D.Q.M. Craig

An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy

Abstract A series of mixtures comprising Imwitor 742 and Tween 80 have been prepared and their self-emulsifying properties studied using a method of visual examination. The particle size distributions of emulsions prepared from these mixtures at 25°C, 37°C in water and 37°C in 0.1 M HCl have been measured. A marked decrease in mean particle size was observed for 30 and 40% Imwitor 742/Tween 80 mixtures at 25°C with a decrease in particle size also being noted for the majority of Imwitor 742/Tween 80 compositions at higher temperatures. Low frequency dielectric spectroscopy was performed on the pure components and on binary systems to which water had been added to make 50% v/v mixtures. Evidence was shown for the formation of liquid crystalline phases at concentrations corresponding to those shown to be efficient self-emulsifying systems. The study therefore suggests that self-emulsification may be associated with liquid crystal formation and that low frequency dielectric spectroscopy may be of considerable use in understanding the factors leading to self-emulsification.

An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis

Abstract The structure and behaviour of self-emulsifying drug delivery systems (SEDDS) containing Labrafil M2125 CS and Tween 80 have been examined and the effects of changing the formulation via the addition of a non-polar model drug (L-365,260) investigated. Low frequency dielectric spectroscopy (LFDS) was used to examine the individual components in order to investigate the effects of drug inclusion. The presence of the drug resulted in a decrease in the dielectric response of the Labrafil M2125 CS, Tween 80 and the oil-surfactant vehicles. The surface tension of the emulsions decreased on addition of the drug, while particle size analysis showed that the emulsions containing no drug and 2% w/v drug had a bimodal distribution and the emulsions containing 6% w/v drug were unimodal. It was found that the bimodal distribution changed over a period of 14 h, with a decrease in modal value of the larger distribution peak and, for samples containing no drug, an increase in the proportion of droplets in the lower size distribution. The results therefore indicate that the drug interacts with one or more components of the self-emulsifying system, leading to a change in droplet size distribution which varies as a function of drug concentration.

Characterisation of the glass transition of HPMC using modulated temperature differential scanning calorimetry

The glass transitional behaviour of HPMC powder and film samples has been studied using modulated temperature differential scanning calorimetry (MTDSC) in order to explore the ability of the technique to detect transitions which involve small changes in heat capacity. HPMC E4M Prem samples were studied in both powder and film form using a TA Instruments MDSC 2920 using a range of pans, modulation amplitudes and underlying heating rates. Moisture contents were measured using a TA Instruments TGA 2950. Studies on HPMC powder demonstrated the greater clarity with which the glass transition, seen at approximately 162 degrees C, may be seen using MTDSC compared to conventional DSC. The practical difficulties associated with casting suitable HPMC films are discussed, with similar results for Tg being found for hermetically sealed pans and pin-holed pans. Increasing the modulation amplitude from 0.212 to 0.5 degrees C improved the signal to noise ratio and increased the magnitude of the measured Tg. Increasing the underlying heating rate from 2 to 5 degrees C/min also improved the signal. The study has outlined several features which need to be considered in association with the measurement of HPMC glass transitions using MTDSC; these include the method of sample preparation, the choice of pans, the modulation amplitude and the underlying heating rate.

Characterisation of polyethylene glycols using differential scanning calorimetry

Abstract The melting behaviour of a range of different molecular weight polyethylene glycol (PEG) samples has been studied using differential scanning calorimetry (DSC). It was demonstrated that the shape of the endotherm was sensitive to the sample particle size, while the heat of fusion and melting points of the samples varied with scanning speed. Using standardised conditions, the PEG samples were solidified from the melt either by controlled cooling at 5 k/h or by immersing the sample in liquid nitrogen. The endotherms obtained indicated that the thermal history may determine both the degree of crystallinity and the crystal form of the polyethylene glycols, as shown by changes in the heat of fusion and melting points respectively. Studies using solid state nuclear magnetic resonance supported the conclusions drawn from the DSC studies. The study has therefore indicated that DSC is a suitable technique for detecting solid state changes in polyethylene glycols, thus facilitating standardisation of these materials.

An evaluation of the mechanisms of drug release from glyceride bases

A series of dispersions containing theophylline in Gelucires 43/01, 54/02, 50/02, 50/13 and 55/18 was prepared and the physical structures studied using differential scanning calorimetry. The dissolution, erosion and swelling profiles of the drug dispersions were assessed.

