Prediction of the Crystal Packing of Di-Tetrazine-Tetroxide (DTTO) Energetic Material

Previous calculations suggested that di-tetrazine-tetroxide (DTTO), aka tetrazino-tetrazine-tetraoxide, might have a particularly large density (2.3 g/cm^3) and high energy release (8.8 kJ/kg), but it has not yet been synthesized successfully. We report here density functional theory (DFT) (M06, B3LYP, and PBE-ulg) on 20 possible isomers of DTTO. For the two most stable isomers, c1 and c2 we predict the best packings (i.e., polymorphs) among the 10 most common space groups for organic molecular crystal using the Universal force field and Dreiding force field with Monte Carlo sampling. This was followed by DFT calculations at the PBE-ulg level to optimize the crystal packing. We conclude that the c1 isomer has the P2_12_12_1 space group with a density of 1.96 g/cm^3, while the c2 isomer has the Pbca space group with a density of 1.98 g/cm^3. These densities are among the highest of current energetic materials, RDX (1.81 g/cm^3) and CL20 (2.01 g/cm^3). We observe that the stability of the polymorphs increases with the density while the planarity decreases

Mechanistic Understanding of Co-crystal solubility and dissolution by using a combination of Experimental and Molecular Modelling Techniques

The purpose of this study is to improve the solubility, dissolution rate and permeability of poorly water-soluble drugs by understanding the mechanism of dissolution at molecular level of Flufenamic acid and Carbamazepine co-crystals in the presence of polymers. This study has been separated into four sections: (1) Formation of pharmaceutical co-crystals: Three pharmaceutical co-crystals of poorly water soluble active pharmaceutical ingredient (API) of Flufenamic acid (FFA) and Carbamazepine (CBZ) were synthesized, including 1:1 Flufenamic acid-theophylline co-crystal (FFATP CO), 1:1 Flufenamic acid-nicotinamide co-crystal (FFA-NIC CO) and 1:1 Carbamazepine-nicotinamide co-crystal (CBZ-NIC CO). The results of Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray Powder Diffraction (XRPD) confirmed the formation of co-crystals. (2) The effect of polymers on the surface dissolution of co-crystals: The influence of three polymers (polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2- pyrrolidone (60%) and vinyl acetate (40%) (PVP-VA)) on the surfaces of FFA-TP CO, FFA-NIC CO and CBZ-NIC CO was studied using Atomic force Microscopy (AFM), Scanning electron microscopy (SEM) and Raman spectroscopy. It was found that the co-crystals have different dissolution mechanisms, and that addition of polymers can alter the dissolution properties of co-crystals by interacting with the crystal faces. (3) The molecular interactions between the drugs, co-formers and polymers were investigated using Nuclear Magnetic Resonance (NMR) and Diffusion Ordered Spectroscopy (DOSY). It was found that the type of a polymer, its concentration, and the interaction of the polymer with a co-former in solution will significantly affect the FFA and CBZ co-crystals (4). Molecular modelling of free drug molecules with coformers and polymers in the presence of water molecules: Results indicate bulk precipitation could be occurring for FFA molecules in solution and that PVP-VA was an effective precipitation inhibitor for all three co-crystals studied in solution. Overall, PVP was an effective polymer for surface precipitation inhibitor and PVP-VA was the most effective inhibitor for precipitation in solution