Yes / Properties of a matter are intrinsically dependent upon the internal arrangement of molecules in the solid state. Therefore, knowledge of 3-dimensional structure of the matter is prerequisite for structure-property correlations and design of functional materials. Over the past century, X-ray crystallography has evolved as a method of choice for accurate determination of molecular structure at atomic resolution. The structural information obtained from crystallographic analysis paved the way for rapid development in electronic devices, mineralogy, geosciences, materials science, pharmaceuticals, etc. Knowledge of the structural information of active pharmaceutical ingredients (APIs) is prerequisite for rational drug design and synthesis of new chemical entities for development as new medicines. Over the past two decades, X-ray crystallography has played a key role in the design of pharmaceutical cocrystals-crystalline solids containing an API and one or more of pharmaceutically acceptable coformers. These materials have proved promising for fine-tuning several important properties of APIs. This short review highlights the history of crystallography, early breakthroughs, and the role of crystallography in understanding physicochemical properties of pharmaceutical cocrystals. / S. Aitipamula gratefully acknowledges the financial support from the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore. V. R. Vangala thanks Royal Society of Chemistry for Researcher Mobility Grant (2015/17).

Crystal engineering is a rapidly developing area of research with goals aimed at designing molecular solids with desired physical and chemical properties. By utilizing reliable intermolecular interactions, the principles of supramolecular chemistry are exploited in the solid state in order to achieve favorable arrangements of molecules in a crystal lattice. We have applied crystal engineering strategies to further develop the strategy of template-directed reactivity in the solid state. An evaluation of catechol, a regioisomer of the commonly used resorcinol template, was performed. Co-crystallization of the template candidate with a bis-pyridyl olefin produced a discrete self-assembled architecture wherein hydrogen-bonded dimers of catechol pre-organize the olefins for a [2+2] photodimerization in the solid state. The dimerization was determined to proceed quantitatively and X-ray studies of a partial single-crystal-to-single-crystal reaction supported the hypothesis of the reaction proceeding exclusively within the discrete assemblies, despite the infinite stacking of the olefins. A study of substituent effects on the conformational bias of additional catechol- based template candidates was carried out. Candidates with bulky substituents a the 3- and 4-positions were observed to adopt a favorable syn-anti or syn-gauche conformer in most cases. Though conformational bias was induced and discrete assembly achieved, only one of the synthesized cocrystals met the geometric requirements for a photodimerization, however, extended UV exposure produced no evidence of product formation. We discuss the fortuitous discovery of a catechol-based cocrystal system that produces an infinite linear assembly. The fluorine atom of 3-fluorocatechol was observed to be too small to induce conformational bias in the template candidate. However, the system was observed to progress through a three-step solvent-mediated phase transformation. The second and third crystal phases were isolated and characterized by single-crystal X-ray diffraction. The X-ray data revealed that the zig-zag assembly of the first phase spontaneously transforms to a double helix topology in the second phase, before transforming to the final phase, which exhibits a quadruple helix topology. In our studies of pharmaceutical cocrystals, we sought to perform a systematic study of the solid-state behavior of the anti-cancer drug 5-fluorouracil. Inspired by previously published cocrystal structures, we performed co-crystallization experiments with a small series of structurally similar coformers. Comparison of the three structures revealed an inconsistent degree of synthon disruption between the coformers. Curiously, one of the cocrystals obtained displayed a packing arrangement consistent with the requirements of a [2+2] cycloaddition. Irradiation of the sample with UV light resulted in the quantitative formation of a cross-photocycloaddition product. The product was characterized as a pyrimidine-fused cyclobutane, the first reported synthetic derivative of 5-fluorouracil obtained from a solid-state reaction. Lastly, we utilize crystal engineering strategies to study the behavior of 2- iodohippuric acid, a common radio-imaging target. The pharmacokinetic properties of 2- iodohippuric acid make it an ideal target for renal imaging. We sought to approach a solid formulation of the target in a similar manner to that of a drug or other metabolized pharmaceutical. In doing so, we hoped to study the compound’s behavior in the solid state so that we may eventually use co-crystallization as a means of altering the properties of the target for the purpose of generalizing its use in imaging the body.

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 / 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.