A crystallographic route to understand drug solubility: the case of 4- aminoquinoline antimalarials

Most Active Pharmaceutical Ingredients (API) can be prepared in various crystalline forms [1] displaying largely different physical/chemical properties and bioavailability. Salt formation represents the most common and simplest chemical way to modify the overall features but also the toxicity and biopharmaceutical availability of a drug substance. However, it is often unclear how and why the chemical and crystallographic characters can cooperate in determining these changes. We here face the problem from the perspective of the antiplasmodial drug piperaquine (PQ, C29H32Cl2N6) [2]. Being highly lipophilic, both neutral PQ and its commercial hydrogen phosphate tetrahydrate salt are poorly soluble in water, resulting in a reduced oral bioavailability. We synthesized five novel PQ salts and characterized them by both single crystal X\u2013ray diffraction methods and T-dependent (20 \u2013 50 \ubaC) UV\u2013Vis spectroscopy. Our aim was to explore possible relationships among non-covalent interaction networks in the crystals and measured solubilities. We also estimated changes in thermodynamic state functions related to the solvation process by DFT simulations, both in vacuo and in the solid state. We found that solubilities of PQ salts conform in most cases to the Hard and Soft Acid and Bases (HSAB) rules, i.e. less soluble compounds bear ions of comparable hardness. Crystal packing plays a far less important role, even though disorder-related entropic effects can influence the response of solubility to temperature. A possible take-home message is that intensive thermodynamic properties stem from a non-trivial cooperation several physicochemical effects. A first-principle understanding of the drug solubility cannot rely just on the description of the crystal packing, but must take into account the explicit evaluation of interaction energetics and pertinent electronic factors. [1] R. Hilfiker and M. von Raumer, Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development. 2019, Wiley-VCH, Weinheim (Germany). ISBN: 978-3-527-34040-8. [2] P. Sacchi, L. Loconte, G. Macetti, S. Rizzato and L. Lo Presti Crystal Growth Des. 2019. 19, 139

The TACO Puzzle: A Phase-Transition Mystery Revisited

The organic salt (5-methyl-1-thia-5-azacyclo-octane-1-oxide) perchlorate (TACO) is known to undergo a single-crystal-to-single-crystal phase transition in the 276-298 K T range without a change in the external shape of the sample. Despite extensive computational and experimental investigations, no safe conclusions about the transition mechanism could be drawn till now. The two packing patterns are very similar, and symmetry is conserved, apart from an interchange of cell axes from P21/c (\u3b1-TACO, low-T) to P21/a (\u3b2-TACO, high-T). Yet, the phase transition implies a significant conformational rearrangement, coupled with 3c180\ub0-wide rotations, of 1/2 of the cations, in conjunction with reorientation of the anions. Here, we analyze the crystal packing of the two phases in terms of pairwise molecule-molecule interaction energies, as derived from the PIXEL approach. Rigid-body molecular reorientations are simulated by solid-state Monte Carlo calculations, while the likelihood of conformational rearrangements is estimated through gas-phase density functional theory M06/6-311G(p,d) simulations. We demonstrate that rotational motion of the cations is not hampered by substantial energetic barriers, while the ring flip can be described as a two-step process with a main kinetic barrier of 3c45 kJ\ub7mol-1, which might explain the metastable behavior of the \u3b2 phase at low T. A possible mechanism of the phase transition is proposed, accounting for the present computational evidences in the context of the former experimental findings

Optimal regularizations for data generation with probabilistic graphical models

Understanding the role of regularization is a central question in Statistical Inference. Empirically, well-chosen regularization schemes often dramatically improve the quality of the inferred models by avoiding overfitting of the training data. We consider here the particular case of L 2 and L 1 regularizations in the Maximum A Posteriori (MAP) inference of generative pairwise graphical models. Based on analytical calculations on Gaussian multivariate distributions and numerical experiments on Gaussian and Potts models we study the likelihoods of the training, test, and 'generated data' (with the inferred models) sets as functions of the regularization strengths. We show in particular that, at its maximum, the test likelihood and the 'generated' likelihood, which quantifies the quality of the generated samples, have remarkably close values. The optimal value for the regularization strength is found to be approximately equal to the inverse sum of the squared couplings incoming on sites on the underlying network of interactions. Our results seem largely independent of the structure of the true underlying interactions that generated the data, of the regularization scheme considered, and are valid when small fluctuations of the posterior distribution around the MAP estimator are taken into account. Connections with empirical works on protein models learned from homologous sequences are discussed

Gate stability of GaN-Based HEMTs with P-Type Gate

status: publishe

Chaotic Interaction of Langmuir Solitons and Long Wavelength Radiation

In this work we analyze the interaction of isolated solitary structures and ion-acoustic radiation. If the radiation amplitude is small solitary structures persists, but when the amplitude grows energy transfer towards small spatial scales occurs. We show that transfer is particularly fast when a fixed point of a low dimensional model is destroyed.Comment: LaTex + 4 eps file

