ABSTRACT
Environmental impacts of the industrial revolution necessitate adoption of sustainable practices in all areas of development. The pharmaceutical industry faces increasing pressure to minimize its ecological footprint due to its significant contribution to environmental pollution. Over the past two decades, pharmaceutical cocrystals have received immense popularity due to their ability to optimize the critical attributes of active pharmaceutical ingredients and presented an avenue to bring improved drug products to the market. This review explores the potential of pharmaceutical cocrystals as an ecofriendly alternative to traditional solid forms, offering a sustainable approach to drug development. From reducing the number of required doses to improving the stability of actives, from eliminating synthetic operations to using pharmaceutically approved chemicals, from the use of continuous and solvent-free manufacturing methods to leveraging published data on the safety and toxicology, the cocrystallization approach contributes to sustainability of drug development. The latest trends suggest a promising role of pharmaceutical cocrystals in bringing novel and improved medicines to the market, which has been further fuelled by the recent guidance from the major regulatory agencies.
Subject(s)
Crystallization , Drug Development , Drug Development/methods , Pharmaceutical Preparations/chemistry , Drug Industry/methods , Humans , Chemistry, Pharmaceutical/methodsABSTRACT
OBJECTIVE: This research investigates how particle parameters, such as zeta potential, size, functional group, material composition, and hydrophobicity affect their affinity and deposition of particles onto hair. METHODS: Streaming potential was used as the technique for analysis. The streaming potential data obtained was then converted to surface coverage data. Scanning electron microscopy (SEM) was also done to visualize particle localization on the hair surface. RESULTS: This study found stronger particle affinity on healthy than on damaged (oxidatively bleached) hair, due to diminished interaction sites from the removal of the hair shaft's external lipid layer. SEM imaging supported these findings and offered insights into particle localization. Hydrophilic silica particles accumulated along the exposed hydrophilic cuticle edges of healthy hair, due to hydrogen bonding with the exposed endocuticle. This localization is hypothesized to be due to the limited hydrophilic binding sites on the hydrophobic healthy hair cuticle surface. In damaged hair, an abundance of hydrophilic sites across the cuticle surface results in more dispersed binding. Hydrogen bonding and electrostatic attraction were shown to be the predominant forces influencing deposition, with hydrophobic interactions playing a less influential role. The affinity studies also proved that electrostatic attractions work over a longer range and are more effective at lower particle conditions compared with hydrogen bonding which only start to play a bigger role at higher particle concentrations. Steric hindrance of bulky side groups acted as a significant repulsive force. Results also revealed that larger particles deposit poorly on both healthy and damaged hair compared with smaller ones. Compared with neutrally charged silica nanoparticles (SN-2), positively charged PMMA particles (PN+16) have a stronger affinity to healthy hair, with highly charged particles (PN+49) depositing most rapidly. CONCLUSION: This study provides a fundamental understanding of how particle-surface parameters influence their affinity to hair and how damaging hair affects deposition.
