(42c) Spray Dried Submicron Sized Particles for Pharmaceutical Application

The low water solubility of newly identified active pharmaceutical ingredients necessitates new strategies, since the dissolution of the drug in an aqueous solution is essential to ensure pharmacological response. So far, different approaches and strategies were developed to increase the bioavailability (physical and chemical modifications) by increasing their aqueous solubility and dissolution rate. This work focusses on the generation of submicron sized particles (0.1-1 µm) of the pure drug. Due to the increased specific surface area of submicron sized drugs, the dissolution rate increases according to the Nernst Brunner equation. Particle size reduction down to the submicron range also leads to increased saturation concentration, described by the Ostwald-Freundlich equation.

One possibility for the generation of submicron sized particles is the spray drying process. The pure solution is firstly atomized, dried and finally separated from the drying gas, usually by a cyclone. Spray drying is a single step process, beginning with the liquid to the dry powder. Particle size, shape and morphology can be adjusted by controlling the spray drying conditions.

However, spray drying for the preparation of submicron particles is challenging. The particle size during spray drying is mainly limited by the droplet size and the feed concentration. Thus, small droplet sizes with the use of higher concentrations are preferable. Conventional atomizer show limitations in the generation of small droplets (d_50,3<3 µm). Next to the atomization step, the precipitation of particles down to the submicron range with conventional cyclone particle separator is limited.

In this work, the advantages of the spray drying process is used and additional methods were integrated to generate a robust process with a long-term stability for the preparation of submicron particles.

To overcome the challenge of the production of fine droplet, a two-fluid nozzle with internal mixing is combined with a cyclone droplet separator. Two-fluid-nozzles show advantages regarding atomization of higher viscous solutions and concentration, thus generating the smallest droplet sizes (d_50,3=10 µm), compared to other atomization techniques. According to a specific cut-off diameter of the cyclone droplet separator, bigger droplets were separated and returned back into the liquid feed. Thus, only droplets smaller the cut-off diameter reaches the following drying stage. The dried submicron sized particles are then separated from the drying gas. This is done by using an electrostatic precipitator. The particles were collected at the inner wall of the precipitator.

The experiments were figured out with a 10 w.-% mannitol (Roquette ^® Pharma, Lestrem, France) solution as a physiologically uncritical model substance. First, the volumetric droplet size distribution of the conditioned aerosol after the cyclone separator process was analyzed by laser diffraction technique (Malvern Instruments, Spraytec, Malvern, Worcestershire, United Kingdom). The mean volumetric droplet size d_50,3 and the span value were extracted from the distribution. Different liquid-to-gas mass flow ratios in the range of 0.8 to 1.8 were used and the gas pressure was held constant at about Δp=5 bar. It could be shown, that the mean volumetric droplet size is constant (1.9 µm) for different liquid-to-gas mass flow ratios µ. Thus, the droplet size only depends on the cut-off-size of the droplet separator. The droplet size distribution generated by a two fluid nozzle depends on the characteristics of the liquid feed, the liquid-to-gas mass flow ratio and the gas pressure Δp. In addition, the mean volumetric droplet size was measured for different Polyvinylpyrrolidone K30 (BASF; Ludwigshafen, Germany) solutions with viscosities of 9, 20 and 41 mPas. Even for different viscosities, the mean droplet size depends only on the cut-off size of the separator, and is still constant at about 1.9 µm. With this concepts, fluctuation in the primary aerosol were compensated, thus a well defined spray is introduced into the drying chamber.

The mass flow of droplets in the conditioned aerosol is determined by the amount of droplets smaller than the cut-off size in the primary aerosol. Thus, the useful yield of the primary aerosol essentially determines the particle yield after drying.

A compact spray dryer was designed. The aerosol conditioning step with the two-fluid nozzle and the cyclone droplet separator was combined with the drying step and the electrostatic precipitator. First drying experiments with a 10 wt. - % mannitol solution confirm the generation of submicron particles with a mean volumetric diameter of d_50m,3=0.7 µm.

Spray drying experiments will be realized by using pure pharmaceutical model drugs. The particle size will be determined by laser diffraction and the morphology and shape will be analyzed by evaluating scanning electron microscopy images of the dried particles. In addition, the crystallinity of the particles will be determined by X-ray diffraction. Finally, in order to test the in vitro drug release of the spray dried submicron sized particles, dissolution tests will be presented.