Anna Millqvist-Fureby

Surface composition of spray-dried milk protein-stabilised emulsions in relation to pre-heat treatment of proteins.

Several important technical properties of spray-dried food powders depend on particle-liquid interactions (e.g. wettability, dispersability) and particle-particle interactions (e.g. flowability). It can be assumed that the chemical composition of the surface layer of the particles to a large extent determine these properties. The present study has been aimed to investigate the relation between the surface composition of spray-dried milk protein-stabilised emulsions and pre-heat treatment of the proteins. Solutions of WPC were heat-treated at low (60-90 degrees C) and high (140 degrees C) temperature and the degree of denaturation was determined, prior to the preparation of emulsions with rapeseed oil. The surface composition of the dry powders were established by using ESCA (electron spectroscopy of chemical analysis). The emulsions were characterised by droplet size distribution before spray drying and after dissolution of the powders. Also free fat extractions and estimations of wettability (dissolution rates) were performed. The powder surface coverage of protein decreased with increasing degree of protein denaturation before the emulsification, whereas the emulsion droplet size increased both before spray drying and after reconstitution of powders. The free fat extraction as well as the dissolution rate, whereof the latter decreased with increasing surface fat coverage, correlated well with the fat coverage of the powder surface.

Spray-drying of trypsin — surface characterisation and activity preservation

In the present study trypsin mixed with various carbohydrates, i.e. lactose, sucrose, mannitol, alpha-cyclodextrin and dextrin, was spray-dried in order to investigate the effects of spray-drying on this enzyme, with particular emphasis on the effects of interactions between trypsin and the surface formed during spray-drying. The protein was strongly over-represented at the surface of the powder particles, the surface coverage ranging from 10 to 65%, depending on the amount of trypsin in the solids (0.2-5%). This indicates that the protein adsorbs at the air/liquid interface of the spray-droplets, and that this surface is also largely preserved after drying. The surface concentration of protein in the spray-dried powders could be controlled by adding a surfactant to the mixture before drying, since the surfactant adsorbs preferentially at the air/liquid interface of the spray droplets, thus expelling protein from the surface. In general, the residual activity of trypsin in these non-optimised formulations was 90% or higher, and in no case less than 82%. It was found that the loss of activity could partly be explained by inactivation of the protein adsorbed at the surface. For mannitol and sucrose, however, the level of inactivation was higher than could be explained by surface inactivation alone, and additional mechanisms must also be considered.

Surface characterisation of freeze-dried protein/carbohydrate mixtures

In the present investigation freeze-drying of proteins (BSA or trypsin) together with various carbohydrates, i.e. lactose, sucrose, mannitol, alpha-cyclodextrin and dextrin, has been studied with particular emphasis on the surface composition of the freeze-dried powders. The proteins were found to be over-represented on the powder surface as compared to the bulk concentration of protein. The mechanism behind the surface accumulation is believed to be that proteins adsorb preferentially over carbohydrates to the ice/liquid interface in the frozen sample. The degree of surface accumulation depended on the carbohydrate used, and was increased in annealed samples compared to reference samples. The activity of trypsin was fairly well preserved (58-90%) in the freeze-dried powders, but depended on the carbohydrate excipient, whilst the surface composition had little effect on the activity. The activity preservation was improved when the protein concentration was raised from 1 to 10% in the solids. The surface composition of powders containing mixtures of mannitol and dextrin as excipients depended on the ratio between the two carbohydrates, with the lowest surface coverage of protein obtained in 50/50 mixtures.

Surface composition and contact angle relationships for differently prepared solid dispersions

Solid dispersions are promising drug delivery forms which offer the possibility to disperse a hydrophobic drug in a hydrophilic matrix and thereby improve the dissolution behavior and the bioavailability of the drug. One important aspect and a prerequisite in understanding the drug dissolution mechanism from solid dispersions is a better analytical monitoring of the solid dispersion surface properties, such as powder surface composition and water adsorption properties. In this paper, we have considered chemical and structural surface analysis data for solid dispersions processed by spray drying or roto-evaporation and compared these data with information obtained by contact angle measurements. Firstly, we establish the usefulness and suitability of X-ray photoelectron spectroscopy (XPS) for determination of surface chemical composition and scanning electron microscopy (SEM) for determining the structure of solid dispersions composed of different types of carriers, drugs and drug concentrations. Secondly, we measure contact angles of solid dispersions to describe wettability, to finally establish a link between the surface chemical composition, the powder structure and the wetting behavior. These experimental methods offer a rapid screening tool for the selection of carrier, drug concentration and/or process in early development. In addition, they provide a useful tool for investigating structural aspects of solid dispersions which have intrinsic relevance for drug dissolution and stability.

