Maggie Aldén

Protection mechanism of Tween 80 during freeze-thawing of a model protein, LDH.

The purpose of the study was to investigate the protective mechanism of a non-ionic surfactant, Tween 80, at freeze-thawing with controlled temperature history of a model protein, lactate dehydrogenase (LDH). The system was examined by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). LDH activity assays were performed spectrophotometrically. In all samples, independent of temperature history and addition of surfactant, all water was crystallized to polycrystalline ice at temperatures below -20 degrees C. The size and perfection of the ice crystals could be varied by a range of cooling rates giving different degrees of undercooling. At Tween concentrations below the cmc at crystallization, lower concentrations were required at low cooling rates compared to higher cooling rates to protect LDH. Concentrations above cmc of Tween reduced the protection at a cooling rate of 5 degrees C min(-1) and at quenching in N(2)(l). The amount of Tween needed for complete protection correlated to the surface area of the ice crystals at a certain temperature history. Tween 80 protects LDH from denaturation at freeze-thawing by hindering its destructive interaction with the ice crystals. The protective effect might be obtained when Tween molecules compete with the protein for sites on the ice surface. The optimum concentration of Tween needed for complete protection is dependent on the temperature history.

Physicochemical aspects of drug release. XIV. The effects of some ionic and non-ionic surfactants on properties of a sparingly soluble drug in solid dispersions

Abstract The nonionic surfactants polysorbate 80 and polyethylene dodecyl ether (Brij 35), the anionic surfactant sodium dodecyl sulphate (SDS) and the cationic surfactant, dodecyltrimethylammonium bromide (DTAB) were incorporated in dispersions of 10% w/w griseofulvin with PEG 3000 as a carrier. An almost instant and complete dissolution was obtained for dispersions with 1 and 2% w/w SDS. X-ray diffraction revealed that a complete molecular dispersion i.e. a solid solution, of griseofulvin in PEG/SDS was obtained when 2% w/w SDS was incorporated. A continuous increase in dissolution rate with increase in concentration was observed for dispersions containing the other surfactants but polysorbate 80, Brij 35 and DTAB were not as effective as SDS in increasing the dissolution rate. X-ray diffraction revealed a decrease in the amount of crystalline griseofulvin with increase in surfactant concentration except with polysorbate 80, for which no changes were observed. Differential scanning calorimetry studies supported the results obtained by X-ray diffraction. A relationship between the solubilizing efficiency of the surfactant in aqueous solutions and its ability to increase the solid solubility of a drug in PEG, and subsequently the dissolution rate, was observed. Measurements after 12 months of storage revealed that the dissolution rate was unchanged for the dispersions without surfactant or with polysorbate 80. However, at higher concentrations of Brij 35, DTAB and SDS, the dissolution rates were decreased upon storage.

Physicochemical aspects of drug release. XVI. The effect of storage on drug dissolution from solid dispersions and the influence of cooling rate and incorporation of surfactant

Abstract Solid dispersions of 10% w w griseofulvin were prepared with polyethylene glycol (PEG) 3000 or xylitol as carriers, with or without the incorporation of 2% w w sodium dodecyl sulphate (SDS). The dispersions were cooled either slowly at room temperature or rapidly in liquid nitrogen. The dispersions were stored under controlled conditions at 25, 35 and 45°C and dissolution rate studies, particle size measurements, phase analysis and heat of fusion measurements were performed at intervals during 10 months. In dispersions with PEG as carrier, without SDS, griseofulvin was present in crystalline form. The dissolution rate was unchanged during storage for dispersions prepared with slow cooling, but decreased for dispersions prepared with rapid cooling. This may have been caused by an increase in PEG crystallinity with storage time. With the incorporation of SDS, the dissolution rate initially increased considerably for dispersions with PEG as carrier. Griseofulvin was dissolved in the carrier/ surfactant system in dispersions prepared with slow cooling, whereas griseofulvin was present in pure crystalline form in corresponding dispersions prepared with rapid cooling. Dispersions stored at 45°C liquified on storage independent of cooling procedure and were excluded from the study. The dissolution rate decreased considerably for dispersions prepared with slow cooling, since the dissolution of PEG was impaired by the incorporation of SDS. The dissolution rate of dispersions prepared with rapid cooling also decreased with storage temperature. Griseofulvin was present in crystalline form in all dispersions with xylitol as carrier and the dissolution rate and particle size remained unchanged irrespective of storage temperature and time. The dissolution rate was increased with the incorporation of SDS, but not to the same extent as in PEG dispersions. With increase in storage temperature the dissolution rate decreased, because of decreased dissolution of xylitol with the incorporation of SDS.

