Yes / A green approach has been used for co-crystallization of non-congruent co-crystal pair of caffeine – maleic acid using water. Ultrasound is known to affect crystallization hence the effect of high power ultrasound on the ternary phase diagram has been investigated in detail using a slurry co-crystallization approach. A systematic investigation was performed to understand how the accelerated conditions during ultrasound assisted co-crystallization will affect different regions of the ternary phase diagram. Application of ultrasound showed considerable effect on the ternary phase diagram; principally on caffeine/maleic acid 2:1 (disappeared) and 1:1 co-crystal (narrowed) regions. Also, the stability regions for pure caffeine and maleic acid in water were narrowed in the presence of ultrasound, expanding the solution region. The observed effect of ultrasound on the phase diagram was correlated with solubility of caffeine and maleic acid and stability of co-crystal forms in water.

The research described in this dissertation mainly covers the development of novel technologies for co-crystallisation along with the discovering of plumbagin co-crystal and thermodynamic interrelationship between the co-crystal polymorphs. Co-crystallisation is a fast growing field in the area of crystal design and has shown potential advantages in the field of pharmaceutical. Currently, many research groups are working on the development of new technologies for the synthesis of pure and stoichiometrically controlled co-crystals. In present study, three novel technologies have been developed for co-crystallisation, which include microwave assisted co-crystallisation, spherical crystallisation and microwave assisted sub-critical water processing. The microwave assisted co-crystallisation is a slurry based technology where, effects of drug solubility and dielectric properties of the solvent were investigated using caffeine / maleic acid as a model co-crystal pair. The mechanism of co-crystallisation under microwave irradiation has been proposed. The co-crystals of plumbagin with improved solubility were obtained with the coformers such as hydroquinone, resorcinol and urea using microwave assisted co-crystallisation technique. The spherical crystallisation technology was developed for co-crystallisation of carbamazepine / saccharin co-crystal pair and demonstrated its application for polymorphic control and as a potential technique for the purification of desired crystal form through surface energetic based separation. The thermodynamic interrelationship between Form I and Form II of carbamazepine / saccharin co-crystal was studied using different thermodynamic tests. The results obtained suggest that the carbamazepine / saccharin co-crystal polymorphs are monotropic. Microwave assisted sub-critical water processing has been explored as a green technology for the synthesis of co-crystals. Carbamazepine / saccharin co-crystal pair has been used as a model pair and effects of processing variables on the resulting crystal form and degradation of an API have been studied.

Innovations and process understanding is the current focus in pharmaceutical industry. The objective of this research was to explore application of high power ultrasound in the slurry crystallisation and application of low power ultrasound (3.5 MHz) as process analytical technology (PAT) tool to understand pharmaceutical processing such as hot melt extrusion. The effect of high power ultrasound (20 kHz) on slurry co-crystallisation of caffeine / maleic acid and carbamazepine / saccharin was investigated. To validate low power ultrasound monitoring technique, it was compared with the other techniques (PAT tools) such as in-line rheology and in-line NIR spectroscopy. In-line rheological measurements were used to understand melt flow behaviour of theophylline / Kollidon VA 64 system in the slit die attached to the hot melt extruder. In-line NIR spectroscopic measurements were carried out for monitoring any molecular interactions occurring during extrusion. Physical mixtures and the processed samples obtained from all experiments were characterised using powder X-ray diffraction, thermogravimetry analysis, differential scanning calorimetry, scanning Electron Microscopy, dielectric spectroscopy and high performance liquid chromatography, rotational rheology, fourier transform infrared spectroscopy and near infrared spectroscopy. The application of high power ultrasound in slurry co-crystallisation of caffeine / maleic acid helped in reducing equilibrium time required for co-crystal formation. During carbamazepine / saccharin co-crystallisation high power ultrasound induced degradation of carbamazepine was negligible. Low power ultrasound can be used as a PAT tool as it was found to be highly sensitive to the changes in processing temperatures and drug concentration.

