Crystal and co-crystal Engineering of Isoniazid, 4-Aminoantipyrine, benzophenone and their derivatives
Date
2018
Authors
Smith, Mark Gordon
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Abstract
Isoniazid is the primary drug used for the treatment of tuberculosis. Covalent modifications to the amine group of isoniazid are currently under investigation and such modifications have been shown to render the drug effective against multiple-drug-resistant strains of Mycobacterium tuberculosis.
In this thesis, crystal and co-crystal engineering was applied to synthesize crystals and co-crystals of covalently modified isoniazid. Isoniazid was modified by bulky modifiers, namely benzophenone and benzophenone derivatives, and crystallized in the absence and presence of co-formers. A series of co-crystals of modified isoniazid was prepared and their supramolecular structures were studied. All co-crystals were synthesized with salicylic acid and control over the dimensionality of packing was achieved. It was found that the benzophenone modifiers sterically masked the amide functional groups from participating in any intermolecular interactions. This steric masking is predictable and consistent and provides a general method whereby an amide functional group can be sterically blocked from intermolecular interactions.
The effects of reaction and crystallization conditions on the supramolecular structure of isoniazid are also reported. Several pairs of co-crystals of modified isoniazid were synthesized under different crystallization conditions. Change in reflux time of the reagents resulted in stoichiometric variation in the resulting co-crystals. The addition of excess reagents as an additive resulted in polymorphism. Addition or absence of an acid catalyst either promoted or prevented solvate formation. The addition of either one or two methyl groups to the benzophenone aromatic rings did not substantially alter the packing patterns of the crystal structures.
As the presence of co-formers may either enhance or inhibit the bioavailability of pharmaceutical drugs, the covalent modification of isoniazid was repeated in the absence of co-formers. The covalent modification without co-formers presented several synthetic difficulties and use of new catalysts and the development of new synthetic strategies such as refluxing in high-pressure glass vials were developed. A full structural study on the covalently modified isoniazid crystals is reported.
Side reactions of benzophenone were observed during the crystallization of isoniazid derivatives. These resulted in the formation of benzophenone azine crystals. The origin and mechanism of the formation of these benzophenone azine crystals were determined to occur via a two-step photodimerization process. The benzophenone azine crystals were found to be held together through weak interactions and a structural study of the packing of these crystals was reported.
4-Aminoantipyrine is a pharmaceutical drug previously used as an antipyretic and is considered a prophylactic against oxidative stress. Two of its derivatives, aminoantipyrine and 4-(N,N-dimethyl)-aminoantipyrine, have been used as analgesic and anti-inflammatory drugs since the late 19th century. Their concurrent use with aspirin is particularly beneficial as they have been shown to prevent or attenuate the anti-platelet effects of aspirin. However, their use has been discontinued due to side effects and this discontinuation warrants further studies of methods to possibly increase the bioavailability and alter the physical properties of the drug, including via covalent modification and co-crystallization. To date, all reported attempts at co-crystallizing this drug have failed.
In this study, co-crystal design strategies were developed to synthesize the first co-crystal of 4-aminoantipyrine, and the methods leading up to the successful supramolecular synthesis of 4-aminoantipyrine with co-formers are detailed. The synthesis of two novel salts of 4-aminoantipyrine and two co-crystals of covalently modified 4-aminoantipyrine are also reported. A series of crystals of covalently modified 4-aminoantipyrine were also synthesized and a full structural study of these crystals is presented.
Description
Submitted in accordance with the requirements for the degree of
Doctor of Philosophy
In the subject
Chemistry
At the
University of the Witwatersrand
May 2018
Keywords
Citation
Smith, Mark Gordon (2018) 0 Crystal and Co-crystal engineering of Isoniazid, 4-Aminoantipyrine, benzophenone and their derivatives, University of the Witwatersrand, Johannesburg, <http://hdl.handle.net/10539/25746>