Yes / Caffeic acid phenethyl ester (CAPE) is a polyphenolic active compound present in popular apiproduct, ‘propolis’ obtained from beehives. Though it has broad therapeutic capability, the bioavailability of CAPE is limited due to poor solubility. In this study, we report novel cocrystals of CAPE engineered using coformers such as caffeine (CAF), isonicotinamide (INIC), nicotinamide (NIC) with enhanced solubility and bioavailability of CAPE. The cocrystals were prepared by microwave-assisted cocrystallization and characterized using PXRD, DSC and Raman spectroscopy. PXRD and DSC confirm the successful formation and phase purity of CAPE-CAF, CAPE-INIC and CAPE-NIC cocrystals. Raman spectra of CAPE cocrystals complement these results in confirming the formation of novel crystalline phases. CAPE-NIC cocrystal was further subjected to X-ray crystallography to understand its molecular arrangement and hydrogen bonding in the crystal structure. The CAPE-NIC cocrystal structure is found to be stabilized by a rare 1,2-benzenediol-amide heterosynthon. Cocrystallization of CAPE with NIC improved its aqueous solubility and pharmacokinetic profile thereby demonstrating 2.76 folds escalation in bioavailability. / We thank UKIERI: UK-India Education and Research Initiative (TPR26) and EPSRC (EP/J003360/1, EP/L027011/1) for providing financial support during this study.

Yes / Polymorphism of crystalline drugs is a common phenomenon. However, the number of reported polymorphic cocrystals is very limited. In this work, the synthesis and solid state characterisation of a polymorphic cocrystal composed of sulfadimidine (SD) and 4- aminosalicylic acid (4-ASA) is reported for the first time. By liquid-assisted milling, the SD:4-ASA 1:1 form I cocrystal, the structure of which has been previously reported, was formed. By spray drying, a new polymorphic form (form II) of the SD:4-ASA 1:1 cocrystal was discovered which could also be obtained by solvent evaporation from ethanol and acetone. Structure determination of the form II cocrystal was calculated using high resolution X-ray powder diffraction. The solubility of the SD:4-ASA 1:1 cocrystal was dependent on the pH and predicted by a model established for a two amphoteric component cocrystal. The form I cocrystal was found to be thermodynamically more stable in aqueous solution than form II, which showed transformation to form I. Dissolution studies revealed that the dissolution rate of SD from both cocrystals was enhanced when compared to a physical equimolar mixture and pure SD. / Science Foundation Ireland (SFI) under Grant Number 07/SRC/B1158 and SFI/12/RC/2275.

The synthesis of new molecules is often initiated with the desire to create unique materials that have specific functions and/or properties. The materials are often used in areas such as pharmaceuticals, medical imaging, and energetics. Preparation of these materials utilizes fundamental rules that define how molecules interact with each other in a solid. My research focuses on employing the established concepts to predict how certain molecules interact and assessing the solid form that results (crystal structure) from these interactions. The solids investigated in my research are composed of two different molecules that can combine in various ways based on complementary interactions. Once the two molecules interact to form a crystal structure, external stimuli, such as heat, can cause the atoms within the crystal to move in specific directions to allow for events such as water loss, or it can initiate atoms to rearrange completely to form a new molecule. My work evaluates how the crystal structure changes when the atoms move and how the interactions between the molecules are impacted. The results of my research indicate the crystal structure can be controlled by aspects such as physical size and the properties of the individual molecules within the crystal. Additionally, my work involves assessing new ways to synthesize the described molecules by using technology that avoids the use of harmful solvents. My research has demonstrated a new mixing method that can prepare molecules in the lab and production facilities that reduces the amount of solvent needed and improves sustainability through chemistry.

Crystal engineering is attracting attention in the pharmaceutical industry because the design of new crystal form of drugs can improve their stability, bioavailability and other relevant physical characteristic properties. Therefore, crystal engineering of nutraceuticals such as flavonoids by exploring their hydrogen bonding interactions can generate novel compounds such as pharmaceutical cocrystals. Flavonoids are polyphenolic secondary plant metabolites that are present in varying levels in fruits, vegetables and beverages. The "French paradox", low cardiovascular mortality rate in spite of high intake of saturated fat among the Mediterranean populations made flavonoids an appropriate target for therapeutic researchers. The work herein deals with the crystal engineering of two flavonoids, quercetin and hesperetin, which are already known to exhibit antioxidant properties and reduce cardiovascular effects in humans. However, they have limited bioavailability and poor water solubility. Several new forms of quercetin and hesperetin in the form of solvates and cocrystals were synthesized. These new crystal forms were characterized by various techniques: FT-IR, DSC (Differential Scanning Calorimetry), single X-ray diffraction, powder X-ray diffraction, TGA (Thermal Gravimetric Analysis) and melting point. The new compounds were also studied via dissolution studies performed in 1:1 ethanol/water (V/V%). Thus, crystal engineering proves to be effective way to enhance the solubility and bioavailability of the target flavonoid molecules.

