Herein we describe a straight-forward and reproducible method for the preparation of homogeneous, multicomponent cocrystals and supramolecular solid solutions. We prepared these multicomponent materials based on small organic molecules that employ a two-point supramolecular hydrogen bond synthon. We report the creation and characterization of two, three, four, five, and seven component crystals containing a variety of 2-aminopyridines and monosubstituted benzoic acids. These systems exhibit the ability to accommodate multiple components in varying proportions while coordinating into an identical packing structure. The flexibility of the system to incorporate multiple components also gives rise to gradual modulation of physical properties.

Pour l’industrie pharmaceutique, la conception de cocristaux permet de moduler les propriétés physico-chimiques de composés d’intérêt sans en altérer l’activité thérapeutique.Ces solides monophasés sont définis comme étant des structures comportant plusieurs espèces reliées entre elles par des liaisons faibles et neutres. Alors que la majorité des études de cocristallisation sont centrées sur la génération et la caractérisation de nouvelles phases, ce travail a eu pour objectif d’explorer une nouvelle méthode de fabrication de cocristaux, en utilisant des procédés assistés au CO2 supercritique. La possibilité de formerdes interactions entre composés de différentes natures par recristallisation au CO2antisolvant a été étudiée avec les versions discontinue GAS (Gaseous Anti-Solvent) et semicontinue SAS (Supercritical Anti-Solvent) sur deux systèmes: naproxène-nicotinamide et acétazolamide-théophylline. Le naproxène étant chiral, la cocristallisation à partir du mélange naproxène racémique-nicotinamide a également été abordée. Un cocristal connu etdeux phases cocristallines jamais observées, dont une racémique, ont pu être synthétisés.L’étude de l’influence de divers paramètres opératoires des procédés GAS et SAS, tels que la concentration de la solution initiale, le ratio des espèces ou le débit d’ajout de l’antisolvant,a permis une meilleure compréhension de la cocristallisation induite par CO2 supercritique.Les résultats ont montré que la pureté en cocristaux des poudres obtenues était influencée à la fois par la proportion de CO2 dans le mélange solution/CO2 et les concentrations des espèces en solution (contribution des équilibres thermodynamiques) mais également par l’homogénéité du réacteur de précipitation. / For the pharmaceutical industry, cocrystal design allows tuning physicochemical propertiesof an active compound without altering its therapeutic activity. These monophasic solidscontain two or more different species interacting by weak and neutral bonds. Whereas themajority of cocrystallization studies pertain to generation and characterization of newcocrystalline phases, this work was aiming at exploring a new way of cocrystal fabrication,using supercritical CO2-assisted processes. The possibility of interaction formation betweendifferent types of compounds when these are precipitated by antisolvent CO2 has beenstudied by the batch GAS (Gaseous Anti-Solvent) and the semi-continuous SAS(Supercritical Anti-Solvent) versions of the antisolvent method on two different molecularsystems: naproxen-nicotinamide and acetazolamide-theophylline. Naproxen being a chiralcompound, its cocrystallization with nicotinamide from a racemic mixture has also beenaddressed. A known naproxen-based cocrystal and a new racemic cocrystalline phase havebeen obtained thanks to the antisolvent precipitation. A new acetazolamide-theophyllinecocrystal has also been produced for the first time with the GAS process. The influence ofGAS and SAS operational parameters such as CO2 feed rate, species molar ratio andconcentrations in the initial solution, has been investigated to allow a better understanding ofthe mechanisms involved in supercritical CO2-induced cocrystallization. Results have shownthat purity in cocrystal of the produced powders is influenced by the CO2 composition of thesolution/antisolvent mixture and by the ratio and concentrations of the solutes(thermodynamic equilibria), but also by the homogeneity of the mixture in the precipitationchamber of the process.