The research described in this thesis seeks to explore a concept that has the potential to make a step-change for the control of the properties of energetic materials (sensitivity, long-term storage, processability, performance, etc.), resulting in safer munitions with enhanced performance. This concept is co-crystallisation and involves crystallisation of the energetic material with one or more molecular components in order to modify the properties of the composition. The concept has been demonstrated in the pharmaceutical sector as a successful means of altering the physical properties of active pharmaceutical ingredients, e.g. solubility, bioavailability, stability to humidity. This project therefore aims to exploit the concepts of crystal engineering and co-crystallisation as applied to selected energetic materials in order to achieve the following objectives: (i) develop an enhanced understanding of how structure influences key properties such as sensitivity, (ii) control the sensitivity of existing, approved energetic materials, and (iii) identify new energetic materials with enhanced properties, e.g. reduced sensitivity, higher performance, and increased thermal stability. The compound 3,5-nitrotriazolone (NTO) was crystallised with a selection of co-formers to produce salts and co-crystals. The structure properties of these materials were explored using single-crystal and powder X-ray diffraction, and structural features were correlated with properties such as crystal density, difference in pKa of co-formers, thermal properties, and sensitivity to impact. Detonation velocities of the co-crystals were calculated based on densities, chemical composition, and heats of formation. Co-former molecules included a series of substituted anilines, substituted pyridines (including 4,4’-bipyridine, 2-pyridone), and substituted triazoles. A co-crystal was formed between NTO and 4,4’-bipyridine on crystallisation from ethanol, whilst a salt was formed when crystallised from water. Upon heating the salt to 50ºC, the co-crystal was formed. Structural differences between the salts formed by NTO with 3,5-DAT and 3,4- DAT were correlated with structural features. 3,5-DAT.NTO is substantially less impact sensitive than 3,4-DAT.NTO, and this is attributed to the layered structure of 3,5-DAT.NTO. An investigation into triazole-based NTO salts under high pressure was conducted. A new polymorph of 3,5-DAT.NTO was discovered upon increasing the pressure to 2.89 GPa. The high-pressure phase appears to retain the layered structure and remains in this phase up to 5.33 GPa, although it was not recoverable upon decompression to atmospheric pressure. The compression behaviour of the unit cell volume for phase I of 3,5-DAT.NTO has been fitted to a 3rd-order Birch- Murnaghan equation of state (EoS) with V0 = 957.7 Å3, B0 = 8.2 GPa and B’0 = 14.7. The unit cell was found to be most compressible in the a and c directions. Under high pressure 3,4-DAT.NTO does not give any indication of a phase change occurring up to 6.08 GPa. The coefficients of the 3rd-order Birch-Murnaghan EoS have been determined to be V0 = 915.9 Å3, B0 = 12.6 GPa and B’0 = 6.5.

Innovations and process understanding is the current focus in pharmaceutical industry. The objective of this research was to explore application of high power ultrasound in the slurry crystallisation and application of low power ultrasound (3.5 MHz) as process analytical technology (PAT) tool to understand pharmaceutical processing such as hot melt extrusion. The effect of high power ultrasound (20 kHz) on slurry co-crystallisation of caffeine / maleic acid and carbamazepine / saccharin was investigated. To validate low power ultrasound monitoring technique, it was compared with the other techniques (PAT tools) such as in-line rheology and in-line NIR spectroscopy. In-line rheological measurements were used to understand melt flow behaviour of theophylline / Kollidon VA 64 system in the slit die attached to the hot melt extruder. In-line NIR spectroscopic measurements were carried out for monitoring any molecular interactions occurring during extrusion. Physical mixtures and the processed samples obtained from all experiments were characterised using powder X-ray diffraction, thermogravimetry analysis, differential scanning calorimetry, scanning Electron Microscopy, dielectric spectroscopy and high performance liquid chromatography, rotational rheology, fourier transform infrared spectroscopy and near infrared spectroscopy. The application of high power ultrasound in slurry co-crystallisation of caffeine / maleic acid helped in reducing equilibrium time required for co-crystal formation. During carbamazepine / saccharin co-crystallisation high power ultrasound induced degradation of carbamazepine was negligible. Low power ultrasound can be used as a PAT tool as it was found to be highly sensitive to the changes in processing temperatures and drug concentration.

