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This study demonstrates that the simple direct-compression process can be enabled for low-dose tablet manufacturing through the preparation of an optimal ordered mixture. By producing low-dose tablets containing a micron-sized active pharmaceutical ingredient (API), we showed that excellent content uniformity of a drug product can be accomplished through direct compression, when ordered mixing was introduced as part of the manufacturing process. To incorporate content uniformity into the final drug product, we systematically investigated the material attributes of API and excipients leading to the optimal ordered units. We discovered that excipients with round morphology and rugged surface, which enabled “depth-filling” pattern and multi-layer coverage of API on carrier particles, can give rise to ordered mixtures with greater carrier capacity, stronger adhesive forces, and reduced ordered unit segregation tendency. We developed a sample-saving, bench-scale diagnostic tool which can successfully evaluate the sifting-driven segregation tendency of powder blends. We further identified the conical screen milling process as a robust approach to produce stable ordered mixtures, due to the physical impact and mixing behavior involved in the milling process. This systematic approach, developed on the basis of mechanistic understanding of the critical material and process attributes for ordered mixing and segregation, allowed us to consistently manufacture tablets with high content uniformity both at 1-kg scale and 40-kg scale. Through this study, we demonstrated that common risks associated with the direct-compression process at production scale, such as content uniformity, can be mitigated by understanding and manipulating the particle–particle structures and interactions of the formulation components.

A new coordination synthon, Zn···NO2 recognition, is used in the synthesis of a layered porphyrin coordination polymer (Zn-5,15-di(4-nitrophenyl)-10,20-di(p-tolyl)-porphyrin, 1-Zn) with 44 topology. This solid is thermally stable and incorporates nitrobenzene molecules between the layers to form 1-Zn−PhNO2. The Zn···NO2 recognition exists in 1-Zn and 1-Zn−PhNO2; it is formed by coordination bonding between a Zn2+ ion embedded in a porphyrin core and one of the O-atoms of the nitro group. The structure of 1-Zn−PhNO2 is also layered and contains 44 networks such as those found in 1-Zn. The two structures, however, differ significantly in several intra- and interlayer parameters. Despite these differences, removal of nitrobenzene from the crystals of 1-Zn−PhNO2 yields crystalline 1-Zn. When soaked in nitrobenzene, these desolvated 1-Zn crystals yield crystalline 1-Zn−PhNO2. These reversible solid-to-solid transformations demonstrate the robustness of Zn···NO2 recognition in holding the 44 networks together i...

A new supramolecular crystal engineering approach toward quadratic nonlinear optics is inferred from an acentric cocrystalline template made of two different bi-dimensional octupolar molecules: tr...

This paper describes an approach to the fabrication of three-dimensional (3-D) structures of millimeter-scale spherical beads having a range of lattices-tetragonal, cubic, and hexagonal-using hierarchical self-assembly. The process has five steps: (i) metal-coated beads are packed in a rod-shaped cavity in an elastomeric polymer (poly(dimethylsiloxane), PDMS); (ii) the beads are embedded in a second polymer (PDMS or polyurethane, PU) using a procedure that leaves the parts of the beads in contact with the PDMS exposed; (iii) the exposed areas of the beads are coated with a solder having a low melting point; (iv) the polymer rods-with embedded beads and exposed solder drops-are suspended in an approximately isodense medium (an aqueous solution of KBr) and allowed to self-assemble by capillary interactions between the drops of molten solder; and (v) the assembly is finished by several procedures, including removing the beads from the polymer matrix by dissolution, filling the voids left with another material, and dissolving the matrix. The confinement of the beads in regular structures in polymer rods makes it possible to generate self-assembled structures with a variety of 3-D lattices; the type of the lattice formed can be controlled by varying the size of the beads, and the size and shape of the cross-section of the rods.

Single-crystal X-ray diffraction analyses of α,ω-alkanedicarboxylic acids (HOOC−(CH2)n-2−COOH, n = 2−10) have been carried out at 130 and 298 K. Dimorphism is prevalent in odd carbon members, and the crystal structures of α- and β-forms of C7-diacid have been determined. Diacids show an alternation in their melting points with members containing an even number of carbon atoms exhibiting systematically higher melting points compared to odd ones. On the contrary, the solid-state densities of odd members with Cn ≥ 5 are higher than those of even members. Closest packing is therefore not the reason for alternating melting points in diacids. Diacids with Cn ≥ 5 show distinct packing regularities within even series and also within α- and β-series of odd members. The gross structural features are similar in even and (both forms of) odd diacids: (a) carboxy groups form hydrogen bonded dimers at both ends of the molecules, leading to infinite chains, and (b) methylene chains stack into columns through hydrophobic...

