Doctor of Philosophy / Chemistry / Christer B. Aakeroy / A series of co-crystallizations between four biimidazole based compounds with nine symmetric aliphatic di-acids and fifteen perfluorinated halogen-bond donors were carried out to determine if a MEPS based ranking can be used to effectively assign selectivity in hydrogen- and halogen-bond interactions. The results suggested that a simple electrostatic view provides a reliable tool for successfully implementing the practical co-crystal synthesis with desired connectivity. MEPS based selectivity guidelines for halogen-bond interactions were explored in co-crystallizations between twelve asymmetric ditopic acceptors and nine halogen-bond donors. If the difference between the two acceptor sites is below 35 kJ/mol, no selectivity was observed; above 65 kJ/mol halogen bond selectivity dominates and mid ΔE range was recognized as the grey area where predictions cannot be made. To examine competition between hydrogen and halogen bonds, five heteroaryl-2-imidazoles were co-crystallized with fifteen halogen-bond donors. It was found that halogen bonds prefer best the acceptor site, demonstrating that a suitably activated halogen-bond donor can compete with a strong hydrogen-bond donor. The benefits of ‘double activation’ for promoting halogen bond effectiveness was explored with nine haloethynylnitrobenzenes. The positive potential on halogen atoms was enhanced through a combination of an sp-hybridized carbon and electron-withdrawing nitro group(s). Iodoethynylnitrobenzenes were identified as the most effective halogen-bond donors reported to date and the compounds were exploited for the interaction preferences of nitro group and nitro⋯X-Csp interactions were identified as synthetic tools for energetic co-crystal assembly. A synthetic strategy for the deliberate assembly of molecular polygons was developed utilizing bifurcated halogen bonds constructed from N-oxides and complementary halogen-bond donors via co-crystallization. A convenient, effective, and scalable protocol for stabilizing volatile liquid chemicals with co-crystallization was achieved. Through the use of halogen-bonding, liquid iodoperfluoroalkanes were transformed into crystalline materials with low-vapor pressure, considerable thermal stability and moisture resistance. To stabilize the energetic compound ethylenedinitramine, a co-crystallization approach targeting the acidic protons was employed. Eight co-crystals were obtained and the acceptors were identified as supramolecular protecting groups leading to diminished reactivity and enhanced stability while retaining the desirable energetic properties.

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.

Neutral or charge-assisted hydrogen bonds occurring between organic molecules represent strong and directional forces that mediate the molecular self-assembly into well defined supramolecular architectures. A proper understanding of hydrogen bonding interactions, their types, geometries, and occurrence in supramolecular motifs, is a prerequisite to crystal engineering, i.e. to the rational design of functional solid materials.Multiple-component organic crystals represent ideal systems to study the intermolecular interactions between the constituent molecules that can be pre-selected for their hydrogen bonding sites and geometrical capabilities. In particular, the systematic structural analysis of supramolecular systems that are comprised of simple molecules facilitates the development of strategies for the rational design of new multiple-component compounds involving more complex components such as drug molecules.The work presented herein shows a combination of systematic database and experimental studies in the context of reliability and hierarchy of several hydrogen bonded supramolecular synthons that exist in a series of model co-crystals and organic salts. The acquired paradigms are ultimately utilized in crystal engineering of pharmaceuticals. In addition, the viability of a mechanichemical approach toward supramolecular synthesis in the context of its efficacy and the effect on polymorphism in multiple-component compounds is also addressed.

In the context of pharmaceutical development, it is abundantly clear that there is a need for greater understanding and control of crystalline phases. The field of crystal engineering is poised to address such issues and has matured into a paradigm for the supramolecular synthesis of new compounds with desired properties. Crystal structures are unpredictable by nature, however, the interactions that lead to crystal formation are becoming much more predictable. By means of model compound studies, the delineation of the hierarchy of hydrogen bonding between complementary functional groups or supramolecular heterosynthons can be accomplished. Competitive co-crystallization studies along with data extracted from the Cambridge Structural Database (CSD) can be utilized in understanding the reliability of supramolecular heterosynthons without the need for endless co-crystallization experiments. In effect, this ability to understand supramolecular heterosynthons can allow crystal engineers to rationally design co-crystals with a high rate of success. It has been suggested that pharmaceutical co-crystals could play a significant part in the future of API formulation since in principle they will outnumber pharmaceutical salts, polymorphs and solvates combined. The focus of this thesis is the understanding of the primary amide functional group and its hydrogen bonding capabilities; as well as the synthesis of model compounds in order to develop a blueprint for the design of pharmaceutical co-crystals using APIs that contain a primary amide functional group.

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.

