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; cocrystal酰胺-吡啶N-氧化物异超分子合成子（carboxamide−pyridine N-oxide heterosynthon）由顺式（酰胺）N−H···O-(氧化物)氢键以及辅助性（N-氧化物）C−H···O(酰胺)相互作用所稳定（Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369）。本研究评估了该异超分子合成子在含酰胺分子与含吡啶N-氧化物共晶形成分子（cocrystal former molecules, CCFs）的活性药物成分（active pharmaceutical ingredients, APIs）中的适用范围与应用价值。本研究中的10种共晶以及此前工作中的7种复合物中，12种结构存在酰胺-N-氧化物异超分子合成子，另有5种结构出现酰胺二聚同超分子合成子（homosynthon）。当存在其他氢键官能团竞争时（例如4-羟基苯甲酰胺），或是因空间位阻因素（如卡马西平API），共晶中酰胺二聚体相较于酰胺-N-氧化物合成子更易形成。卡马西平·喹喔啉N,N'-二氧化物1:1共晶的分子排布由酰胺同二聚体以及反式（酰胺）N−H···O-(氧化物)氢键主导。其X射线晶体结构与多晶型预测器（Polymorph Predictor，Cerius2，COMPASS力场）计算得到的第三低能构象一致。除了构建新颖多样的超分子结构外，该合成子还可调控一种物质的水合行为：4-甲基吡啶N-氧化物可在一天内潮解，但其与巴比妥形成的共晶在50%相对湿度、30℃条件下放置四周仍不会吸收水分。酰胺-N-氧化物异超分子合成子在带有互补性共晶形成分子的酰胺类与N-氧化物类药物分子中均具有潜在应用价值。在剑桥结构数据库（Cambridge Structural Database）的27种无竞争性受体的结构中，其出现概率为87%；在包含OH、NH、H₂O官能团的41种结构中，该合成子的出现概率为78%。关键词：同超分子合成子；异超分子合成子；甲酰胺；吡啶N-氧化物；药物制剂；共晶