The structural details of a,w-alkanediols and a,w-alkanediamines which are characterized by H bonding and hydrophobic interactions. These systems represent a balance between structural simplicity and interaction complexity, which makes the study of interference between interactions a feasible exercise. The anal. of the crystal structures of diols and diamines revealed the interplay between 2 important intermol. interactions that are possible in these amphiphilic compds., namely, H bonding and hydrophobic interactions. While H bonding and hydrophobic interactions operate in consonance in even members, and therefore culminate in dense packing, they run into geometrical conflicts in odd members, leading to looser packing. Accordingly, the odd members of the diol and diamine series have relatively lower densities and m.ps. than the even members.

a,w-Alkanedithiols show an alternation in their m.ps. with even members exhibiting systematically higher m.ps. than odd members. Single crystals of the 1st nine members of a,w-alkanedithiols (HS-(CH2)n-SH, n = 2-10) were grown in situ using a miniature zone melting procedure, and their x-ray crystal structure analyses were performed. The structural similarities and differences between even and odd members were analyzed based on the packing arrangements of hydrocarbon chains and SH functionalities. Whereas the hydrocarbon chains maintain an intergrooving pattern, the SH groups assoc. in an antiparallel fashion in both the members. The SH groups do not form H bonds. In the even members the mols. are offset along their length, whereas such an offset is not obsd. in the odd members. The densities of even members are systematically higher than those of odd members and show an alternating trend. Using a simple geometrical model, describing even and odd members as modified parallelograms and trapezoids, resp., the d. features of the packing patterns in both the members are illustrated. The m.p. alternation in dithiols is attributed to the geometry allowed or forbidden mol. offset toward a higher packing d.

γ-Hydroquinone (1) and its tetrafluoro, tetrachloro and tetrabromo derivatives (2), (3) and (4) adopt crystal structures that have an almost invariant system of O—H...O hydrogen bonds. However, within this O—H...O framework, the four structures display variations that are characteristic of the C—H, C—F, C—Cl and C—Br groups. In the parent compound (1) aromatic rings are packed with a herringbone geometry, whilst in the halogenated derivatives (3) and (4), polarization-type halogen...halogen contacts are optimized. The fluoro derivative (2) is exceptional in that neither of the above possibilities is adopted, even though the O—H...O scaffolding does not per se prohibit either of them geometrically.

In the crystal structure of the title compd., C25H20O.C8H15OP, the components are linked through O-H...O and C-H...O H bonds. The Ph rings of OPPh3 are close packed, while those of 4-(triphenylmethyl)phenol are involved in sextuple embrace type of packing. Crystallog. data are given.

A new type of crystalline structure for nonlinear optics whereby octupolar symmetry features are displayed at both molecular and crystalline levels is exemplified by the prototype 2,4,6-triaryloxy-1,3,5-triazine (TPOT) crystal and analyzed in terms of both individual molecular responses and crystal packing features. Polarized harmonic light scattering permits the full determination of the molecular β hyperpolarizability tensor and confirms the octupolar trigonal symmetry of the TPOT molecule. An oriented gas model is used to infer therefrom an estimate of the crystalline nonlinear d tensor which is predicted to be of the same order as that of the reference dipolar N-4-nitrophenyl-(L)-prolinol crystal. The concept of optimal packing toward quadratic nonlinear optics, which had been initially introduced in the realm of quasi-one-dimensional structures, is revisited and enlarged to encompass more isotropic uniaxial structures potentially amenable, in the case of octupoles, to larger optimal values than in the one-dimensional case. Moreover, considerations pertaining to phase matching which had been left aside in the earlier one-dimensional optimization framework are now considered and the various type I and type II configurations compared for both one-dimensional and octupolar uniaxial structures. Application perspectives of octupolar structures toward short pulse nonlinear optics are discussed: their structurally built-in polarization independence is outlined as a major asset in contrast with the more traditional one-dimensional structures.

Structural studies currently underway in our group are reported in this paper. Molecular symmetry is rarely carried over into the crystal, posing problems when high-symmetry networks are desired. This is illustrated by the low-symmetry structure of 2,4,6-trinitromesitylene. However, the involvement of the Cl3 supramolecular synthon ensures a hexagonal network structure for 2,4,6-tris-(4-chlorophenoxy)-1,3,5-triazine. Arguments following from the equivalence between molecular and supramolecular synthons lead to the tetragonal network structure of the 1:1 complex of tetraphenylmethane and CCl4. With a similar reasoning, 4-(triphenylmethyl)benzoic acid is identified as a precursor of a supramolecular wheel-and-axle host substance. The study of novel and weaker intermolecular interactions is often useful. In N,N′-dibenzyl-1,4-cubanedicarboxamide, the acidity of the cubyl C-H groups leads to the formation of C-H···O hydrogen bonds. Polymorphism is a difficult challenge for the crystal engineer and, in its most intriguing manifestation, two crystalline forms of a substance appear in the same crystallization batch. This is observed for 4,4-diphenyl cyclohexadienone. The ultimate frontier in the subject is an understanding of the phenomenon of crystallization, and the unexpected crystal structure of quinoxaline, with five symmetry-independent molecules, could possibly represent a case of arrested crystallization.

