The Role of π-Stacking in the Composition of Phloroglucinol and Phenazine Cocrystals

Cocrystallization of phloroglucinol (PHG) and phenazine (Phen) afforded cocrystals of 1:1.5, 1:1.75, and 1:2 PHG·Phen stoichiometry upon grinding the two components in different starting ratios and then using suitable solvents for single crystal growth. The phenol···pyridine O−H···N synthon directs 1:1.5 bimolecular organization of PHG and Phen molecules in a π-stacked motif (cocrystal 1). Additional phenazine molecules insert in the π-stacks to give a higher proportion of the aromatic species in cocrystals 2 and 3 (1:1.75 and 1:2). A hydrate cocrystal of 1:2:1 composition (4) was also obtained. The π-stack dimer motif of phenazine templated by the 1,3-(OH)2 moiety of phloroglucinol at about van der Waals distance in these crystal structures is postulated to promote the crystallization of the β-phenazine polymorph having a sandwich herringbone motif. These results suggest a role for cocrystal formers as hydrogen bond additives that favor and stabilize specific motifs for the crystallization of new polymorphs

The Role of π-Stacking in the Composition of Phloroglucinol and Phenazine Cocrystals

Cocrystallization of phloroglucinol (PHG) and phenazine (Phen) afforded cocrystals of 1:1.5, 1:1.75, and 1:2 PHG·Phen stoichiometry upon grinding the two components in different starting ratios and then using suitable solvents for single crystal growth. The phenol···pyridine O−H···N synthon directs 1:1.5 bimolecular organization of PHG and Phen molecules in a π-stacked motif (cocrystal 1). Additional phenazine molecules insert in the π-stacks to give a higher proportion of the aromatic species in cocrystals 2 and 3 (1:1.75 and 1:2). A hydrate cocrystal of 1:2:1 composition (4) was also obtained. The π-stack dimer motif of phenazine templated by the 1,3-(OH)2 moiety of phloroglucinol at about van der Waals distance in these crystal structures is postulated to promote the crystallization of the β-phenazine polymorph having a sandwich herringbone motif. These results suggest a role for cocrystal formers as hydrogen bond additives that favor and stabilize specific motifs for the crystallization of new polymorphs

The Role of π-Stacking in the Composition of Phloroglucinol and Phenazine Cocrystals

Cocrystallization of phloroglucinol (PHG) and phenazine (Phen) afforded cocrystals of 1:1.5, 1:1.75, and 1:2 PHG·Phen stoichiometry upon grinding the two components in different starting ratios and then using suitable solvents for single crystal growth. The phenol···pyridine O−H···N synthon directs 1:1.5 bimolecular organization of PHG and Phen molecules in a π-stacked motif (cocrystal 1). Additional phenazine molecules insert in the π-stacks to give a higher proportion of the aromatic species in cocrystals 2 and 3 (1:1.75 and 1:2). A hydrate cocrystal of 1:2:1 composition (4) was also obtained. The π-stack dimer motif of phenazine templated by the 1,3-(OH)2 moiety of phloroglucinol at about van der Waals distance in these crystal structures is postulated to promote the crystallization of the β-phenazine polymorph having a sandwich herringbone motif. These results suggest a role for cocrystal formers as hydrogen bond additives that favor and stabilize specific motifs for the crystallization of new polymorphs

Phenyl-Perfluorophenyl Synthon Mediated Cocrystallization of Carboxylic Acids and Amides