Physicochemical aspects of drug release. XIII, The effect of sodium dodecyl sulphate additions on the structure and dissolution of a drug in solid dispersions

Abstract Solid dispersions of the sparingly soluble drug griseofulvin were prepared by the melting method with polyethylene glycol (PEG) 3000 as a carrier. The anionic surfactant sodium dodecyl sulphate (SDS) was incorporated during the preparation, in order to study the effect on incorporated state and dissolution of the drug. Dissolution rate measurements were performed according to USP XXI (paddle method) on dispersion particles in media of pure distilled water or distilled water with different concentrations of SDS, all below the critical micelle concentration. For solid dispersions without SDS incorporated, the dissolution rate was reduced with an increase in griseofulvin content. When SDS was added to the medium the dissolution rate increased in proportion to the concentration of SDS. These results support the assumption that wetting the dispersion particles is important in the dissolution process of these systems. The fastest drug dissolution was obtained for dispersions incorporating SDS. In dispersions containing 1% w/w SDS, 90% of the griseofulvin was dissolved within 2 min, independent of drug concentration and dissolution medium. It was possible to determine the relative amounts of each phase using the X-ray diffraction method. It was observed that in solid dispersions without SDS incorporated, both the pure griseofulvin phase and the pure PEG phase were present. In samples with SDS incorporated the phase composition changed. A large amount of griseofulvin was dissolved in the PEG/SDS structure forming a solid solution. In solid dispersions of 3 and 10% w/w griseofulvin with 1 and 2% w/w SDS incorporated, respectively, no pure griseofulvin phase was seen and the solid solution of griseofulvin in the PEG/SDS structure was the only phase appearing. The heat of fusion values, obtained by DSC, supported the idea of a change in the phase composition in the systems with the incorporation of SDS.

Solid state studies of drug–cyclodextrin inclusion complexes in PEG 6000 prepared by a new method

The melting method was investigated as a possible method for producing drug-cyclodextrin (CD) inclusion compounds in a carrier. Various solid dispersions of alpha-, beta- and gamma-CD in polyethylene glycol (PEG) 6000 with and without the addition of 5% w/w indomethacin or griseofulvin were prepared using the original components. Characterisations of the samples included X-ray powder diffraction, modulated-temperature differential scanning calorimetry and dissolution tests by the paddle method according to USP XXI standard. Evidence of a complex between indomethacin and beta-CD in PEG 6000 was found. An indomethacin-gamma-CD complex formed a well defined phase in the PEG carrier, with tetragonal structure and unit cell parameters a=23.885(35) A and c=23.181(64) A. No complexation of indomethacin with alpha-CD, or with griseofulvin and beta-CD could be detected. It is suggested that competition between PEG and the drug for the binding to different CDs along with varying patterns of water loss from the CDs influence the inclusion reaction. The formation of complexes was accompanied by a decrease in the relative crystallinity of the dispersions. Dissolution tests showed that the CDs have a delaying effect on the release of indomethacin from PEG 6000 in the order alpha-CD

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.

Phase equilibria in drug-polymer-surfactant systems☆

Abstract Solid dispersions of griseofulvin were prepared by the melting method with polyethylene glycols (PEGs) of molecular weights 3000, 6000 and 20 000 as carriers, with or without the incorporation of the anionic surfactant sodium dodecyl sulphate (SDS). The state diagrams for griseofulvin and different PEGs with SDS added and the state diagram with PEG 6000 and griseofulvin alone were obtained using X-ray powder diffraction and differential scanning calorimetry. Solid solutions of griseofulvin in both pure polyethylene glycol and polyethylene glycol with SDS incorporated were formed. The pure polymers dissolved less than 3% w/w griseofulvin. When SDS was incorporated in the polyethylene glycols, the solid solubility of griseofulvin increased to 40% w/w in PEG 6000 and to 25% w/w in PEG 3000 and PEG 20 000. The solid solutions of griseofulvin in PEG with SDS incorporated melted close to the melting temperature of the pure PEG phases. Their heat of fusion values differed significantly from those of the solid dispersions. The effect of different alkali dodecyl sulphates, LiDS, SDS and KDS, forming solid solutions with PEG 3000 and griseofulvin was analysed using oscillating differential scanning calorimetry in the temperature interval −60°C to 80°C. The thermal behaviour of the LiDS-containing solid solution was different from those of SDS- and KDS-containing compounds, with respect to both the C p (reversible) component and the kinetic (irreversible) component. The enthalpy changes exposed by the ΔH C p and ΔH K components were extremely sample-dependent, whereas the conventional ΔH values were constant.

