Molecular Simulation and Statistical Learning Methods toward Predicting Drug–Polymer Amorphous Solid Dispersion Miscibility,Stability, and Formulation Design

Amorphous solid dispersions (ASDs) have emerged as widespread formulations for drug delivery of poorly soluble active pharmaceutical ingredients (APIs). Predicting the API solubility with various carriers in the API–carrier mixture and the principal API–carrier non-bonding interactions are critical factors for rational drug development and formulation decisions. Experimental determination of these interactions, solubility, and dissolution mechanisms is time-consuming, costly, and reliant on trial and error. To that end, molecular modeling has been applied to simulate ASD properties and mechanisms. Quantum mechanical methods elucidate the strength of API–carrier non-bonding interactions, while molecular dynamics simulations model and predict ASD physical stability, solubility, and dissolution mechanisms. Statistical learning models have been recently applied to the prediction of a variety of drug formulation properties and show immense potential for continued application in the understanding and prediction of ASD solubility. Continued theoretical progress and computational applications will accelerate lead compound development before clinical trials. This article reviews in silico research for the rational formulation design of low-solubility drugs. Pertinent theoretical groundwork is presented, modeling applications and limitations are discussed, and the prospective clinical benefits of accelerated ASD formulation are envisioned.     

Investigate oxoazolidine-2,4-dione based eutectic mixture via DFT calculations and SAR

In this work, DFT calculations for the designed eutectic mixtures (EMs) using oxoazolidine 2,4-dione (OZD) and zinc chloride (ZnCl2) are done. The interaction between the hydrogen bond donor and hydrogen bond acceptor at atomic level to get EMs are studied using DFT calculations. At room temperature, the stability of these various systems have been investigated using thermodynamic values or parameters such as enthalpy, free energy and others. DFT calculations is used to investigate the possibility of forming the systems (EMs). Further, the impact of varying the temperature on each system was also investigated (323K, 348K). Various other thermodynamic parameters are studied like dipole moment, hardness, chemical potential of the systems (individual molecules and EMs) at different temperatures. The results of the calculations showed that O1Z4 and O4Z1 have maximum dipole moment having values 8.1291, 9.8801 respectively, indicating maximum polarizability. Change in free energy for O1Z4 is least and was found to be ?37.2496 kcal/ mol. Further on changing the temperature, the parameters do not show much variation. Additionally, we have analyzed structure activity relationship (SAR) method to understand the physico-chemical properties of designed EMs and predict their regression and correlation to optimized energy. From the calculated values of pOE model, the value of r² is 0.9995 confirms the validity of the equation obtained. The results of this study suggest a link between the structures that have been utilized to describe the intermolecular interaction between the hydrogen bond donor and acceptor, as well as the stability of the EMs.     

Kinetics and Mechanism of the Oxidation of Propan-1-ol and Propan-2-ol by Permanganate in the Absence and Presence of Tween-20 in Perchloric Acid Medium

The kinetics of the oxidation of propan-1-ol and propan-2-ol by KMnO₄ in HClO₄ medium has been studied in absence and presence of Tween-20. In the absence of Tween-20 the reaction is of first order with respect to each of permanganate and H⁺, but of complex order with respect to substrate. The active oxidant species HMnO₄ reacts with the alkanol molecule to form an intermediate complex, which decomposes in the rate-determining step to form the respective product and Mn^v. In the presence of Tween-20, both the oxidant and the substrate are distributed between the aqueous phase and the micellar pseudo-phase and then react. Different kinetic and thermodynamic parameters have been evaluated. Compensation between water structure destruction and substrate–micelle interaction plays an important role in the presence of the surfactant.     

Microstructural characterization of acrylonitrile/pentyl acrylate copolymers by one and 2‐D NMR spectroscopy

Acrylonitrile/pentyl acrylate (A/P) copolymers of different monomer composition were prepared by solution polymerization using benzoyl peroxide as initiator. Copolymer compositions were determined by elemental analysis and quantitative ¹³C¹H‐NMR spectroscopy. The comonomer reactivity ratios, determined by both Kelen Tudos (KT) and nonlinear error in variables (EVM) methods are r_A = 0.75 and r_p = 0.45. 2‐D heteronuclear correlation spectroscopy (HSQC) was used to simplify the complex ¹H spectra of A/P copolymers in terms of configurational and compositional sequences. The microstructure was obtained in terms of the distribution of A‐ and P‐ centered triad sequences from ¹³C¹H‐NMR spectra of the copolymers. The copolymerization mechanism was found to follow a first order Markov Model. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 533–543, 1999     

