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Excipients and Their Attributes in Granulation
Published in Dilip M. Parikh, Handbook of Pharmaceutical Granulation Technology, 2021
Conducting pre-formulation studies can arm the formulator with a thorough understanding of the physicochemical characteristics and behavior of the active ingredient. However, to achieve the best results in the formulation, it is just as important to have a similar understanding of the characteristics, that is, the functionality and limitations of the excipients under consideration. Excipients are chemicals, and though many may be chemically inert, some do react with certain materials, and knowing this before including a particular excipient in a formulation can save the formulator a lot of time and heartache. Having a thorough understanding of their functionality gives the formulator a well-equipped toolbox with many options to manipulate the manufacturing process and performance of a drug product. Moreover, from the standpoint of Quality by Design (QbD) the rationale for selection of an excipient and the level at which it is used must be justified in the development of any pharmaceutical product. The good news is that in today’s market, there is extensive information regarding the properties and functionality of most excipients available, both in the literature and from reputable excipient manufacturers who routinely evaluate the functionality of their products as part of quality control.
Radioactive Noble Gases for Medical Applications
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
The noble gases are not completely chemically inert; the first noble-gas compound, xenon hexafluoroplatinate was prepared by Bartlett in 1962.79 Subsequent developments in noble-gas chemistry have been reviewed in References 80 and 81. The conditions for production of noble-gas compounds, however, are not likely to be encountered in biological systems. More relevant are the formation of inclusion compounds or clathrates, defined by Powell82 as “those compounds in which two or more components are associated without ordinary chemical union but through complete enclosure of one set of molecules in a suitable structure formed by the other”. Inert gases are held in these “cages” by van der Waals interactions with bond strengths of the order of 2.5 kcal/mol as compared to bond strengths of 40 to 140 kcal/mol for cova-lent bonds.83 Potentially significant clathrates in biological systems are the hydrates, in which groups of water molecules form cages through multiple hydrogen-bond formation.84 The formation of inert-gas hydrates in vivo has indeed been proposed85, 86 as an explanation for the anesthetic properties of noble gases such as krypton and xenon.87, 88 However, the existence of noble-gas hydrates has not been demonstrated at physiological temperature and pressure.
Gases
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Unlike the pulmonary irritants or the chemical asphyxiants (described later), simple asphyxiants are nonirritating, chemically inert gases. Simple asphyxiants interfere with pulmonary function by overwhelming the oxygen concentration in inspired air. The net result is a lowered oxygen content of inspired air and decreased oxygen availability for gas exchange. The toxicity of these agents depends on the available oxygen concentration remaining.
The Toxic Effects of Ethylene Glycol Tetraacetate Acid, Ferrum Lek and Methanol on the Glutathione System: correction Options
Published in Expert Review of Clinical Pharmacology, 2021
The structure of the toxic substance determines its properties, such as molecular size and mass, solubility, volatility, and state of aggregation under both normal conditions and chemical stress. Although all of these properties affect toxicity, none of them has a significant impact alone. Chemically inert substances with low molecular weight, such as gas or solutions, normally can easily make their way into the bloodstream through the lungs, gastrointestinal tract, and sometimes skin, and are rapidly distributed into tissues, as they perfectly pass through the histohematological barriers. However, the ability of low molecular weight compounds to penetrate barriers is largely determined by solubility. Hydrophilic molecules, even those with a molecular weight of 50–100 D, for example, have a limited ability to penetrate through mucous membranes. Compounds with high molecular weight are likely to encounter more challenges when passing through the barriers. On the one hand, lipophilic substances can sometimes make their way through biological barriers relatively easily, despite their large molecular size. On the other hand, large molecules of substances that are poorly soluble in water and lipids (artificial and natural polymers) practically do not penetrate into the internal environment of a body and thus have no general toxic effect.
Emerging PEGylated non-biologic drugs
Published in Expert Opinion on Emerging Drugs, 2019
Eun Ji Park, Jiyoung Choi, Kang Choon Lee, Dong Hee Na
PEGylation is a pharmaceutical technology that attaches one or more polyethylene glycol (PEG) molecules to therapeutic molecules, thereby improving their pharmaceutical properties [1]. PEG, a synthetic polymer comprised of repeating ethylene oxide units, is chemically inert and has low toxicity, and has been approved by Food and Drug Administration (FDA) for oral, intravenous, and dermal applications in the pharmaceutical industry [2]. The PEG is known to entangle two to three water molecules per ethylene oxide unit, which makes its hydrodynamic radius between 5 and 10 times larger than that of a globular protein of a similar molecular weight [3]. Owing to these properties of PEG, PEGylation affords the prolonged circulation lifetime owing to reduced renal clearance, improved stability against proteolytic enzymes, enhanced solubility in biological fluids, and reduced toxicity/immunogenicity [4]. Based on these effects, numerous PEGylated biomolecules have shown enhanced therapeutic efficacy and fewer undesirable effects compared with their unmodified forms [5].
Safety of recombinant coagulation factors in treating hemophilia
Published in Expert Opinion on Drug Safety, 2019
Massimo Morfini, Carlo Antonio Paolo Rapisarda
The safety of the pegylated drug depends on the adverse effects of the non-conjugated drug and those of PEG itself. PEG is chemically inert and has theoretically low toxicity. Until now, the adverse events observed in post-marketing observational studies were primarily related to the pharmacological action of the active drug and not to PEG [77,78]. It is therefore essential to know the distribution, metabolism, and excretion of PEG: unfortunately, there is little data on its metabolism, the majority of which about the low molecular weight formulations. PEG is quite resistant to hydrolytic mechanisms; its decay is the result of the dependent CY450 oxidation, and the alkyl or aldehyde dehydrogenase [79] while the renal filtration depends on the shape, size, and stiffness of PEG [79–81].