OBJECTIF: Cette étude examine comment les paramètres des particules, tels que le potentiel zêta, la taille, le groupe fonctionnel, la composition du matériau et l'hydrophobie, affectent l'affinité et le dépôt des particules sur les cheveux. MÉTHODES: Le potentiel d'écoulement a été utilisé comme technique d'analyse. Les données de potentiel d'écoulement obtenues ont ensuite été converties en données de couverture de surface. Une microscopie électronique à balayage (MEB) a également été réalisée pour visualiser la localisation des particules à la surface des cheveux. RÉSULTATS: Cette étude a mis en évidence une affinité plus forte des particules sur des cheveux sains que sur des cheveux abîmés (décolorés par oxydation), en raison de la diminution des sites d'interaction due à l'élimination de la couche lipidique externe de la tige du cheveu. L'imagerie MEB a confirmé ces résultats et a permis d'obtenir des informations sur la localisation des particules. Des particules de silice hydrophile se sont accumulées en bordure des cuticules hydrophiles exposées des cheveux sains, en raison de la liaison de l'hydrogène avec l'endocuticule exposée. Il est supposé que cette localisation est due au nombre réduit de sites de liaison hydrophiles à la surface hydrophobe saine de la cuticule capillaire. Sur des cheveux abîmés, l'abondance de sites hydrophiles sur la surface des cuticules entraîne une liaison plus dispersée. La liaison de l'hydrogène et l'attraction électrostatique se sont avérées être les forces prédominantes qui influencent le dépôt, les interactions hydrophobes jouant un rôle moins influent. Les études d'affinité ont également démontré que les attractions électrostatiques fonctionnent sur une plus longue plage et sont plus efficaces dans des conditions de concentration de particules inférieures par rapport à la liaison de l'hydrogène qui ne commence à jouer un rôle plus important qu'à des concentrations de particules plus élevées. L'entrave stérique des groupes latéraux volumineux a agi comme une force répulsive significative. Les résultats ont également révélé que les particules plus grosses se déposent faiblement sur des cheveux sains et des cheveux abîmés par rapport aux particules plus petites. Par rapport aux nanoparticules de silice à charge neutre (SN2), les particules de PMMA à charge positive (PN+16) ont une affinité plus forte avec les cheveux sains, les particules fortement chargées (PN+49) se déposant le plus rapidement. CONCLUSION: Cette étude apporte une compréhension fondamentale de la façon dont les paramètres de la surface et des particules influencent leur affinité avec les cheveux et dans quelle mesure les cheveux abîmés affectent les dépôts.
ABSTRACT
Secondary phosphines are important building blocks in organic chemistry as their reactive P-H bond enables construction of more elaborate molecules. In particular, they can be used to construct tertiary phosphines that have widespread applications as organocatalysts, and as ligands in metal-complex catalysis. We report here a practical synthesis of the bulky secondary phosphine synthon 2,2,6,6-tetramethylphosphinane (TMPhos). Its nitrogen analogue tetramethylpiperidine, known for over a century, is used as a base in organic chemistry. We obtained TMPhos on a multigram scale from an inexpensive air-stable precursor, ammonium hypophosphite. TMPhos is also a close structural relative of di-tert-butylphosphine, a key component of many important catalysts. Herein we also describe the synthesis of key derivatives of TMPhos, with potential applications ranging from CO2 conversion to cross-coupling and beyond. The availability of a new core phosphine building block opens up a diverse array of opportunities in catalysis.
ABSTRACT
Dioxaphosphabicyclo[2.2.2]octanes (L1-L4) have been prepared in a one-pot reaction from tris(hydroxymethyl)phosphine and various α,ß-unsaturated ketones. The non-volatile phosphines oxidise very slowly in air. They possess highly upfield 31P chemical shifts (-59 to -70 ppm), small cone angles (121-140°) and a similar electronic parameter to PPh3. Reaction of L1 with [Rh(acac)(CO)2] gave the complex [Rh(acac)(CO)(L1)] with a ν(CîO) of 1981.5 cm-1, whereas reaction L1 with [Rh(CO)2Cl]2 gave [Rh(CO)(L1)2Cl] with a ν(CîO) of 1979.9 cm-1, remarkably similar to the CO stretching frequencies reported for analogous PPh3 complexes. The cage phosphines were explored as ligands in rhodium catalysed hydroformylation of 1-octene. All of the ligands gave a linear selectivity to n-nonanal of 68%, regardless of the substituents. However the ligand substituents had a significant effect on the catalyst activity, with increased steric bulk around the coordination environment giving a three-fold increase in aldehyde yield. The phosphines undergo ligand subsitution with [Pd(MeCN)2Cl2] forming square planar trans-[Pd(L)2Cl2] complexes. Subsequent reduction with hydrazine furnishes homoleptic tetravalent [Pd(L1)4] which was applied as a catalyst in Suzuki-Miyaura couplings, furnishing the C-C coupled products in moderate yields.
ABSTRACT
In the crystal structure of the title co-crystal, C(4)H(5)N(3)·C(12)H(14)O(2), the components are linked by N-Hâ¯O and O-Hâ¯N hydrogen bonds. Self-assembly of these dimeric units results in a four-component supra-molecular unit featuring a homosynthon between two mol-ecules of the pyrimidin-2-amine involving two N-Hâ¯O hydrogen bonds, and two heterosynthons between each one mol-ecule of pyrimidin-2-amine and 1-phenyl-cyclo-pentane-1-carb-oxy-lic acid involving N-Hâ¯O and O-Hâ¯N hydrogen bonds.
