Insights into the Mechanism of Enhanced Dissolution in Solid Crystalline Formulations.

Solid dispersions are a promising approach to enhance the dissolution of poorly water-soluble drugs. Solid crystalline formulations show a fast drug dissolution and a high thermodynamic stability. To understand the mechanisms leading to the faster dissolution of solid crystalline formulations, physical mixtures of the poorly soluble drugs celecoxib, naproxen and phenytoin were investigated in the flow through cell (apparatus 4). The effect of drug load, hydrodynamics in the flow through cell and particle size reduction in co-milled physical mixtures were studied. A carrier- and drug-enabled dissolution could be distinguished. Below a certain drug load, the limit of drug load, carrier-enabled dissolution occurred, and above this value, the drug defined the dissolution rate. For a carrier-enabled behavior, the dissolution kinetics can be divided into a first fast phase, a second slow phase and a transition phase in between. This study contributes to the understanding of the dissolution mechanism in solid crystalline formulations and is thereby valuable for the process and formulation development.

Intrinsic dissolution rate modeling for the pharmacopoeia apparatus rotating disk compared to flow channel method.

For a solid understanding of drug characteristics, in vitro measurement of the intrinsic dissolution rate is important. Hydrodynamics are often emphasized as the decisive parameter influencing the dissolution. In this study, experiments and computational fluid dynamic (CFD) simulations showed that the mixing behavior in the rotating disc apparatus causes an inhomogeneous flow field and a systematic error in the calculation of the intrinsic dissolution rate. This error is affected by both the experimental time and the velocity. Due to the rotational movement around the tablet center, commonly utilized in pharmacopeia methods, a broad variance is present with regard to the impact of fluid velocity on individual particles of the specimen surface. As this is significantly reduced in the case of uniform overflow, the flow channel is recommended for investigating the dissolution behavior. It is shown that rotating disc measurements can be compared with flow channel measurements after adjusting the measured data for the rotating disc based on a proposed, representative Reynolds number and a suggested apparatus-dependent correction factor. Additionally, modeling the apparatus-independent intrinsic dissolution rate for different temperatures in the rotating disc apparatus is possible using the adapted Levich's equation.

Determination of Inherent Dissolution Performance of Drug Substances.

The dissolution behavior of novel active pharmaceutical ingredients (API) is a crucial parameter in drug formulation since it frequently affects the drug release. Generally, a distinction is made between surface-reaction- and diffusion-controlled drug release. Therefore, dissolution studies such as the intrinsic dissolution test defined in the pharmacopeia have been performed for many years. In order to overcome the disadvantages of the common intrinsic dissolution test, a new experimental setup was developed within this study. Specifically, a flow channel was designed and tested for measuring the mass transfer from a flat, solid surface dissolving into a fluid flowing over the surface with well-defined flow conditions. A mathematical model was developed that distinguishes between surface-reaction- and diffusion-limited drug release based on experimental data. Three different drugs-benzocaine, theophylline and griseofulvin-were used to investigate the mass flux during dissolution due to surface reaction, diffusion and convection kinetics. This new technique shows potential to be a valuable tool for the identification of formulation strategies.

Preparation of submicron drug particles via spray drying from organic solvents.

Manufacturing poorly water-soluble active pharmaceutical ingredients (API) with sufficient bioavailability is a significant challenge in pharmaceutical research. A higher bioavailability can reduce both the applied dosage and the side effects for the patient. One method of increasing the bioavailability is to reduce the particle size of the drug down to the nanoscale. An innovative procedure for the preparation of particles in the submicron size range is spray drying with aerosol conditioning, followed by subsequent separation of the particles in an electrostatic precipitator (ESP). This process has been tested before in an earlier work with aqueous model substances at high production rates (1 g/h) and narrow particle-size distributions (mannitol: d50,0 = 455 nm, span = 0,8) in the submicron range. Spray drying from an aqueous solution with low drug concentrations (<1 wt-%) leads to particles in the lower nanosize range, but the low concentrations make this process inefficient. A custom-made plant was modified in order to handle the organic spray-drying process. In addition, explosion protection had to be considered. This work focuses on the spray drying of submicron particles from organic solvents for the purpose of increasing the dissolution rate of the API griseofulvin. API particles were successfully produced in the submicron size-range, characterized and the dissolution behavior was investigated. The dissolution time to dissolve 80% of the drug, t80, was reduced from 21.5 min for the micronized grade API to 8.5 min for the submicron product.

Preparation of spray dried submicron particles: Part A - Particle generation by aerosol conditioning.

The preparation of submicron-sized particles is relevant in chemical, food and pharmaceutical applications. In pharmaceutics, spray dried submicron-sized particles (0.1-1 µm) can increase the dissolution rate as well as the solubility of poorly water-soluble drugs. Since the particle size during spray drying is mainly influenced by the droplet size, the preparation of uniform droplets smaller than 3 µm is of particular interest. In this work, a two-fluid nozzle was combined with a cyclone droplet separator. Droplets larger than the cut-off size were separated with a cyclone droplet separator and returned to the liquid feed. The aerosol at the outlet of the droplet separator was subsequently dried. The drop size of the conditioned aerosol was small, d50,3=2 µm, and independent of the liquid-to-gas mass flow ratio and the viscosity of the liquid feed. Thus it only depended on the characteristics of the separator. Finally, the dried particles were spherical in shape and in the submicron-sized range.