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The thermodynamic stability of caffeine (CA) cocrystals with dicarboxylic acids (DAs) as coformers was investigated in the presence of a range of structurally related dicarboxylic acids (SRDs). Two experimental conditions (slurry and dry-grinding) were studied for mixing the cocrystal and the SRD additive. The additives oxalic, malonic, and glutaric acid led to the replacement of the acid coformer for certain cocrystals. Interestingly, a change in stoichiometry was observed for the CA:maleic acid system. A stability order among the cocrystals was established depending on their tendency to replace the coformer. To understand the factors controlling the relative stabilities, lattice energies were calculated using dispersion corrected density functional theory (DFT). Gibbs free energy changes were calculated from experimental solubilities. The observed stability order corroborated well with lattice energy and Gibbs free energy computations. [ABSTRACT FROM AUTHOR]

Spurred by the enormous interest in co-crystals from the pharmaceutical industry, many novel co-crystals of active pharmaceutical ingredients have been discovered in recent years, and this has in turn led to an increasing number of reports on polymorphs of co-crystals. Hence, a thorough characterization and understanding of co-crystal polymorphs is a valuable step during drug development. The purpose of this study is to perform in situ structural analysis and to determine thermodynamic stability of a dimorphic co-crystal system, 1:1 caffeine-glutaric acid (CA-GA, Forms I and II). We performed thermal and structural characterizations by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), and slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also redetermined crystal structures of CA-GA Forms I and II at 180 K using single crystal X-ray diffraction. Our results revealed that Form II is stable and Form I is metastable at ambient conditions. Further, the results suggest that the dimorphs are enantiotropically related and the transition temperature is estimated to be 79 °C. [ABSTRACT FROM AUTHOR]

Spurred by the enormous interest in co-crystals from the pharmaceutical industry, many novel co-crystals of active pharmaceutical ingredients have been discovered in recent years, and this has in turn led to an increasing number of reports on polymorphs of co-crystals. Hence, a thorough characterization and understanding of co-crystal polymorphs is a valuable step during drug development. The purpose of this study is to perform in situ structural analysis and to determine thermodynamic stability of a dimorphic co-crystal system, 1:1 caffeine-glutaric acid (CA-GA, Forms I and II). We performed thermal and structural characterizations by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), and slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also redetermined crystal structures of CA-GA Forms I and II at 180 K using single crystal X-ray diffraction. Our results revealed that Form II is stable and Form I is metastable at ambient conditions. Further, the results suggest that the dimorphs are enantiotropically related and the transition temperature is estimated to be 79 °C. [ABSTRACT FROM AUTHOR]

Herein the potential of a relatively new water soluble fiber, resistant maltodextrin (RMD) to encapsulate grapefruit polyphenol, naringin, using spray drying was evaluated. Full factorial Design Of Experiments (DOE) for spray drying with two levels of fiber–naringin ratio and spray dryer inlet temperature was executed. Resulting powders were characterized with respect to particle size and morphology, crystallinity, thermal properties, moisture sorption and naringin aqueous solubility increase. A 60–80% encapsulation was achieved. Thermal and moisture sorption behaviors of these dispersions were found to be dominated by RMD. By varying fiber–naringin ratio and spray drying temperatures, naringin was able to disperse in amorphous form in RMD matrix, which led to 20–55% increase in aqueous solubility. Solubility enhancement was found to correlate positively with increasing fiber: naringin ratio and spray drying temperature due to multiple factors discussed in this study. In conclusion, fiber–polyphenol bicomponent nutraceutical was successfully developed based on a well-established encapsulation technology i.e. spray-drying. [ABSTRACT FROM AUTHOR]

Well-dispersed palladium(0) nanoparticles with small and narrow size distributions were synthesized conveniently on a graphene oxide (GO) surface. The GO-supported nano-Pd0 was found to be a highly efficient and recyclable catalyst for the carbonylative cross-coupling reaction between arylboronic acids and aryl and carboranyl iodides, respectively. Benzophenone and a series of carboranylaryl ketones, 1-R-2-[C(vO)Ar]-1,2-C2B10H10 (R = H, Me, Ph; Ar = C6H5, C6H4-4-OMe and C6H4-4-F), were synthesized and fully characterized. The catalyst was recyclable at least three times with sustained activity. [ABSTRACT FROM AUTHOR]

