Clifford S. Todd

Development and Characterization of a Scalable Controlled Precipitation Process to Enhance the Dissolution of Poorly Water-Soluble Drugs

AbstractPurpose. Poorly water-soluble compounds are being found with increasing frequency among pharmacologically active new chemical entities, which is a major concern to the pharmaceutical industry. Some particle engineering technologies have been shown to enhance the dissolution of many promising new compounds that perform poorly in formulation and clinical studies (Rogers et. al., Drug Dev Ind Pharm 27:1003-1015). One novel technology, controlled precipitation, shows significant potential for enhancing the dissolution of poorly soluble compounds. In this study, controlled precipitation is introduced; and process variables, such as mixing zone temperature, are investigated. Finally, scale-up of controlled precipitation from milligram or gram to kilogram quantities is demonstrated. Methods. Dissolution enhancement capabilities were established using two poorly water-soluble model drugs, danazol and naproxen. Stabilized drug particles from controlled precipitation were compared to milled, physical blend, and bulk drug controls using particle size analysis (Coulter), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), dissolution testing (USP Apparatus 2), and residual solvent analysis. Results. Stabilized nano- and microparticles were produced from controlled precipitation. XRD and SEM analyses confirmed that the drug particles were crystalline. Furthermore, the stabilized particles from controlled precipitation exhibited significantly enhanced dissolution properties. Residual solvent levels were below FDA limits. Conclusions. Controlled precipitation is a viable and scalable technology that can be used to enhance the dissolution of poorly water-soluble pharmaceutical compounds.

Closed-cell foam skin thickness measurement using a scanning electron microscope.

Closed cell polymer foam skin thickness can be assessed by taking backscatter electron (BSE) images in a scanning electron microscope (SEM) at a series of accelerating voltages. Under a given set of experimental conditions, the electron beam mostly passes through thin polymer skin cell walls. That cell appears dark compared to adjacent thicker-skinned cells. Higher accelerating voltages lead to a thicker skin being penetrated. Monte Carlo modeling of beam-sample interactions indicates that at 5 keV, skin less than ∼0.5 μm in thickness will appear dark, whereas imaging at 30 keV allows skin thicknesses up to ∼4 μm to be identified. The distribution of skin thickness can be assessed over square millimeters of foam surface in this manner. Qualitative comparisons of the skin thicknesses of samples can be made with a simple visual inspection of the images. A semiquantitative comparison is possible by applying image analysis. The proposed method is applied to two example foams. Characterizing foam skin thickness by this method is possible using any SEM that is capable of collecting useful BSE images over a range of accelerating voltages. Imaging in low vacuum, where an electrically conductive metal coating is not required, leads to more sensitivity in skin thickness characterization.

Characterization of the thickness and distribution of latex coatings on polyvinylidene chloride beads by backscattered electron imaging.

Polyvinylidene chloride (PVDC) co-polymer resins are commonly formulated with a variety of solid additives for the purpose of processing or stabilization. A homogeneous distribution of these additives during handling and processing is important. The Dow Chemical Company developed a process to incorporate solid materials in latex form onto PVDC resin bead surfaces using a coagulation process. In this context, we present a method to characterize the distribution and thickness of these latex coatings. The difference in backscattered electron signal from the higher mean atomic number PVDC core and lower atomic number latex coating in conjunction with scanning electron microscopy (SEM) imaging using a range of accelerating voltages was used to characterize latex thickness and distribution across large numbers of beads quickly and easily. Monte Carlo simulations were used to quantitatively estimate latex thickness as a function of brightness in backscatter electron images. This thickness calibration was validated by cross-sectioning using a focused ion-beam SEM. Thicknesses from 100 nm up to about 1.3 µm can be determined using this method.

Automated Image Acquisition at High Spatial Resolutions in a Field Emission Gun Scanning Electron Microscope

Extended abstract of a paper presented at Microscopy and Microanalysis 2008 in Albuquerque, New Mexico, USA, August 3 – August 7, 2008

Silver Nanowire Diameter and Yield Characterization by High-Throughput SEM and Image Analysis

An interconnected random network of nano-sized metal wires can be used as a Transparent Conductive Material [1]. TCMs are widely used in electronic devices from TVs and solar panels to touch screen applications such as tablets and phones. Potential advantages of such TCMs over incumbent indium tin oxide are lower sheet resistance at equal or better optical properties, low temperature deposition on polymer or other flexible substrates, cost advantages from capital expenditure reductions, and high throughput when applied by roll-to-roll coating. A scalable hydrothermal synthesis for silver nanowires (AgNW) was developed [2,3] necessitating the efficient and statistically rigorous characterization of wire dimensions and wire-to-particle yield in order to track synthesis and purification developments.

Image Texture Analysis and Application to Acicular Mullite Porous Ceramic Microstructure

Acicular mullite porous ceramic [1,2] can display a range of microstructures, impacted by elemental formulation, raw materials, and processing conditions. The microstructure in turn impacts performance metrics such as strength, modulus and back pressure for filtration applications. During research and development and later during scale-up and production, assessment of microstructure was done in a completely subjective manner; a small group of experienced individuals assessed SEM images. The goal of the project described here was to develop an objective way to quantify aspects of this microstructure. The approach was to apply computational image analysis to SEM images. A set of 32 samples that displayed a range of microstructures were used (Fig. 1).