Physicochemical aspects of drug release. IX: Investigation of some factors that impair dissolution of drugs from solid particulate dispersion systems

Abstract Solid dispersions of different concentrations of griseofulvin (3, 10 and 20 w/w%) have been prepared by the melting method with polyethylene glycol (PEG) 3000 as a carrier. Different concentrations of the viscosity-enhancing agent Aerosil, colloidal silicon dioxide, and Ac-Di-Sol, a disintegrant of an internally cross-linked form of sodium carboxy methyl cellulose, alone or in combination, were added to the melts before solidification. In all samples investigated the PEG and griseofulvin phases were identified by X-ray powder diffraction. No solid solution or intermediate phase was observed. The dispersions were present as physical mixtures of the carrier and the drug. Dissolution rate measurements were performed according to USP XXI, paddle method 100 rpm, at 21 ± 1°C in a medium of deionized water with 0.9% sodium chloride and 0.01% polysorbate 80. The fastest dissolution of griseofulvin was obtained for dispersions containing the lowest concentration of drug, in the absence of additives. An increase in drug content, to 10 and 20 w/w%, or the addition of Aerosil markedly decreased the release and dissolution rate of griseofulvin. The further addition of Ac-Di-Sol improved the dissolution only for dispersions containing Aerosil, but no such effect was obtained for dispersions with higher concentrations of drug. A high concentration of fine particulate griseofulvin in the dispersion corresponds to a dissolution surface area of pronounced hydrophobic nature. In these systems inadequate wetting may be the rate-limiting step in the dissolution process, and the incorporatino of the disintegrant does not affect the dissolution. The observed decrease in drug dissolution for systems with Aerosil incorporated may be explained by a lower solubility of PEG 3000 due to a change in its crystallinity, as observed by X-ray powder diffraction. The change in crystallinity was confirmed by DSC measurements where the heats of fusion for samples containing Aerosil, were increased compared to predicted values.

Structures formed by interactions in solid dispersions of the system polyethylene glycol-griseofulvin with charged and non charged surfactants added

Abstract Solid dispersions of polyethylene glycol (PEG) 3000 and 10% w/w griseofulvin with incorporation of different types of surfactants were prepared by the melting method. The anionic surfactant sodium dodecyl sulphate (SDS), the cationic surfactant dodecyltrimethylammonium bromide (DTAB) and the nonionic surfactant polyoxyethylene dodecyl ether (Brij) were added in equivalent amounts. Phase analysis was made by X-ray powder diffraction and investigation of the short-range structure by 13 C-CP/MAS solid-state NMR. The addition of the different types of surfactants influences the structure of the dispersions in a varying manner. The anionic surfactant SDS forms a solid solution, the nonionic Brij does not influence the particulate dispersion and the cationic DTAB creates a dispersion, that only to a certain extent is a solid solution. The extent of interaction between polymer and surfactant aggregates (micelles) seems to be crucial for the formation of solid solutions of griseofulvin in the polymer phase. The charged surfactants can interact with the polymer forming aggregates, while the nonionic ones show no interaction. When a solid solution is formed, the hydrophilic parts of the griseofulvin molecule are significantly influenced. The surfactant aggregates bind griseofulvin in a molecular form at the surface or, more probably, in the interior of the aggregate.

Interaction Between Lactate Dehydrogenase and Tween 80 in Aqueous Solution

AbstractPurpose. The weak aqueous interaction between the protein lactate dehydrogenase (LDH) and the nonionic surfactant Tween 80 has been investigated, because weak protein-amphiphile interactions are of significant importance in pharmaceutical formulations, but are experimentally hard to determine. The system LDH/sodium dodecyl sulphate (SDS) was used as reference because SDS, by its strong protein binding, denatures LDH completely. Methods. Fluorescence spectroscopy with pyrene and 1,3-bis(1-phenyl)propane (P3P) as probes, intrinsic protein fluorescence and NMR spectroscopy have been used. Results. The fluorescence probe pyrene monitors a weak Tween-LDH interaction, detectable below the critical micelle concentration of ordinary Tween micelles. The microviscosity probe P3P shows a surfactant-induced denaturation in the case of LDH/SDS but not in the case of LDH/Tween 80. Intrinsic LDH fluorescence verifies this behavior. Pulsed-gradient spin-echo NMR was also used to verify the weak LDH-Tween 80 interaction. Conclusions. A weak interaction between LDH and Tween 80 occurs at hydrophobic zones of the protein, but it is not strong enough to denature LDH. The experimental outline used here provides a useful approach for mapping the very weak protein-amphiphile interactions often present in pharmaceutical formulations.