The current phase of drug development is witnessing an oncoming crisis due to the combined effects of increasing R&D costs, decreasing number of new drug molecules being launched, several blockbuster drugs falling off the patent cliff, and a high proportion of advanced drug candidates exhibiting poor aqueous solubility. The traditional approach of salt formulation to improve drug solubility is unsuccessful with molecules that lack ionizable functional groups, have sensitive moieties that are prone to decomposition/racemization, and/or are not sufficiently acidic/basic to enable salt formation. Several novel examples of pharmaceutical cocrystals from the past decade are reviewed, and the enhanced solubility profiles of cocrystals are analyzed. The peak dissolution for pharmaceutical cocrystals occurs in a short time (<30 min), and high solubility is maintained over a sufficiently long period (4–6 h) for the best cases. The enhanced solubility of drug cocrystals is similar to the supersaturation phenomenon characteristic of amorphous drugs. However, in contrast to the metastable nature of amorphous phases, cocrystals are stable owing to their crystalline nature. Yet, cocrystals can exhibit dramatic solubility advantage over the stable crystalline drug form, often comparable to amorphous pharmaceuticals. The “spring and parachute” concept for amorphous drug dissolution is adapted to explain the solubility advantage of pharmaceutical cocrystals. Thus (1) the cocrystal dissociates to amorphous or nanocrystalline drug clusters (the spring), which (2) transform via fast dissolving metastable polymorphs to the insoluble crystalline modification following the Ostwald’s Law of Stages, to give (3) high apparent solubility for cocrystals and optimal drug concentration (the parachute) in the aqueous medium.

Two polymorphs of the well-known diuretic drug Lasix, generic name furosemide, are characterized by single crystal X-ray diffraction to give a trimorphic cluster of polymorphs: known form 1 in P1 space group, and novel forms 2 and 3 in P2 1 /n and P1 space groups. The conformationally flexible molecule 4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid has variable torsions at the sulfonamide and furyl ring portions in conformers which lie in a 6 kcal mol -1 energy window. A conformer surface map was calculated to show that the two conformations in crystal form 1 are ∼4.5 kcal mol -1 less stable than conformers present in forms 2 and 3 (0.7, 0.0 kcal mol -1 ). The stabilization of molecular conformations is analyzed in terms of attractive intramolecular N-H 3 3 3 Cl hydrogen bonds and minimization of repulsive SdO 3 3 3 Cl interactions. Phase stability relationships confirm the thermodynamic nature of form 1 in grinding and slurry experiments by X-ray powder diffraction and infrared spectroscopy. Despite the large difference in molecular conformer energies, crystal lattice energies of polymorphs 1-3 are very close (-41.65, -41.78, -41.53 kcal mol -1 ). These results show that the thermodynamic stability of polymorph 1 of furosemide concluded in crystallization experiments is not possible to predict through computations. Moreover, the presence of metastable conformers in the stable crystal structure reemphasizes that there is no substitute for experimental validation in polymorphic systems. The greater stability of polymorph 1 is ascribed to its more efficient crystal packing, higher density, and the presence of R 4 2 (8) sulfonamide N-H 3 3 3 O dimer synthon. Because of the differences in torsion angles and hydrogen bonding in polymorphs 1-3, they are more appropriately classified as conformational and synthon polymorphs.

The antitumor prodrug temozolomide (TMZ) decomposes in aqueous medium of pH≥7 but is relatively stable under acidic conditions. Pure TMZ is obtained as a white powder but turns pink and then brown, which is indicative of chemical degradation. Pharmaceutical cocrystals of TMZ were engineered with safe coformers such as oxalic acid, succinic acid, salicylic acid, d,l-malic acid, and d,l-tartaric acid, to stabilize the drug as a cocrystal. All cocrystals were characterized by powder X-ray diffraction (PXRD), single crystal X-ray diffraction, and FT-IR as well as FT-Raman spectroscopy. Temozolomide cocrystals with organic acids (pK(a) 2-6) were found to be more stable than the reference drug under physiological conditions. The half-life (T(1/2)) of TMZ-oxalic and TMZ-salicylic acid measured by UV/Vis spectroscopy in pH 7 buffer is two times longer than that of TMZ (3.5 h and 3.6 h vs. 1.7 h); TMZ-succinic acid, TMZ-tartaric acid, and TMZ-malic acid also exhibited a longer half-life (2.3, 2.5, and 2.8 h, respectively). Stability studies at 40 °C and 75 % relative humidity (ICH conditions) showed that hydrolytic degradation of temozolomide in the solid state started after one week, as determined by PXRD, whereas its cocrystals with succinic acid and oxalic acid were intact at 28 weeks, thus confirming the greater stability of cocrystals compared to the reference drug. The intrinsic dissolution rate (IDR) profile of TMZ-oxalic acid and TMZ-succinic acid cocrystals in buffer of pH 7 is comparable to that of temozolomide. Among the temozolomide cocrystals examined, those with succinic acid and oxalic acid exhibited both an improved stability and a comparable dissolution rate to the reference drug.