Polymer–drug interactions and wetting of solid dispersions

We demonstrate the ability of drugs to influence the wetting of solid dispersion tablets in unexpected ways. Five model drugs of different water solubility and ability to interact with the involved polymers were incorporated in hydrophilic polymer matrices, made of either hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP). The physical mixtures of all combinations of drug and polymer presented surface hydrophobicities, as measured by the equilibrium advancing contact angle of water, which are expected for materials that do not influence the interactions of each other with water. However, the solid dispersions containing HPMC deviated from this regular behaviour and displayed contact angles below those of the pure compounds involved, either drug or polymer. This behaviour is explained by changed surface exposure of HPMC side groups, as a result of changes in intermolecular hydrogen bonds. In addition to water contact angle measurements, we employed NMR imaging to monitor the time course of water ingress and swelling.

Relationships between solid dispersion preparation process, particle size and drug release : an NMR and NMR microimaging study

Solid dispersion tablets prepared by either spray drying or rotoevaporation and exhibiting different grain and pore sizes were investigated under the process of hydration-swelling-gelation. (2)H and (1)H NMR microimaging experiments were used to selectively follow water penetration and polymer mobilization kinetics, respectively, while the drug release kinetics was followed by (1)H NMR spectroscopy. The obtained data, in combination with morphological information by scanning electron microscopy (SEM), reveal a complex process that ultimately leads to release of the drug into the aqueous phase. We find that the rate of water ingress has no direct influence on release kinetics, which also renders air in the tablets a secondary factor. On the other hand, drug release is directly correlated with the polymer mobilization kinetics. Water diffusion into the originally dry polymer grains determines the rate of grain swelling and the hydration within the grains varies strongly with grain size. We propose that this sets the stage for creating homogeneous gels for small grain sizes and heterogeneous gels for large grain sizes. Fast diffusion through water-rich sections of the inhomogeneous gels that exhibit a large mesh size is the factor which yields a faster drug release from tablets prepared by rotoevaporation.

Surface Composition and Morphology of Particles Dried Individually and by Spray Drying

This study investigates how the morphology of spray-dried particles is related to the formulation and properties of the components in the formulation. Further, the scale effects in comparisons of levitation-dried single particles and spray-dried particles in a lab-scale spray dryer have been addressed. The Drying Kinetics AnalyzerTM generates single particles from a levitated drop under simulated spray-drying conditions. A set of surface-active polymers (bovine serum albumin, hydroxypropyl methyl cellulose, and triblock co-polymer Poloxamer), in combination with lactose, were analyzed for their dynamic surface properties in solution, and their effect on particle morphology and surface composition were determined by low-vacuum SEM and XPS analyses. The morphology obtained in spray drying was reproduced in the single-particle drying. The surface compositions were also similar, but higher levels of surface-active materials were found at the surface of the single particles as compared to the spray-dried particles. Further, the adsorption rate of surface-active compounds at the drop surface estimated by dynamic surface tension was found to be an important parameter to estimate the surface composition at different drying scales. The particle morphology was primarily determined by the surface rheological properties of the feed solution and, to a lesser extent, by the surface composition.

Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure

Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle-particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture.

Stability of spray-dried protein- stabilized emulsions—effects of different carbohydrate additives

Stability of spray-dried protein-stabilized emulsions : Effects of different carbohydrate additives

Phase segregation in individually dried particles composed of biopolymers

Mixing of two biopolymers can results in phase separation due to their thermodynamically incompatibility under certain conditions. This phenomenon was first reported when the solution was allowed to equilibrate, but it has later been observed also as a consequence of drying. The challenges of this study were to observe phase segregation by confocal Raman microscopy and LV-SEM on dried film, individually dried particles, and spray dried particles. The influence of the solid content and the phase ratio (composition) of a HPMC/maltodextrin mixture on the localization of the ingredients in the individually dried particles was investigated. We observed that phase segregation of HPMC and maltodextrin is induced by solvent evaporation in film drying, single particle drying, as well as spray drying. The phase ratio is an important parameter that influences the localization of the HPMC-enriched phase and maltodextrin-enriched phase, i.e., to the particle surface, to the core, or in a more or less bicontinuous pattern. The drying time, affected by the solids content, was found to control the level of advancement of the phase segregation.