In this study, the ability of pharmaceutical cocrystals on improving solubility and dissolution behaviour of poorly water soluble drug has been studied by a novel technique SDI300 UV imaging surface dissolution system. Pharmaceutical cocrystals of poorly water soluble drug carbamazepine (CBZ) were synthesized, which are 1: 1 carbamazepine - nicotinamide (CBZ-NIC) cocrystal, and 2:1 carbamazepine - succinic acid (CBZ-SUC) cocrystal. Firstly, dissolution and solution mediated phase transformation behaviour (SMPT) of CBZ-NIC cocrystal was studied by in situ techniques of UV imaging and Raman spectroscopy. This study has shown that in situ UV imaging and Raman spectroscopy with a complementary technique of SEM can provide an in depth understanding of cocrystal dissolution processes. It has been found that CBZ-NIC cocrystal including other polymorphs of CBZ III and I and mixture are converting to CBZ DH during dissolution. The influence of surfactants, SLS and Tween 80, on the solubility and dissolution behavior of the CBZ-NIC cocrystal has been studied. Results show that the SMPT of CBZ III and CBZ-NIC cocrystal can be altered by inclusion of a surfactant in dissolution medium. However, CBZ III and CBZ-NIC cocrystal have shown different transformation behavior with different surfactants. The solubility and dissolution behaviour of CBZ-NIC cocrystal, CBZ-SUC cocrystal in four biomedia (simulated gastric fluid, pH1.2 HCl buffer, simulated intestinal fluid, and pH 6.8 PBS buffer) were studied. Results have shown that equilibrium solubility of CBZ samples varied in different media. The two cocrystals dissolution rates show different trends as that of parent drug CBZ III. This can be explained by that the formation of cocrystal change the dissolution ability of CBZ III.

Yes / The thermodynamic stability of caffeine (CA) cocrystals with dicarboxylic acids (DAs) as coformers was investigated in the presence of a range of structurally related dicarboxylic acids (SRDs). Two experimental conditions (slurry and dry-grinding) were studied for mixing the cocrystal and the SRD additive. The additives oxalic, malonic and glutaric acid led to the replacement of the acid coformer for certain cocrystals. Interestingly, a change in stoichiometry was observed for the CA:maleic acid system. A stability order among the cocrystals was established depending on their tendency to replace the coformer. To understand the factors controlling the relative stabilities, lattice energies were calculated using dispersion corrected Density Functional Theory (DFT). Gibbs free energy changes were calculated from experimental solubilities. The observed stability order corroborated well with lattice energy and Gibbs free energy computations.

Yes / Solid state shear milling (S3M) is reported as a scalable, continuous, polymer-assisted cocrystallization technique. A specially designed milling pan was employed to provide high levels of applied shear, and the addition of a polymeric processing aid enabled generation of high stress fields. Carbamazepine–salicylic acid cocrystals were produced with 5–25 wt % of poly(ethylene oxide) (PEO). A systematic study was carried out to understand the effect of process variables on properties and performance of the cocrystals. S3M offers an important new route for continuous manufacturing of pharmaceutical cocrystals.

