Can spray freeze-drying improve the re-dispersion of crystalline nanoparticles of pure naproxen?

Spray freeze drying (SFD) was used to prepare re-dispersible powders of crystalline, pure-drug nanodispersions of naproxen in lactose and stabilized with hydroxypropyl cellulose. The particle size of the rehydrated powders was determined using static light scattering/Mie analysis. The nanoparticles present in the SFD powders were aggregated but could be dispersed on re-dispersion with water and stirring either with or without additional ultrasonic treatment. The disaggregation of the SFD nanoparticles was superior to that reported in the literature for spray dried nanoparticles of the same composition. It appears that the moderately-rapid freezing of the large spray droplets in LN2 during SFD produces less aggregation than does evaporative drying of the much smaller droplets during spray drying. Re-dispersion was also found to depend strongly on the pH of the original nanodispersion. The solubility of this weak acid is greater at higher pH which resulted in formation of a dissolved fraction of drug in the nanodispersions during media milling. After SFD, the dissolved naproxen fraction formed an amorphous solid which re-dissolves on re-hydration whereas the crystalline nanoparticles disaggregate.

Effects of pH of processing-medium on re-dispersion of spray dried, crystalline nanoparticles of pure naproxen.

Crystalline nanodispersions of naproxen stabilized with hydroxypropyl cellulose were prepared at different pHs both below and above the pKa of the drug. After spray drying together with lactose, the measured particle size of the rehydrated dispersions using laser light scattering/Mie analysis was found to depend strongly on the pH of the original, processed nanodispersion. The pH-dependent solubility of this weak acid resulted in formation of a dissolved fraction of drug in the nanodispersions, this being higher as the pH increases. There was therefore a loss of crystalline naproxen during processing at higher pH, with fewer and/or smaller nanoparticles in the nanodispersion after nanomilling. After spray drying, the dissolved naproxen fraction formed an amorphous solid, as shown by differential scanning calorimetry and X-ray powder diffraction. The amorphous fraction re-dissolves on re-hydration. An improved disaggregation and smaller particle size of the nanoparticles at higher pH was observed because of the lower amount of crystalline nanoparticles now present. If the pH of the nanodispersion during processing is kept below the pKa for a weak acid, then a high yield of nanoparticles should be expected with little formation of an amorphous phase of the drug.

Enhanced dissolution of naproxen from pure-drug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets.

This is a case study of the use of rapidly-dissolving naproxen crystalline nanoparticles to prepare compressed tablets. The dissolution rates of different formulations were determined: the crystalline pure-drug nanodispersion, a pure-drug microsuspension, a granule prepared by spray drying the nanodispersion with mannitol, and a tablet prepared by compressing the granule with a bulking agent and a disintegrant. The goal was to determine the influence of each of the process steps on the rapid dissolution of the nanodispersion. A procedure was developed to allow sampling during the first 120 s of dissolution. Dissolution of the nanodispersion was completed after 60 s under both sink and non-sink conditions. Spray drying with mannitol delayed dissolution slightly under both sink and non-sink conditions. Under sink conditions a microsuspension (volume median size 11 µm) showed similar rapid dissolution to the nanodispersion. We propose this to be a result of rapid shrinkage of the microparticles on dissolution under sink conditions. This nullifies any effects of specific surface on dissolution rate. Under non-sink conditions the microparticles retain their lower specific surface for a longer time during dissolution and dissolve therefore more slowly. When compressed into tablets, the dissolution rates of nanoparticles or microparticles were determined primarily by the tablet disintegration time; the influence of sink or non-sink conditions was only observable after disintegration.

Effect of polymer species and concentration on the production of mefenamic acid nanoparticles by media milling.

The effect of four structurally different polymer species (hydroxypropylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and polyvinyl alcohol) on the production of mefenamic acid nanoparticles during media milling has been studied. It was found that product particle sizes are strongly determined by the type of polymeric stabiliser as well as by its concentration at constant process conditions. With respect to small product particle sizes an optimum excipient concentration was identified and adjusted for colloidal stability of the drug nanosuspensions. Furthermore, it was found that overdosing of excipients must be omitted to suppress ripening due to enhanced solubilisation phenomena. Hence, the smallest product particle sizes were obtained using a polymeric stabiliser which exhibits a high affinity to the model drug compound and a low solubilisation capacity. Affinities of each polymer species to mefenamic acid and corresponding surface concentrations were determined using straightforward and simple viscosity measurements of the supernatant. A relationship between polymer affinity, solubilisation capacity and limiting product particle size has been observed, which supports the hypothesis that final product particle sizes are rather determined by the solid-liquid equilibrium than by pure mechanical fracture.

pH effects on the molecular structure of ß-lactoglobulin modified air-water interfaces and its impact on foam rheology.

Macroscopic properties of aqueous ß-lactoglobulin (BLG) foams and the molecular properties of BLG modified air-water interfaces as their major structural element were investigated with a unique combination of foam rheology measurements and interfacial sensitive methods such as sum-frequency generation and interfacial dilatational rheology. The molecular structure and protein-protein interactions at the air-water interface can be changed substantially with the solution pH and result in major changes in interfacial dilational and foam rheology. At a pH near the interfacial isoelectric point BLG molecules carry zero net charge and disordered multilayers with the highest interfacial dilatational elasticity are formed at the air-water interface. Increasing or decreasing the pH with respect to the isoelectric point leads to the formation of a BLG monolayer with repulsive electrostatic interactions among the adsorbed molecules which decrease the interfacial dilational elasticity. The latter molecular information does explain the behavior of BLG foams in our rheological studies, where in fact the highest apparent yield stresses and storage moduli are established with foams from electrolyte solutions with a pH close to the isoelectric point of BLG. At this pH the gas bubbles of the foam are stabilized by BLG multilayers with attractive intermolecular interactions at the ubiquitous air-water interfaces, while BLG layers with repulsive interactions decrease the apparent yield stress and storage moduli as stabilization of gas bubbles with a monolayer of BLG is less effective.