The objective of this study is to investigate cocrystal solubility and dissolution behavior to elucidate the factors affecting these processes in various media. Six cocrystals with xanthines (theophylline (THP), caffeine (CAF) and theobromine (THB)) were prepared and characterized by powder X-ray diffraction and thermal methods. Two cocrystals (CAFCA I and THBSA) are new solids and their crystal structures were determined by single crystal X-ray diffraction. Cocrystal solubility behavior depended on the dissolving complex solubility and its dissociation behavior in solution. Two THP cocrystals - one with acetaminophen (ACE) and one with citric acid (CA) created different degrees of free THP supersaturation in solubility and dissolution studies. High transient THP supersaturation caused almost immediate THP hydrate crystallization from THPCAH and led to non-congruent solubility behavior. Such behavior was not observed with the ACETHP because free THP supersaturation was not sufficient to induce rapid crystallization but did so over longer equilibration times. Three salicylic acid (SA) cocrystals with xanthines (THP, CAF, and THB) were prepared; two (THPSA and CAFSA) had low aqueous solubility compared to their pure components and one (THBSA) had higher solubility. Both cocrystal components in these cocrystals produced higher solubility/dissolution rates in alkaline media due to ionization. Also, at higher pH, THB precipitated from THBSA solutions because of higher THB supersaturation under alkaline conditions. Caffeine (CAF) and theophylline (THP) both form cocrystals with citric acid (CA) which is a highly water-soluble cocrystal former. Both CAFCA Form I and II solubility and dissolution behavior were studied. THPCAH exhibited non-congruent dissolution because of rapid precipitation of THP hydrate on the dissolving cocrystal surface. CAFCA exhibited congruent dissolution because it did not produce sufficient supersaturation to precipitate CAF hydrate during dissolution. CA cocrystals also have the unusual behavior of high viscosities produced in the dissolution boundary layer due to CA’s high solubility. These viscosities alter diffusion coefficients which reduce dissolution rates from that expected based purely on solubility. To further understand cocrystal dissolution, a diffusion-convection-reaction (DCR) model was developed to predict cocrystal dissolution rates in various media. This model predicted concentration profiles of all species (complex, free components and reactive species) in the diffusion layer of a rotating disk intrinsic dissolution system. Predicted dissolution rates had varying degrees of agreement with experimental data depending on the cocrystal model and the medium into which the cocrystal dissolved.

Supramolecular chemistry and crystal engineering seek to control molecular packing in the solid state to influence the physical and chemical properties of crystalline solid materials. A goal of supramolecular chemistry that seeks to control molecular packing in the solid state focuses on exploiting non-covalent interactions to assemble molecules into desirable arrangements. Strategies implemented to control molecular packing rely on strong, directional interactions such as hydrogen bonding, halogen bonding, and metal coordination to direct localized arrangement of molecules in solids. In this context, small molecules can be used as linear templates in co-crystals to assemble reactive alkenes into specific geometries allowing reactivity in the solid state. A linear template method has been used to achieve [2+2] photocycloadditions of discrete assemblies containing alkenes to afford cyclobutanes in high stereospecificity and in quantitative yield. Herein, we describe the use of a nonlinear template, in the form of 1,4-butynediol (1,4-bd), to pre-organize alkenes in the solid state. The nonlinear template of 1,4-bd hydrogen-bonds to the alkene 1,2-bis(N-pyridyl)ethene (where N = 3 or 4) to form 1D hydrogen-bonded polymers. The hydrogen-bonded polymer chains form infinite stacks which are sustained by C-H···O interactions occurring between polymer chains. The stacked alkenes undergo a UV-induced [2+2] photocycloaddition to produce rctt-tetrakis(N-pyridyl)cyclobutane photoproducts (where N = 3 and 4) in non-quantitative yields. The yield of the photoreaction is increased to nearly quantitative by applying a supramolecular catalysis approach with the 1,4-bd template. Functional groups on reactant molecules can compete via non-covalent interactions with templates employed for the self-assembly process. One method to inhibit competition between functional groups involves chemically modifying a functional group employing a supramolecular protecting group. Here, we describe an acetyl supramolecular protecting group approach employed to mask alkenes containing phenolic and pyridyl functional groups. The acetyl protecting group prevents the phenolic substituents of the targeted alkene from participating in non-covalent interactions employed for the template-mediated self-assembly process. Thus, a cyclobutane molecule was obtained using the novel acetyl supramolecular protecting group strategy applied to a solid-state [2+2] photodimerization that affords a head-to-head cyclobutane. After deprotection, the resulting cyclobutane