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Journal of Pharmaceutical Sciences

Christoph Dorn, Alexander Kratzer, Uwe Liebchen, Michael Schleibinger, Alexandra Murschhauser, Jens Schlossmann, Frieder Kees, Philipp Simon, Martin G Kees
Tigecycline, a tetracycline derivative, shows atypical plasma-protein-binding behavior. The unbound fraction decreases with increasing concentration at therapeutic concentrations. Moreover, uncertainty exists about the magnitude of tigecyline's protein binding in man. Unbound fractions between 2.5 and 35% have been reported in plasma from healthy volunteers, and between 25 and 100 % in patients, respectively. In the present study, the protein binding of tigecycline has been investigated by ultrafiltration using different experimental conditions...
September 16, 2017: Journal of Pharmaceutical Sciences
Li Di, Christopher Breen, Rob Chambers, Sean T Eckley, Robert Fricke, Avijit Ghosh, Paul Harradine, J Cory Kalvass, Stacy Ho, Caroline A Lee, Punit Marathe, Everett J Perkins, Mark Qian, Susanna Tse, Zhengyin Yan, Maciej J Zamek-Gliszczynski
Regulatory agencies have recently issued drug-drug interaction (DDI) guidelines, which require determination of plasma protein binding (PPB). To err on the conservative side, the agencies recommend that a 0.01 lower limit of fraction unbound (fu) be used for highly bound compounds (>99%), irrespective of the actual measured values. While this may avoid false negatives, the recommendation would likely result in a high rate of false positive predictions, resulting in unnecessary clinical studies and more stringent inclusion/exclusion criteria, which may add cost and time in delivery of new medicines to patients...
September 16, 2017: Journal of Pharmaceutical Sciences
Preeti Wavikar, Rohan Pai, Pradeep Vavia
Present investigation explores the potential of Nanostructured Lipid Carriers (NLCs) for nose to brain delivery of Rivastigmine (RV), which is further enhanced by incorporating into an in-situ gelling system, increasing retention in nasal cavity. NLC's having particle size of 123.2±2.3 nm, entrapment efficiency of 68.3±3.4% and zeta potential of 32±1.2 mV was fabricated by a scalable method. Pharmacokinetics showed sustained release of intranasal (IN) and intravenous (IV) NLC's compared to RV solution by same route, with significantly higher AUC and Thalf...
September 15, 2017: Journal of Pharmaceutical Sciences
Satoshi Ohtake, Shaoxin Feng, Evgenyi Shalaev
Role of water in chemical (in)stability is revisited, with focus on deamidation in freeze-dried amorphous proteins and peptides. Two distinct patterns for deamidation vs. water have been reported, i.e., a consistent increase in rate constant with water, and a "hockey stick"-type behavior. For the latter, deamidation is essentially independent of water at lower water contents, and accelerates when water content increases above a threshold value. Two simple kinetic models are developed to analyze literature-reported relationships between water content and deamidation rate constants...
September 15, 2017: Journal of Pharmaceutical Sciences
Alexander Russell, Rok Šibanc, Rok Dreu, Peter Müller
To ensure robust manufacturing of unit-based oral solid dosage forms with minimal structural imperfections and high mechanical reliability across subsequent processing unit operations (for e.g. withstanding mechanical stresses during coating, optional axial compression, handling, packaging, storage and transport conditions), process design should include consideration of precise limits of accurate micro, macro and bulk properties of the constituent pellets. This communication presents a comprehensive intricate database of micro-mechanical properties' and breakage probability distribution functions of pellets, illustrating the stiffening and strengthening effects of coatings and the softening and weakening effects of structural moisture...
September 15, 2017: Journal of Pharmaceutical Sciences
Dipen Desai, Harpreet Sandhu, Navnit Shah, Waseem Malick, Hossein Zia, Wantanee Phuapradit, Siva Ram Kiran Vaka
The objective of the study was to select solid state plasticizers for hot melt extrusion (HME) process. The physical and mechanical properties of plasticizers, in selected binary (polymer: plasticizer) and ternary (API: polymer: plasticizer) systems, were evaluated to assess their effectiveness as processing aids for HME process. Indomethacin (INM) and Eugradit® E PO were selected as model Active Pharmaceutical Ingredient (API) and polymer, respectively. Solubility parameters, thermal analysis and rheological evaluation were used as assessment tools...