Cocrystallization of an antifungal drug, griseofulvin(GF), withan artificial sweetener, acesulfame (Ace-H), resulted in a cocrystalmonohydrate with GF and Ace-H in a 2:1 stoichiometric ratio. The cocrystalwas characterized by differential scanning calorimetry and thermogravimetricanalysis, and its crystal structure was determined by single-crystalX-ray diffraction. The Ace-H molecule is in its enol form in the crystalstructure. The cocrystal hydrate shows remarkable thermal stability,which was traced to strong hydrogen bonds in the crystal structure.The dissolution rate of the (GF)2·Ace-H hydrate issignificantly improved compared to that of the parent GF, and theaqueous solubility of the cocrystal hydrate is greater than the solubilityof GF at 37 °C. Furthermore, the cocrystal hydrate is found tobe stable at different relative humidity conditions for up to 13 weeks.The remarkable thermal stability, improved solubility and dissolutionrate, and pharmaceutical acceptability of Ace-H make the (GF)2·Ace-H hydrate a preferable solid form for developmentof GF formulations (Singapore patent application 201107310-3 (ref1)). [ABSTRACT FROM AUTHOR]

The current contribution aims to prepare a family ofnitrofurantoin (NF) co-crystals and to investigate the ability ofthese co-crystals in enhancing the photostability and clinically relevantphysicochemical properties of NF. Accordingly, supramolecular synthesisof the antibiotic drug NF with the co-formers 3-aminobenzoic acid(3ABA), 4-aminobenzoic acid (4ABA), urea, 4-hydroxybenzamide(4HBAM), phenazine (PHEN), melamine (MELA), 4,4′-bipyridine(BIPY) and 1,2-bis(4-pyridyl ethane) (BIPE) have produced five co-crystalsand three co-crystal hydrates. Solid-state physical characterizationshave been conducted by powder X-ray diffraction (PXRD), single crystalX-ray diffraction, differential scanning calorimetry (DSC), thermogravimetricanalysis (TGA), hot-stage microscopy (HSM) and spectroscopy (Ramanand 1H NMR). Crystal structures have been analyzed basedon homo- and heterosynthons. Six out of eight multicomponent crystalsare primarily stabilized by heterosynthons, whereas the remainingtwo co-crystals (NF-4ABA and NF-UREA) contain homosynthons. Notably,thermal analysis of co-crystal hydrates showed high thermal stability(∼166 °C, NF-MELA-H2O) or upon dehydrationprovided new anhydrous co-crystals, NF-BIPY and NF-BIPE in a 2:1 molarratio. Physicochemical properties such as aqueous solubility, intrinsicdissolution rate and photostability have been investigated for NF-3ABA,NF-4ABA, NF-UREA and NF-4HBAM. Co-crystals display enhanced physicochemicalproperties as compared to that of NF: NF-4HBAM > NF-3ABA > NF-4ABA> NF-UREA > NF (β-form). The results suggest that co-crystalscan be a viable alternative for improving the biopharmaceutical propertiesof API. [ABSTRACT FROM AUTHOR]

Dibasic calcium phosphate occurs as an anhydrate (DCPA; CaHPO) and as a dihydrate (DCPD; CaHPO•2HO). Our objective was to investigate the unusual behavior of these phases. Dibasic calcium phosphate dihydrate was dehydrated in a (i) differential scanning calorimeter (DSC) in different pan configurations; (ii) variable-temperature X-ray diffractometer (XRD) at atmospheric and under reduced pressure, and in sealed capillaries; and (iii) water vapor sorption analyzer at varying temperature and humidity conditions. Dehydration was complete by 210°C in an open DSC pan and under atmospheric pressure in the XRD. Unlike 'conventional' hydrates, the dehydration of DCPD was facilitated in the presence of water vapor. Variable-temperature XRD in a sealed capillary and DSC in a hermetic pan with pinhole caused complete dehydration by 100°C and 140°C, respectively. Under reduced pressure, conversion to the anhydrate was incomplete even at 300°C. The increase in dehydration rate with increase in water vapor pressure has been explained by the Smith-Topley effect. Under 'dry' conditions, a coating of poorly crystalline product is believed to form on the surface of particles and act as a barrier to further dehydration. However, in the presence of water vapor, recrystallization occurs, creating cracks and channels and facilitating continued dehydration. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1456-1466, 2011 [ABSTRACT FROM AUTHOR]