The effects of ageing on the thermal behaviour and mechanical properties of pharmaceutical glycerides

Abstract The thermal behaviour of stored Gelucires 43/01, 50/02, 54/02, 50/13 and 55/18 has been studied, particularly with a view to examining the relationship between preparation conditions and physical stability. The endotherms of Gelucire 43/01 samples were found to approach an equilibrium shape on storage, with samples which had been fast cooled from the melt adopting this shape over the shortest period of time. Tempering of these materials at elevated temperatures resulted in alterations in the distribution of endotherms and represents a possible method of accelerating the transition to the equilibrium form. Ageing of Gelucires which contain mixes of glycerides and polyethylene glycol (PEG) esters resulted in changes in the endotherm shape but no evidence for an equilibrium profile was obtained. Studies on Gelucire 55/18, which contains only PEG esters, showed that the main endothermic peak exhibited little evidence for ageing effects, although a lower temperature shoulder was observed on storage. Tensile strength (/gs) measurements indicated that the strength of the Gelucires also changed on storage. It was noted that materials containing either glycerides or PEG esters tended to show an increase in /gs on storage, while Gelucires containing a mixture of the two components showed a decrease in strength.

THE DISSOLUTION OF NORTRIPTYLINE HCL FROM POLYETHYLENE-GLYCOL SOLID DISPERSIONS

Abstract The dissolution characteristics of nortriptyline hydrochloride dispersions in a range of different molecular weight polyethylene glycol carriers have been investigated. The release rate was found to be higher from dispersions in PEG 3400 than from the drug alone, while a logarithmic decrease was seen with increasing carrier molecular weight. Studies indicated that there was little difference in release rate from flash- and slow-cooled dispersions. A linear relationship was found between drug dissolution rate and concentration in PEG 20 000 up to 25% w/w drug. The release rate was shown to increase with rotation speed, although the results obtained were not consistent with the relationship proposed by Levich (Levich, V.G., Physicochemical Hydrodynamics , Prentice Hall, NJ, 1962, pp. 60–72). A hypothesis has been presented for the involvement of solubilisation of the drug at the solid-liquid interface as a mechanism for the observed dissolution behaviour.

AN INVESTIGATION INTO THE EFFECTS OF PREPARATION CONDITIONS AND STORAGE ON THE RATE OF DRUG-RELEASE FROM PHARMACEUTICAL GLYCERIDE BASES

The effects of preparation conditions on the release of theophylline from Gelucires 50/13 and 55/18 have been investigated. Samples were prepared by melting physical mixes under controlled conditions, followed by either slow or fast (ambient) cooling to the solid state.

Characterization of polyethylene glycol solid dispersions using differential scanning calorimetry and solution calorimetry

Abstract Solid dispersions of nortriptyline HCl in a range of molecular weight PEG samples were manufactured using a low temperature fusion method, whereby the drug remained intact within the dispersion. The phase diagrams obtained using differential scanning calorimetry were monotectic in nature, suggesting that these diagrams represent systems whereby little or no interaction is present between the solid components. Electron micrographs also showed the drug particles to remain largely intact following the fusion process. Studies using solution calorimetry indicated that the heats of solution of the binary systems were lower than theoretically predicted, indicating an interaction between the two components during the dissolution process.

An investigation into the critical surfactant concentration for solid solubility of hydrophobic drug in different polyethylene glycols

Abstract Solid dispersions of 10% w/w griseofulvin in different polyethylene glycols (PEGs) with or without incorporation of alkali dodecyl sulphates (MDS) were prepared by the melting method. The investigations concerned the solid state (X-ray powder diffraction), the transition from solid to liquid state (Oscillating DSC) and the liquid state (low frequency dielectric spectroscopy). The critical concentrations of SDS for the formation of solid solutions in varying PEGs were evaluated. In PEG 3000 this formation occurs at 1.4% w/w SDS, whereas PEG 6000 and PEG 20 000 require solely 1.0% w/w SDS to transfer a dispersion into a solid solution. PEG 3000 was also investigated with the addition of MDS. The critical surfactant concentrations for the formation of solid solutions with the counterions Li + , Na + and K + were 1.0%, 1.4% and 2.1% w/w, respectively. The investigated systems had varying degrees of crystallinity. With the addition of SDS to PEGs with a range of molecular weights, the highest crystallinity was seen in the PEG 3000 sample. The different polymers contained different amounts of folded and extended chains which influences the amount of amorphous material within the polymer structure. When surfactants with different counterions were added to PEG 3000, the lithium sample showed the highest crystallinity. In the melt the Li + sample showed the lowest dielectric mobility. The results show that concentration and structure of surfactant together with the presence of folded and extended chains form the conditions for the formation of solid solutions.