September 15, 2017: Journal of Pharmaceutical Sciences
Yasuhiro Tsume, Naoto Igawa, Adam J Drelich, Gregory E Amidon, Gordon L Amidon
The formulation developments and the in vivo assessment of Biopharmaceutical Classification System (BCS) class II drugs are challenging due to their low solubility and high permeability in the human gastrointestinal (GI) tract. Since the GI environment influences the drug dissolution of BCS class II drugs, the human GI characteristics should be incorporated into the in vitro dissolution system to predict bioperformance of BCS class II drugs. An absorptive compartment may be important in dissolution apparatus for BCS class II drugs, especially for bases (BCS IIb) because of high permeability, precipitation and supersaturation...
September 14, 2017: Journal of Pharmaceutical Sciences
Antonios Zavaliangos, Jeffrey M Katz, Dominick Daurio, Michael Johnson, Armen Pirjanian, Fernando Alvarez-Nunez
Αn approximate solution is presented for the prediction of air entrapment during tableting. Assuming weak coupling of the deformation of the solid phase, the flow of interstitial air and a set of reasonable additional geometric assumptions, the general problem is reduced to one dimension. Experimental values of air permeability through tablet specimens of commonly used pharmaceutical excipients were obtained using a 3D printed test cell outfitted to a powder rheometer. Using these values, combined with a numerical solution of the governing partial differential equation, parametric studies are presented that demonstrate the importance of permeability, compaction speed, tablet size, and punch-die tolerance on air entrapment...
September 14, 2017: Journal of Pharmaceutical Sciences
Seema Thakral, Naveen K Thakral, Raj Suryanarayanan
The average grain size of a crystalline material can be determined from the γ-profile of Debye rings in two-dimensional X-ray diffraction (2D XRD) frames. Our objectives were to: (i) validate the method for organic powders and use it to determine the grain size in intact tablets, and (ii) demonstrate the pharmaceutical application of this technique by determining the grain size of the active pharmaceutical ingredient (API) in marketed formulations. Six sieve fractions of sucrose were prepared and the particle size distribution was confirmed by laser diffraction...
September 9, 2017: Journal of Pharmaceutical Sciences
W P Forrest, M A Mackey, V M Shah, K M Hassell, P Shah, J L Wylie, J Gopinath, H Balderhaar, L Li, W P Wuelfing, R Helmy
As science evolves, the need for more efficient and innovative knowledge transfer capabilities becomes evident. Advances in drug discovery and delivery sciences have directly impacted the pharmaceutical industry, though the added complexities have not shortened the development process. These added complexities also make it difficult for scientists to rapidly and effectively transfer knowledge to offset the lengthened drug development timelines. While webcams, camera phones and iPads have been explored as potential new methods of real-time information sharing, the non-"hands-free" nature and lack of viewer and observer point-of-view render them unsuitable for the R&D laboratory or manufacturing setting...
September 1, 2017: Journal of Pharmaceutical Sciences
Jayasree M Srinivasan, Lindsay A Wegiel, Lisa M Hardwick, Steven L Nail
The objective of this research was to study the atypical secondary drying dynamics observed during the freeze-drying of a formulation consisting of mannitol, disaccharide, and sodium chloride, where "bursts" of water vapor release were observed during secondary drying as detected by comparative pressure measurement. "Thief" samples were removed at the end of primary drying and during secondary drying as the shelf temperature was increased in stepwise fashion. These samples were examined by X-ray powder diffraction (XRPD) and thermal analysis...
August 31, 2017: Journal of Pharmaceutical Sciences
Sudarshan Ganesh, Rachel Troscinski, Nicholas Schmall, Jongmook Lim, Zoltan Nagy, Gintaras Reklaitis
The progress in continuous downstream manufacturing of oral solid doses demands effective real-time process management, with monitoring at its core. This study evaluates the feasibility of using a commercial sensor to measure the mass flow rate of the particulates, a critical process variable in continuous manufacturing. The sensor independently measures x-ray attenuation and cross-correlation velocimetry of particulate flow in real-time. Steady-state flow rates of blends comprised primarily of acetaminophen and microcrystalline-cellulose are monitored using the sensor, with simultaneous weighing scale measurements, in order to calibrate the sensor and investigate the measurement accuracy...
August 31, 2017: Journal of Pharmaceutical Sciences
Andreas Niederquell, Martin Kuentz
It is for the pharmaceutical sciences of vital importance to understand how drugs are solubilized in biorelevant media. However, the complexity of fasted state simulated intestinal fluid (FaSSIF) has so far hampered adequate solubility modeling. The present study focuses on apparently neutral compounds at physiological pH and a linear free energy relationship is introduced for biorelevant drug solubilization. Based on literature data of 40 compounds, the Abraham solvation descriptors were calculated from chemical structure to then predict the ratio of solubility enhancement, log(SE) in FaSSIF compared to aqueous buffer solubility at pH 6...