Pharmaceutical co-crystallizing ability of an antibiotic agent, nitrofurantoin, is screened with three isomeric monohydroxybenzoic acids. 1 : 1 co-crystal of nitrofurantoin-4-hydroxybenzoic acid has been prepared and structurally characterized. Further, the co-crystal displays superior physicochemical and photo-stability compared to nitrofurantoin. [ABSTRACT FROM AUTHOR]

The crystal structures and packing features of a family of 13 aminophenols, or supraminols, are analyzed and correlated. These compounds are divided into three groups: (a) compounds 1-5 with methylene spacers of the general type HO-C[sub6]H[sub4]-(CH[sub2])[subn]-C[sub6]H[sub4]-NH[sub2] (n = 1 to 5) and both OH and NH[sub2] in a para position; (b) compounds 1a, 2a, 2b, 2c, and 3a in which one or more of the methylene linkers in 1 to 3 are exchanged with an S-atom; and (c) compounds 2d, 1b, and 6a prepared with considerations of crystal engineering and where the crystal structures may be anticipated on the basis of structures 1-5, 1a, 2a, 2b, 2c, and 3a. These 13 aminols can be described in terms of three major supramolecular synthons based on hydrogen bonding between OH and NH[sub2] groups: the tetrameric loop or square motif, the infinite N(H)O chain, and the β-As sheet. These three synthons are not completely independent of each other but interrelate, with the structures tending toward the more stable β-As sheet in some cases. Compounds 1-5 show an alternation in melting points, and compounds with n = even exhibit systematically higher melting points compared to those with n = odd. The alternating melting points are reflected in, and explained by, the alternation in the crystal structures. The n = odd structures tend toward the β-As sheet as n increases and can be considered as a variable series whereas for n = even, the β-As sheet is invariably formed constituting a fixed series. Substitution of a methylene group by an isosteric S-atom may causes a change in the crystal structure. These observations are rationalized in terms of geometrical and chemical effects of the functional groups. This study shows that even for compounds with complex crystal structures the packing may be reasonably anticipated provided a sufficient number of examples are available. [ABSTRACT FROM AUTHOR]

Acesulfame is found to exist in two crystalline forms of which Form I (needles) shows bending upon mechanical stress. Crystal structures explain their mechanical response. This is the first case of aliphatic organic compounds featuring a bending phenomenon. Form I is physically more stable than Form II in ambient conditions. [ABSTRACT FROM AUTHOR]

Describes the centrosymmetric crystal structure of a 1:1 molecular complex of bis(4-aminophenyl) disulfide and 4-aminothiophenol. Stabilization of the crystal structure by the interplay of strong and weak intermolecular interactions; Presence of cooperative hydrogen-bonded chains.

