Reaction of isoniazid with benzoic acid, sebacic acid,
suberic
acid, and cinnamic acid results in formation of cocrystals. Two polymorphs
of isoniazid–suberic acid and two polymorphs of isoniazid–cinnamic
acid cocrystals were isolated. Crystal structure analysis shows the
presence of a pyridine–carboxylic acid synthon in the studied
cocrystals. The hydrazide group of isoniazid participates in N–H···O
and N–H···N hydrogen bond formation, producing
different supramolecular synthons. The stability study of isoniazid
cocrystals has been performed over a 22 week period. A comparison
of melting points of isoniazid–dicarboxylic acid 2:1 cocrystals
shows the decrease of melting point with an increasing length of the
acid. Solubility of isoniazid–carboxylic acid cocrystals tends
to increase with increasing solubility of the acid.
Solid-state cocrystallization is of contemporary interest because it offers an easy and efficient way to produce cocrystals, which are recognized as prospective pharmaceutical materials. Research explaining solid-state cocrystallization mechanisms is important but still too scarce to give a broad understanding of factors governing and limiting these reactions. Here we report an investigation of the mechanism and kinetics of isoniazid cocrystallization with benzoic acid. This reaction is spontaneous; however, its rate is greatly influenced by environmental conditions (humidity and temperature) and pretreatment (milling) of the sample. The acceleration of cocrystallization in the presence of moisture is demonstrated by kinetic studies at elevated humidity. The rate dependence on humidity stems from moisture facilitated rearrangements on the surface of isoniazid crystallites, which lead to cocrystallization in the presence of benzoic acid vapor. Furthermore, premilling the mixture of the cocrystal ingredients eliminated the induction time of the reaction and considerably increased its rate.
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