A Rational Hierarchy to Capture Raw Material Attribute Variability in the Pharmaceutical Drug Product Development and Manufacturing Lifecycle.

Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of pharmaceutical product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of new product registration and for subsequent process maintenance, we review practices to explore RM variations. We describe limitations that can arise when active ingredients and excipients invariably undergo changes during a drug product lifecycle.

An Integrated Approach for High-Shear Wet Granulation (HSWG) Processing of TPGS-Based Formulations: Demonstration of Process Robustness through Experimental Design Conditions.

The goal of this study was to understand the impact of high-shear wet granulation (HSWG) processing conditions on product attributes for a tablet formulation containing the non-ionic surfactant TPGS. The use of TPGS in oral solid drug products has been reported to be challenging due to the low melting temperature of TPGS. In addition, literature on TPGS-based HSWG formulations, especially practical processing and scale-up knowledge, is limited.

Detecting and Quantifying Microscale Chemical Reactions in Pharmaceutical Tablets by Stimulated Raman Scattering Microscopy.

It has been estimated that approximately 50% of all marketed drug molecules are manufactured and administered in the form of salts, often with the goal of improving solubility, dissolution rate, and efficacy of the drug. However, salt disproportionation during processing or storage is a common adverse effect in these formulations. Due to the heterogeneous nature of solid drug formulations, it is essential to characterize the drug substances noninvasively at micrometer resolution to understand the molecular mechanism of salt disproportionation.

Dispersive Raman Spectroscopy for Quantifying Amorphous Drug Content in Intact Tablets.

Process-induced inadvertent phase change of an active pharmaceutical ingredient in a drug product could impact chemical stability, physical stability, shelf life, and bioperformance. In this study, dispersive Raman spectroscopy is presented as an alternative method for the nondestructive, high-throughput, at-line quantification of amorphous conversion. A quantitative Raman method was developed using a multivariate partial least squares (PLS) regression calibration technique with solid-state nuclear magnetic resonance (ssNMR) spectroscopy as the reference method.

Application of in vitro transmucosal permeability, dose number, and maximum absorbable dose for biopharmaceutics assessment during early drug development for intraoral delivery.

Intraoral (IO) administration is a unique route that takes advantage of transmucosal absorption in the oral cavity to deliver a drug substance locally or systemically. IO delivery can also enhance or enable oral administration, providing a better therapeutic benefit/safety risk profile for patient compliance. However, there are relatively few systematic biopharmaceutics assessments for IO delivery to date.

Development of amorphous solid dispersion formulations of a poorly water-soluble drug, MK-0364.

The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364. The potential solid dispersions would enable an oral solid dosage form as a monotherapy or combination product of MK-0364. Preliminary screening included sample preparation via a solvent casting method, physical characterization, and in vitro dissolution testing.

Penalized-likelihood reconstruction for metal artifact reduction in cone-beam CT.

CT reconstruction from metal-embedded data usually produces streak artifacts that reduce the quality of the reconstructed images. In this paper, we propose a new technique for metal artifact reduction in cone-beam CT based on statistical reconstruction. First, the metal objects are segmented in the reconstructed images and then reprojected to obtain the measurement data of the metal objects using cone-beam reconstruction.

3D left ventricular segmentation using double active contours and double active surfaces.

We propose a 3D left ventricular segmentation method for cardiac MR images. There are two steps in our method. In the first step, we improve our double active contours for segmenting the endocardial and the epicardial boundaries simultaneously without requiring any training sets.

Release mechanisms of a sparingly water-soluble drug from controlled porosity-osmotic pump pellets using sulfobutylether-beta-cyclodextrin as both a solubilizing and osmotic agent.