Polymorphism in active pharmaceutical ingredients can be regarded as critical for the potential that crystal form can have on the quality, efficacy, and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII has been performed using thermokinetic methods and systematically characterized by differential scanning calorimetry, powder X-ray diffraction, solubility, and slurry measurements. According to the heat of fusion rule by Burger and Ramberger, FI (ΔH fus = 121.1 J/g; melting point, 172.5°C) and FII (ΔH fus = 110.3 J/g; melting point, 164.7°C) are monotropically related. The solubility and van't Hoff plot results suggest FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat-induced stresses; however, FII converts to FI during solution-mediated transformation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Computational and experimental work has been performed on HCTZ as well as HCTZ- 4ABA. • Two functionals B3LYP and wB97X-D have been used to study hydrogen bonding interactions. • NH, NH 2 and O=S=O groups were involved in neighboring interactions. • NBO analysis and QTAIM are used to analyze the nature and the strength of hydrogen bonding. In this study, the molecular, electronic, and chemical properties of the drug hydrochlorothiazide (HCTZ) are determined after cocrystallization with 4-aminobenzoic acid (4-ABA). Analysis has been performed to understand how those variations lead to alteration of physical properties and chemical reactivity in the cocrystal HCTZ-4ABA. IR and Raman characterizations were performed along with quantum chemical calculations. A theoretical investigation of hydrogen bonding interactions in HCTZ-4ABA has been conducted using two functionals: B3LYP and wB97X-D. The results obtained by B3LYP and wB97X-D are compared which leads to the conclusion that B3LYP is the best applied function (density functional theory) to obtain suitable results for spectroscopy. The chemical reactivity descriptors are used to understand various aspects of pharmaceutical properties. Natural bond orbital (NBO) analysis and quantum theory of atoms (QTAIM) are used to analyze nature and strength of hydrogen bonding in HCTZ-4ABA. QTAIM analyzed moderate role of hydrogen bonding interactions in HCTZ-4ABA. The calculated HOMO-LUMO energy gap shows that HCTZ-4ABA is chemically more active than HCTZ drug. These chemical parameters suggest that HCTZ-4ABA is chemically more reactive and softer than HCTZ. The results of this study suggest that cocrystals can be a good alternative for enhancing physicochemical properties of a drug without altering its therapeutic properties. [ABSTRACT FROM AUTHOR]

Abstract: The condensation reaction of carboranylmethyl ammonium chloride, 1-(CH2NH3Cl)-1,2-C2B10H11 (1) with phenyl aldehydes produced phenyl(carboranylmethyl)imine ligands, 1-(CH2N = CC6H4R-2)-1,2-C2B10H11 (2 R = H; 3 R = OH). Deprotonation of 2 and 3 with n-BuLi followed by metalation with TiCl4 led to the formation of phenyl(carboranylmethyl)imidotitanium (IV) chlorides, [1-(CH2N = CC6H4R-2)-1,2-C2B10H10]TiCl3 (4 R = H; 5 R = O). Compounds 4 and 5 were found to catalyze the polymerization of ethylene in the presence of co-catalyst MAO to produce high molecular weight polyethylene. In addition, compounds 4 and 5 were also active for copolymerization of ethylene and methyl-10-undecannoate to generate corresponding copolymers. [Copyright &y& Elsevier]

The urea tape α-network of bifurcated N−H···O hydrogen bonds is a common motif in diaryl ureas and their molecular complexes. We analyzed the X-ray crystal structures of N,N'-bis(3-pyridyl)urea 3 and some of its derivatives: hydrates of stoichiometry 3·(4/3)H2O and 3·2H2O, cocrystals 3·SA and 3·FA·H2O with succinic acid and fumaric acid, bis pyridine N-oxide 8, and bis N-methylpyridinium iodide 9. Crystal packing in pyridyl urea structures is directed by N−H···Npyridyl, N−H···Owater, N−H···Oacid, and N−H···I- hydrogen bonds instead of the common one-dimensional N−H···Ourea tape. We postulated that the urea tape is absent in these structures because the CO acceptor is weakened by two intramolecular C−H···Ourea interactions (synthon III) in a planar molecular conformation. Electrostatic surface potential (ESP) charges (DFT-B3LYP/6-31G*) showed that the C−H···O interactions sufficiently reduce the electron density at the urea O, and so other electronegative atoms, such as pyridyl N, H2O, COOH, and I-, become viable hydrogen-bond acceptors for the strong NH donors. 1H NMR difference nOe confirmed that the planar conformation of dipyridyl urea 3 in the solid-state persists in solution. Interestingly, even though the strong hydrogen-bond motifs changed in structures of 3, the C−H···O interactions of synthon III (energy 4.6−5.0 kcal/mol) occurred throughout the family. In addition to dipyridyl urea, other electron-withdrawing diaryl ureas, e.g., those with phenylpyridyl and phenyl-nitrophenyl groups, also deviated from the prototype N−H···O tape because of the interference from weak C−H···O hydrogen bonds. Therefore, when one or both aryl rings have hydrogen-bond acceptor groups (e.g., pyridine, PhNO2), the NH donor(s) preferentially bond to pyridyl N, nitro O, or solvent O atom instead of the urea CO acceptor. We classify supramolecular organization in diaryl ureas into those with the α-network (twisted molecular conformation) or non-urea tape structures (stable, planar conformation) depending on the substituent group. Our results suggest a model to steer urea crystal structures toward the tape synthon (Ph and electron-donating groups) or with non-urea hydrogen-bond motifs and a high probability for urea···solvent hydrogen bonding (electron-withdrawing groups) by appropriate selection of functional aryl and heterocyclic groups. Intramolecular C−H···O interactions in dipyridyl urea stabilize the planar molecular conformation and weaken the CO acceptor strength so that N−H···Npyridyl, N−H···Owater hydrogen bonds are preferred over the one-dimensional N−H···Ourea tape. A model for crystallization in the α-network (phenyl and electron-donating group) or as non-urea tape structures (electron-withdrawing group) depending on the aryl functional group is discussed. [ABSTRACT FROM AUTHOR]