SILVA, K. F. Estudo do polimorfismo e desenho de cocristais dos anti-helminticos ricobendazol e albendazol. 2016. 80 f. Dissertação (Mestrado em Física) – Centro de Ciências, Universidade Federal do Ceará, Fortaleza, 2016. / Submitted by Giordana Silva (giordana.nascimento@gmail.com) on 2017-04-18T18:18:26Z No. of bitstreams: 1 2016_dis_kfbatista.pdf: 28307438 bytes, checksum: 68389a7bb1335fb08ea6dab7e0ce7b95 (MD5) / Approved for entry into archive by Giordana Silva (giordana.nascimento@gmail.com) on 2017-04-18T18:18:45Z (GMT) No. of bitstreams: 1 2016_dis_kfbatista.pdf: 28307438 bytes, checksum: 68389a7bb1335fb08ea6dab7e0ce7b95 (MD5) / Made available in DSpace on 2017-04-18T18:18:45Z (GMT). No. of bitstreams: 1 2016_dis_kfbatista.pdf: 28307438 bytes, checksum: 68389a7bb1335fb08ea6dab7e0ce7b95 (MD5) Previous issue date: 2016 / The physico-chemical properties of drugs are directly related to their therapeutic efficacy, and these, in turn, are linked to the structural arrangement presented by the drug, which comes from the different conformations and/or intra and intermolecular interactions that define the crystalline packing of molecules in the different solid forms. In this way, knowing and controlling these characteristics is of fundamental importance in the pharmaceutical area. In this context, the present work applied different strategies involving crystal engineering, aiming at the improvement of the biopharmaceutical properties of the drugs: ricobendazole and albendazole. In the case of ricobendazole, crystals were obtained from the slow evaporation technique and, making use of single crystal x-ray diffraction, the crystalline structure of the drug has been clarified, as well as a careful characterization in the solid state was performed. Ricobendazole crystallizes in a monoclinic system belonging to P21/c space group. The crystalline structure is composed of four molecules per unit cell (Z = 4), accommodating a molecule in the asymmetric unit (Z = 1), and possessing the following lattice parameters: a = 7.5960 (16) Å, b = 9.3047 (18) Å, c = 18,726 (4) Å, and β = 82.198 (5)°. For albendazole the objective was to investigate the polymorphic forms reported in the literature, as well as seek new crystalline phases of the drug. There are reported two polymorphic forms, forms I and II, which are enantiotropically related. However, we found that there are three crystalline forms for albendazole, where form I refers to the commercially distributed form, which, when recrystallized in methanol yields a third polymorph, form III. Therefore, the characterization of the polymorphic forms of albendazole was performed, making a comparative study between polymorphic crystal structures which allowed us to investigate their thermodynamic stability. Another strategy applied to drugs covered the development of multi-component crystals with several coformers. Thus, we do a search for co-crystals for both drugs through the solvent-assisted milling and slurry techniques, using a variety of coformers. Promising results were obtained with oxalic acid, salicylic acid, 2.6-dihydroxybenzoic acid, 3.5- dihydroxybenzoic acid and 3.5- dinitroxybenzoic acid. In this way, we obtained possible co-crystals for ricobendazole and albendazole, being these unpublished results for these drugs. / As características físico-químicas dos fármacos estão diretamente relacionadas à sua eficácia terapêutica, e estas, por sua vez, estão vinculadas ao arranjo estrutural apresentado pelo fármaco, o qual é oriundo das diferentes conformações e/ou interações intra e intermoleculares que definem o empacotamento cristalino das moléculas nas diferentes formas sólidas. Desta forma, conhecer e controlar estas características é de fundamental importância na área farmacêutica. Neste contexto, o presente trabalho aplicou diferentes estratégias envolvendo a engenharia de cristais, visando a melhora das propriedades biofarmacêuticas dos fármacos ricobendazol e albendazol. No caso do ricobendazol, cristais foram obtidos a partir da técnica de evaporação lenta e fazendo uso da difração de raio X de monocristal a estrutura cristalina do fármaco foi elucidada, bem como uma cuidadosa caracterização no estado sólido foi realizada. O ricobendazol cristaliza no sistema monoclínico pertencente ao grupo espacial P21/c. A estrutura cristalina é composta por quatro moléculas por cela unitária (Z=4), acomodando uma molécula na unidade assimétrica (Z’ =1), e possuindo os seguintes parâmetros de rede: a = 7.5960(16) Å, b = 9.3047(18) Å, c= 18.726(4) Å e β = 82,198(5)°. Já para o albendazol o objetivo foi investigar as formas polimórficas reportadas na literatura, bem como buscar novas fases cristalinas do fármaco. Uma vez que encontra-se reportada duas formas polimórficas, as formas I e II que estão enantiotropicamente relacionadas. Entretanto, concluímos que há três formas cristalinas para o albendazol, no qual a forma I refere-se à forma comercialmente distribuída que, quando recristalizada em metanol, obtém-se um terceiro polimorfo, a forma III. Sendo assim, realizamos a caracterização das formas polimórficas do albendazol, fazendo um estudo comparativo entre os polimorfos, o que nos permitiu investigar sua estabilidade termodinâmica. Outra estratégia aplicada aos fármacos abrangeu o desenvolvimento de cristais multicomponentes com diversos coformadores. Ou seja, realizamos uma busca por co-cristais para ambos os fármacos através das técnicas de moagem assistida por solvente e slurry, usando uma variedade de coformadores. Resultados promissores foram obtidos com ácido oxálico, ácido salicílico, ácido 2,6-dihidroxibenzoico, ácido 3,5-dihidroxibenzoico e ácido 3,5- dinitroxibenzoico. Deste modo, obtivemos possíveis co-cristais para o ricobendazol e o albendazol, sendo estes resultados inéditos para os referidos fármacos.

