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Novel Technology for Crystal Engineering of Pharmaceutical Solids
The research work described in this thesis, the environmentally
friendly novel "Microwave Assisted Sub-Critical water (MASCW)" technology
for particle engineering of active pharmaceutical ingredients and excipients
was developed. The present novel technology MASCW process is described
as green technology as water is used as the solvent medium and microwave
energy as external source of heat energy for generation of a particle with
different morphological and chemical properties.
In MASCW process supersaturated solution of APIs is prepared by
dissolving solute in water at high temperature and pressure conditions. Upon
rapid and controlled cooling, based on the aqueous solubility of solute,
solute/solvent concentration and dielectric constant of water rapid
precipitation of API with narrow particle size distribution occurs.
Using paracetamol (pca) as API moiety understanding of the
mechanism of MASCW crystallisation process was investigated. The effect
of different process and experimental parameters on crystallisation pathway
and end product attributes were analysed. Correlation between the degree of
supersaturation concentration of pca solution against temperature and
pressure parameters was explained by generating binary phase diagram.
Determination of polymorphic transformation pathway of pca from form I
(stable) to form II metastable polymorphs in solution was analysed using Raman spectroscopy. The difference between conventional heating and
subcritical treatment was explored by determining the change in the solvent
dielectric constant and solubility of hydrophobic API molecule.
Based on the process understanding results, this technology was
further implemented to explore its application in generating phase pure
stable and metastable cocrystal phase. Based on the solubility of API and
cocrystal former congruent (CBZ/SAC, SMT/SAC, SMZ/SAC) and
incongruent (CAF/4HBA) cocrystal pairs were selected. For the first time
generation of anhydrous phase of CAF: 4HBA cocrystal in 1:1 stoichiometric
ration was reported and generation of metastable cocrystal phase of CA
CBZ: SAC form II was reported.
The application of this technology was explored in generating phase
pure metastable polymorph of paracetamol which retain higher
compressibility and dissolution rate. The potential of MASCW micronisation
process, theophylline is used as the model component to produce micro sized particles for pulmonary drug delivery system via dry powder inhaler
(Foradil inhaler). The results demonstrate that the THF particles generated
using MASCW process displayed greater aerodynamic performance
compared to conventional spray-dried THF sample.
In the final chapter, synthesis of inorganic biomaterial (nano crystalline hydroxyapatite) was reported for the first time and the prospects of
combining API like ibuprofen (IBU) with a biologically active component like
nano-crystalline hydroxyapatite (HA) through hydrogen bonding was
mechanistically explained using X-ray diffractometer and spectroscopic
techniques
Study of molecular structure, chemical reactivity and H-bonding interactions in the cocrystal of nitrofurantoin with urea
YesThe 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
Mechanism of Hydrogen-Bonded Complex Formation between Ibuprofen and Nanocrystalline Hydroxyapatite.
Nanocrystalline hydroxyapatite (nanoHA) is the main hard component of bone and has the potential to be used to promote osseointegration of implants and to treat bone defects. Here, using active pharmaceutical ingredients (APIs) such as 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 nanoHA 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 (Fourier transform infrared (FTIR) and Raman) and X-ray diffraction techniques, as well as quantum chemistry calculations, while comparing the behavior 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 Ca center. 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 relationship between the noncovalent bonding and drug release properties
Thermodynamic investigation of carbamazepine-saccharin co-crystal polymorphs
YesPolymorphism 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.Authors would like to acknowledge UKIERI (TPR 26), EPSRC (EP/J003360/1, EP/L027011/1) for the support.
Open Access funded by Engineering and Physical Sciences Research Counci