Publications by authors named "Allan S Myerson"

Non-invasive characterization of powders may take one of two approaches: imaging and counting individual particles; or relying on scattered light to estimate the particle size distribution (PSD) of the ensemble. The former approach runs into practical difficulties, as the system must conform to the working distance and other restrictions of the imaging optics. The latter approach requires an inverse map from the speckle autocorrelation to the particle sizes.

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Raman spectroscopy has been used to measure the concentration of a pharmaceutically relevant model amine intermediate for positive allosteric modulators of nicotinic acetylcholine receptor in a ω-transaminase-catalyzed conversion. A model based on a one-dimensional convolutional neural network was developed to translate raw data augmented Raman spectra directly into substrate concentrations, with which the conversion from ketone to amine by ω-transaminase could be determined over time. The model showed very good predictive capabilities, with R values higher than 0.

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Article Synopsis
  • Extracting quantitative information from highly scattering surfaces is difficult due to complex speckle patterns caused by scattered light, which complicates the measurement process.
  • In the pharmaceutical industry, accurately measuring particle size distribution (PSD) during the drying of wet powders is crucial, yet there is no existing non-invasive real-time monitoring solution.
  • The report introduces a theoretical link between PSD and speckle images, presenting a machine learning algorithm called PEACE that combines physics with data analysis to effectively measure PSD and enhance interpretability.
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Recent changes in the pharmaceutical sector call for the development of novel manufacturing approaches to reduce costs and improve control over product quality. In this area, the development of compact, plug-and-play devices that fit in a continuous manufacturing system has gained interest in recent years. Most Nutsche filters offer a versatile solution as compact filtration and drying devices.

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Purpose: Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs).

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Six ionic liquids (ILs) were selected based on their chemical and physical properties to study the solubility of cyclosporine A. Of these, cyclosporine exhibited higher room temperature solubility in 1-ethyl-3-methylimidazolium acetate ([Cmim][OAc]) than in acetone, an effective molecular solvent used to solubilize and purify cyclosporine. The solubility of cyclosporine in the ILs dramatically increased at higher temperatures, a critical factor that cannot be varied in a wide range with low boiling molecular solvents.

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Crystal morphology is one of the key crystallographic characteristics that governs the macroscopic properties of crystalline materials. The identification of crystal faces, or face indexing, is an important technique that is used to get information regarding a crystal's morphology. However, it is mainly limited to single crystal X-ray diffraction (SCXRD) and it is often not applicable to products of routine crystallizations becasue it requires high quality single crystals in a narrow size range.

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While molecular solvents are commonly used in the screening of polymorphs, the choices are often restricted. Ionic liquids (ILs) - also referred as - have immense possibility in this regard because of their wide flexibility of tunability. More importantly, the interactions among the IL components are completely unique compared to those present in the molecular solvents.

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To alleviate the problem of solid salt precipitation when using inorganic bases in cross-coupling reactions, basic anions were combined with the trihexyl(tetradecyl)phosphonium ([P]) cation to ensure an ionic liquid byproduct. If the starting base is also an ionic liquid, as is the case for [P][OH]·4MeOH, it can be used as both base and solvent.

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We demonstrate the coating of tablets using an injection molding (IM) process that has advantage of being solvent free and can provide precision coat features. The selected core tablets comprising 10% w/w griseofulvin were prepared by an integrated hot melt extrusion-injection molding (HME-IM) process. Coating trials were conducted on a vertical injection mold machine.

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We investigated the ability of the ions comprising protic ionic liquids to strongly interact with their neutral acid and base forms through the characterization of n-butylammonium acetate ([CNH][OAc]) in the presence of excess n-butylamine (CNH) or excess acetic acid (HOAc). The conjugate and parent acid or base form new nonstoichiometric, noncovalently bound species (i.e.