The principles of crystal engineering have been used to design a family of structures with potential as octupolar nonlinear optical (NLO) materials. The major aim in such an exercise, a carry-over of molecular symmetry into the crystal, is possible with a retrosynthetic approach. An appropriate choice of precursor trigonal molecules leads from the concept of the dimeric Piedfort unit. The crystal structures and NLO properties of a series of 2,4,6-triaryloxy-1,3,5-triazines, 1−6, are reported. These compounds consistently form quasi-trigonal or trigonal networks that are two-dimensionally noncentrosymmetric. Substitutional variations on the phenyl moieties that were expected to maintain or to perturb this trigonal network have been explored. Molecular nonlinearities have been measured by Harmonic Light Scattering (HLS) experiments. Among the compounds studied, 2,4,6-triphenoxy-1,3,5-triazine, 1 adopts a noncentrosymmetric crystal structure with a measurable SHG powder signal. All these crystal structures a...

Single-crystal neutron diffraction analyses of 2- and 3-aminophenols have been performed. In addition to O−H···N and N−H···O hydrogen bonds, both these structures contain previously unidentified N−...

Ethane, propane and n-butane form layer structures in the solid state. By describing their molecular geometries as a rectangle, an irregular pentagon and an irregular hexagon, respectively, it is shown here that propane cannot close-pack like its congeners. The melting point of propane is therefore lower than expected in the series.

The crystal structure of the title compound, C 24 H 21 N 3 , is stabilized by C-H...N and C-H...π interactions. Its crystallization in a lower symmetry space group highlights an important problem in crystal engineering, that is the failure of symmetry carry-over from the molecule to the crystal.

Carboxy terminated alkanethiol self-assembled monolayers promote the face-selective nucleation of the P-monoclinic polymorph of carbamazepine; the type of face nucleated depends on the parity of the alkyl chain.

2,4-Dinitrocinnamic acid [3-(2,4-dinitrophenyl)prop-2-enoic acid], C9H6N2O6, crystallizes as a normal centrosymmetrical carboxy dimer. O-H⋯O and C-H⋯O hydrogen bonds are found in the structure.

A new physical model based on mesoscale self-assembly is developed to simulate indentation fracture in crystalline materials. Millimeter-scale hexagonal objects exhibiting atom-like potential functions were designed and allowed to self-assemble into two-dimensional (2D) aggregates at the interface between water and perfluorodecalin. Indentation experiments were performed on these aggregates, and the stresses and strains involved in these processes were evaluated. The stress field in the aggregates was analyzed theoretically using the 2D elastic Hertz solution. Comparison of the experimental results with theoretical analysis revealed that fracture develops in regions subjected to high shear stress and some, albeit low, tensile stress. The potential for the broader application of the model is illustrated using indentation of assemblies with point defects and adatoms introduced at predetermined locations, and using a two-phase aggregate simulating a compliant film on a stiff substrate.

A new technique-crystallization in asymmetric microwells-generates arrays of small crystals with controlled size, orientation, and arrangement in space. These arrays of crystals can be generated in a form completely encapsulated in polymer.

Single crystal x-ray diffraction analyses of the 2:1 complexes of phenazine with hydroquinone and 1,5-dihydroxynaphthalene and the 3:1 complex of phenazine with 4,4'-dihydroxybiphenyl were performed. In these complexes and also in the 3:1 complex of phenazine with 5,10-dihydrophenazine, phenazine forms a host framework consisting of 1-dimensional channels. The variation of guest mols. and attendant variations in the H bond patterns, and the reproducibility of phenazine mol. stacks are described. Crystallog. data are given.