O pró-fármaco antimetabólito 5-Fluorocitosina (5-FC) foi investigado no campo da Engenharia de Cristais (EC) segundo a abordagem de cocristais farmacêuticos, a fim de modular sua baixa estabilidade física em ambientes úmidos, o que leva à incorporação irreversível de uma molécula de água a nível estrutural em condições de armazenamento variáveis. A forma anidra da 5-FC é um análogo fluorado da citosina muito bem conhecido por sua atividade antifúngica e com isto tornou-se um dos insumos farmacêuticos ativos (IFAs) mais utilizados para o tratamento anticâncer direcionado por meio de terapia gênica. Neste estudo, novos cocristais de 5-FC foram obtidos a partir da reação supramolecular deste IFA com o IFA tuberculostático Isoniazida (INH), bem como com outros três coformadores listados como não tóxicos: cafeína (CAF), ácido p-aminobenzóico (PABA) e ácido caprílico (CA). As amostras foram caracterizadas por difração de raios X em monocristal e policristal (DRXM e DRXP), espectroscopia na região do infravermelho (IV) e espalhamento Raman (Raman); assim como pelas técnicas de análise termogravimétrica (TG), calorimetria exploratória diferencial (CED) e microscopia termo-óptica (MTO). A estabilidade física da 5-FC e seus respectivos cocristais foi avaliada em ambiente com aproximadamente 100% de umidade relativa e a solubilidade no equilíbrio medida em meio tamponado a pH 1,2 – mimetizando valores próximos ao do suco gástrico. Os estudos estruturais mostraram que a 5-FC é capaz de formar diferentes homo e heterossíntons que levam à formação de formas multicomponentes estáveis. Dados de IV e Raman forneceram evidências espectroscópicas sobre o envolvimento dos grupos funcionais na manutenção dos principais síntons e, por tanto, do empacotamento cristalino, confirmando assim a natureza neutra necessária para a obtenção de um cocristal. Pelas análises térmicas foi possível observar que todas as amostras apresentaram uma maior preferência pela degradação do que pela mudança da fase sólida para a líquida com o fornecimento de calor, corroborando que as ligações intermoleculares de hidrogênio que mantém estas formas sólidas são fortes. Adicionalmente, constatou-se que os perfis de solubilidade dos quatro cocristais são similares ao IFA de partida, um fármaco classificado como de classe I pelo Sistema Biofarmacêutico, exibindo, assim, alta solubilidade. A instabilidade frente à hidratação bem como sua irreversibilidade foram estudadas por DRXP à temperatura ambiente (25 °C) e por DRXP em função da temperatura (até 150 °C), respectivamente. Nos cocristais, por sua vez, nenhuma transição de fase pode ser assinalada. Deste modo, todos os cocristais de 5-FC aqui reportados mantiveram uma solubilidade aceitável e não hidrataram ou sofreram transição de fase sob condições extremas de armazenamento (estudo de estabilidade acelerada em atmosfera úmida) e muito menos ao final de 12 meses de estoque (estudo de estabilidade a longo prazo), sendo mais estáveis que o IFA 5-FC forma comercializada. Além disso, o cocristal fármaco-fármaco intitulado 5FC-INH é um potencial candidato para o tratamento concomitante de infecções fúngicas, tuberculose e câncer; principalmente de pulmão. / The prodrug antimetabolite 5-Fluorocytosine (5-FC) was investigated in the field of Crystal Engineering (CE) according to the Pharmaceutical Cocrystals approach, in order to modulate its poor physical stability in humid environments, which leads to the irreversible incorporation of a water molecule at structural level under variable storage conditions. 5-FC anhydrous form is a well-known fluorinated analog of cytosine with antifungal activity and it has become one of the most used active pharmaceutical ingredients (IFAs) for anticancer treatment directed through gene therapy. In this study, novel 5-FC cocrystals were obtained from the reaction of 5-FC with the tuberculostatic IFA Isoniazid (INH) as well as with other three coformers listed as nontoxic: caffeine (CAF), p-aminobenzoic acid (PABA) and caprylic acid (CA). The samples were characterized by single-crystal and powder X-ray diffraction (SCXRD and PXRD), spectroscopic (IR and Raman) and thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and Hot-Stage microscopy (HSM) techniques. The physical stability of 5-FC and its cocrystals were evaluated in environment with high relative humidity (approximately 100 %) and the equilibrium solubility was measured in pH 1.2 buffer media – mimicking values close to that of gastric juice. The structural studies show that the prodrug 5-FC is able to form different homo and heterosynthons that lead to the formation of stable multicomponent forms. IR and Raman data provided spectroscopic evidence on the involvement of functional groups in the maintenance of major synthons and crystal packing assembly, thereby confirming the neutral nature required to obtain a cocrystal. From the thermal analyses it was possible to observe that all the samples presented a preference for degradation instead of phase transition form solid to liquid with the heat supply, corroborating the strength of intermolecular hydrogen bonds that maintain these solid forms. Additionally, the solubility profiles were found to be similar to those of the 5-FC API raw material, a Biopharmaceutical System classified as Class I drug, exhibiting high solubility profile. The instability against hydration and its irreversibility was studied by PXRD at room temperature (25 °C) and by PXRD as a function of temperature (up to 150 °C), respectively. In the cocrystals, in turn, no phase transition was found. Thus, all 5-FC cocrystals reported maintained acceptable solubility and did not hydrate or undergo phase transition under extreme storage conditions (accelerated stability study in moist atmosphere) even at the end of 12 months of storage (long-term stability study), being more stable than the commercially available IFA 5-FC. Furthermore, the drug-drug cocrystal (5FC-INH) is a potential candidate for the treatment of concomitantly fungal infections, tuberculosis and cancer, mainly lung cancer.

No / The design of new functional crystalline materials requires an understanding of the factors that control salt and co-crystal formation. These states often only differ in the location of the proton and are influenced by chemical and crystallographic factors. The interaction between a carboxylic acid and a pyridine is a frequently used supramolecular synthon in crystal engineering which can exist as either a co-crystal (CO2H center dot center dot center dot N) or salt (CO2-center dot center dot center dot HN+). The results of a Cambridge Structure Database search indicate that the nature of the functional groups on the pyridine play a stronger role in selection of the phase than those of the acid. However, the nature of the local hydrogen bonding of the interaction also adjusts the potential for proton transfer. This was demonstrated by ab initio modelling of the energy landscape for binary and ternary co-crystals by inclusion of varying components of the local environment.

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.