Modeling of Particle Dissolution Behavior Using a Geometrical Phase-Field Approach.

Material dissolution is a critical attribute of many products in a wide variety of industries. The idealized view of dissolution through established prediction tools should be reconsidered because the number of new substances with low aqueous solubility is increasing. Due to this, a fundamental understanding of the dissolution process is desired. The aim of this study was to develop a tool to predict crystal dissolution performance based on experimentally measurable physical parameters. A numerical simulation, called the phase-field method, was used to simultaneously solve the time evolution of the phase and concentration fields of dissolving particles. This approach applies to diffusion-limited as well as surface reaction-limited systems. The numerical results were compared to analytical solutions, and the influence of particle shape and interparticle proximity on the dissolution process was numerically investigated. Dissolution behaviors of two different substances were modeled. A diffusion-limited model compound, xylitol, with a high aqueous solubility and a surface reaction-limited model compound, griseofulvin, with a low aqueous solubility were chosen. The results of the simulations demonstrated that phase-field modeling is a powerful approach for predicting the dissolution behaviors of pure crystalline substances.

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.

Groundwater Development Stress: Global-Scale Indices Compared to Regional Modeling.

The increased availability of global datasets and technologies such as global hydrologic models and the Gravity Recovery and Climate Experiment (GRACE) satellites have resulted in a growing number of global-scale assessments of water availability using simple indices of water stress. Developed initially for surface water, such indices are increasingly used to evaluate global groundwater resources. We compare indices of groundwater development stress for three major agricultural areas of the United States to information available from regional water budgets developed from detailed groundwater modeling. These comparisons illustrate the potential value of regional-scale analyses to supplement global hydrological models and GRACE analyses of groundwater depletion. Regional-scale analyses allow assessments of water stress that better account for scale effects, the dynamics of groundwater flow systems, the complexities of irrigated agricultural systems, and the laws, regulations, engineering, and socioeconomic factors that govern groundwater use. Strategic use of regional-scale models with global-scale analyses would greatly enhance knowledge of the global groundwater depletion problem.

Residence time modeling of hot melt extrusion processes.

The hot melt extrusion process is a widespread technique to mix viscous melts. The residence time of material in the process frequently determines the product properties. An experimental setup and a corresponding mathematical model were developed to evaluate residence time and residence time distribution in twin screw extrusion processes. The extrusion process was modeled as the convolution of a mass transport process described by a Gaussian probability function, and a mixing process represented by an exponential function. The residence time of the extrusion process was determined by introducing a tracer at the extruder inlet and measuring the tracer concentration at the die. These concentrations were fitted to the residence time model, and an adequate correlation was found. Different parameters were derived to characterize the extrusion process including the dead time, the apparent mixing volume, and a transport related axial mixing. A 2(3) design of experiments was performed to evaluate the effect of powder feed rate, screw speed, and melt viscosity of the material on the residence time. All three parameters affect the residence time of material in the extruder. In conclusion, a residence time model was developed to interpret experimental data and to get insights into the hot melt extrusion process.

Determination of the scale of segregation of low dose tablets using hyperspectral imaging.

In this work, near infrared (NIR) hyperspectral imaging was used to quantify the spatial distribution of drug in tablets containing tolmetin sodium dihydrate. Hyperspectral data cubes were generated by imaging the same spatial region of a sample while illuminated by a laser at a different wavelength for each image. Images were generated for wavelengths ranging from 1100 to 2200 nm. Ten tablets with concentrations ranging from 0.0 to 10.0% w/w tolmetin were imaged, and the scales of segregation were calculated for the tablets. Lactose anhydrous was used as the diluent, and all mixtures contained 0.5% magnesium stearate as a lubricant. This research has shown hyperspectral imaging to be viable tool for quantifying segregation of low dose drugs in tablets.

Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions.

We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.

Vibrational imaging of tablets by epi-detected stimulated Raman scattering microscopy.

Proper chemical imaging tools are critical to the pharmaceutical industry due to growing regulatory demand for intermediate and end-product content uniformity testing. Herein we demonstrate stimulated Raman scattering (SRS) imaging of active pharmaceutical ingredient (API) and four excipients within tablets. Tablets from six manufactures were imaged with a speed of 53 s per frame of 512 × 512 pixels (i.e., 200 µs per pixel) and a lateral spatial resolution as high as 0.62 µm. The SRS chemical imaging was compared to confocal Raman mapping and coherent anti-Stokes Raman scattering (CARS) chemical imaging in terms of speed and chemical selectivity. The acquisition speed of SRS imaging is ca. 10(4) times faster than confocal Raman mapping and SRS technique showed superior to CARS chemical selectivity for studied samples. Our data demonstrate the potential of SRS microscopy in high-speed screening of pharmaceutical solid dosage forms.