109016-71-9

Upstream product

• 54-85-3 isoniazid 
• 99-96-7 4-hydroxy-benzoic acid 

Relevant academic research and scientific papers

Single-Crystal Plasticity Defies Bulk-Phase Mechanics in Isoniazid Cocrystals with Analogous Coformers

The crystal structures of four INZ cocrystals with analogous crystal coformers were probed to understand the relationships among molecular packing, H-bonding dimensionality, single-crystal plasticity, and bulk mechanical behavior. These structurally analogous coformers coherently directed H-bonds by "philic" functionalities (-OH and -COOH) and vdW interactions by a "phobic" scaffold (- C6H5-n, where n = 0, 1, 3). In comparison to INZ:2HBA and INZ:4HBA, INZ:BA and INZ:GA exhibited higher plasticity and, hence, better tableting performance due to larger bonding area and higher tensile strength. The rank order of apparent yield pressure and incipient plasticity quantified from "in-die" Heckel analysis of the bulk phase, INZ:2HBA > INZ:4HBA > INZ:GA > INZ:BA, however, does not match that of nanomechanical hardness and elastic modulus, INZ:BA > INZ:2HBA > INZ:4HBA > INZ:GA. The discrepancy may be attributed to the anisotropy in crystal mechanical properties, where the stiffness of the dominant crystal faces probed with nanoindentation may grossly deviate from the bulk mechanical behavior. Therefore, nanomechanical attributes are more predictive of more isotropic molecular crystals, such as 3D H-bonded or interlocked structures, in comparison to those exhibiting gross structural anisotropy, such as crystals with distinct molecular layers that favor facile slip. Hence, the accurate prediction of bulk behavior on the basis of nanomechanical characterization requires the incorporation of crystal shape and packing as well as knowledge of facet-specific mechanical properties. Moreover, the prediction of bonding strength on the basis of molecular packing is still warranted when the crystallographic molecular slip may cause a deviation in the proposed relationship.

Novel solid forms of the anti-tuberculosis drug, Isoniazid: Ternary and polymorphic cocrystals

Novel cocrystals of an anti-tuberculosis drug, Isoniazid (INH), with pharmaceutically acceptable coformers such as nicotinamide (NA), 4-hydroxybenzoic acid (HBA), fumaric acid (FA), and succinic acid (SA) are reported. Cocrystallization experiments involving INH and HBA produced two polymorphs of a novel hydrate of the INH·HBA cocrystal. Similarly, cocrystallization of INH and FA produced a novel polymorph of the reported INH·FA cocrystal. We have successfully explored the idea of designing ternary cocrystals involving INH with NA and FA or SA. All the novel solids were thoroughly characterized and their crystal structures determined. All the crystal structures feature an acid-pyridine heterosynthon involving INH and the carboxylic acid. Stability of the novel cocrystals was evaluated by slurry experiments and dynamic vapor sorption studies. In addition, stability of the cocrystals at accelerated test conditions (40°C, 75% RH) was also tested. Anhydrous INH·HBA cocrystal and Form I of INH·HBA cocrystal hydrate were found to convert to Form II of the INH·HBA hydrate, and Form II of INH·FA cocrystal converted to Form I of the INH·FA cocrystal. Ternary cocrystals remain stable at all test conditions. Solubility and dissolution experiments revealed a greater solubility of the INH·NA·SA cocrystal and its dissolution rate is comparable to the dissolution rate of the native INH. All other cocrystals showed lower solubility and dissolution rate compared to INH.