The research described in this dissertation mainly covers the development of novel technologies for co-crystallisation along with the discovering of plumbagin co-crystal and thermodynamic interrelationship between the co-crystal polymorphs. Co-crystallisation is a fast growing field in the area of crystal design and has shown potential advantages in the field of pharmaceutical. Currently, many research groups are working on the development of new technologies for the synthesis of pure and stoichiometrically controlled co-crystals. In present study, three novel technologies have been developed for co-crystallisation, which include microwave assisted co-crystallisation, spherical crystallisation and microwave assisted sub-critical water processing. The microwave assisted co-crystallisation is a slurry based technology where, effects of drug solubility and dielectric properties of the solvent were investigated using caffeine / maleic acid as a model co-crystal pair. The mechanism of co-crystallisation under microwave irradiation has been proposed. The co-crystals of plumbagin with improved solubility were obtained with the coformers such as hydroquinone, resorcinol and urea using microwave assisted co-crystallisation technique. The spherical crystallisation technology was developed for co-crystallisation of carbamazepine / saccharin co-crystal pair and demonstrated its application for polymorphic control and as a potential technique for the purification of desired crystal form through surface energetic based separation. The thermodynamic interrelationship between Form I and Form II of carbamazepine / saccharin co-crystal was studied using different thermodynamic tests. The results obtained suggest that the carbamazepine / saccharin co-crystal polymorphs are monotropic. Microwave assisted sub-critical water processing has been explored as a green technology for the synthesis of co-crystals. Carbamazepine / saccharin co-crystal pair has been used as a model pair and effects of processing variables on the resulting crystal form and degradation of an API have been studied.

The study of pharmaceutical preformulation includes the evaluation of pharmacokinetic, pharmacodynamic and physicochemical properties of the drug molecules that aid the formulation. However, it has a limited role in determining drug dosage optimisation in the formulation. The study of drug-Plasma Protein Binding (PPB), and the lipophilicity, solubility, and ionic behaviours of the desired drug molecules addresses the gap and enhances our undertraining related to the behaviour of the drug molecules in the body. The High-Performance Liquid Chromatography (HPLC) technique was used in the current study to assess drug-PPB interaction. Using Michael Abraham’s ‘Linear Free Energy Relationship’ (LFER) method, two major plasma proteins namely, Human Serum Albumin as HSA and α-1-Acid Glycoprotein as AGP, were used and the structural properties governing drug-plasma protein binding was determined. This is the first time that the effect of ionised species on PPB has been quantitatively evaluated. In addition, the molecular interactions also play a key role in the supramolecular complexes of co-crystals. The project also evaluated the co-crystallisation process and its effect on physicochemical properties of the drug. In the current study, amino acids (AAs) have been observed to be a prominent source of coformers. The AAs showed co-crystals formation with carboxylic acids, nonsteroidal anti-inflammatory drug (NSAID) and citric acid which overcome the hygroscopicity problems and improved the physical stability issues during storage. This study has also identified a new formulation which is helpful for improvement in the stability of effervescent tablets at various relative humidity (RH) conditions which will reduce the manufacturing cost associated with the production of effervescent tablets.

