• Mechanism of hydrogen-bonded complex formation between ibuprofen and nanocrystalline hydroxyapatite

      Ryabenkova, Yulia; Jadav, Niten B.; Conte, M.; Hippler, M.F.A.; Reeves-McLaren, N.; Coates, Philip D.; Twigg, Peter C.; Paradkar, Anant R. (2017)
      Nanocrystalline hydroxyapatite (nanoHA) is the main hard component of bone and has potential to be used to promote osseointegration of implants and to treat bone defects. Here, using active pharmaceutical ingredients (APIs) like ibuprofen, we report on the prospects of combining nanoHA with biologically active compounds to improve the clinical performance of these treatments. In this study we designed and investigated the possibility of API attachment to the surface of nano-HA crystals via the formation of a hydrogen-bonded complex. The mechanistic studies of an ibuprofen/nanoHA complex formation have been performed using a holistic approach encompassing spectroscopic (FT-IR and Raman) and X-ray diffraction techniques as well as quantum chemistry calculations (DFT), while comparing the behaviour of the ibuprofen/nanoHA complex with that of a physical mixture of the two components. Whereas ibuprofen exists in dimeric form both in solid and liquid state, our study showed that the formation of the ibuprofen/nanoHA complex most likely occurs via the dissociation of the ibuprofen dimer into monomeric species promoted by ethanol, with subsequent attachment of a monomer to the HA surface. An adsorption mode for this process is proposed; this includes hydrogen bonding of the hydroxyl group of ibuprofen to the hydroxyl group of the apatite, together with the interaction of the ibuprofen carbonyl group to an HA calcium centre. Overall, this mechanistic study provides new insights into the molecular interactions between APIs and the surfaces of bioactive inorganic solids and sheds light on the relation between the non-covalent bonding and drug release properties.
    • Study of molecular structure, chemical reactivity and H-bonding interactions in the cocrystal of nitrofurantoin with urea

      Khan, E.; Shukla, A.; Jadav, Niten B.; Telford, Richard; Ayala, A.P.; Tandon, P.; Vangala, Venu R. (2017)
      The cocrystal of nitrofurantoin with urea (C8H6N4O5)·(CH4N2O), a non-ionic supramolecular complex, has been studied. Nitrofurantoin (NF) is a widely used antibacterial drug for the oral treatment of infections of the urinary tract. Characterization of the cocrystal of nitrofurantoin with urea (NF–urea) was performed spectroscopically by employing FT-IR, FT- and dispersive-Raman, and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. With the purpose of having a better understanding of H-bonding (inter- and intra-molecular), two different models (monomer and monomer + 3urea) of the NF–urea cocrystal were prepared. The fundamental vibrational modes were characterized depending on their potential energy distribution (PED). A combined experimental and theoretical wavenumber study proved the existence of the cocrystal. The presence and nature of H-bonds present in the molecules were ascertained using quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. As the HOMO–LUMO gap defines the reactivity of a molecule, and this gap is more for the API than the cocrystal, this implies that the cocrystal is more reactive. Global descriptors were calculated to understand the chemical reactivity of the cocrystal and NF. Local reactivity descriptors such as Fukui functions, local softness and electrophilicity indices were analysed to determine the reactive sites within the molecule. The comparison between NF–urea (monomer) and NF showed that the cocrystal has improved overall reactivity, which is affected by the increased intermolecular hydrogen bond strength. The docking studies revealed that the active sites (C[double bond, length as m-dash]O, N–H, NO2, N–N) of NF showed best binding energies of −4.89 kcal mol−1 and −5.56 kcal mol−1 for MUL and 1EGO toxin, respectively, which are bacterial proteins of Escherichia coli. This cocrystal could potentially work as an exemplar system to understand H-bond interactions in biomolecules.
    • Thermodynamic investigation of carbamazepine-saccharin co-crystal polymorphs

      Pagire, Sudhir K.; Jadav, Niten B.; Vangala, Venu R.; Whiteside, Benjamin R.; Paradkar, Anant R. (2017)
      Polymorphism in active pharmaceutical ingredients (APIs) can be regarded as critical for the potential that crystal form can have on the quality, efficacy and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII have been performed using thermo-kinetic methods and systematically characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), solubility and slurry measurements. According to Berger and Ramberger’s heat of fusion rule, FI (ΔHfus = 121.1 J/g, mp 172.5 °C) and FII (ΔHfus= 110.3 J/g, mp 164.7 °C) are monotropically related. The solubility and van’t Hoff plot results suggest that FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat induced stresses, however, FII converts to FI during solution mediated transformation.