possessed tetrahedrally-disposed cis-hydrogen-bond-donor and cis-hydrogen-bond-acceptor groups. Thus, a purely organic three-dimensional hydrogen-bonded network based on a rare Michael O'Keeffe (mok) topology was constructed using an organic molecule synthesized in the organic solid state. The phenolic substituents of the cyclobutane adopt different orientations (syn-, anti-, and gauche-) to conform to the structural requirements of the mok net. A challenge surrounding template-directed solid-state reactivity requires alkenes to be lined with functional groups that coordinate (or bind through other non-covalent interactions) to the template. Herein, we describe a dual approach of supramolecular assistance to covalent bond formation that utilizes a combination of imine and metal-organic chemistry to generate cyclobutanes lined with aldehyde groups. Specifically, dynamic imine chemistry was implemented to install a temporary recognition site on an aldehyde-containing alkene of cinnamaldehyde for a template-directed [2+2] photocycloaddition in the solid state. The resulting modified alkene aligns using Ag(I) ions into desirable arrangements for the covalent-bond-forming [2+2] photocycloaddition. The result is a 1D coordination polymer undergoes a UV-induced, regio-controlled [2+2] photocycloaddition in the solid state. The photoreaction proceeds stereospecifically with quantitative yield of the corresponding aldehyde-functionalized photodimer, α-truxilaldehyde. Additionally, we investigate the influence of the Ag(I) counterions on the assembly of imine containing alkenes to generate reactive assemblies for the purpose of producing aldehyde-containing cyclobutanes. This dissertation also encompasses research pertaining to pharmaceutical solids and mechanical properties of organic molecular crystals. Specifically, we describe the discovery of two polymorphic co-crystals containing acetylsalicylic acid (aspirin) combined with 4,4’-bipyridine. The initial discovery of the form I polymorph was aided by mechanical dry-grinding, while an additional form II polymorph was revealed by rapid cooling in ethanol. The polymorphs differ by relative twists of carboxylic acid groups of the aspirin molecules and of the pyridyl rings of 4,4’-bipyridine. Additionally, the form I polymorph contains aspirin molecules that are linked via discrete catemeric methyl C-H···O interactions, while the form II polymorph is linked via both infinite methyl C-H···O catemers and centrosymmetric dimers. These results demonstrate the importance of dry mechanical grinding for the discovery of pharmaceutical co-crystals and polymorphs.

Chemistry is on the verge of a new era where the attention of chemists has shifted from covalent bonds to noncovalent interactions and their use as a predictable way to guide reactions pathways and product formation. Nature synthesizes elegant molecules under mild conditions and the designed syntheses have been demonstrated to be largely dependent on recognition, self-assembly and templating effects between molecular building blocks. Although covalent synthesis in fluidic medium via supramolecular control has been achieved with limited success, organic solid state has been of particular interest since it avoids solvent effects, and is able to provide unique materials with remarkable stereoselectivity under environment-friendly conditions. Although reactions in solids have resulted in a number of remarkable discoveries in chemistry and materials science, solid-state synthesis is generally not considered as a mainstream synthetic medium and solid-state reactions are seldom appreciated as an efficient way to access molecular targets. Owing to the limited number of solid-state reactions and the uncontrollable nature of crystal packing, solid state has not been utilized readily as a primary synthetic medium. In this context, reactions conducted in multicomponent molecular assemblies or co-crystals have been attracting much attraction in recent years as a general way of controlling the reactivity of molecules in solid state. A molecular component in the multicomponent molecular solid, acting as a linear template, has been shown to preorganize molecules in a modular way via intermolecular interactions and engineer their physical and/or chemical properties. The [2+2]photodimerization of olefins is a successful demonstration how templated solid state synthesis can efficiently synthesize complex targets that are synthetically challenging via conventional routes. In this dissertation, the generality and synthetic applicability of the templated synthetic approach in solid state will be described. How supramolecular interactions in molecular co-crystals precisely guide covalent bond formation in order to construct complex molecular targets will be demonstrated. Finally, co-crystallization will be shown as a general way to control optical properties in crystals.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第23728号 / 理博第4818号 / 新制||理||1689(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 北川 宏, 教授 吉村 一良, 教授 竹腰 清乃理 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Yes / Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform –infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P21/n, P21/c and P21/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs.

