Metal Organic Frameworks in Biomedicine Patricia Horcajada,* Ruxandra Gref, Tarek Baati, Phoebe K. Allan, Guillaume Maurin, Patrick Couvreur, G erard F erey, Russell E. Morris, and Christian Serre* Institut Lavoisier, UMR CNRS 8180, Universit e de Versailles St-Quentin en Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France Facult e de Pharmacie, UMR CNRS 8612, Universit e Paris-Sud, 92296 Châtenay-Malabry Cedex, France Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Universit e Montpellier 2, 34095 Montpellier cedex 05, France EaStChem School of Chemistry, University of St. Andrews Purdie Building, St Andrews, KY16 9ST U.K.

Metal-organic frameworks in biomedicine.

The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal–organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

/pdf/mechanochemistry-opportunities-for-new-and-cleaner-synthesis-15fcwynvnd.pdf

Mechanochemistry: opportunities for new and cleaner synthesis

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 current phase of drug development is witnessing an oncoming crisis due to the combined effects of increasing R&D costs, decreasing number of new drug molecules being launched, several blockbuster drugs falling off the patent cliff, and a high proportion of advanced drug candidates exhibiting poor aqueous solubility. The traditional approach of salt formulation to improve drug solubility is unsuccessful with molecules that lack ionizable functional groups, have sensitive moieties that are prone to decomposition/racemization, and/or are not sufficiently acidic/basic to enable salt formation. Several novel examples of pharmaceutical cocrystals from the past decade are reviewed, and the enhanced solubility profiles of cocrystals are analyzed. The peak dissolution for pharmaceutical cocrystals occurs in a short time (<30 min), and high solubility is maintained over a sufficiently long period (4–6 h) for the best cases. The enhanced solubility of drug cocrystals is similar to the supersaturation phenomenon ...

Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals

Pharmaceutical cocrystals: along the path to improved medicines.

Pharmaceutical cocrystals can improve solubility, dissolution, and bioavailability of poorly water soluble drugs. However, true cocrystal solubility is not readily measured for highly soluble cocrystals because they can transform to the most stable drug form in solution. The objectives of this study are to develop a method to estimate the cocrystal solubility in pure solvent and establish the influence of constituent drug and ligand (i.e., coformer) properties. Cocrystal solubility and solubility product were derived from transition concentration measurements where a solution is in equilibrium with solid drug and cocrystal. Transition concentrations and solubilities are reported for carbamazepine cocrystals in water, ethanol, isopropanol, and ethyl acetate. The aqueous solubility for seven carbamazepine cocrystals was estimated to be 2−152 times greater than the solubility of the stable carbamazepine dihydrate form. Cocrystal solubility is shown to be directly proportional to the solubility of constituent...

Solubility Advantage of Pharmaceutical Cocrystals

The purpose of this study is to determine the mechanisms by which moisture can generate cocrystals when solid particles of cocrystal reactants are exposed to deliquescent conditions (when moisture sorption forms an aqueous solution). It is based on the hypothesis that cocrystallization behavior during water uptake can be derived from solution chemistry using models that describe cocrystal solubility and reaction crystallization of molecular complexes. Cocrystal systems were selected with active pharmaceutical ingredients (APIs) that form hydrates and include carbamazepine, caffeine, and theophylline. Moisture uptake and crystallization behavior were studied by gravimetric vapor sorption, X-ray powder diffraction, and on-line Raman spectroscopy. Results indicate that moisture uptake generates cocrystals of carbamazepine−nicotinamide, carbamazepine−saccharin, and caffeine or theophylline with dicarboxylic acid ligands (oxalic acid, maleic acid, glutaric acid, and malonic acid) when solid mixtures with cocry...

Mechanisms by Which Moisture Generates Cocrystals

Cocrystal eutectic constants (Keu), the ratio of solution concentrations of cocrystal components at the eutectic point, are a fundamental indicator of phase behavior and are shown to be a function of the solubility ratio of cocrystal and drug in pure solvent. Keu is shown to depend on solution chemistry including (i) solvent, (ii) complexation, and (iii) ionization, as does the solubility of cocrystals. More than 40 eutectic constants are presented and shown to provide essential information for cocrystal synthesis, selection, and formulation.

