Srinivasulu Aitipamula

Multiple molecules in the crystallographic asymmetric unit. Self host–guest and doubly interpenetrated hydrogen bond networks in a pair of keto-bisphenols

The presence of two molecules in the crystallographic asymmetric unit in a pair of closely related keto-bisphenols that differ by a methyl substituent only, leads to open frameworks that fill space through self-inclusion in one case, and through interpenetration in the other.

Engineering the weak N–H⋯π hydrogen bond in 4-tritylbenzamide host and controlling the interaction through guest selection

The title amide host 1 crystallizes in the wheel-and-axle framework via amide N–H⋯O dimer and includes several aromatic and aliphatic guest molecules in cavities of 40 A2 size between supramolecular axles. Bulky triphenylmethyl groups make it impossible for the second NH donor to engage in strong hydrogen bonding and this promotes a weak intermolecular N–H⋯π interaction in inclusion adducts of aromatic and hydrophobic guests (structure type 1, guest = xylenes, chloro/bromo-toluene). On the other hand, the N–H⋯π interaction is absent for guests with CO groups because of stronger N–H⋯Oguest hydrogen bonding (type 2, guest = EtOAc, MeNO2). Crystal structures of both types are virtually identical except for the rotation of CONH2 group that transforms the N–H⋯π interaction to the N–H⋯O hydrogen bond. In addition to controlling the occurrence of the weak N–H⋯π hydrogen bond through host⋯guest recognition, a third structure type with N–H⋯Ohost and N–H⋯π hydrogen bonds is present in the anisole adduct. Amide group conformations, strong and weak hydrogen bonds, and close packing of aromatic residues determine the three structure types of composition 1·(guest)0.5 in space group P. The CH2Cl2 solvate, 1·(CH2Cl2)1.5, has a different crystal packing in space group C2/c with guest molecules included in channels between amide dimers and also between Ph3C groups. The design and control of the weak N–H⋯π hydrogen bond are shown for the first time in a family of isomorphous crystal structures. Infrared spectroscopy and variable temperature X-ray diffraction are consistent with the hydrogen bond nature of the N–H⋯π interaction. Differential scanning calorimetry and thermal gravimetric analysis confirm the functional behavior of inclusion host 1 and show differences in the release of CH2Cl2 molecules from the two types of channels. Crystal latttice energies follow the order structure type 3 < type 2 < type 1 in the range of −90 to −76 kcal mol−1 per host molecule.

Host–guest and network structures of some tetraphenylmethane derivatives

Dinitro and tetracyano derivatives of tetraphenylmethane (TPM) are identified as new host materials that include THF, water and MeCN. The crystal structures of the host–guest complexes are reminiscent to those of the related host compound tetranitrotetraphenylmethane (TNTPM) studied by us previously. Guest loss has been measured quantitatively. The crystal structures are characterized by O–H⋯O, C–H⋯O, C–H⋯N and C–H⋯π interactions. It is interesting to note that while the unsubstituted TPM and some of its other derivatives form guest-free crystals, the nitro and cyano derivatives form more open structures.

Ladder and Hexagonal Hydrogen-bond Networks from a Self-complementary H-shaped Tecton

Self-assembly of the H-shaped tecton 1,4-di[bis(4′-hydroxyphenyl)methyl]benzene 1 via O-H ⃛O hydrogen bonds leads to a ladder or hexagonal network depending on the included solvent molecule. MeOH and EtOH solvates of 1 have isostructural hexagonal networks whereas inclusion of MeCN or dioxane results in a ladder structure. The ladder rung distance is modularly expanded from 11 to 20 Å in the cocrystal of 1 with 4,4′-bipyridine. The novel H-tecton adds to the library of T- and Y-shaped and tetrahedral organic nodes for network construction.