Yes / The cocrystal of nitrofurantoin with urea (C8H6N4O5)·(CH4N2O), a non-ionic supramolecular complex, has been studied. Nitrofurantoin (NF) is a widely used antibacterial drug for the oral treatment of infections of the urinary tract. Characterization of the cocrystal of nitrofurantoin with urea (NF–urea) was performed spectroscopically by employing FT-IR, FT- and dispersive-Raman, and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. With the purpose of having a better understanding of H-bonding (inter- and intra-molecular), two different models (monomer and monomer + 3urea) of the NF–urea cocrystal were prepared. The fundamental vibrational modes were characterized depending on their potential energy distribution (PED). A combined experimental and theoretical wavenumber study proved the existence of the cocrystal. The presence and nature of H-bonds present in the molecules were ascertained using quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. As the HOMO–LUMO gap defines the reactivity of a molecule, and this gap is more for the API than the cocrystal, this implies that the cocrystal is more reactive. Global descriptors were calculated to understand the chemical reactivity of the cocrystal and NF. Local reactivity descriptors such as Fukui functions, local softness and electrophilicity indices were analysed to determine the reactive sites within the molecule. The comparison between NF–urea (monomer) and NF showed that the cocrystal has improved overall reactivity, which is affected by the increased intermolecular hydrogen bond strength. The docking studies revealed that the active sites (C[double bond, length as m-dash]O, N–H, NO2, N–N) of NF showed best binding energies of −4.89 kcal mol−1 and −5.56 kcal mol−1 for MUL and 1EGO toxin, respectively, which are bacterial proteins of Escherichia coli. This cocrystal could potentially work as an exemplar system to understand H-bond interactions in biomolecules.

Yes / We report formation of polymorphs and new eutectics and cocrystals of curcumin, a sparingly water-soluble active component in turmeric, structurally similar to cinnamic acid. The curcumin polymorphs were formed using liquid antisolvent precipitation, where acetone acted as a solvent and water was used as the antisolvent. The metastable form 2 of curcumin was successfully prepared in varied morphology over a wide range of solvent-to-antisolvent ratio and under acidic pH conditions. We also report formation of new eutectics and cocrystals of curcumin with cinnamic acid acting as a coformer. The binary phase diagrams were studied using differential scanning calorimetry and predicted formation of the eutectics at the curcumin mole fraction of 0.15 and 0.33, whereas a cocrystal was formed at 0.3 mole fraction of curcumin in the curcumin–cinnamic acid mixture. The formation of the cocrystal was supported with X-ray powder diffraction, the enthalpy of fusion values, Fourier-transform infrared spectroscopy, and scanning electron microscopy. The hydrogen bond interaction between curcumin and cinnamic acid was predicted from Fourier-transform infrared spectra, individually optimized curcumin and cinnamic acid structures by quantum mechanical calculations using Gaussian-09 and their respective unit cell packing structures.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The ability to predict and control molecular arrangements without compromising the individual molecules themselves still remains an important goal in supramolecular chemistry. This can be accomplished by establishing a hierarchy of intermolecular interactions such as hydrogen and halogen bond, which may facilitate supramolecular assembly processes. Several acetaminopyridine/acetaminomethylpyridine supramolecular reactants (SR’s) were prepared with aliphatic carboxylic acids in order to determine patterns of molecular recognition preferences of the N-H moiety. The results obtained revealed the formation of molecular cocrystals through heteromeric O-H…N/N-H…O hydrogen bonds with the acetaminopyridine/acetaminomethylpyridine binding site. Furthermore, the SR’s also reacted with metal ions resulting in robust 1D and 2D metal-containing architectures. A series of pyridyl/pyrazine mono-N-oxide compounds were synthesized and reacted with a variety of halogenated benzoic acids, in order to assess the ability of these molecules to establish binding selectivity when both a hydrogen and halogen bond donor is present. The results obtained revealed that the pyridyl/carboxylic acid synthon formed 7/7 times and halogen bonds (N-O…I or N-O…Br) extended the SR/acid dimers into 1D and 2D networks. These results were rationalized via charge calculations as well as through the hierarchical view of intermolecular interactions consisting of hydrogen and halogen bonds. Furthermore, a series of thienyl compounds were synthesized and allowed to react with halogen bond donors to determine whether the halogen bond is purely electrostatic or based on the hard and soft acids and bases principles. The results obtained showed that of the 34 reactions between a halogen bond donor and thienyl compounds, the halogen bond is predominantly electrostatic in nature. Finally, as a result of our improved understanding on molecular recognition, we were able to carry out systematic structure-property studies on a series of cocrystals of anti-cancer drug molecules with aliphatic carboxylic acids. This study revealed that systematic changes to the molecular nature of the co-crystallizing agent combined with control over the way individual building blocks are organized within the crystalline lattice makes it possible to establish predictable links between molecular structure and macroscopic physical properties, such as melting behavior, solubility, dissolution rate, etc.