In this thesis novel configurations and operating strategies in the mixed suspension mixed product removal (MSMPR) crystalliser are investigated, aided by integrated process analytical technologies (PAT) and crystallisation informatics system (CryPRINS) tools. The MSMPR is an idealised crystalliser model that assumes: steady-state operation; well mixed suspension with no product classification, such that all volume elements contain a mixture of particles (small and large) and crystal size distribution (CSD) that is independent of location in the crystalliser and is identical of the product withdrawn; and uniform supersaturation thought, leading to constant nucleation and growth rates. Single-stage MSMPR designs with continuous recycle/recirculation and modified heat exchanger were investigated and found to minimise fouling, encrustation and transfer line blockages. In particular, a modified MSMPR with baffled heat exchanger was found to significantly reduce the temperature between incoming feed hot feed solution and the cooled crystalliser, leading to a significant reduction in fouling, encrustation and blockages. In addition, the concept of the periodic mixed suspension mixed product removal (PMSMPR) crystallisation process is demonstrated for the first time viz single- and multi-stage cascaded operations. This method of operation involves the periodic transfer of slurry (addition and withdrawal) at high flow rates from either a single stirred vessel or between a number of stirred vessels arranged in series. The PMSMPR is therefore characterised by periodic withdrawals of product slurry. Similar to the MSMPR, the product withdrawn from a PMSMPR has exactly the same composition as the vessel at the time of removal. The rapid withdrawal of slurry at high flow rates in PMSMPR operation leads to the prevention of particle sedimentation and blockage of transfer lines. The transfer of slurry (to/from) the PMSMPR is followed by a holding (or pause) period when no addition or withdrawal of slurry takes place. The holding period extends the mean residence time of the PMSMPR relative to a typical MSMPR, thereby increasing the yield and productivity of crystallisation as more time is allowed for consumption of available supersaturation viz crystal growth and nucleation. A state of controlled operation (SCO) in the periodic flow process, defined as a state of the system that maintains itself despite regular, but controlled disruptions was characterised using the PAT tools and CryPRINS within an intelligent decision support (IDS) framework. The crystallisation of paracetamol (PCM) from isopropyl alcohol (IPA) using different configurations of a single-stage continuous MSMPR crystalliser that incorporated continuous recycle and recirculation loop, and a novel design with baffled heat exchanger was investigated. Crystallisations of PCM-IPA carried out in the MSMPR without heat exchanger suffered from severe fouling, encrustation and blockage problems due to the high level of supersaturation (S = 1.39) in the crystalliser, which was required for the initial burst of nucleation to generate enough particles for later growth, as well as the large temperature difference between the incoming feed (45 oC) and the crystalliser (10 oC). Using the modified MSMPR design with baffled heat exchanger, the challenges of fouling, encrustation and blockage were significantly reduced due to the rapid lowering of the feed stream temperature prior to entering the crystalliser. In addition, the closed loop system led to conservation of material, which is a great benefit since large amounts of materials would otherwise be required if the MSMPR was operated with continuous product removal. This design is great for research purposes, in particular, to investigate process design and optimisation. Continuous crystallisation of PCM in the presence of hydroxyl propyl methyl cellulose (HPMC) additive was investigated in the modified MSMPR design with heat exchanger. HPMC was found to improve the crystallisation performance, leading to complete avoidance of fouling, encrustation and blockages at a concentration of 0.05 wt%. However, the yield of crystallisation was significantly reduced (28.0 %) compared to a control experiment (98.8 %, biased due to fouling/encrustation) performed without additive addition. Regardless, the productivity of crystallisation was more than four times that achieved in batch linear cooling (LC) (0.62 0.86 g/L-min) and batch automated dynamic nucleation control (ADNC) (0.24 0.25 g/L-min) runs. Aspects of the periodic flow crystallisation of single- and multi-component (co-crystals) molecular systems have also been examined to demonstrate the concept of state of controlled operation . The single component systems studied were PCM and glycine (GLY), each representative of compounds with slow and fast growth kinetics, respectively. The co-crystal systems investigated were urea-barbituric acid (UBA) and p Toluenesulfonamide-Triphenylphosphine oxide (p-TSA-TPPO). UBA is a polymorphic co-crystal system with three known forms (I, II and III). Form I UBA was successfully isolated in a three-stage periodic flow PMSMPR crystalliser. This study demonstrates the capability of periodic flow crystallisation for isolation of a desired polymorph from a mixture. p-TSA-TPPO exists in two known stoichiometric co-crystal forms, 1:1 and 3:2 mole ratio p-TSA-TPPO, respectively. The two crystalline forms exhibit solution mediated transformation, which proves to be a difficulty for separation. For this study, the implementation of temperature cycles in batch and flow control in semi-batch and periodic PMSMPR crystallisers were investigated to isolate pure 1:1 and 3:2 p-TSA-TPPO, respectively. Different regions of the ternary diagram of p-TSA, TPPO and acetonitrile (MeCN) were investigated. The desired co-crystal form was isolated all crystallisation platforms investigated. However, greater consistency was observed in the semi-batch and PMSMPR operations respectively. Periodic flow crystallisation in PMSMPR is a promising alternative to conventional continuous MSMPR operation, affording greater degrees of freedom operation, slightly narrower RTD profiles, consistent product crystal quality (size, shape and distribution), longer mean residence times, higher yield and productivity and significant reduction in fouling, encrustation and transfer line blockages over prolonged operating periods. Furthermore, the PMSMPR is a versatile platform that can be used to investigate a range of different molecular systems. Relative to batch operation, the PMSMPR can operate close to equilibrium, however, this is dependent on the system kinetics. In addition, retrofitting of batch crystallisers to operate as PMSMPRS fairly simple and require only subtle changes to the existing design space. The integrated array of PAT sensors consisted of attenuated total reflectance ultra violet/visible spectroscopy (ATR-UV/vis), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), focused beam reflectance measurement (FBRM), particle vision microscopy (PVM) and Raman spectroscopy. The results from the studies reported here illustrate very well the use of PAT and information system tools together to determine when the continuous and periodic MSMPR operations reaches a steady-state or state of controlled operation (i.e. periodic steady-state). These tools provided a better understanding of the variables and operating procedures that influence the two types of operations.

