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

Abstract

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 uC, 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.

Synthesis, Structure, and Magnetic Properties of New Spin Crossover Fe(II) Complexes Forming Short Hydrogen Bonds with Substituted Dicarboxylic Acids

“…Overall, 1-Cl and 1-Br form a two-dimensional network structure; one-dimensional hydrogen bond chains interact through π-π interactions, forming a two-dimensional structure. between the Py ring in isonicotinic acid hydrazide, a precursor of L, and the carboxyl group tends to increase with increasing temperature [16][17][18]. The increment of N4•••O3 and N8•••O5 bond distances from 123 K to 320 K was observed in 1-Cl and 1-Br.…”

“…The N4···O3 hydrogen bond distance in the terminal pyridine ring was relatively long (N4···O3 = 2.663 Å), whereas the N8···O5 hydrogen bond distance was relatively short (N8···O5 = 2.552 Å) at 123 K. The N4···O3 and N8···O5 hydrogen bond distances in 1-Br were slightly longer (N4···O3 = 2.681 Å, N8···O5 = 2.560 Å) than those in 1-Cl at 123 K. The N8···O5 bond distances in 1-Cl and 1-Br were short for a N···O-type hydrogen bond but slightly longer than those commonly observed in organic compounds that exhibit proton migration induced by temperature change [13][14][15]. Regarding the temperature dependency of hydrogen bond distances, studies have reported that the hydrogen bond distance between the Py ring in isonicotinic acid hydrazide, a precursor of L, and the carboxyl group tends to increase with increasing temperature [16][17][18]. The increment of N4···O3 and N8···O5 bond distances from 123 K to 320 K was observed in 1-Cl and 1-Br.…”

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

“…Aitipamula et al studied the polymorphic behavior of isoniazid: 4 hydroxybenzoic acid cocrystal monohydrate [124]. They observed that anhydrous isoniazid: hydroxybenzoic acid cocrystal and Form I of isoniazid: hydroxybenzoic acid cocrystal hydrate were converted to Form II of the isoniazid: hydroxybenzoic acid hydrate when held for an accelerated stability study at 40°C and 75% RH [124].…”

“…They observed that anhydrous isoniazid: hydroxybenzoic acid cocrystal and Form I of isoniazid: hydroxybenzoic acid cocrystal hydrate were converted to Form II of the isoniazid: hydroxybenzoic acid hydrate when held for an accelerated stability study at 40°C and 75% RH [124]. Jones et al carried out polymorph screening of the caffeine: anthranilic acid cocrystal (1:1).…”

Synthesis, crystal structure and Hirshfeld surface analysis of tetraaquabis(isonicotinamide-κN 1)cobalt(II) fumarate

“…A search of the Cambridge Structural Database for fumaric acid and isonicotinamide revealed the presence of seven structures: isonicotinohyrazide nicotinamide fumaric acid (Aitipamula et al, 2013), catena-poly [[aquabis[N-(pyridin-3-yl) et al, 2013) and catena-[bis(-but-2-enedioato)bis(-pyridine-4-carbohydrazide)dizinc(II)] (Naskar et al, 2017). In these compounds, the C-HÁ Á ÁO hydrogen bonds have HÁ Á ÁO distances ranging from 2.56 to 3.59 Å and CÁ Á ÁO distances ranging from 3.27 to 3.96 Å .…”