The significance of face-to-face π−π stacking of phenyl and perfluorophenyl rings (Ph-PhF), a robust supramolecular synthon in aromatic and perfluoroaromatic crystal structures, is studied in the cocrystallization of simple aromatic carboxylic acids and amides. X-ray crystal structures of C6H5COOH·C6F5COOH 1, C6H5CONH2·C6F5CONH2 2, and C6H5CONH2·C6F5COOH 3 are analyzed to understand the role of Ph-PhF synthon in directing self-assembly and hydrogen bonding in these cocrystals. The strong hydrogen bond donor acidity of C6F5COOH and C6F5CONH2 together with mixed stacks of phenyl and perfluorophenyl rings steer acid···acid and amide···amide hydrogen bonding in cocrystals 1 and 2. Acid···amide hydrogen bonding is sufficiently strengthened by donor acidity and acceptor basicity in 3 that the role of the Ph-PhF synthon is weaker because the aromatic rings stack with lateral offset. The complex C6H5COOH·C6F5CONH2 4 could not be obtained under similar crystallization conditions. The crystal structure of C6F5CONH2 is determined to compare molecular conformation and hydrogen bonding with motifs in the cocrystals. This study shows the viability of the Ph-PhF synthon in the presence of strong hydrogen bonding COOH and CONH2 groups for crystal engineering

Amide−<i>N</i>-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine <i>N</i>-Oxides

The carboxamide−pyridine N-oxide heterosynthon is sustained by syn(amide)N−H···O-(oxide) hydrogen bond and auxiliary (N-oxide)C−H···O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide−N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide−N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine·quinoxaline N,N‘-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N−H···O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius2, COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 °C up to four weeks. Amide−N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H2O functional groups. Keywords: Homosynthon; heterosynthon; carboxamide; pyridine N-oxide; pharmaceutical; cocrysta

Amide−<i>N</i>-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine <i>N</i>-Oxides

The carboxamide−pyridine N-oxide heterosynthon is sustained by syn(amide)N−H···O-(oxide) hydrogen bond and auxiliary (N-oxide)C−H···O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide−N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide−N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine·quinoxaline N,N‘-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N−H···O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius2, COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 °C up to four weeks. Amide−N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H2O functional groups. Keywords: Homosynthon; heterosynthon; carboxamide; pyridine N-oxide; pharmaceutical; cocrysta

Amide−<i>N</i>-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine <i>N</i>-Oxides

The carboxamide−pyridine N-oxide heterosynthon is sustained by syn(amide)N−H···O-(oxide) hydrogen bond and auxiliary (N-oxide)C−H···O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide−N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide−N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine·quinoxaline N,N‘-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N−H···O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius2, COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 °C up to four weeks. Amide−N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H2O functional groups. Keywords: Homosynthon; heterosynthon; carboxamide; pyridine N-oxide; pharmaceutical; cocrysta

Amide−<i>N</i>-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine <i>N</i>-Oxides

The carboxamide−pyridine N-oxide heterosynthon is sustained by syn(amide)N−H···O-(oxide) hydrogen bond and auxiliary (N-oxide)C−H···O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide−N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide−N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine·quinoxaline N,N‘-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N−H···O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius2, COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 °C up to four weeks. Amide−N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H2O functional groups. Keywords: Homosynthon; heterosynthon; carboxamide; pyridine N-oxide; pharmaceutical; cocrysta

Amide−<i>N</i>-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine <i>N</i>-Oxides

The carboxamide−pyridine N-oxide heterosynthon is sustained by syn(amide)N−H···O-(oxide) hydrogen bond and auxiliary (N-oxide)C−H···O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide−N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide−N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine·quinoxaline N,N‘-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N−H···O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius2, COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 °C up to four weeks. Amide−N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H2O functional groups. Keywords: Homosynthon; heterosynthon; carboxamide; pyridine N-oxide; pharmaceutical; cocrysta

Amide−<i>N</i>-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine <i>N</i>-Oxides

The carboxamide−pyridine N-oxide heterosynthon is sustained by syn(amide)N−H···O-(oxide) hydrogen bond and auxiliary (N-oxide)C−H···O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide−N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide−N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine·quinoxaline N,N‘-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N−H···O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius2, COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 °C up to four weeks. Amide−N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H2O functional groups. Keywords: Homosynthon; heterosynthon; carboxamide; pyridine N-oxide; pharmaceutical; cocrysta