tests and can be taken as measurement of the incorporation capacity of the carriers. Hexadecylphosphocholine (HDPC) is a new antineoplastic agent and was taken as a model drug. When administered intravenously hemolytic side effects occur, which are comparable to those of lysolecithin. Former investigations showed that fat emulsions most effectively reduce hemolysis of the model drug in in vitro tests as compared to other carder systems such as liposomes or mixed micelles [1]. Incorporation of the model drug depends on the sudace properties of the emulsion droplets. In this study medium chain triglycarides were used as oil phase. The emulsions were stabilized by soybean lecithin and additionally contained different amounts of poloxamer 188. One system was prepared containing only potoxamer 188 as emulsifier. The emulsions were characterized with regard to the hemolytic activity of the incorporated drug using an in vitro red blood cell test [2]: Corpuscles of blood ware added to the carder systems containing different amounts of HDPC. After incubation intact cells were removed by centrifugation and the hemoglobin concentration in the supernatant was determined. The relative percentages of hemolysis were calculated and the concentrations of the drug which resulted in hemolysis of fifty percent of the added erythrocytes were computed, in order to compare the different formulations. The incorporation capacity of emulsions stabilized by mixtures of poloxamer and lecithin increased with increasing concentration of the poloxamer. Emulsions containing only poloxamer 1 88 as emulsifier incorporated the model drug most effectively. 1 Bock& MOiler, Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 21 (1994) 2 Bock& MO,er, Pharm. Res. (in press)

1=264THE INFLUENCE OF INTERRACIAL PROPERTIESOF EMULSIONSTABILIZERS ON EMULSION STABILITY N.O. Sahin

DepartmentofPharmaceuticsandPharmacodycamics,CollegeofPharmacy,Universityof Illinois,Chicago,IL,USA The purpose of this study was to investigate the interracial properties of emulsion stabilizers and to correlate these data to emulsion stability. The interracial properties of various emulsifiers (albumin, casein, egg yolk, phosvitin and egg yolk components) were investigated under different conditions (pH, ionic strength, concentration, temperature, aging and addition of chemical agents) at air/aqueous interface, inteffaciai tension, rheology and charge of the molecules were investigated using a Wilhelmy plate method, a surface oscillatory technique and microelectrephoresis respectively. Factors which affect the configuration and charge of the molecules were investigated: pH (3-10), ionic strength (1-1000raM), concentration (0.0001 to 9°/o w/v), temperature (25 to 60 °C) and the addition of chemical agents (small suffactant molecules, NaCI, EDTA, Guanidinium-HCI, urea, copper suffate and phospholipids). Emulsifiers were selected based on the interfacial characterizationdata and emulsions were prepared by ultrasonication. The addition of emulsion stabilizers to emulsion systems can reduce interfacia~ tension and create an interfacial mechanical barrier, both of which improve emulsion stability. The interfaeialactivity of emulsifiers was measured by monitoring the kinetics of decrease in interfacial tension. The rigidity of the interfacial film, which prevents droplet coalescence, was investigated using intedacial oscillatory technique. It was predicted, that the conditions which increase interfacial rheology and/or increase interfacialcharge and/or decrease interfacial tension would improve emulsion stability. Emulsion stability data were shown to follow these predictions. This study was funded by Kraft General Foods Inc. and Parentera( Drug Association and won the "Excellence in Research"award from Procter and Gamble Co..