Cocrystal Eutectic Constants and Prediction of Solubility Behavior

The purpose of this study was to determine the influence of water vapor sorbed by and dissolved in an amorphous polymer on the formation and thermodynamic stability of cocrystals that are incongruently saturating in water. The conversion of crystalline phases of a hydrophobic drug (carbamazepine) and a hydrophilic coformer (nicotinamide) to cocrystal as a function of moisture sorption (43%, 62% and 75% RH) by an amorphous polymer (polyvinylpyrrolidone, PVP), molecular weight (K12 and K90) and fraction of polymer in ternary mixtures (25 and 50 wt%) was investigated. Moisture uptake and crystallization behavior were studied by gravimetric and dynamic vapor sorption, X-ray powder diffraction, FT-IR, Raman microscopy, and polarized optical microscopy. Results indicate that moisture uptake by PVP can generate cocrystals at moisture contents as low as 3.3% in a ternary mixture corresponding to 13.1% moisture sorbed by PVP. Cocrystal formation rate increased with moisture uptake. The same level of moisture sorption by PVP resulted in higher cocrystal formation rates with lower PVP molecular weight and higher PVP fraction in mixture. This behavior is explained by the increased mobility of water and PVP leading to more effective dissolution of components and higher supersaturation with respect to cocrystal. PVP was also found to change the eutectic point associated with the cocrystal/drug hydrate/solution equilibrium such that the ratio of cocrystal to drug solubility decreases with increasing PVP. Thus, PVP increases the thermodynamic stability of this cocrystal relative to drug.

Dependence of cocrystal formation and thermodynamic stability on moisture sorption by amorphous polymer


 Mafic intrusions in the Coldwell Complex have previously been interpreted as forming from a metasomatized mantle source. To build upon our understanding of this metasomatism, the Mg–Fe isotope compositions of these rocks have been determined, and variations are assessed with respect to the magmatic processes that could have occurred at different stages of their formation. The mineralized Marathon Series (δ26Mg = -0.28‰ to -0.19‰), associated metabasalt (δ26Mg = -0.24‰ to -0.23‰), and the Geordie Lake gabbro (δ26Mg = -0.31‰ to -0.22‰) are characterized by δ26Mg values that are within the range of mantle values, whereas the unmineralized Layered Series (δ26Mg = -0.2‰ to -0.05‰) is heavier than mantle. In contrast, the δ56Fe values of all the Coldwell basaltic–gabbroic rocks (δ56Fe = 0.07 ± 0.08‰) are heavier than mantle, but within the range of terrestrial basalts and mafic–ultramafic layered intrusions. We propose that the Mg–Fe isotope compositions of these rocks was not significantly modified by processes such as partial melting or garnet retention/fractionation in the mantle, fractional crystallization, or contamination during ascent through the crust, as the isotope values do not correlate with proxies for these processes (e.g., La/Sm and La/Yb, Gd/Yb, MgO–CaO–TiO2, and Th/Nb and Th/La, respectively). Their isotope compositions are, therefore, proposed to reflect the compositions of their metasomatized mantle sources. We conclude that metasomatism was not caused by a carbonate melt, subduction-altered oceanic crust and sediments, or an evolved silicate melt, as these processes generate light δ26Mg, variably fractionated δ56Fe, and heavy δ56Fe values, respectively, which are not observed in our dataset for the Coldwell Complex. The agent that metasomatized the mantle beneath the Coldwell Complex was likely slab-derived fluids characterized by isotopically heavy δ26Mg and basaltic δ56Fe values. This scenario can account for the lack of Fe isotope fractionation from basaltic values in all of the Coldwell rocks. The variably heavier δ26Mg of the Layered Series (-0.20 ± 0.01‰ to -0.05 ± 0.05‰) relative to the mantle (-0.25 ± 0.07‰) suggests that the magmas for the Coldwell rocks were derived by tapping of an isotopically heterogeneous mantle source that had undergone variable degrees of metasomatism. The distinctive geochemistry of mafic sequences in the Coldwell and numerous mafic dykes located in the northeast shoulder of the Midcontinent Rift suggests the presence of a variably metasomatized mantle source beneath a large area of the rift.

David J. Good

Papers

Solubility Advantage of Pharmaceutical Cocrystals

Mechanisms by Which Moisture Generates Cocrystals

Cocrystal Eutectic Constants and Prediction of Solubility Behavior

Dependence of cocrystal formation and thermodynamic stability on moisture sorption by amorphous polymer

Mg–Fe isotopes link the geochemical complexity of the Coldwell Complex, Midcontinent Rift to metasomatic processes in the mantle