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.

Die Mechanochemie wird als Alternative zu konventionellen Syntheserouten mittlerweile vielfältig eingesetzt. In dieser Arbeit wurden verschiedene Ansätze genutzt, um die mechanochemischen Mechanismen systematisch aufzuklären. Anhand von Modellsystemen (Cokristalle) wurden die mechanochemischen Synthesewege durch in situ-Verfolgung aufgeklärt, die kinetischen sowie thermodynamischen Stabilitäten der Edukte und Produkte ermittelt sowie die Aktivierungsenergie quantitativ abgeschätzt. Die Ergebnisse führten zur Hypothese, dass die mechanochemische Cokristallisation über einen nicht-kristallinen – wahrscheinlich amorphen – Übergangszustand abläuft und ähnlich der Kristallisation aus Lösung ist. / Mechanochemistry is a widely used alternative for conventional synthesis methods. In this work, different approaches were considered to evaluate the mechanochemical formation pathways. Based on model systems (cocrystals) the synthesis pathways were elucidated using in situ monitoring techniques and thermodynamic and kinetic aspects were investigated. The activation energy of a mechanochemical reaction was quantitavely estimated. The results lead to the assumption that the mechanochemical cocrystallisation proceeds via a non-crystalline phase and that it is similar to the crystallisation from solution.

Cocristais fármaco-fármaco envolvem a junção de dois ou mais insumos farmacêuticos ativos (IFAs), preservando seu caráter neutro e sem a necessidade de quebra ou formação de ligação covalente, mantendo desta maneira sua eficácia. Propriedades dos IFAs em estado sólido, como as interações entre grupos farmacofóricos e receptores, são determinadas pela polaridade dos grupos funcionais e potencial eletrostático assim como pelas interações intermoleculares, que por sua vez dependem das características eletrônicas e moleculares do arranjo tridimensional. Propriedades eletrônicas moleculares e sua relação com a topologia da densidade de carga eletrônica é parte dos estudos teóricos apresentados neste trabalho. Estes estudos envolvem cálculos da distribuição da densidade de carga eletrônica e sua topologia por meio da Teoria Quântica de Átomos em Moléculas AIM (do inglês, atoms in molecules) de Bader. Neste contexto, o presente trabalho apresentou cálculos teóricos da densidade de carga em um sistema periódico tridimensional, utilizando como modelo de partida os dados cristalográficos do cocristal fármaco-fármaco constituído da 5-Fluorocitosina (antimetabólito) e da Isoniazida (tuberculostático), nomeado por 5FC-INH. A função de onda deste sistema foi calculada por meio da teoria do funcional da densidade DFT (do inglês, density functional theory), com alguns níveis de teoria em conjunto com funções de base, utilizando o pacote de programas CRYSTAL14. A distribuição da densidade de carga, resultante destes cálculos, foi analisada por meio da AIM utilizando alguns descritores topológicos, como densidade de carga, Laplaciano da densidade de carga e a elipticidade nos pontos críticos das ligações de enlace covalentes e as interações intermoleculares da unidade assimétrica. Uma análise preliminar dos valores da densidade de carga eletrônica, calculada nos pontos críticos de ligação da 5FC-INH, permitiu selecionar o nível de teoria e conjunto de funções base que melhor reproduziu os dados experimentais, como sendo o B3LYP/6-311++G**. Os valores dos descritores, obtidos dos cálculos com este nível de teoria, foram comparados com os provenientes dos experimentos de difração de raios X de alta resolução e resultaram em boa concordância na descrição da topologia da densidade de carga eletrônica. Os descritores apresentaram valores muito próximos dos reportados na literatura para os grupos funcionais da 5-FC e da INH. Imagens dos mapas das trajetórias do gradiente e do Laplaciano da densidade de carga, dos caminhos de ligação e dos contornos das bacias atômicas, permitiram visualizar as regiões de depleção e acúmulo da densidade de carga. Por meio destas representações foi possível descrever as ligações de hidrogênio responsáveis pela estabilização do cocristal, as ligações químicas covalentes, as deformações das bacias atômicas que caracterizam as polarizações e os mapas do Laplaciano que permitem observar os pares solitários de elétrons, como dos átomos de flúor, oxigênio e nitrogênio. / Drug-drug cocrystals involve the formation of crystals of two or more active pharmaceutical ingredients (APIs) preserving their original chemical characteristics since no breakage or formation of covalent bonds is observed, thus maintaining their effectiveness. APIs solid state properties, such as pharmacophoric and receptor group interactions are determined by the polarity of functional groups, electrostatic potential and potential intermolecular interactions, which in turn depend on the electronic and molecular characteristics of the three-dimensional arrangement. Molecular electron properties and their relationship with charge density topology is part of the theoretical studies presented in this dissertation. These studies involve electron charge density distribution calculations and their topology through the Bader’s quantum theory of atoms in molecules (AIM). To that aim, the present work presents theoretical calculations of the charge density in a three-dimensional periodic system, using crystallographic data of the drug-drug cocrystal involving the antimetabolite prodrug 5-Fluorocytosine (5-FC) and the tuberculostatic drug Isoniazid (INH), namely, 5FC-INH, as a starting model. The wave function of this system was calculated through density functional theory (DFT), with some levels of theory together with an adequate basis set, using the CRYSTAL14 program package. The charge density distribution resulting from these calculations was analyzed for the asymmetric unit using the AIM model where topological descriptors such as charge density, charge density Laplacian and ellipticity at bond critical points (for covalent bonds and intermolecular interactions). A preliminary analysis of the electronic charge density values, calculated at the bond critical points of 5FC-INH, allowed us to select the level of theory and basis set that best reproduced the experimental data, in this case B3LYP/6-311++G**. The values of the descriptors obtained from the calculations with this level of theory were compared with those obtained from the high resolution X-ray diffraction experiments and resulted in good agreement in the description of the topology of the electronic charge density. The descriptors presented values are very close to those reported in the literature for the functional groups in the 5-FC and INH molecules. Images of the maps of the gradient trajectory and Laplacian of charge density, bond paths and atomic basins contours, allowed visualizing the regions of depletion and accumulation of charge density. Through these representations it was possible to describe the hydrogen bonds responsible for the stabilization of the cocrystal, the covalent chemical bonds and the deformations of the atomic basins that characterize the polarizations and the maps of the Laplacian that allow to observe the pairs of isolated electrons, such as those in fluorine, oxygen and nitrogen atoms.

