Pharmaceutical solids tend to exist in different physical forms termed as polymorphs. Issues about pharmaceutical systems are mainly concerned with the active ingredient's physico-chemical stability and bioavailability. The main aim of this study is to investigate the non-bonded interactions in pharmaceutical solids that govern the physical pharmaceutics performance of such materials and through the use of structural techniques and correlation of these results with crystal structural database to establish the presence of physical motifs in selected systems. Structural motifs were identified by the use of single crystal and crystal packing analysis on diverse range of pharma-relevant materials including chalcones, cryptolepines, biguanides and xanthines. These selected systems were validated using functional group and molecular analysis and correlating them to the Cambridge Structural Database. Crystallization studies are done on these selected systems as well as exploiting those using synthetic analogues. A total of 51 crystal structures were investigated including 16 new structure determinations. Addition synthesis of new xanthines to investigate novel intermolecular patterns was also undertaken. The understanding and exploitation of intermolecular interactions involving hydrogen bonds and coordination complexation during packing can be used in the design and synthesis of solid state molecular structures with desired physical and chemical properties.

The studies on cocrystals and salts presented in the the chapters clearly bring out the influence of intermolecular interactions as the main evaluators of the cocrystal-salt regime. The observations made in Chapter 2 indicate that in case if the cocrystal formation is through hydrogen bonds the location of the proton decides the nature of the complex in the energy landscape. The observation that the coformer controls the topology of intermolecular space as demonstrated in Chapter 3 provides insights into the importance of directionality rather than strength of intermolecular interactions. Indeed halogen bonding in cocrystals gain importance in this context.

Pharmaceutical solids tend to exist in different physical forms termed as polymorphs. Issues about pharmaceutical systems are mainly concerned with the active ingredient's physico-chemical stability and bioavailability. The main aim of this study is to investigate the non-bonded interactions in pharmaceutical solids that govern the physical pharmaceutics performance of such materials and through the use of structural techniques and correlation of these results with crystal structural database to establish the presence of physical motifs in selected systems. Structural motifs were identified by the use of single crystal and crystal packing analysis on diverse range of pharma-relevant materials including chalcones, cryptolepines, biguanides and xanthines. These selected systems were validated using functional group and molecular analysis and correlating them to the Cambridge Structural Database. Crystallization studies are done on these selected systems as well as exploiting those using synthetic analogues. A total of 51 crystal structures were investigated including 16 new structure determinations. Addition synthesis of new xanthines to investigate novel intermolecular patterns was also undertaken. The understanding and exploitation of intermolecular interactions involving hydrogen bonds and coordination complexation during packing can be used in the design and synthesis of solid state molecular structures with desired physical and chemical properties.

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.

Le polymorphisme revêt un grand intérêt dans le domaine pharmaceutique puisqu’il concerne plus de 80% des principes actifs (PA). Les différences de propriétés physicochimiques entre deux polymorphes peuvent influer sur la mise en forme galénique de la molécule active, sa biodisponibilité, sa stabilité lors du stockage voire même sur son activité. D'un point de vue industriel, l'hétérogénéité de surface d'un solide pharmaceutique semble jouer un rôle fondamental, lors de sa mise en forme mais aussi lors de son stockage. Néanmoins, les interactions de surface avec l’environnement de ce type de solides sont des phénomènes de faible amplitude et donc très difficiles à quantifier. Les techniques de mouillabilité, les plus utilisées, relient le travail d’adhésion à l’énergie de surface par la mesure de l’angle de contact entre le solide et un liquide. La valeur de l’énergie de surface obtenue, n’a qu’un caractère statistique qui caractérise un comportement macroscopique global du solide d’étude. Cette notion perd toute signification à l’échelle microscopique et donc ne répond pas aux besoins actuels de l’industrie pharmaceutique. L’objectif de cette étude est donc de quantifier l’anisotrope énergétique de surface des solides d’intérêt pharmaceutique. La Chromatographie Gazeuse Inverse (CGI) apparaît alors comme une méthode de choix pour caractériser les propriétés de surface de solides divisés. L’étude de l’énergie de surface par CGI à dilution infinie, au travers d’une étude rigoureuse du domaine de Henry, nous a permis de distinguer, en surface, les formes polymorphes α, β et δ du D-mannitol. De plus, elle nous a permis de faire un lien entre la composante dispersive de l’énergie de surface et des procédés de génération et de mise en forme, tels que l’atomisation et le cryobroyage. Les augmentations d’énergie de surface à la suite de ces procédés ont été attribués aux changements intrinsèques de la particule, telles que sa taille et sa morphologie. / The polymorphism phenomenon is of great interest in the pharmaceutical field since it concerns more than 80% of the active pharmaceutical ingredients (API). Differences in physicochemical properties between polymorphs are known to influence the formatting dosage of the active molecule (compression during tableting), bioavailability, toxicity and stability under storage conditions. From an industrial point of view, the surface heterogeneity of pharmaceutical solids seems to play a fundamental role in formatting but also during storage. However, organic solid’s surface interactions are small amplitude phenomenon and therefore very difficult to quantify. Wettability techniques, the most commonly used, relate the work of adhesion to the surface energy by measuring the contact angle between the solid and a liquid. The value of the surface energy obtained has a statistical nature that characterizes a global macroscopic behavior of the solid. This concept becomes meaningless at microscopic level and therefore does not respond to the existing and growing needs of the pharmaceutical industry. The objective of this study is to quantify the anisotropic surface energy of pharmaceutical solids. The inverse gas chromatography (IGC) will appear as the technique of choice for characterizing divided solid surface properties. The study of the surface energy using IGC at infinite dilution, through a rigorous study of Henry’s domain, allowed us to distinguish the polymorphic forms α, β and δ of D-mannitol. In addition, we were able to make a connection between the dispersive component of the solid’s surface energy and the generation and forming processes, such as spray drying (SD) and cryo-milling (CM). Surface energy increments after SD and CM were attributed to changes of the intrinsic characteristics of the particles such as size and morphology.