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.
A detailed thermochemical
and structural study of the phenylpiracetam
enantiomer system was performed by characterizing the solid solutions,
rationalizing the structural driving force for their formation, as
well as identifying a common structural origin responsible for the
formation of solid solutions of enantiomers. Enantiomerically pure
phenylpiracetam forms two enantiotropically related polymorphs (enant–A and enant–B). The
transition point (70(7) °C) was determined based on isobaric
heat capacity measurements. Structural studies revealed that enant–A and enant–B crystallize
in space groups P1 (Z′ =
4) and P212121 (Z′ = 2), respectively. However, pseudoinversion centers
were present resulting in apparent centrosymmetric structures. The
quasi centrosymmetry was achieved by a large variety of phenylpiracetam
conformations in the solid state (six in total). As a result, miscibility
of the phenylpiracetam enantiomers in the solid state is present for
scalemic and racemic samples, which was confirmed by the melt phase
diagram. Racemic phenylpiracetam (rac–A) was
determined to crystallize in the P1̅ space
group being isostructural to enant–A; furthermore,
disorder is present showing that enantiomers are distributed in a
random manner. The lack of enantioselectivity in the solid state is
explained. Furthermore, structural aspects of phenylpiracetam solid
solutions are discussed in the scope of other cases reported in the
literature.
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