The process of milling drugs to obtain samples with a desirable particle size range has been widely used in the pharmaceutical industry, especially for the production of drugs for inhalation. However by subjecting materials to milling techniques surfaces may become thermodynamically activated which may in turn lead to formation of amorphous material. Polymorphic conversions have also been noted after milling of certain materials. Salt and cocrystal formation is a good way of enhancing the properties of an API but little or no work has been published which investigates the stability of these entities when subjected to milling. Different milling techniques (ball and jet) and temperatures (ambient and cryogenic) were used to investigate the milling behaviour of polymorphs, salts and cocrystals. All materials were analysed by XRPD and DSC to investigate any physical changes, i.e. changes in melting point and by inverse gas chromatography (IGC) to investigate whether any changes in the surface energetics occurred as a result of milling. Another aim of this thesis was to see if it was possible to predict the milling behaviour of polymorphs by calculating the attachment energies of the different crystal facets using Materials Studio 4.0. These results were compared to the IGC data to see if the predicted surface changes had occurred. The data collected in this study showed that different milling techniques can have a different effect on the same material. For example ball milling at ambient temperature and jet micronisation of the SFZ tosylate salt caused a notable increase in the melting point of the material whereas ball milling at cryogenic temperatures did not cause this to happen. The IGC data collected for this form also showed a contrast between cryomilling and the other two techniques. The study also showed that the formation of salts and cocrystals does not necessarily offer any increased stability in terms of physical properties or surface energetics. Changes in melting point were observed for the SFZ tosylate salt and the IMC:Benzamide cocrystal. Changes in the specific surface energies were also observed indicating that the nature of the surfaces was also changing. The materials which appeared to be affected the least were the two stable polymorphs, gamma IMC and SFZ III. The computational approach used has many limitations. The software does not allow for conversion to the amorphous form or polymorphic conversions. Such conversions were seen to occur, particularly for the metastable polymorphs used, meaning that this computational approach may only be suitable for stable polymorphs.