ABSTRACT
The cation of the title salt, C(7)H(11)N(2) (+)·C(12)H(13)O(2) (-)·H(2)O, is planar (r.m.s. deviation = 0.0184â Å). In the crystal, the cation, anion and water mol-ecule are linked by O-Hâ¯O and N-Hâ¯O hydrogen bonds, forming a chain running along the a axis.
ABSTRACT
In the title co-crystal solvate, 2-ethoxy-benzamide-2,5-dihydroxy-benzoic acid-ethanoic acid (2/1/1), 2C(9)H(11)NO(2)·C(7)H(6)O(4)·C(2)H(4)O(2), two nonsteroidal anti-inflammatory drugs, ethenzamide (systematic name: 2-ethoxy-benzamide) and gentisic acid (systematic name: 2,5-dihydroxy-benzoic acid), together with acetic acid (systematic name: ethanoic acid) form a four-component mol-ecular assembly held together by N-Hâ¯O and O-Hâ¯O hydrogen bonds. This assembly features two symmetry-independent mol-ecules of ethenzamide, forming supra-molecular acid-amide heterosynthons with gentisic acid and acetic acid. These heterosynthons involve quite strong O-Hâ¯O [Oâ¯O = 2.5446â (15) and 2.5327â (15)â Å] and less strong N-Hâ¯O [Nâ¯O = 2.9550â (17) and 2.9542â (17)â Å] hydrogen bonds. The overall crystal packing features several C-Hâ¯O and π-π stacking inter-actions [centroid-centroid distance = 3.7792â (11)â Å].
ABSTRACT
In the title salt, C(5)H(7)N(2) (+)·C(10)H(9)O(2) (-), 2-amino-pyridine and 1-phenyl-cyclo-propane-1-carb-oxy-lic acid crystallize together, forming a 2-amino-pyridinium-carboxyl-ate supra-molecular heterosynthon involving two N-Hâ¯O hydrogen bonds, which in turn dimerizes to form a four-component supra-molecular unit also sustained by N-Hâ¯O hydrogen bonding. A C-Hâ¯π inter-action between a pyridine C-H group and the centroid of the phenyl ring of the anion further stabilizes the four-component supra-molecular unit. The overall crystal packing also features C-Hâ¯O inter-actions.
ABSTRACT
Renaissance of cocrystals as alternative solid forms for fine-tuning physicochemical properties of active pharmaceutical ingredients (APIs) has paved way for development of marketable cocrystals. The current literature reveals established strategies for the design, synthesis and characterization of cocrystals. However, barring a few isolated case studies, strategies for development of cocrystal formulations have been underdeveloped. Herein we report topical formulations of an antioxidant, ferulic acid (FA), which contain the active in its cocrystal form. Cocrystals of FA with the coformers relevant to skin care such as urea, nicotinamide (NA) and isonicotinamide (INA) have been prepared and oleogel formulations of these have been developed. The cocrystal with urea and an anhydrous cocrystal with INA have been identified for the first time in this study. The novel cocrystals were structurally characterized by single crystal X-ray diffraction. Solubility and stability studies have revealed higher solubility of the cocrystals with NA and INA than the parent active and greater stability of FA in formulations that contained the cocrystals with INA and urea than the corresponding formulations containing physical mixtures or parent active. In vitro membrane permeation tests have ascertained sustained release profile of active from the formulation that contained the FAâ¢INA cocrystal. The higher solubility, greater stability and sustained active release profile of the FAâ¢INA cocrystal formulation make it a promising topical formulation of FA.
