Limited drug solubility can be decisive even for freely soluble drugs in highly swollen matrix tablets.

The aim of this study was to elucidate the importance of potential limited solubility effects for the control of drug release from hydrophilic matrix tablets loaded with a freely water-soluble drug. It is often assumed that the considerable amounts of water penetrating into this type of advanced drug delivery systems are sufficient to rapidly dissolve the entire drug loading, and that limited drug solubility is not playing a role for the control of drug release. Here, we show that this assumption can be erroneous. HPMC/lactose matrix tablets were loaded with 5 to 60% diprophylline (e.g. solubility in 0.1M HCl at 37°C: 235mg/mL), and drug release was measured at low and neutral pH, respectively. A mechanistically realistic mathematical theory was applied, considering drug diffusion in axial and radial direction in the cylindrical matrices and the potential co-existence of dissolved and non-dissolved drug. Importantly, only dissolved drug is available for diffusion. It is demonstrated that during major parts of the release periods, non-dissolved drug excess exists within tablets containing 30% or more diprophylline, despite of the substantial water contents of the systems. This leads to partially almost linear drug concentration distance profiles within the tablets, and reveals a major contribution of limited drug solubility effects to the control of drug release, even in the case of freely water-soluble diprophylline. It can be expected that also in other types of drug delivery systems, e.g. microparticles and implants (containing much less water), limited drug solubility effects play a much more important role than currently recognized.

Predicting drug release from HPMC/lactose tablets.

Three mathematical models were applied to quantify drug release from HPMC/lactose-based matrix tablets loaded with varying amounts of theophylline: (i) a numerical model considering drug diffusion in axial and radial direction in cylinders as well as limited drug solubility effects, (ii) an analytical solution of Fick's second law of diffusion considering axial and radial mass transport in a cylinder, but neglecting limited drug solubility effects, and (iii) a simple early time approximation of the analytical solution, considering only radial mass transport and neglecting axial diffusion as well as limited drug solubility effects. The three models were fitted to experimentally determined drug release kinetics from various types of tablets in 0.1M HCl and phosphate buffer pH 7.4. Interestingly, the agreement between fitted theories and experimental data was similar in all cases. However, the determined system specific model parameters (apparent diffusion coefficients of theophylline in the polymeric matrices) were significantly biased when using simplified theories. Nevertheless, the reliability of theoretical predictions was similar for all three models, since the determined apparent diffusivities are partially "lumped" parameters. Thus, from a practical point of view, very simple equations can be used during product optimization, allowing estimating the effects of formulation parameters on drug release.

Extreme thermostability of tarantula hemocyanin.

Biotops with extreme temperatures such as deserts force animals to avoid or escape high temperatures by biochemical, behavioural or morphological adaptation. In this context we tested the resistance to heat of the oxygen carrier hemocyanin from the ancient tarantula Eurypelma californicum, which is found in arid zones of North America. Differential scanning calorimetry, light scattering, crossed immunogelelectrophoresis and oxygen binding experiments show that the 24-meric hemocyanin is conformationally stable and fully functioning at temperatures up to 90 degrees C. Our results demonstrate that the cation-mediated state of oligomerization is not only crucial for the high cooperativity of oxygen binding of this hemocyanin, but also for its extreme stability in the physiological temperature and pH range.