Crystal engineering offers a rational way of analyzing crystal structures and designing new structures with properties. The supramolecular synthon concept was introduced in 1995 and has shown versatility and utility in the design of molecular solids. Chapter 1 gives a general introduction about the development of the concept of supramolecular synthons over the years which has seen a transition from synthesis to structures and dynamics. This thesis focuses on the later phase of the development of the concept of supramolecular synthons. Chapter 2 introduces the idea of structural landscape and describes a structural landscape of a conformationally flexible molecule, orcinol, and explores the synthon preferences of this particular molecule towards cocrystal formation. Chapter 3 explores a combinatorial matrix to show both global and local features of a structural landscape. Chapter 4 takes a component of this landscape namely 4,4'-bipyridine and 4-hydroxybenzoic acid and shows the occurrence of synthon polymorphism in cocrystals which originates from the interplay of geometrical and chemical factors. Chapter 5 introduces a four step method for the identification of multiple synthons by FTIR spectroscopy. Along with, it shows that the rarity of synthon polymorphism is not a case of overlooking of crystals in the process of selecting good looking crystals. Chapter 6 takes a series of dihalogenated phenols and indicates that the Br prefers type II. This chapter also explains elastic bending on the basis of halogen bonds. Chapter 7 attempts to explore the Cl/Br isostructurality in the light of type I and type II contacts and concludes that Cl/Br isostructurality arises from a geometrical model and therefore it is quite similar to Cl/Me isostructurality. Chapter 8 attempts to analyze the class of trichlorophenols and reveals structural modularity in this class of compounds. The modularity of 3,4,5-trichlorophenol is explored in crystal design in chapter 9 in terms of LSAM (Long Range Synthon Aufbau Module) A subsequent study in solution by NMR reveals the presence of LSAM in solution and establishes a hierarchy of the dissociation of its components. The concept of supramolecular synthon has come a long way from being a tool in a crystal engineer’s toolbox to a structural unit responsible for crystallization and therefore offer multiple possibilities both in terms of structures and dynamics. This thesis attempts to explore some of these possibilities based mainly on the concepts of structural landscape and halogen bonds which are blended with the concept of supramolecular synthons.

Die Mechanochemie findet zunehmend Verwendung für die Synthese neuer Verbindungen. Dennoch sind die beim Mahlen stattfindenden Prozesse weitestgehend unverstanden. Dahingehend wurde in dieser Arbeit eine Dreifachkopplung aus in situ Synchrotron-Röntgenbeugung, Raman-Spektroskopie und Thermographie entwickelt, um mechanochemische Reaktionen unter realistischen Bedingungen in Echtzeit zu verfolgen. Dadurch konnten tiefgreifende Einblicke in den Reaktionsverlauf und Temperaturverlauf beim Mahlen erhalten und neue metastabile Verbindungen isoliert werden. Für die Bildung pharmazeutischer Cokristalle diente Pyrazinamid als Modellsystem. Es konnten neue binäre und ternäre Verbindungen synthetisiert, detailliert charakterisiert und deren Kristallstruktur aufgeklärt werden. Die Abhängigkeit der Stabilität polymorpher Cokristalle von der Temperatur und den Synthesebedingungen konnte gezeigt werden. In Konkurrenzreaktionen konnten Trends hinsichtlich der bevorzugten Bildung eine bestimmten Cokristalls beobachtet werden. Mittels in situ Untersuchungen wurde der Einfluss zentraler Reaktionsparameter, wie die Mahlfrequenz, der Kugeldurchmesser, der eingesetzte Ausgangsstoff und die Zugabe von Lösungsmittel, auf die Induktions- und Reaktionszeit der Reaktion ermittelt. Basierend auf den gewonnenen Erkenntnissen konnte ein Diffusionsmechanismus für die mechanochemische Cokristallbildung abgeleitet werden. / Mechanochemistry is increasingly applied for the synthesis of new compounds. Still, the processes taking place during milling are far from being understood. In this thesis, a triple coupling of in situ synchrotron X-ray diffraction, Raman spectroscopy and thermography has been developed to follow mechanochemical reactions under realistic conditions in real time. This allowed deep insights into the reaction and temperature progression during milling and the isolation of new metastable compounds. For the formation of pharmaceutical cocrystals pyrazinamide served as a model system. New binary and ternary compounds were synthesized, characterized in detail and their crystal structure solved. The dependence of the stability of polymorphic cocrystals on temperature and synthesis conditions could be shown. In competitive reactions, trends regarding the preferred formation of a certain cocrystal have been observed. The influence of important reaction parameters, such as the milling frequency, the ball diameter, the starting material used and the addition of solvent, on the induction and reaction time of the reaction was determined by means of in situ investigations. Based on the gained knowledge, a diffusion mechanism for the mechanochemical cocrystal formation could be derived.