Isolation of dithiocarbazate salts as oxinato-complexes of titanium(IV), zirconium(IV) and hafnium(IV)

Summary Ionic chelate complexes of the type, [(⁵-R)₂ML][dtz] [R=cyclopentadienyl (Cp) or indenyl (C₉H₇); M=Ti^IV, Zr^IV or Hf^IV; HL=oxine; dtz=phenyldithiocarbazate (PhNHNHCS₂)] have been synthesised and characterised. Conductance measurements indicate that the complexes are 11 electrolytes. From i.r. and u.v. spectral studies we conclude that the oxinato-group is chelating. Consequently there is tetrahedral coordination around the metal ion.¹H and¹³C N.m.r. studies are consistent with the stoichiometries. X-ray powder diffraction studies have been made for [(⁵-Cp)₂ZrL][dtz]. For [(⁵-Cp)₂TiL][dtz] and [(⁵-Cp)₂ZrL][dtz] thermal (t.g. and d.t.a.) and mass spectral studies have been carried out.     

Polymer‐supported palladium: A hybrid system for multifunctional catalytic application

Polymer‐supported palladium was synthesized by applying a single‐step wet chemical synthesis route and the resultant composite material was characterized by means of various techniques. Infrared and UV–visible spectra provided information on the chemical structure of the polymer. Microscopy techniques showed the general morphology of the polymer. The oxidation state of palladium was determined using the X‐ray photoelectron spectroscopy method. The synthesized material was applied as a heterogeneous catalyst for the Heck coupling reaction and also as an electrocatalyst for the oxidation of cysteine.     

DIRECT‐ID: An automated method to identify and quantify conformational variations—application to β2‐adrenergic GPCR

The conformational dynamics of a macromolecule can be modulated by a number of factors, including changes in environment, ligand binding, and interactions with other macromolecules, among others. We present a method that quantifies the differences in macromolecular conformational dynamics and automatically extracts the structural features responsible for these changes. Given a set of molecular dynamics (MD) simulations of a macromolecule, the norms of the differences in covariance matrices are calculated for each pair of trajectories. A matrix of these norms thus quantifies the differences in conformational dynamics across the set of simulations. For each pair of trajectories, covariance difference matrices are parsed to extract structural elements that undergo changes in conformational properties. As a demonstration of its applicability to biomacromolecular systems, the method, referred to as DIRECT‐ID, was used to identify relevant ligand‐modulated structural variations in the β₂‐adrenergic (β₂AR) G‐protein coupled receptor. Micro‐second MD simulations of the β₂AR in an explicit lipid bilayer were run in the apo state and complexed with the ligands: BI‐167107 (agonist), epinephrine (agonist), salbutamol (long‐acting partial agonist), or carazolol (inverse agonist). Each ligand modulated the conformational dynamics of β₂AR differently and DIRECT‐ID analysis of the inverse‐agonist vs. agonist‐modulated β₂AR identified residues known through previous studies to selectively propagate deactivation/activation information, along with some previously unidentified ligand‐specific microswitches across the GPCR. This study demonstrates the utility of DIRECT‐ID to rapidly extract functionally relevant conformational dynamics information from extended MD simulations of large and complex macromolecular systems. © 2015 Wiley Periodicals, Inc.     

Organotin(IV) complexes of thiohydrazones: synthesis, characterization and antifungal study

Some new organotin(IV) complexes with salicylaldehyde aniline-N-thiohydrazone (L1) and cinamaldehyde aniline-N-thiohydrazone (L2) of the type (p-ClC6H4)3Sn[L] Cl and (p-ClC6H4)2Sn[L]Cl2 have been synthesized (where L = L1 and L2). The complexes and ligands were characterized by elemental analysis and spectral (UV-vis, IR and 1H NMR) studies. In all the complexes, ligands act as bidentate, coordination through sulphur and azomethane nitrogen. Complexes are 1:1 metal ligands complexes. Antifungal studies of some complexes against Rhizoctonia bataticola fungal strain have been carried out.