Hexagonal Host Framework of sym-Aryloxytriazines Stabilised by Weak Intermolecular Interactions

ABSTRACT 2,4,6-Tris(4-halophenoxy)-1,3,5-triazine 1 is a convenient C3 starting material for the self-assembly of hexagonal open frameworks mediated via the halogen…halogen trimer synthon and the π-stacked Piedfort Unit (PU). We examine in this paper crystal structures of 2,4,6-tris(2-iodo-3-pyridyloxy)-1,3,5-triazine 2 , 2,4,6-tris(3-iodophenoxy)-1,3,5-triazine 3 , 2,4,6-tris(6-methyl-3-pyridyloxy)-1,3,5-triazine 4 , and 2,4,6-tris[4-(4′-bromophenyl) phenoxy)]-1,3,5-triazine 5 . Triazine 2 forms isostructural 2:1 host⋅guest adducts (guest = mesitylene, collidine) in the rhombohedral space group R3¯ such that the host architecture is stabilised by the C3i-PU and a helix of C─H…N interactions. The crystal structure of 3 is different from its chloro/bromo derivatives signifying the importance of the more polarisable I atom compared to Cl, Br. Pairs of C─H…O and C─H…N hydrogen bonds and C3i-PU sustain the columnar structure of 3 (space group R3¯). The PU has pseudo trigonal symmetry in picolinoxy triazine 4 (space group P21/n). In contrast to the phenyl derivatives, the extended aryl arms in biphenyl 5 do not adopt a trigonal conformation: two biphenyl groups are oriented parallel that participate in Br…Br and Br…π interactions. We note that 1 and 2 readily form hexagonal host lattices for guest inclusion, while 3 , 4 , and 5 crystallise in solvent-free form. Thermal measurements (TGA, DSC) indicate that guest release occurs at a higher temperature in the cage type host⋅guest clathrates compared to the channel inclusion compounds for the same solvent. Statistics from the Cambridge Structural Database using CSD Symmetry show that the phenoxytriazine scaffold is unique among the trigonal molecules for the carry-over of symmetry relation from molecule to crystal. The ease of predicting crystal packing and space group in this family of compounds ( 1 , 2 ) makes them good candidates for the crystal engineering of host frameworks.

Solvates of the antifungal drug griseofulvin: structural, thermochemical and conformational analysis.

Four solvates of an antifungal drug, griseofulvin (GF), were discovered. All the solvates were characterized by differential scanning calorimetry, thermogravimetric analysis, and their crystal structures were determined by single-crystal X-ray diffraction. The solvents that form the solvates are acetonitrile, nitromethane and nitroethane (2:1 and 1:1). It was found that all the solvates lose the solvent molecules from the crystal lattice between 343 and 383 K, and that the melting point of the desolvated materials matched the melting point of the solvent-free GF (493 K). The conformation of the GF molecule in solvent-free form was found to be significantly different from the conformations found in the solvates. Solution stability studies revealed that the GF-acetonitrile solvate transforms to GF and that GF-nitroethane (1:1) solvate transforms to GF-nitroethane (2:1) solvate. On the other hand, GF-nitromethane and GF-nitroethane (2:1) solvates were found to be stable in solution. Our results highlight the importance of the co-crystallization technique in the pharmaceutical drug development; it not only expands the solid form diversity but also creates new avenues for unraveling novel solvates.

Chapter 5:Pharmaceutical Co-crystals—Molecular Design and Process Development

Over the past decade, pharmaceutical co-crystals have gained prominent interest in drug development, due to their ability to modify the physicochemical properties of active pharmaceutical ingredients (APIs). Design of co-crystals generally relies on functional groups present on the API and co-former molecules, and hence intermolecular hydrogen bonds (synthons) that are prevalent between these functional groups act as design elements. Molecules that are devoid of potential hydrogen bonding sites have proved to be challenging for co-crystal design. Hence, alternative methods such as a knowledge-based method are useful for such compounds. The method works on a predictive methodology comprising a breadth of knowledge acquired from Cambridge Structural Database, interaction mapping, molecular descriptors, etc. Once a potential co-crystal is selected for further development, it is prerequisite to develop a robust process for preparation of co-crystal in bulk. Solution co-crystallization is a promising method; however, it presents challenges for large scale manufacturing. Hence, understanding ternary phase diagrams and the co-crystallization process is desired. With this background, the current chapter highlights knowledge-based co-crystal design strategies with some representative examples. Process development aspects such as the ternary phase diagram, and the critical parameters that should be considered in process monitoring and control by process analytical technologies will also be highlighted.