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This study provides a framework for robust tablet development using an integrated hot-melt extrusion-injection molding (IM) continuous manufacturing platform. Griseofulvin, maltodextrin, xylitol and lactose were employed as drug, carrier, plasticizer and reinforcing agent respectively. A pre-blended drug-excipient mixture was fed from a loss-in-weight feeder to a twin-screw extruder.

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The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process technology for continuous manufacturing of tablets. However, there has been limited research on its application to formulate crystalline drug-containing immediate-release tablets. Furthermore, studies that have applied the HME-IM process to molded tablets have used a noncontinuous 2-step approach.

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In this paper we derive a straightforward computational approach to predict the optimal ionic liquid (IL) solvent for a given compound, based on COSMO-RS calculations. These calculations were performed on 18 different active pharmaceutical ingredients (APIs) using a matrix of 210 hypothetical ILs. These results indicated that the 18 APIs could be classified into three distinct categories based on their relative hydrogen bond donating or accepting ability, with similar optimal IL solvent predictions within each class.

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The paper provides a novel method for the reversible control of solubility by use of functionalized nanoparticles. The nanoparticles are functionalized with functional groups that can act as a co-solvent or anti-solvent and thus can induce either dissolution or crystallization. The process is reversible, as the solution will go back to its original state when the nanoparticles are removed.

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Although roughly 40% of pharmaceuticals being developed are poorly water soluble, this class of drugs lacks a formulation strategy capable of producing high loads, fast dissolution kinetics, and low energy input. In this work, a novel bottom-up approach is developed for producing and formulating nanocrystals of poorly water-soluble active pharmaceutical ingredients (APIs) using core-shell composite hydrogel beads. Organic phase nanoemulsion droplets stabilized by polyvinyl alcohol (PVA) and containing a model hydrophobic API (fenofibrate) are embedded in the alginate hydrogel matrix and subsequently act as crystallization reactors.

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Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform.

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The diterpene steviol glycoside, rebaudioside A, is a natural high potency non-caloric sweetener extracted from the leaves of Stevia rebaudiana. This compound shows a parabolic change in sweet taste intensity with temperature which contrasts with the general finding for other synthetic or natural sweeteners whose sweet taste increases with temperature. The nonmonotonic taste behavior was determined by sensory analysis using large taste panels.

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Understanding phase transitions of fluids confined within nanopores is important for a wide variety of technological applications. It is well known that fluids confined in nanopores typically demonstrate freezing-point depressions, ΔTf, described by the Gibbs-Thomson (GT) equation. Herein, we highlight and correct several thermodynamic inconsistencies in the conventional use of the GT equation, including the fact that the enthalpy of melting, ΔHm, and the solid-liquid surface energy, γ(SL), are functions of pore diameter, complicating their prediction.

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Methods to produce nano-sized organic molecular crystals in thin films are of great interest in the pharmaceutical industry due to the potential benefit of increased solubility of poorly soluble drugs and the advantages of film-based dosage forms over traditional tablet/capsule-based dosage form. One method to directly form organic nanocrystals is by crystallization in confined environments where the overall crystallization volume is constrained. We report the use of a novel solution impregnation method to form nanocrystals in polymer matrices with various microstructures in order to study the structure of the confined nanocrystals and the role of soft confinement and polymer chemistry on the nucleation process of nano-sized crystals.

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Concluding remarks.

Faraday Discuss

May 2016

Crystallization from solution is a crucial process used in the manufacture of a wide variety of materials. The first step in the crystallization process is the birth of a new crystalline phase, which is known as nucleation. Nucleation plays a key role in determining the results of any crystallization process with respect to the size, shape and crystal form obtained.

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This white paper provides a perspective of the challenges, research needs, and future directions for control systems engineering in continuous pharmaceutical processing. The main motivation for writing this paper is to facilitate the development and deployment of control systems technologies so as to ensure quality of the drug product. Although the main focus is on small-molecule pharmaceutical products, most of the same statements apply to biological drug products.

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We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to continuous manufacturing. We also give the key motivations for moving to continuous manufacturing, some of the exciting new technologies, and the barriers to implementation of continuous manufacturing.

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