August 29, 2017: Journal of Pharmaceutical Sciences
Shantanu V Sule, Jason E Fernandez, Vincent J Mecozzi, Yana Kravets, William C Yang, Pamela Feng, Suli Liu, Li Zang, Allan D Capili, Tia B Estey, Kapil Gupta
Characterizing molecular charge variants or isoforms is essential for understanding safety, potency and bioavailability of antibody therapeutics. However, there is little information on how they influence stability and viscosity - properties governing immunogenicity and delivery. To bridge this gap, we studied antibody stability as a function of charge variant content generated via bioreactor process. We were able to systematically vary acidic variant levels as a function of bioreactor harvest time. Importantly, we do not observe any impact on aggregation behavior of a formulated antibody at high protein concentration as a function of acidic variant level...
August 28, 2017: Journal of Pharmaceutical Sciences
Faisal Usman, Zaheer Ul-Haq, Ruqaiya Khalil, Kittiya Tinpun, Teerapol Srichana
This study presents the mode of interaction, structural features and micellization of AmB with sodium deoxycholate sulphate (SDCS) as small lipid molecule at different ratios, as revealed by molecular docking simulations and NMR. AmB-SDCS micelles were synthesized by single pot rinsing method. Solid state (13)C NMR revealed hydrogen bonding as main interaction, occurring at different positions between AmB and SDCS at various ratios. Molecular docking elucidated that AmB-SDCS complex was stabilized by multiple hydrogen bonds as well as Van der Waals forces between SDCS and AmB...
August 25, 2017: Journal of Pharmaceutical Sciences
Lorena F B Malaquias, Heidi L Schulte, Juliano A Chaker, Kapish Karan, Thomas Durig, Ricardo N Marreto, Tais Gratieri, Guilherme M Gelfuso, Marcílio Cunha-Filho
This work aimed to obtain an optimized itraconazole (ITZ) solid oral formulation in terms of palatability and dissolution rate by combining different polymers using hot melt extrusion (HME), according to a simplex centroid mixture design. For this, the polymers Plasdone® (PVP/VA), Klucel ELF® (HPC) and Soluplus® (SOL) were processed using a laboratory HME equipment operating without recirculation at constant temperature. Samples were characterized by physicochemical assays, as well as dissolution rate and palatability using an E-tongue...
August 25, 2017: Journal of Pharmaceutical Sciences
John Chung, Filippos Kesisoglou
Physiologically-based oral absorption models are in-silico tools primarily used to guide formulation development and project the clinical performance of formulation variants. This commentary briefly discusses additional oral absorption model applications, focusing on gut level drug interactions. Gut level drug interactions can involve drug degradation, metabolic enzymes, transporters, GI motility modulators, acid reducing agents, and food. The growth in publications reporting physiologically-based oral absorption model utilization and successful pharmacokinetic prediction (e...
August 25, 2017: Journal of Pharmaceutical Sciences
Kyle L Hogan, Danielle Leiske, Cleo M Salisbury
N-Acetyl-tryptophan (NAT) is used as a stabilizer for preparations of human serum albumin and has more recently been demonstrated to provide oxidative protection for labile Trp residues in monoclonal antibodies. As a component in the formulations of protein therapeutics, NAT is sacrificially degraded; therefore understanding the identity and quantity of NAT degradants potentially formed in these drug products is essential to understanding the potential patient impact of this additive. Here we report a simple reversed phase chromatography approach that allows systematic investigation of NAT degradation in relevant formulations under stressed conditions...
August 24, 2017: Journal of Pharmaceutical Sciences
Paul Myrdal, Ken Morris, Rodolfo Pinal, Neera Jain, Peter L D Wildfong, George Zografi
No abstract text is available yet for this article.
August 24, 2017: Journal of Pharmaceutical Sciences
Surinder M Singh, Swati Bandi, David N M Jones, Krishna M G Mallela
We examined how polysorbate 20 (PS20; Tween 20) and polysorbate 80 (PS80; Tween 80) affect the higher order structure of a monoclonal antibody (mAb) and its Fab and Fc fragments, using near-UV circular dichroism and 2D NMR. Both polysorbates bind to the mAb with sub-millimolar affinity. Binding causes significant changes in the tertiary structure of mAb with no changes in its secondary structure. 2D (13)C-(1)H methyl NMR indicates that with increasing concentration of polysorbates, the Fab region showed a decrease in crosspeak volumes...
August 23, 2017: Journal of Pharmaceutical Sciences
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