Porosity and crystal morphology of heterometallic coordination networks from β-diketonate ligands

Porous coordination polymers (PCPs) or metal-organic-frameworks (MOFs) are considered very promising porous materials that can be exploited in many different technological fields such as gas storage, heterogeneous catalysis and separation of mixtures. In the field of MOF materials, many efforts are devoted to the search of rational synthetic procedures. Among others, a useful synthetic strategy is the so-called Metalloligand (MLs) approach. MLs are coordination complexes containing suitably oriented exo donor-groups that, used in place of organic linkers, can orient the formation of desired homo and heterometallic polymeric architectures [1]. Functionalized chelating ligands suited to obtain useful MLs are \uf062-diketonate molecules.[2] We report the synthesis and the structural characterization of two families of coordination frameworks obtained through the use of different \uf062-diketonate ligands with copper salts of several counter-ions. The first family of polymers have a two-dimensional layered structure whereas the members of the second family adopt a three-dimensional flexible framework structure. We have focused our attention to the correlations between the crystal structure, the dimensionality, the topology and porosity of the networks and the crystal morphologies, as well as to the investigation of the surface phenomena during the crystal growing process. Moreover, we have mapped a continuous set of crystal morphologies by controlling experimental variables such as the solvent system, the metal-ligand molar ratio and the nature of the counter-anion. The aim is to develop a method to tune the crystal habit according to the specific requirement of some important applications.[3] [1] S. Kitagawa, R. Kitaura, S. Noro Angew. Chem., Int. Ed., 43 (2004) 2334. [2] L. Carlucci, G. Ciani, S. Maggini, D.M. Proserpio, M. Visconti, Chem. Eur. J, 16 (2010) 12328. [3] L. Carlucci, G. Ciani, J. M. Garc\ueca-Ruiz, M. Moret, D. M. Proserpio and S. Rizzato , Cryst. Growth Des., 2009, 9(12), 5024-5034

Unravelling the Chemistry of the [Cu(4,7-Dichloroquinoline)2Br2]2 Dimeric Complex through Structural Analysis: A Borderline Ligand Field Case

Large dark prismatic crystals (P 1\uaf ) consisting of closely packed centrosymmetric [Cu(4,7-dichloroquinoline)2]2Br4 binuclear units are formed when 4,7-dichloroquinoline (DCQ, C9H5NCl2) binds copper(II). Cu2+ adopts a strongly distorted square pyramidal coordination geometry, perturbed by electrostatic interactions with two axial \u3bc\u2013Br ligands acting as highly asymmetric bridges. It is shown that, as electronic states of ligands are higher in energy than the metal ones, antibonding orbitals bear significant ligand-like character and electronic charge is partially transferred from inner-sphere coordinated halogen atoms to copper. Overall, the title compound sits on the Hoffman\u2019s border between main group and transition chemistry, with non-negligible contributions of the ligands to the frontier orbitals. The relative energy placement of metal and ligand states determines an internal redox process, where the metal is slightly reduced at the expense of partial oxidation of the bromide ligands. In fact, the crystal structure is partially disordered due to the substitution of some penta-coordinated Cu(II) centers with tetra-coordinated Cu(I) ions. The geometry of the complex is rationalized in terms of electrostatic-driven distortions from an ideal octahedral prototype. Implications on the reactivity of Cu(II)\u2013quinoline complexes are discusse

On the molecular basis of the activity of the antimalarial drug chloroquine : EXAFS-assisted DFT evidence of a direct Fe–N bond with free heme in solution

4-aminoquinoline antiplasmodials interfere with the biocrystallization of the malaria pigment, a key step of the malaria parasite metabolism. It is commonly believed that these drugs set stacking \u3c0 \ub7\ub7\ub7 \u3c0 interactions with the Fe-protoporphyrin scaffold of the free heme, even though the details of the heme:drug recognition process remain elusive. In this work, the local coordination of Fe(III) ions in acidic solutions of hematin at room temperature was investigated by extended x-ray absorption fine structure (EXAFS) spectroscopy in the 4.0\u20135.5 pH range, both in the presence and in the absence of the antimalarial drug chloroquine. EXAFS results were complemented by DFT simulations in polarizable continuum media to model solvent effects. We found evidence that a complex where the drug quinoline nitrogen is coordinated with the iron center might coexist with formerly proposed adduct geometries, based on stacking interactions. Charge-assisted hydrogen bonds among lateral chains of the two molecules play a crucial role in stabilizing this complex, whose formation is favored by the presence of lipid micelles. The direct Fe\u2013N bond could reversibly block the axial position in the Fe 1st coordination shell in free heme, acting as an inhibitor for the crystallization of the malaria pigment without permanently hampering the catalytic activity of the redox center. These findings are discussed in the light of possible implications on the engineering of drugs able to thwart the adaptability of the malaria parasite against classical aminoquinoline-based therapies