The novel carboxamide-pyridine N-oxide synthon, sustained via N-H...O- hydrogen bonding and C-H...O interaction, is shown to assemble isonicotinamide N-oxide in a triple helix architecture and the same heterosynthon is exploited to synthesize cocrystals of barbiturate drugs with 4,4'-bipyridine N,N'-dioxide.

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Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4'-bipyridine-N,N'-dioxide (BPNO), and solid-state stability were studied. Apart from a known X-ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3-hydroxypyridine-N-oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N--HN(imidazole) and N--HN(tetrazine) interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZBPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen-bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N-H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C==O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen-bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen-bond reorganization.

Very short OsH‚‚‚O hydrogen bonds (O‚‚‚O ) 2.2-2.5 Å) usually occur when the H-bond is stabilized by a negative or positive charge (OsH‚‚‚O -, O + sH‚‚‚O) or by resonance assistance (‚‚‚OdCsCdCsOsH‚‚‚). We have characterized a very short intermolecular O acid sH‚‚‚O water hydrogen bond in the title crystal structure, 1, by variable temperature neutron diffraction (O‚‚‚O ) 2.4751(11), 2.4765(10), 2.4807(12), and 2.4906(16) Å at 20, 100, 200, and 293 K). The COOH donor is activated by π-cooperative hydrogen bonding (O acid sH‚‚‚OdC acid ), and the water-acceptor ability is enhanced by polarization assistance (σ-cooperative, O w sH‚‚‚O acid , O w sH‚‚‚N pyrazine ). The absence of proton migration in the temperature range 20-293 K to give ionic or tautomer forms rules out contribution from the charge-or resonance-assisted H-bonds in 1. The shortening of the O acid sH‚‚‚O w hydrogen bond through synergistic π-and σ-cooperativity in the finite, neutral array I, named as a synthon-assisted hydrogen bond (SAHB), adds a new category to the current classification of very short hydrogen bonds in three main types: negative charge-assisted H-bonds ((-)CAHBs), positive charge-assisted H-bonds ((+)CAHBs), and resonance-assisted H-bonds (RAHBs). The very short hydrogen bond in the X-ray crystal structure of 2,3,5-pyrazinetricarboxylic acid dihydrate, 5 (O‚‚‚O ) 2.4726(12) Å at 120 K), and the short hydrogen bonds in pyrazine dicarboxylic acids 2-4 (2.5513(11), 2.5269(12), and 2.5148(13) Å) validate the novel SAHB model. A comparison of the short O acid sH‚‚‚O w hydrogen bond with short O w sH‚‚‚O acid distances in carboxylic acids with similar motifs, for example, 1 and 5 and 2 and 4, shows that the activation of water oxygen by polarization assistance makes a significant contribution to the SAHB. The behavior of the short O acid sH‚‚‚O w bond in 1 is similar to short-strong CAHB/RAHB systems:(1) quasi-covalent character of 0.27-0.30 valence units, (2) red shift in the OsH stretching frequency to 1200-1400 cm -1 , and (3) hydrogen-bond energy of ∼16 kcal mol -1 . Some examples retrieved from the Cambridge Structural Database together with crystal structures from this study provide 21 cases of short O acid sH‚‚‚O w hydrogen bonds in multicenter synthons.

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 (Cerius(2), 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 degrees 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, H(2)O functional groups.