no / The increasing prevalence of poorly soluble drugs in development provides notable risk of new products demonstrating low and erratic bioavailabilty with consequences for safety and efficacy, particularly for drugs delivered by the oral route of administration. Although numerous strategies exist for enhancing the bioavailability of drugs with low aqueous solubility, the success of these approaches is not yet able to be guaranteed and is greatly dependent on the physical and chemical nature of the molecules being developed. Crystal engineering offers a number of routes to improved solubility and dissolution rate, which can be adopted through an in-depth knowledge of crystallisation processes and the molecular properties of active pharmaceutical ingredients. This article covers the concept and theory of crystal engineering and discusses the potential benefits, disadvantages and methods of preparation of co-crystals, metastable polymorphs, high-energy amorphous forms and ultrafine particles. Also considered within this review is the influence of crystallisation conditions on crystal habit and particle morphology with potential implications for dissolution and oral absorption.

Yes / Spurred by the enormous interest in co-crystals from the pharmaceutical industry, many novel co-crystals of active pharmaceutical ingredients have been discovered in recent years and this has in turn led to an increasing number of reports on polymorphs of co-crystals. Hence, a thorough characterization and understanding of co-crystal polymorphs is a valuable step during drug development. The purpose of this study is to perform in situ structural analysis and to determine thermodynamic stability of a dimorphic co-crystal system, 1:1 caffeine-glutaric acid (CA-GA, Forms I and II). We performed thermal and structural characterizations by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also re-determined crystal structures of CA-GA Forms I and II at 180 K using single crystal X-ray diffraction. Our results revealed that Form II is stable and Form I is metastable at ambient conditions. Further, the results suggest that the dimorphs are enantiotropically related and the transition temperature is estimated to be 79 Celcius degrees. / This work was supported by Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.

No description available.