Crystal structures of methyl-, 2,3-, 2,5- and 2,6-dimethyl-, and trimethylpyrazine (2–6) have been determined by X-ray diffraction analysis. Four of these compounds (2–4 and 6) are liquids and their single crystals have been grown in situ on the diffractometer using a miniature zone melting procedure. These structures are analysed together with those of pyrazine (1) and tetramethylpyrazine (7) in the context of C–H···N interactions. Compounds 1–7 were chosen because they contain only C, H and N atoms, and also C–H groups of variable acidity. This facilitates the comparison of C–H···N geometries with respect to the C–H group acidity. Compounds 1 and 2 are dominated by sp2 C–H groups in their molecules and their supramolecular structures are generated by sp2 C–H···N. On the other hand the domination of sp3 C–H groups at the molecular level in 6 and 7 results in crystal structures that are governed by sp3 C–H···N. A balance of sp2 and sp3 C–H groups in the dimethyl derivatives 3–5 leads to a situation where both kinds of C–H groups play a structure directing role. While the sp2 C–H groups form C–H···N, the sp3 C–H groups are involved in C–H···π interactions. Thus the C–H group interactions follow a property unique to hydrogen bonds—stronger donors interact with stronger acceptors while weaker donors approaching weaker acceptors. Inter-structural comparison revealed that H···N distances decrease with increasing C–H acidity and therefore C–H···N interactions could be considered as weak hydrogen bonds.

Phenazine (1) and 5,10-dihydrophenazine (2) form not only a 1:1 complex (3), as expected from N–H···N hydrogen bond requirements, but surprisingly also a 3:1 complex (4). Single crystal X-ray analyses of compound 2 and complexes 3 and 4 have been carried out. While the overall packing in complex 3 is as efficient as in pure 1 and 2, acidic C–H groups, which contribute actively to the structural assembly in pure 2, are not involved in hydrogen bonding in 3. It is shown that the quest for hydrogen bonding by these C–H groups steers the formation of complex 4 with an unprecedented N–H···N and C–H···N hydrogen bond mediated tape structure.

The ability of CH3 groups to form helical chains of C–H‥π interactions with phenyl rings leads to polar stacking of trigonal octupolar networks in a substituted triazine, and therefore to three-dimensional non-centrosymmetry.

Ethynylpyridines show straight and zigzag chain patterns formed by ⋮C−H···N hydrogen bonds; cross-stitching of zigzag chains by C−H···N hydrogen bonds leads to two-dimensional networks with predictable topology in 5-ethynylpyrimidine.

The crystal structures of trimethyl isocyanurate, C6H9N3O3, (1), and triethyl isocyanurate, C9H15N3O3, (2), contain topologically similar C--H...O hydrogen-bonded networks. In (1), there are two symmetry-independent molecules and each forms its own layer structure. In (2), two of the ethyl groups point one way with respect to the heterocyclic ring, while the third points in the opposite direction.

The existence and nature of C−H···F−C interactions in crystalline fluorobenzenes 1−3 and 7−10 are discussed. These compounds were chosen because they contain only C, H, and F atoms; this is necessary in the evaluation of the weak acceptor capabilities of the C−F group. All of these compounds are liquids at room temperature, and single crystals for X-ray diffraction were grown in situ. The analysis of the C−H···F interactions that are found in all of these crystal structures takes the form of comparisons with related C−H···O/C−H···N analogues. Fluorobenzene, 1, bears a close relationship to pyridinium fluoride, pyridine 1-oxide, and benzonitrile at the level of individual interactions, showing that the character of the structure-determining intermolecular interactions in these four crystal structures are the same. Similarly, 1,4-difluorobenzene, 3, and 1,4-benzoquinone are related, the C−H···F interactions in the former playing the same structural role as the C−H···O interactions in the latter. A compariso...

The title compound has a C–H···O hydrogen bond-mediated trigonal network structure that leads to octupolar NLO behaviour in the solid state.

This Communication describes a new strategy for the design of adaptive structures based on reconfigurable mesoscale self-assembly. Several sets of millimeter-scale objects have been designed that can self-assemble into two different, regular aggregates at the interface between an aqueous solution and perfluorodecalin; the choice between the two aggregates is determined by the density of the aqueous phase.

This communication demonstrates an approach to generate simple nanostructures with critical dimensions down to 30 nm over cm2-sized areas using composite PDMS masks. These masks were patterned with feature sizes down to 100 nm. When used in phase-shifting lithography, these masks generated arrays of structures in photoresist with line widths as small as 30 nm, slots in metal with features down to 40 nm, and wells in epoxy with diameters as small as 100 nm. The wells were used to prepare arrays of uniformly sized nanocrystals of salts.

A new technique-crystallization in asymmetric microwells-generates arrays of small crystals with controlled size, orientation, and arrangement in space. These arrays of crystals can be generated in a form completely encapsulated in polymer.

Trimethylisocyanurate 2 and 1,3,5-trinitrobenzene 3 form a hexagonal C–H ⋯ O mediated 1:1 complex wherein distinct molecular layers are formed, the molecular symmetry of the components being retained in the crystal.

The analogy between crystal engineering and traditional organic synthesis is outlined with reference to a family of crystal structures which incorporate iodo⋯nitro and carboxyl dimmer supramolecular synthons.