The process of milling drugs to obtain samples with a desirable particle size range has been widely used in the pharmaceutical industry, especially for the production of drugs for inhalation. However by subjecting materials to milling techniques surfaces may become thermodynamically activated which may in turn lead to formation of amorphous material. Polymorphic conversions have also been noted after milling of certain materials. Salt and cocrystal formation is a good way of enhancing the properties of an API but little or no work has been published which investigates the stability of these entities when subjected to milling. Different milling techniques (ball and jet) and temperatures (ambient and cryogenic) were used to investigate the milling behaviour of polymorphs, salts and cocrystals. All materials were analysed by XRPD and DSC to investigate any physical changes, i.e. changes in melting point and by inverse gas chromatography (IGC) to investigate whether any changes in the surface energetics occurred as a result of milling. Another aim of this thesis was to see if it was possible to predict the milling behaviour of polymorphs by calculating the attachment energies of the different crystal facets using Materials Studio 4.0. These results were compared to the IGC data to see if the predicted surface changes had occurred. The data collected in this study showed that different milling techniques can have a different effect on the same material. For example ball milling at ambient temperature and jet micronisation of the SFZ tosylate salt caused a notable increase in the melting point of the material whereas ball milling at cryogenic temperatures did not cause this to happen. The IGC data collected for this form also showed a contrast between cryomilling and the other two techniques. The study also showed that the formation of salts and cocrystals does not necessarily offer any increased stability in terms of physical properties or surface energetics. Changes in melting point were observed for the SFZ tosylate salt and the IMC:Benzamide cocrystal. Changes in the specific surface energies were also observed indicating that the nature of the surfaces was also changing. The materials which appeared to be affected the least were the two stable polymorphs, gamma IMC and SFZ III. The computational approach used has many limitations. The software does not allow for conversion to the amorphous form or polymorphic conversions. Such conversions were seen to occur, particularly for the metastable polymorphs used, meaning that this computational approach may only be suitable for stable polymorphs.

High shear melt granulation (HSMG) is an established technology for a production of densified granules. In this project, it was used as a novel solvent-free method for the preparation of cocrystals. Cocrystals produced by HSMG were compared to those prepared by Hot Melt Extrusion (HME) to investigate the influence of variable parameters and conditions on the process of cocrystal conversion. The potential for the active control of cocrystals polymorphism utilising the intrinsic properties of lipids was also investigated in this project. Different cocrystal pairs were prepared by both cocrystallisation methods using glycol derivative polymers. Thermal analysis, powder X-ray diffraction and Raman spectroscopy were used as analytical techniques to determine the cocrystal yield and purity. The results obtained from HSMG suggest that sufficient binder concentrations (above 12.5% w/w) in a molten state and continuous shearing force are necessary to achieve a complete cocrystals conversion. Further increase in binder concentration (15% w/w) was found to provide more regular shape and smooth surface to the prepared spherical granules. Cocrystals preparation by HME was achievable after introducing a mixing zone to the extruder configuration (Conf B and Conf C) providing densified extrudates containing pure cocrystals. In conclusion, HSMG was found as a versatile technique for the preparation of pure pharmaceutical cocrystals embedded in polymer matrix within a spherical shape granule of smooth surfaces, providing additional desirable characteristics. Intensive surface interaction, enhanced by sufficient mixing under optimal parameters, was found as a key influencing factor in cocrystallisation. Cocrystals polymorphism was actively controlled by employing the intrinsic properties of polymers and lipids.

