Cyclodextrins as pharmaceutical solubilizers.

: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

Cyclodextrins and their pharmaceutical applications.

Objectives Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations.

Key findings  There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes.

Summary  We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.2042-7158.2010.01030.x

Pharmaceutical applications of cyclodextrins: basic science and product development.

Since the first PEGylated product was approved by the Food and Drug Administration in 1990, PEGylation has been widely used as a post-production modification methodology for improving biomedical efficacy and physicochemical properties of therapeutic proteins. Applicability and safety of this technology have been proven by use of various PEGylated pharmaceuticals for many years. It is expected that PEGylation, as the most established technology for extension of drug residence in the body, will play an important role in the next generation therapeutics, such as peptides, protein nanobodies and scaffolds, which due to their diminished molecular size need half-life extension. This review focuses on several factors important in the production of PEGylated biopharmaceuticals enabling efficient preparation of highly purified PEG-protein conjugates that have to meet stringent regulatory criteria for their use in human therapy. Areas addressed are PEG properties, the specificity of PEGylation reactions, separation and large-scale purification, the availability and analysis of PEG reagents, analysis of PEG-protein conjugates, the consistency of products and processes and approaches used for rapid screening of pharmacokinetic properties of PEG-protein conjugates.

https://www.creativepegworks.com/PEGylation%20of%20therapeutic%20proteins%20review%20by%20Jevsevar.pdf

PEGylation of therapeutic proteins.

A method for determining the equilibrium association constant of a complexation reaction A + B left harpoon over right harpoon AB by electrospray ionization mass spectrometry is described. The method consists in measuring the relative intensities of the peaks corresponding to A and to AB in equimolar A-B solutions at different concentrations C(0). The results are fitted by a non-linear least-squares procedure, with the two variable parameters being the equilibrium association constant K(a) and a factor R, defined by I(AB)/I(A) = R x [AB]/[A]. The factor R is the ratio between the response factors of AB and A, and corrects for the relative electrospray responses of the complex and the free substrate A, mass discrimination of instrumental origin and/or moderate in-source dissociation. The method is illustrated with the following two systems: complexes between a double-stranded 12-base pair oligonucleotide and minor groove binders, and cyclodextrin complexes with alpha,omega-dicarboxylic acids. For the oligonucleotide complexes, it is found that the response of the complex is not dramatically different to the response of the free oligonucleotide duplex, as the double helix conformation is disturbed by the drug only to a minor extent. In the case of cyclodextrin complexes, these complexes were found to have a much higher response than free cyclodextrin. This may be due to the fact that cyclodextrin is neutral in solution, whereas the complex is charged, but it can also stem from the fact that a significant proportion of the complex is in a non-inclusion geometry. The present method requires the exact determination of the concentrations of the reactants and is applicable to 1 : 1 complexes.

Influence of response factors on determining equilibrium association constants of non-covalent complexes by electrospray ionization mass spectrometry

The Schiff bases of salicylaldehyde and aminopyridines as highly sensitive analytical reagents

https://link.springer.com/content/pdf/10.1016/S1044-0305(02)00416-6.pdf

On the Specificity of Cyclodextrin Complexes Detected by Electrospray Mass Spectrometry

Fluorescence characteristics of Schiff bases derived from aminopyridines and salicylaldehyde were studied and possibilities of their analytical application were discussed. It is shown that these compounds can be used for spectrofluorimetric monitoring of small pH changes as well as for sensitive metal ion determinations. As an illustration of metal ion determination, a spectrofluorimetric procedure for analysis of Cu2+ is presented. Determination of Cu2+ was based on the quenching effect of Cu2+ on the fluorescence of N, N'-bis(salicylidene)-2, 3-pyridinediamine in dioxan/water 1/1 (volume fraction of dioxan, phi = 50%). Under optimal conditions (pH = 8.9, lambda(ex) = 340 nm, lambda(em) = 385 nm, c(ligand) = 1.0 x 10(-5) M), the linearity range of the calibration curve was 30-350 mu g L-1 Cu2+. The procedure is fast, simple and reproducible. It is characterized by high sensitivity and satisfactory selectivity. An additional advantage of Schiff bases derived from aminopyridines as analytical reagents lies in the simplicity of preparation procedures, enabling improvement of the determination methods not only by optimization of experimental conditions, but also by designing suitable structural characteristics of the reagent.

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Nives Galić

Papers

Influence of response factors on determining equilibrium association constants of non-covalent complexes by electrospray ionization mass spectrometry

The Schiff bases of salicylaldehyde and aminopyridines as highly sensitive analytical reagents

On the Specificity of Cyclodextrin Complexes Detected by Electrospray Mass Spectrometry

Schiff Bases Derived from Aminopyridines as Spectrofluorimetric Analytical Reagents

Structural and spectroscopic characteristics of aroylhydrazones derived from nicotinic acid hydrazide