The supramolecular synthon approach to crystal structure prediction (CSP) takes into account the complexities inherent in crystallization. The synthon is a kinetically favored unit, and through analysis of commonly occurring synthons in a group of related compounds, kinetic factors are implicitly invoked. The working assumption is that while the experimental structure need not be at the global minimum, it will appear somewhere in a list of computationally generated structures so that it can be suitably identified and ranked upward using synthon information. These ideas are illustrated with a set of aminophenols, or aminols. In the first stage, a training database is created of the 10 isomeric methylaminophenols. The crystal structures of these compounds were determined. The prototypes 2-, 3-, and 4-aminophenols were also included in the training database. Small and large synthons in these 13 crystal structures were then identified. Small synthons are of high topological but low geometrical value and are used in negative screens to eliminate computationally derived structures that are chemically unreasonable. Large synthons are more restrictive geometrically and are used in positive screens ranking upward predicted structures that contain these more well-defined patterns. In the second stage, these screens are applied to CSP of nine new aminols carried out in 14 space groups. In each space group, up to 10 lowest energy structures were analyzed with respect to their synthon content. The results are encouraging, and the predictions were classified as good, unclear, or bad. Two predictions were verified with actual crystal structure determinations. [ABSTRACT FROM AUTHOR]

• Computational and experimental work has been performed on cocrystal of hydrochlorothiazide (HCTZ) and nicotinamide (NCT). • H-bonding interaction was studied by using monomeric, dimeric and trimeric models of HCTZ-NCT cocrystal. • NH 2 and C = O groups were involved in neighbouring hydrogen bonding interactions. • QTAIM and NBO analysis were done to explore inter and intramolecular H-bond interactions. • MEPS was performed to observe the reactive sites of the molecules. The present work focuses on the study of structural, vibrational, chemical properties and the effect of hydrogen bonding interaction in the formation of a cocrystal of hydrochlorothiazide (HCTZ, a diuretic drug) with nicotinamide (NCT) using vibrational spectroscopy (FT-IR and FT-Raman) and density functional theory. HCTZ being a BCS class IV drug, has low permeability and solubility; therefore, its cocrystal is studied. Monomer, dimer and trimer of HCTZ-NCT cocrystal were studied to understand hydrogen bonding interactions. The shifting in the wavenumber and the elongation in bond lengths of the amide (NH 2) group of HCTZ and carbonyl (C = O) group of NCT were observed in all the models of HCTZ-NCT cocrystal due to the hydrogen bonding interaction. The importance of hydrogen bonding were also explored by natural bond orbital (NBO) analysis in support of the quantum theory of atom in molecules (QTAIM). The chemical reactivity of HCTZ, NCT and HCTZ-NCT cocrystal was examined by MEPS map, FMOs, global electronic reactivity descriptor, ECT descriptors, and molar refractivity. The lesser value of the HOMO-LUMO energy gap in the cocrystal than API reflects that the chemical reactivity of the cocrystal was better than API itself. The comparison between API(HCTZ) and cocrystal (HCTZ-NCT) implies that pharmaceutical cocrystals may be a better option to improve and enhance the pharmacological properties of drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