Yes / Emtricitabine (ECB) afforded dimorphic cocrystals (Forms I, II) of benzoic acid (BA), whereas with p-hydroxybenzoic acid (PHBA), p-aminobenzoic acid (PABA) are resulted in as high Z'' cocrystals. Intriguingly, the Z'' of cocrystals are trends from two to fourteen based on the manipulation of functional groups on the para position of BA (where H atom is replaced with that of OH or NH2 group). ECB‒PABA cocrystal consists of six molecules each and two water molecules in the asymmetric unit (Z''=14) with 2D planar sheets represents the rare pharmaceutical cocrystal. The findings suggest that the increment of H bond donor(s) systematically via a suitable coformer are in correspondence with attaining high Z'' cocrystals. Further, solid state NMR spectroscopy in conjunction with single crystal X-ray diffraction are demonstrated as significant tools to enhance the understanding of the number of symmetry independent molecules in the crystalline lattice and provide insights to the mechanistic pathways of crystallization. / Department of Science and Technology (DST) Fund for improvement of S & T Infrastructure (FIST) with grant no. SR/FST/CST-266/2015(c) to PS and VP. AN and VV acknowledge the Government of India under National Overseas Scholarship (2012-13) and High Commission of India, London UK for PhD studentship.

The thesis entitled “Structure-function control in organic co-crystals/salts via studies on polymorphism, phase transitions and stoichiometric variants” consists of five chapters. The main emphasis of the thesis is on two aspects, one to characterize co-crystal polymorphism in terms of propensity of intermolecular interactions to form co-crystals/salts or eutectics. The other aspect is to explore the feasibility of using such co-crystals/salts to exhibit properties like proton conduction, dielectric and ferroelectric behaviour. Gallic acid and its analogues possess functionalities to provide extensive hydrogen bonding capabilities and are chosen as the main component while the coformers are carefully selected such that they either accept or reject the hydrogen bonding offered. Such co-crystallization experiments therefore provide an opportunity to unravel the intricate details of the formation of crystalline polymorphs and/or eutectics at the molecular level. Further these co-crystal systems have been exploited to evaluate proton conductivity, dielectric and ferroelectric features since the focus is also on the design aspect of functional materials. In the context of identifying and utilizing Crystal Engineering tools, the discussions in the following chapters address not only the structural details but identify the required patterns and motifs to enable the design of multi-component co-crystals/salts and eutectics. In particular, the presence/absence of lattice water in gallic acid has been evaluated in terms of importing the required physical property to the system. Chapter 1 discusses the structural features of tetramorphic anhydrous co-crystals (1:1; which are synthon polymorphs) generated from a methanolic solution of gallic acid monohydrate and acetamide, all of which convert to a stable form on complete drying. The pathway to the stable form (1:3 co-crystal) is explained based on the variability in the hydrogen bonding patterns followed by lattice energy calculations. Chapter 2A studies the presence/absence and geometric disposition of hydroxyl functionality on hydroxybenzoic acids to drive the formation of co-crystal/eutectic in imide-carboxylic acid combinations. In Chapter 2B the crystal form diversity of gallic acid-succinimide co-crystals are evaluated with major implications towards the design and control of targeted multi-component crystal forms. The co-crystal obtained in this study shows a rare phenomenon of concomitant solvation besides concomitant polymorphism and thus making it difficult to obtain a phase-pure crystal form in bulk quantity. This issue has been resolved and formation of desired target solid form is demonstrated. Thus, this study addresses the nemesis issues of co-crystallization with implications in comprehending the kinetics and thermodynamics of the phenomenon in the goal of making desired materials. Chapter 3 focuses on the systematic co-crystallization of hydroxybenzoic acids with hexamine using liquid assisted grinding (LAG) which show facile solid state interconversion among different stoichiometric variants. The reversible interconversion brought about by varying both the acid and base components in tandem is shown to be a consequence of hydrogen bonded synthon modularity present in the crystal structures analyzed in this context. In Chapter 4A, the rationale for the proton conduction in hydrated/anhydrous salt/co-crystal of gallic acid - isoniazid is provided in terms of the structural characteristics and the conduction pathway is identified to follow Grotthuss like mechanism which is supplemented by theoretical calculations. Chapter 4B describes an extensive examination of the hydrated salt of gallic acid-isoniazid which unravels the irreversible nature of the dielectric property upon dehydration and suggests that the “ferroelectric like” behaviour is indeed not authenticated. This chapter brings out the significance role of lattice water in controlling the resulting physical property (dielectric/ferroelectric in this case). Chapter 5 describes the structural features of two hydrated quaternary salts of hydroxybenzoic acids-isoniazid-sulfuric acid and the phase transitions at both low and high temperatures are shown to be reversible. Single Crystal to Single Crystal (SCSC) in situ measurement corroborated by thermal and in situ Powder X-ray Diffraction studies proves the claim. Further, the properties exhibited by these materials are also governed by lattice water content.