Cyclodextrins as pharmaceutical solubilizers.

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

The utility of cyclodextrins for enhancing oral bioavailability.

A review with 310 references. Photochemical degradation is likely to be an important loss mechanism for many pharmaceutical pollutants in surface waters. This review summarizes the current knowledge of the photochemical behavior of pharmaceuticals and highlights the use of the fundamental photochemistry and phototoxicity literature to help understand and predict the aquatic fate of pharmaceuticals. Naproxen and diclofenac are shown to exemplify the idea that photochemical behavior obtained from fundamental photochemistry studies can be related to environmental conditions. There are, however, numerous compounds that have been found in environmental matrices for which no photochemistry data relatable to environmental conditions are available. It will be necessary to combine the results available in the large body of fundamental photochemistry and phototoxicity literature with laboratory and field experiments designed to determine direct and indirect photolysis rates and to identify photoproducts. This course will lead to a thorough understanding of the role of photodegradation on the fate and impact of pharmaceutical pollutants.

Photodegradation of pharmaceuticals in the aquatic environment: A review

Highly selective detection of phosphate in very complicated matrixes with an off–on fluorescent probe of europium-adjusted carbon dots

Effect of PVP K-25 on the formation of the naproxen:β-ciclodextrin complex

The associative structures between F127 Pluronic micelles and four drugs, namely, lidocaine (LD), pentobarbital sodium salt (PB), sodium naproxen (NP), and sodium salicylate (SAL), were studied by small-angle neutron scattering (SANS). Different outcomes for the micellar aggregates are observed, which are dependent on the chemical nature of the drug and the presence of charge or otherwise: the micelles grow with LD, are hardly modified with PB, and decrease in size with both NP and SAL. The partition coefficient, determined by fluorescence spectroscopy, is directly correlated to the amount of charge, following NP ≈ SAL < PB < LD. All drugs are found to lie at the interfacial layer, with a slightly deeper localization of LD and more superficial for PB. All drugs can form inclusion complexes with heptakis(2,6-di-O-methyl) β-cyclodextrin (hep2,6 β-CD). Hep2,6 β-CD, as shown in previous studies (Joseph, J.; Dreiss, C. A.; Cosgrove, T. Langmuir, 2008, 24, 10005−10010; Dreiss, C. A.; Nwabunwanne, E.; Liu, R.; B...

Growth, Shrinking, and Breaking of Pluronic Micelles in the Presence of Drugs and/or β-Cyclodextrin, a Study by Small-Angle Neutron Scattering and Fluorescence Spectroscopy

Polymeric micelles, in particular PEO-PPO-based Pluronic, have emerged as promising drug carriers, while cyclodextrins (CD), cyclic oligosaccharides with an apolar cavity, have long been used for their capacity to form inclusion complexes with drugs. Dimethylated β-cyclodextrin (DIMEB) has the capacity to fully breakup F127 Pluronic micelles, while this effect is substantially hindered if drugs are loaded within the micellar aggregates. Four drugs were studied at physiological temperature: lidocaine (LD), pentobarbital sodium salt (PB), sodium naproxen (NP), and sodium salicylate (SAL); higher temperatures shift the equilibrium toward higher drug partitioning and lower drug/CD binding compared to 25 °C (Valero, M.; Dreiss, C. A. Growth, Shrinking, and Breaking of Pluronic Micelles in the Presence of Drugs and/or β-Cyclodextrin, a Study by Small-Angle Neutron Scattering and Fluorescence Spectroscopy. Langmuir 2010, 26, 10561−10571). The impact of drugs on micellar structure was characterized by small-angle...

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Competitive and Synergistic Interactions between Polymer Micelles, Drugs, and Cyclodextrins: The Importance of Drug Solubilization Locus

Ternary naproxen:β-cyclodextrin:polyethylene glycol complex formation

Photophysical properties of a non-steroidal anti-inflammatory drug, Naproxen (6-methoxy alpha-methyl-2-naphthalene acetic acid sodium salt), were investigated in solvents of different polarity, hydrogen donor ability and also in cyclodextrins. The results indicate that in all cases the emitting state is the 1L(b) singlet. In alcoholic solvents, an intermolecular hydrogen bond is responsible for the observed photophysical behaviour of the probe whereas in non-protic solvents (polar and weakly polar) an intramolecular hydrogen bond type is postulated to rationalize the data found. In water, the non-radiative rate constant has a value similar to those found in aqueous solutions of alpha- and beta-cyclodextrins where the probe form complexes. The behaviour in water is explained by a water-structure enforced hydrophobic effect. The spectroscopic results are interpreted on the basis of a multiple-parameter model that considers specific solute-solvent interactions. These were also observed in the ground state and detected by Fourier transform infrared spectroscopy. Molecular mechanics (MM) and molecular orbital (AM1) calculations also support the existence of two conformations (rotamers) in Naproxen with non-equivalent intramolecular hydrogen bond-like formation.

Margarita Valero

Papers

Effect of PVP K-25 on the formation of the naproxen:β-ciclodextrin complex

Growth, Shrinking, and Breaking of Pluronic Micelles in the Presence of Drugs and/or β-Cyclodextrin, a Study by Small-Angle Neutron Scattering and Fluorescence Spectroscopy

Competitive and Synergistic Interactions between Polymer Micelles, Drugs, and Cyclodextrins: The Importance of Drug Solubilization Locus

Ternary naproxen:β-cyclodextrin:polyethylene glycol complex formation

Hydrogen bonding in a non-steroidal anti-inflammatory drug--Naproxen.