Subject(s)
Antioxidants/chemistry , Coumaric Acids/chemistry , Niacinamide/chemistry , Urea/chemistry , Administration, Topical , Chemistry, Pharmaceutical , Crystallization , Delayed-Action Preparations , Drug Stability , Organic Chemicals , Solubility , X-Ray DiffractionABSTRACT
In the title 1:1 cocrystal, C(7)H(8)N(4)O(2)·C(7)H(6)O(4), the anti-asthmatic drug theophylline (systematic name: 1,3-dimethyl-7H-purine-2,6-dione) and a non-steroidal anti-inflammatory drug, gentisic acid (systematic name: 2,5-dihydroxy-benzoic acid) crystallize together, forming two-dimensional hydrogen-bonded sheets involving N-Hâ¯O and O-Hâ¯N hydrogen bonds. The overall crystal packing features π-π stacking inter-actions [centroid-centroid distance = 3.348â (1)â Å]. The cocrystal described herein belongs to the class of pharmaceutical cocrystals involving two active pharmaceutical ingredients which has been relatively unexplored to date.
ABSTRACT
Polymorphism of active pharmaceutical ingredients (APIs) is of significance in the pharmaceutical industry because it can affect the quality, efficacy and safety of the final drug product. In this regard, polymorphic behavior of cocrystals is no exception because it can influence the development of cocrystals as potential drug formulations. The current contribution aims to introduce two novel polymorphs [forms (III) and (IV)] of agomelatine-hydroquinone (AGO-HYQ) cocrystal and to describe the thermodynamic relationship between the cocrystal polymorphs. All polymorphs were characterized using powder X-ray diffraction, differential scanning calorimetry, hot-stage microscopy and solubility measurements. In addition, the crystal structure of form (II), which has been previously solved from powder diffraction data [Prohens et al. (2016), Cryst. Growth Des. 16, 1063-1070] and form (III) were determined from the single-crystal X-ray diffraction data. Thermal analysis revealed that AGO-HYQ cocrystal form (III) exhibits a higher melting point and a lower heat of fusion than those of form (II). According to the heat of fusion rule, the polymorphs are enantiotropically related, with form (III) being stable at higher temperatures. Our results also show that the novel form (IV) is the most stable form at ambient conditions and it transforms into form (II) on heating, and therefore, the two polymorphs are enantiotropically related. Furthermore, solubility and van't Hoff plot results suggest that the transition points are approximately 339â K for the pair form (IV)-(II) and 352â K for the pair form (II)-(III).
ABSTRACT
Pharmaceutical cocrystals have garnered significant interest as potential solids to address issues associated with formulation development of drug substances. However, studies concerning the understanding of formulation behavior of cocrystals are still at the nascent stage. We present results of our attempts to evaluate suspension formulations of cocrystals of an antiasthmatic drug, theophylline, with 2 artificial sweeteners. Stability, solubility, drug release, and taste of the suspension formulations were evaluated. Suspension that contained cocrystal with acesulfame showed higher drug release rate, while a cocrystal with saccharin showed a significant reduction in drug release rate. The cocrystal with saccharin was found stable in suspension for over 9 weeks at accelerated test condition; in contrast, the cocrystal with acesulfame was found unstable. Taste analysis using an electronic taste-sensing system revealed improved sweetness of the suspension formulations with cocrystals. Theophylline has a narrow therapeutic index with a short half-life which necessitates frequent dosing. This adversely impacts patient compliance and enhances risk of gastrointestinal and cardiovascular adverse effects. The greater thermodynamic stability, sweetness, and sustained drug release of the suspension formulation of theophylline-saccharin could offer an alternative solution to the short half-life of theophylline and make it a promising formulation for treating asthmatic pediatric and geriatric patients.
Subject(s)
Suspensions/chemistry , Sweetening Agents/chemistry , Theophylline/chemistry , Chemistry, Pharmaceutical/methods , Crystallization/methods , Drug Liberation/drug effects , Saccharin/chemistry , Solubility/drug effects , Thermodynamics , Thiazines/chemistryABSTRACT
The striking resemblance of the rhombohedral and monoclinic forms of the title molecule to beta- and gamma-quinol provides a crystal engineering approach to new polymorphic systems.
ABSTRACT
[structure: see text] Crystal engineering of an organic ladder can be achieved with a T-shaped molecule, 4,4-bis(4'-hydroxyphenyl)-1-cyclohexanol, having three hydroxyl functionalities that can form O-H...O hydrogen-bonded helices. The topology of this network structure finds a parallel in three-connected coordination polymers.
ABSTRACT
Four solvates of an antifungal drug, griseofulvin (GF), were discovered. All the solvates were characterized by differential scanning calorimetry, thermogravimetric analysis, and their crystal structures were determined by single-crystal X-ray diffraction. The solvents that form the solvates are acetonitrile, nitromethane and nitroethane (2:1 and 1:1). It was found that all the solvates lose the solvent molecules from the crystal lattice between 343 and 383â K, and that the melting point of the desolvated materials matched the melting point of the solvent-free GF (493â K). The conformation of the GF molecule in solvent-free form was found to be significantly different from the conformations found in the solvates. Solution stability studies revealed that the GF-acetonitrile solvate transforms to GF and that GF-nitroethane (1:1) solvate transforms to GF-nitroethane (2:1) solvate. On the other hand, GF-nitromethane and GF-nitroethane (2:1) solvates were found to be stable in solution. Our results highlight the importance of the co-crystallization technique in the pharmaceutical drug development; it not only expands the solid form diversity but also creates new avenues for unraveling novel solvates.
Subject(s)
Antifungal Agents/chemistry , Griseofulvin/chemistry , Solvents/chemistry , Acetonitriles/chemistry , Calorimetry, Differential Scanning , Crystallography, X-Ray , Ethane/analogs & derivatives , Ethane/chemistry , Humans , Methane/analogs & derivatives , Methane/chemistry , Models, Molecular , Molecular Conformation , Nitroparaffins/chemistry , Powder Diffraction , Solubility , Solutions , Thermodynamics , ThermogravimetryABSTRACT
Crystal polymorphism of the anti-diabetic drug Tolbutamide (TB) has been studied using various analytical techniques. TB crystallizes in four polymorphic forms (Forms I-IV), which differ in their mode of packing and in molecular conformation but with similar hydrogen bonding synthon (urea tape motif). All the structures were solved from single crystal X-ray data, except for Form IV, which was solved using conventional powder X-ray diffraction (PXRD) data. The conformational differences in the TB molecule arise primarily from torsional variations in the alkyl tail which result in two types of conformers (U and chair). The packing differences are mainly due to the orientation of adjacent molecules in the hydrogen bonding networks. Based on the DSC data, thermodynamic stability relationships of polymorphic pairs were evaluated and graphically visualized in a schematic energy-temperature diagram. Form II is found to be the thermodynamically stable polymorph from absolute zero to approximately 353 K and beyond which Form I(H) is the stable polymorph. The anisotropic lattice contraction of TB polymorphs which resulted in severe variations in PXRD patterns at ambient and low temperature was highlighted. The present work also highlights and resolves several discrepancies in the published data on the structural and thermodynamic features of TB polymorphs.
Subject(s)
Hypoglycemic Agents/chemistry , Tolbutamide/chemistry , Crystallization , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Spectrophotometry, Infrared , ThermodynamicsABSTRACT
Reaction of the amido-bridged zirconium complex (CpSiMe(2)NSiMe(2)Cp)ZrCH(3) (1) (Cp = C(5)H(4)) with half an equivalent of B(C(6)F(5))(3) or Ph(3)CB(C(6)F(5))(4) afforded the binuclear zirconium complexes [(CpSiMe(2)NSiMe(2)Cp)Zr)(2)(mu-CH(3))][RB(C(6)F(5))(3)] (2a, R = CH(3), 2b, R = C(6)F(5)) with a methyl group as the bridge between the two zirconium atoms. In the presence of one equivalent of B(C(6)F(5))(3) or Ph(3)C(C(6)F(5))(4), 1 was transformed to the zwitterionic complexes [(CpSiMe(2)NSiMe(2)Cp)Zr][RB(C(6)F(5))(3)] (3a, R = CH(3), 3b, R = C(6)F(5)) which are free of a metal-bound sigma-alkyl ligand. 2b is stable with Me(3)Al while 3b combined with Me(3)Al to form a hetero-binuclear complex [(CpSiMe(2)NSiMe(2)Cp)Zr(mu-CH(3))]Al(CH(3))(2)][B(C(6)F(5))(4)] (4) as shown by NMR spectroscopy at room temperature. Treatment of 2a or 3a with an excess of Me(3)Al led to (CpSiMe(2)NSiMe(2)Cp)Zr(C(6)F(5)) (5) through a group exchange process. 2b, 3a and 5 have been characterized by X-ray diffraction studies. 2b, 2b, 3a and 3b were highly active catalysts for ethylene polymerization and copolymerization with 1-octene in the presence of trialkylaluminium, but the binuclear zirconium complexes (2a and 2b) showed higher activities than their mononuclear counterparts 3a and 3b. Polymerization activities varied with the trialkylaluminiums and increased with the trialkylaluminium concentration applied in the system. The product existed mainly in the form of Al(PE)(3) with polymeric chains, and its molecular weight and distribution were greatly influenced by the type and amount of trialkylaluminium applied in the catalytic system.