Pharmaceuticals with suitable therapeutic properties often found to encounter challenges with dosage form development due to their poor physicochemical properties. Aim of thesis is to evaluate potential of crystal engineering directed cocrystallisation of active ingredients in modulating their physical attributes. The model compounds considered are isoniazid, caffeine, nifedipine, glyburide, chlorpropamide and riboflavin. Co-formers selected are based on the suitability of functional groups for hydrogen bond formation. Co-crystal screening and preparation methods used include neat grinding (NG), liquid assisted grinding (LAG) and solution crystallisation. Antituberculosis drug, isoniazid, upon cocrystallisation with melamine, solubility has reduced as per high performance liquid chromatography assay, however, antimicrobial properties determined using REMA assay confirms that cocrystal anti-mycobacterial activity is not compromised. Next, caffeine-glutaric acid cocrystal polymorphic forms (Forms I and II) subjected to mechanical property evaluations in multiple faces using nanoindentation and correlated relationship between crystal structure and mechanical property. The results suggest that metastable form, Form I, could display suitable tablet properties to that of thermodynamically stable form, Form II. Subsequently, photosensitive drug, nifedipine, cocrystallised with theophylline and caffeine. Notably, photochemical stability along with solubility and drug release of cocrystals is found to be superior to that of nifedipine. Lastly, crystal engineering principles utilised in preparation of multicomponent crystals of antidiabetic model drugs, glyburide and chlorpropamide with various coformers. Interestingly, during the preparation of chlorpropamide-2-nitrobenzyl alcohol, high Z prime crystal (Z’=3) of 2- nitrobenzyl alcohol is serendipitously identified. In conclusion, crystal engineering based cocrystallisation is a viable technology for modulating physicochemical properties of pharma and nutraceuticals.

The objective of this study was to develop a new method for co-crystal preparation which adhered to green chemistry principles, and provided advantages over conventional methods. A novel, solvent-free, high-power ultrasound (US) technique, for preparing co-crystals from binary systems, was chosen as the technology which could fulfil these aims. The application of this technology for solid state co-crystal preparation was explored for ibuprofen-nicotinamide (IBU-NIC), carbamazepine-nicotinamide (CBZ-NIC) and carbamazepine-saccharin (CBZ-SAC) co-crystals. The effect of different additives and processing parameters such as power level, temperature and sonication time on co-crystallisation was investigated. Characterisation was carried out using DSC, PXRD, FTIR, Raman and HPLC. In addition, an NIR prediction model was developed and combined with multivariate analysis (PLS) and chemometric pre-treatments. It was found to be a robust, reliable and rapid method for the determination of co-crystal purity for the IBU-NIC and CBZ-NIC pairs. Co-crystal quantification of US samples helped to optimise the US method. Finally, a model formulation of paracetamol containing 5% and 10% PEG 8000 was ultrasonicated at maximum power with different exposure times. A comparison of technological and physicochemical properties of the resulting tablets with those of the tablets obtained using the pressing method evidenced significant differences. This suggested that US energy dissipation (mechanical and thermal effects) was the main mechanism which caused the PAR form I tabletability to improve. It was found that the ultrasound–compacted tablets released the drug at a slower rate compared to pure PAR. This technique was shown to be useful for improving tabletability for low-compressible drugs without the need to use a conventional tabletting machine.

The objective of this study was to develop a new method for co-crystal preparation which adhered to green chemistry principles, and provided advantages over conventional methods. A novel, solvent-free, high-power ultrasound (US) technique, for preparing co-crystals from binary systems, was chosen as the technology which could fulfil these aims. The application of this technology for solid state co-crystal preparation was explored for ibuprofen-nicotinamide (IBU-NIC), carbamazepine-nicotinamide (CBZ-NIC) and carbamazepine-saccharin (CBZ-SAC) co-crystals. The effect of different additives and processing parameters such as power level, temperature and sonication time on co-crystallisation was investigated. Characterisation was carried out using DSC, PXRD, FTIR, Raman and HPLC. In addition, an NIR prediction model was developed and combined with multivariate analysis (PLS) and chemometric pre-treatments. It was found to be a robust, reliable and rapid method for the determination of co-crystal purity for the IBU-NIC and CBZ-NIC pairs. Co-crystal quantification of US samples helped to optimise the US method. Finally, a model formulation of paracetamol containing 5% and 10% PEG 8000 was ultrasonicated at maximum power with different exposure times. A comparison of technological and physicochemical properties of the resulting tablets with those of the tablets obtained using the pressing method evidenced significant differences. This suggested that US energy dissipation (mechanical and thermal effects) was the main mechanism which caused the PAR form I tabletability to improve. It was found that the ultrasound–compacted tablets released the drug at a slower rate compared to pure PAR. This technique was shown to be useful for improving tabletability for low-compressible drugs without the need to use a conventional tabletting machine.