Cocrystallization is an attractive approach to improving the physicochemical properties of active pharmaceutical ingredients (APIs), which have great potential in drug development. Accordingly, there is a growing need to understand the physicochemical changes that occur upon co-crystallisation. This work focuses on the combined use of spectroscopy and density functional theory (DFT) calculations to understand the molecular structure, hydrogen bond interactions and physicochemical properties of a pharmaceutical cocrystal. Solid-state NMR (ssNMR) spectroscopy can provide detailed molecular structure information on pharmaceutical cocrystals and complexes. It is non-destructive and usually provides deep structural insights that complement well with vibrational spectroscopy. In this work, a cocrystal of an antibiotic drug, nitrofurantoin (NF), with 4-hydroxybenzoic acid (4HBA) is examined to understand the capability of multiple spectroscopic techniques such as infrared (IR), Raman and solid-state NMR spectroscopies, and to confirm the molecular structure and hydrogen bonding of cocrystal systems. The results of IR and Raman spectroscopy showed that for the cocrystal formation, NF and 4HBA molecules interact through N–H…O–H interactions between the imide N–H of nitrofurantoin and the phenolic –OH of 4-hydroxybenzoic acid, and these interactions are also confirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses. It is critical to understand whether a given cocrystal, upon conceiving a modified crystalline structure compared to that of its API, shows enhanced physical and chemical properties or not. Computationally, it is found that the NF–4HBA cocrystal shows softer (more reactive) behaviour in comparison to NF as its cocrystal, NF–4HBA, has a low band gap in comparison to the API, NF. These results demonstrate that the quantum chemical approach predicts accurately how to relate cocrystal with its physical and chemical properties. [ABSTRACT FROM AUTHOR]

Despite the rising interest in pharmaceutical cocrystals in the past decade, there is a lack of research on the solid processing of cocrystals downstream to crystallization. Mechanical stress induced by unit operations such as milling could affect the integrity of the material. The purpose of this study is to investigate the effect of milling on pharmaceutical cocrystals and to compare the performance of ball mill and jet mill, using caffeine-glutaric acid (1:1) cocrystal as the model compound. Our results show that ball milling induced polymorphic transformation from the stable Form II to the metastable Form I, whereas Form II remained intact after jet milling. Jet milling was found to be effective in reducing particle size, but ball milling was unable to reduce the particle size beyond a certain limit even with increasing milling intensity. The heating effect during ball milling was proposed as a possible explanation for the difference in the performance of the two types of mill. The local increase in temperature beyond the polymorphic transformation temperature may lead to the conversion from stable to metastable form. At longer ball milling duration, the local temperature could exceed the melting point of Form I, leading to surface melting and subsequent recrystallization of Form I from the melt and agglomeration of the crystals. The findings in this study have broader implications on the selection of mill and interpretation of milling results for not only pharmaceutical cocrystals but pharmaceutical compounds in general. [ABSTRACT FROM AUTHOR]

Investigations of structural reactivity, molecular interactions and vibrational characterization of pharmaceutical drugs are helpful in understanding their behaviour. The aim of this study is to determine the molecular, electronic and chemical properties of the antibiotic drug nitrofurantoin (NF), after cocrystallisation with 3-aminobenzoic acid (3ABA) and to understand how those changes lead to variation of properties in the cocrystal NF–3ABA. NF–3ABA formation is explained by stabilization via the hydrogen-bond network between NF and 3ABA molecules. It is thoroughly characterized by IR, Raman and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. The results of IR, Raman, and 13C NMR analyses showed that imide N–H23 and C12=O of NF interact with the acid C=O and –OH groups in 3-ABA, respectively. Therefore the IR, Raman, and 13C NMR spectra verified the formation of N–H…O and O–H…O hydrogen bonds. To study hydrogen bonding interactions theoretically in NF–3ABA, two functionals B3LYP and wB97X-D have been used. A comparison is made between the results obtained by B3LYP and those predicted at the wB97X-D level. It is found that wB97X-D is best applied density functional theory (DFT) functional to describe the hydrogen bonding interactions. The strength and nature of hydrogen bonding in NF–3ABA have been analysed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. To validate the results obtained by QTAIM theory and to study the long-range forces, such as van der Waals interactions, the steric effects in NF–3ABA, the reduced density gradient (RDG) and the isosurface have been plotted using Multiwfn software. QTAIM and isosurface analysis suggested that the hydrogen bonding interactions present in NF–3ABA are moderate in nature. The calculated HOMO–LUMO energy gap shows that NF–3ABA is more active than NF and 3ABA. Chemical reactivity descriptors are calculated to understand the various aspects of pharmacological sciences. Chemical reactivity parameters show that NF–3ABA is softer and chemically more reactive than NF. The results suggest that cocrystals can be a feasible alternative for positively changing the targeted physicochemical properties of an active pharmaceutical ingredient (API). [ABSTRACT FROM AUTHOR]

Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform –infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P 2 1 /n , P 2 1 /c and P 2 1 /n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Computational and experimental work has been performed on hydrochlorothiazide (HCTZ). • H-bonding interaction was studied using monomeric, dimeric and trimeric models. • NH 2 and O S O groups were involved in neighboring interactions. • QTAIM and NBO analysis was done to explore inter and intramolecular H-bond interactions. Hydrochlorothiazide (HCTZ) being a diuretic drug widely used in anti-hypertensive therapy as it lowers the blood pressure by reducing the reabsorption of electrolytes in kidney resulting an increment of urine output and lowering the blood pressure. The purpose of the present work is to study the structural, vibrational and chemical properties of HCTZ based on its monomeric, dimeric and trimeric models by utilizing computational methods and experimental techniques. Density functional theory (DFT) with functional B3LYP and 6-311++G (d, p) basis set was used for a detailed computational study. Monomeric, dimeric and trimeric models of HCTZ have been studied for a better understanding of inter- and intramolecular hydrogen bonding. FT-IR (400–3800 cm−1) and FT-Raman (100–3600 cm−1) spectroscopy have been utilized for the characterization of HCTZ. The shifting in wavenumber of NH 2 and O S O group were observed in dimer and trimer due to the formation of intermolecular hydrogen bonding. Quantum theory of atoms in molecules (QTAIM) along with natural bond orbital (NBO) analysis were performed to examine the nature and strength of hydrogen bonding which showed that all the interactions were medium and partially covalent in nature; transition from LP(3)O15 → σ*(H46 → N32) and LP(3)O39 → σ*(H74 → N51) were responsible for the formation of O15•••H46 and O39•••H74 H-bonds, respectively. HOMO-LUMO energies predicted the chemical reactivity and stability of the molecule and the energy gap for dimer (4.6240 eV) and trimer (4.0493 eV) was found to be lesser than the monomer (5.0888 eV) which showed that the dimer and trimer have predicted more chemical reactivity in comparison to monomer. The most electronegative electrostatic potential was observed around the O S O group and the most electropositive potential around the amide group from MEPS analysis. Global as well as local reactivity descriptors have predicted the reactivity and hence, stability of the title molecule. [ABSTRACT FROM AUTHOR]

