Insights into the Control of Drug Release from Complex Immediate Release Formulations.

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution

Novel Chromatographic Approaches for Class Separations of Small Molecules

Chromatographic separations have been a part of the analytical scientists’ toolkit for over a century and the techniques are constantly being improved upon. As chromatography progresses, more difficult separations become possible, and eventually commonplace. Advances in stationary phase technology, such as superficially porous particles, and the rapid growth of hydrophilic interaction liquid chromatography, have opened the doorway to the exploration of novel separations. The development of analytical methods for the sensitive and quantitative analysis and separation of underivatized amino acids is an example of a very challenging class of small molecules to separate. Here we detail the development, validation and application of the successful separation of these underivatized amino acids. With the advancement of stationary phases that are more resistant to pH than their predecessors were, analyses using wide-ranging pH values can now be explored without damaging the column components. Careful design and application of pH gradients using these columns can therefore be used to not just to separate analytes from each other, but also to sequentially separate by the analyte classes, such as acidic, basic and neutral components. This novel technique developed here is termed sequential elution liquid chromatography. This simplification of the chromatogram by class separation via use of multiple segments within a single analysis allows for a reduction of the amount of peaks that need to be separated, thereby increasing the probability of the successful separation. A set of benzene derivatives was used here to demonstrate the potential of this novel technique and is contrasted to traditional reverse phase separations.Ph.D., Chemistry -- Drexel University, 201

Insights into the Control of Drug Release from Complex Immediate Release Formulations

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution