ABSTRACT
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.
ABSTRACT
N,N,N',N'-Tetramethylimidazolidinium dichloride (1-Im-1 2Cl) has been studied as a model system for cation-anion interactions in the interfacial regions of gemini micelles by X-ray crystallography, density functional theory (DFT) calculations, and infrared spectroscopy. Single crystals of 1-Im-1 2Cl contain 1-Im-1 dications, whose five-membered rings adopt a distorted envelope conformation. Eight chloride anions surround each dication, two of which are cradled above and below the five-membered ring (apical) and six of which are dispersed about the periphery of the ring (equatorial). The cations and anions are linked in the solid state by an extensive network of weak C-H...Cl hydrogen bonds that involve all of the H atoms of the dication. The calculated (DFT at the 6-31+G(d) level) structure of the asymmetric unit, which consists of a dication and two apical chloride ions, closely resembles the equivalent unit in the crystal structure with respect to bond distances and angles, the conformation of the 1-Im-1 ring, and the nature and location of the C-H...Cl hydrogen bonds. The calculated IR spectrum predicts a number of absorptions in the 3000 cm(-1) region, assigned as C-H...Cl stretching modes, which are consistent with the presence of an intense band in the observed IR spectrum of the crystals. Over all, this study supports the notion that apical chloride ions interact more strongly with gemini surfactant headgroups by forming multiple hydrogen bonds in ion pairs of a type that cannot be present in the corresponding ion pairs of quaternary headgroups with counterions of single-chain surfactants.