• Geometry optimization of NF-PHEN (cocrystal) has been done using B3LYP functional. • Spectroscopic (FT-IR and FT-Raman) study of NF-PHEN has been done. • NBO and AIM analysis have been done for the understanding of charge transfer within the cocrystal. • Global and local reactivity descriptors are used to determine chemical reactivity and site selectivity. • The global reactivity parameters of NF-PHEN have been compared with that of other two cocrystals of NF (nitrofurantoin-melamine monohydrate (NF-MELA-H 2 O) and nitrofurantoin-urea (NF-urea)). • Amongst all the cocrystals (NF-MELA-H 2 O, NF-urea and NF-PHEN), NF-PHEN is chemically most reactive. This work gives the unified insight of vibrational spectroscopy (FT-IR and FT-Raman) and density functional theory (DFT) calculations to get an understanding of the hydrogen bonding pattern and chemical reactivity of a cocrystal of nitrofurantoin (NF, an antibacterial drug) with phenazine (PHEN). FT-Raman (100-3700 cm−1) and infrared (400-4000 cm−1) spectroscopic techniques were used for the characterization of the NF-PHEN cocrystal and NF drug itself in the solid state. The intermolecular H-bonding is affirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) studies. The reactivity studies of NF-PHEN through global and local reactivity descriptors have also been performed. The global reactivity parameters of NF-PHEN have been compared with that of NF itself and two other cocrystals of NF [nitrofurantoin-melamine monohydrate (NF-MELA-H 2 O) and nitrofurantoin-urea (NF-urea)] where hetero-atom (nitrogen) rich coformers have been used. It is established that all the three cocrystals show more chemical reactivity than NF itself. And amongst three NF cocrystals, NF-MELA-H 2 O is most stable while NF-PHEN is chemically most reactive. In other words, NF-PHEN is chemically softer than other two cocrystals. Molecular electrostatic potential (MEP) map has also been studied as it is correlated to the electronic density and is advantageous in considering sites for electrophilic and nucleophilic strikes together with hydrogen bonding interactions. Molar refractivity (MR) value of NF-PHEN falls within the range set by Lipinski's modified rule and suggests that the studied cocrystal may show drug likeness. Accordingly, structural and reactivity studies could be successfully employed to a pharmaceutical cocrystal, NF-PHEN, considered in this study and for various other multicomponent crystals in gaining insights into their hydrogen bond interactions and physicochemical properties. [Display omitted] [ABSTRACT FROM AUTHOR]

Cocrystal monohydrate of nitrofurantoin (NF) with melamine (MELA) has been studied as NF is an antibacterial drug used for the treatment of urinary tract infections. The structure of nitrofurantoin-melamine-monohydrate (NF-MELA-H 2 O) is characterized by FT-IR and FT-Raman spectroscopy. The energies and vibrational frequencies of the optimized structures calculated using quantum chemical calculations. Supported by normal coordinate analyses and potential energy distributions (PEDs), the complete vibrational assignments recommended for the observed fundamentals of cocrystal hydrate. With the aim of inclusion of all the H-bond interactions, dimer of NF-MELA-H 2 O has been studied as only two molecules of cocrystal hydrate are present in the unit cell. By the study of dimeric model consistent assignment of the FT-IR and FT-Raman spectrum obtained. H-bonds are of essential importance in an extensive range of molecular sciences. The vibrational analyses depict existence of H-bonding (O-H⋯N) between water O-H and pyridyl N atom of MELA in both monomer and dimer. To probe the strength and nature of H-bonding in monomer and dimer, topological parameters such as electron density (ρ BCP), Laplacian of electron density (∇2ρ BCP), total electron energy density (H BCP) and H-bond energy (E HB) at bond critical points (BCP) are evaluated by quantum theory of atoms in molecules (QTAIM). Natural bond orbitals (NBOs) analyses are carried out to study especially the intra and intermolecular H-bonding and their second order stabilization energy (E(2)). The value of HOMO-LUMO energy band gap for NF-MELA-H 2 O (monomer and dimer both) is less than NF, showing more chemical reactivity for NF-MELA-H 2 O. Chemical reactivity has been described with the assistance of electronic descriptors. Global electrophilicity index (ω = 7.3992 eV) shows that NF-MELA-H 2 O behaves as a strong electrophile than NF. The local reactivity descriptors analyses such as Fukui functions, local softnesses and electrophilicity indices performed to determine the reactive sites within NF-MELA-H 2 O. In MEP map of NF-MELA (monomer and dimer) electronegative regions are about NO 2 and C=O group of NF, although the electropositive regions are around NH 2 , N-H group and H 2 O molecule. Molar refractivity (MR) value of NF-MELA-H 2 O (monomer and dimer) lies within the range set by Lipinski's modified rules. This study could set as an example to study the H-bond interactions in pharmaceutical cocrystals. Unlabelled Image • Geometry optimization of NF-MELA-H 2 O (cocrystal hydrate) has been done using B3LYP functional. • Spectroscopic (FT-IR and FT-Raman) study of NF-MELA-H 2 O has been done. • NBO and AIM analysis have been done for the understanding of charge transfer within the cocrystal hydrate. • Global and local reactivity descriptors are used to determine chemical reactivity and site selectivity. [ABSTRACT FROM AUTHOR]