ABSTRACT
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.
Subject(s)
Antineoplastic Agents, Alkylating/chemistry , Dacarbazine/analogs & derivatives , Crystallization , Dacarbazine/chemistry , Drug Stability , Hydrogen Bonding , Molecular Structure , TemozolomideABSTRACT
The T-shaped host molecule 4,4-bis(4'-hydroxyphenyl)cyclohexanone (1) has an equatorial phenol group and a cyclohexanone group along the arms and an axial phenol ring as the stem. The equatorial phenyl ring adopts a "shut" or "open" conformation, like a windowpane, depending on the size of the guest (phenol or o/m-cresol), for the rectangular voids of the hydrogen-bonded ladder host framework. The adaptable cavity of host 1 expands to 11x15-18 A through the inclusion of water with the larger cresol and halophenol guests (o-cresol, m-cresol, o-chlorophenol, and m-bromophenol) compared with a size of 10x13 A for phenol and aniline inclusion. The ladder host framework of 1 is chiral (P2(1)) with phenol, whereas the inclusion of isosteric o- and m-fluorophenol results in a novel polar brick-wall assembly (7x11 A voids) as a result of auxiliary C-H...F interactions. The conformational flexibility of strong O-H...O hydrogen-bonding groups (host 1, phenol guest), the role of guest size (phenol versus cresol), and weak but specific intermolecular interactions (herringbone T-motif, C-H...F interactions) drive the crystallization of T-host 1 towards 1D ladder and 2D brick-wall structures, that is, supramolecular isomerism. Host 1 exhibits selectivity for the inclusion of aniline in preference to phenol as confirmed by X-ray diffraction, 1H NMR spectroscopy, and thermogravimetry-infrared (TG-IR) analysis. The T(onset) value (140 degrees C) of aniline in the TGA is higher than those of phenol and the higher-boiling cresol guests (T(onset)=90-110 degrees C) because the former structure has more O-H...N/N-H...O hydrogen bonds than the clathrate of 1 with phenol which has O-H...O hydrogen bonds. Guest-binding selectivity for same-sized phenol/aniline molecules as a result of differences in hydrogen-bonding motifs is a notable property of host 1. Host-guest clathrates of 1 provide an example of spontaneous chirality evolution during crystallization and a two-in-one host-guest crystal (phenol and aniline), and show how weak C-H...F interactions (o- and m-fluorophenol) can change the molecular arrangement in strongly hydrogen-bonded crystal structures.
Subject(s)
Cyclohexanones/chemistry , Macromolecular Substances/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Stereoisomerism , TemperatureABSTRACT
In tris(4-hydroxyphenyl)methane (or 4,4',4"-methanetriyltriphenol), C(19)H(16)O(3), molecules are connected by O-H.O hydrogen bonds [O.O = 2.662 (2) and 2.648 (2) A] into two-dimensional square networks that are twofold interpenetrated. In tris(4-hydroxyphenyl)methane-4,4'-bipyridine (1/1), C(19)H(16)O(3).C(10)H(8)N(2), trisphenol molecules form rectangular networks via O-H.O [O.O = 2.694 (3) A] and C-H.O [C.O = 3.384 (3) A] hydrogen bonds. Bipyridine molecules hydrogen bonded to phenol moieties [O.N = 2.622 (3) and 2.764 (3) A] fill the voids to complete the structure.