The purpose of this work is to delineate the release mechanisms of a sparingly water-soluble drug, prednisolone (PDL), from a microporous or controlled porosity-osmotic pump pellet (CP-OPP) using sulfobutylether-beta-cyclodextrin (CD) as both a solubilizing and osmotic agent. All factors, osmotic and diffusional, influencing drug release as described by the Theeuwes and Zentner equation were partially demonstrated in an earlier paper1 and are further quantitatively evaluated here to determine whether the equation may be applied to CP-OPPs. The PDL release rate from the CP-OPPs containing precomplexed PDL follows the zero-order kinetics for up to 30-40% of drug release during the first 1-2 h and subsequently nonzero order kinetics.

Image recovery using partitioned-separable paraboloidal surrogate coordinate ascent algorithms.

Iterative coordinate ascent algorithms have been shown to be useful for image recovery, but are poorly suited to parallel computing due to their sequential nature. This paper presents a new fast converging parallelizable algorithm for image recovery that can be applied to a very broad class of objective functions. This method is based on paraboloidal surrogate functions and a concavity technique.

Controlled porosity-osmotic pump pellets of a poorly water-soluble drug using sulfobutylether-beta-cyclodextrin, (SBE) 7M-beta-CD, as a solubilizing and osmotic agent.

The objective of this work was to demonstrate that the incorporation of sulfobutylether-beta-cyclodextrin, (SBE)(7M)-beta-CD, results in the complete and sustained release of a sparingly water-soluble drug, prednisolone (PDL) from controlled porosity-osmotic pump pellets (CP-OPP). PDL and CD were prepared in various formulations (physical mixtures and presumed preformed complex). Several factors influencing drug and CD release were explored, and the probable mechanisms of drug release were probed and discussed.

Characterization of prednisolone in controlled porosity osmotic pump pellets using solid-state NMR spectroscopy.

The overall objective of this study was to demonstrate the influence of formulation and processing variables on the physical state of prednisolone (PDL) in formulations consisting of PDL, microcrystalline cellulose (MCC), and sulfobutylether-beta-cyclodextrin (CD). PDL was used as a model drug in controlled porosity osmotic pump pellet (CP-OPP) formulations, and was characterized using solid-state NMR spectroscopy and other complimentary analytical techniques. Dosage forms and the solid-state properties of drugs and excipients in a formulation may be influenced by the processing conditions used.

Active contours with automatic initialization for myocardial perfusion analysis.

Quantitative analysis of myocardial perfusion requires detection of myocardial boundaries in many short-axis MR images. Manual tracing of myocardial boundaries is a time-consuming and tedious task, which may limit the clinical use of quantitative analysis. In this paper, we propose an automatic detection algorithmbased on active contours.

Evaluation of various properties of alternative salt forms of sulfobutylether-beta-cyclodextrin, (SBE)7M-beta-CD.

The goal of this study was to evaluate alternative salt forms of (SBE)7M-beta-CD (currently the sodium salt). The potential salt form would ideally decrease the rate of (SBE)7M-beta-CD release from osmotic pump formulations and result in an increase in the rate and extent of drug release in osmotic pump tablet and pellet dosage forms. Several (SBE)7M-beta-CD salt forms (potassium, calcium, and two ethylene diamine salt forms) were prepared by either titration or ultrafiltration and characterized by elemental analysis and capillary electrophoresis, CE.

Penalized-likelihood image reconstruction for digital holography.

Conventional numerical reconstruction for digital holography using a filter applied in the spatial-frequency domain to extract the primary image may yield suboptimal image quality because of the loss in high-frequency components and interference from other undesirable terms of a hologram. We propose a new numerical reconstruction approach using a statistical technique. This approach reconstructs the complex field of the object from the real-valued hologram intensity data.

Relaxed ordered-subset algorithm for penalized-likelihood image restoration.

The expectation-maximization (EM) algorithm for maximum-likelihood image recovery is guaranteed to converge, but it converges slowly. Its ordered-subset version (OS-EM) is used widely in tomographic image reconstruction because of its order-of-magnitude acceleration compared with the EM algorithm, but it does not guarantee convergence. Recently the ordered-subset, separable-paraboloidal-surrogate (OS-SPS) algorithm with relaxation has been shown to converge to the optimal point while providing fast convergence.