Rampant Polymorphism in Pharmaceuticals: An Isoniazid Derivative

Investigations into the polymorphic forms of Active Pharmaceutical Ingredients (APIs) are of vital importance to drug formulations and are often kept a closely guarded secret by pharmaceutical companies. This secrecy is maintained as the nature of the polymorph could either make or break a drug formulation. Polymorphism is the ability of a solid crystalline form to exist in more than one structural arrangement. The variation in the crystalline forms often displays different mechanical, thermal, and chemical properties. These changes can remarkably influence the bioavailability, hygroscopicity, stability and other performance characteristics of the API [1]. Isoniazid, a well-known pharmaceutical, is used as a first-line treatment against Mycobacterium tuberculosis (TB) which is known to possess multiple polymorphs. Derivatives of isoniazid were developed in response to TB drug resistance. One such derivative, isonicotinic acid-(1-phenyl-ethylidenehydrazide) (IPH) [2] was found to exhibit an array of polymorphic behaviour as a result of its hydrogen bond acceptors, donors and conformational freedom along its backbone. To date only one crystal structure of IPH has been reported in the literature [3]. We have discovered and isolated an additional five novel polymorphs of IPH from various crystallization techniques, namely slow cooling, rapid evaporation, sublimation, as well as from hot-stage experiments. All of the polymorphs display hydrogen bonding through the carbonyl acceptor and hydrazide donor. However the torsion of these hydrogen bond acceptors and donors, relative to the molecular backbone, deviate due to the conformational flexibility of the molecule. Structural information of the polymorphs was obtained by SCXRD, PXRD, IR and Raman. The thermal phase relationships of these polymorphs were also investigated using DSC and HSM. Elucidating these novel polymorphs and establishing phase relationships are a key step in the design of isoniazid based pharmaceuticals.

Covalent Assistance to Supramolecular Synthesis

The similarity of crystal engineering to organic synthesis has been noted by Desiraju and many concepts and strategies have been successfully transferred. We aim to combine the two fields of research into one new concept called "Covalent Assistance to Supramolecular Synthesis". The supramolecular reagent isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes (Lemmerer at al., 2010). Due to the covalent reaction of the carbohydrazide functional group with simple ketones and aldehydes, the hydrogen bonding functionality of isoniazid can be modified, where two of the hydrogen bond donors are replaced with hydrogen bonding "inert" hydrocarbons (Lemmerer et al., 2011). The "modifiers" bonded to the isoniazid then give a measure of control of the outcome of the supramolecular synthesis with various carboxylic acids depending on the identity and steric size of the modifier used. The steric size itself can be used to shield or to "mask" the remaining hydrogen bonding functionality of isoniazid such that common homomeric and heteromeric interactions are prevented from taking place.

Uncovering Charge Transfer Interactions of Energetic Molecules

Energetic materials are systems that store a large amount of chemical energy, which can be converted into mechanical energy though molecular decomposition, e.g. explosives, propellants and fuels. Co-crystallization of energetic materials with desirable co-crystal formers provides a novel way of tailoring existing energetic materials without structural manipulation. Examples include trinitrotoluene (TNT) with electron rich aromatics along with other energetic materials (CL-20, DADP) [1-3]. In order to take advantage of this methodology it is necessary to develop an understanding of the synthons involved in non-covalent interactions. The interpretation of non-covalent interactions has been highlighted in many recent publications, notably the publications by Gilli et al. which classifies short contacts as interactions, where the distance between atoms is less than the sum of their van der Waals radii. Depending on the type of interactions, the complexes can be divided into different categories, the most well known and studied are: H-bond theory and charge transfer (CT). In this study, a systematic series of crystal structures of organic CT complexes were determined to allow for the identification of structural packing trends, variations in aromaticity, decomposition temperatures and enthalpies along with non-covalent interactions, focusing mainly on the π···π interactions. The complexes investigated were of the electron donor acceptor type, with polycyclic hydrocarbons acting as the donor (D) molecules, whilst 1,3,5-trinitrobenzene was selected as the energetic acceptor (A) molecule, due to its similarity with TNT. The CT complexes were observed to exhibit strong colours in the yellow to red regions of visible light with the co-crystals forming alternating DA stacks.