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The synthesis and characterization of the multicomponent crystals formed by 2,2′-thiodiacetic acid (H2tda) and 2,6-diaminopurine (Hdap) or N9-(2-hydroxyethyl)adenine (9heade) are detailed in this report. These crystals exist in a salt rather than a co-crystal form, as confirmed by single crystal X-ray diffractometry, which reflects their ionic nature. This analysis confirmed proton transfer from the 2,2′-thiodiacetic acid to the basic groups of the coformers. The new multicomponent crystals have molecular formulas [(H9heade+)(Htda−)] 1 and [(H2dap+)2(tda2−)]·2H2O 2. These were also characterized using FTIR, 1H and 13C NMR and mass spectroscopies, elemental analysis, and thermogravimetric/differential scanning calorimetry (TG/DSC) analyses. In the crystal packing the ions interact with each other via O–H⋯N, O–H⋯O, N–H⋯O, and N–H⋯N hydrogen bonds, generating cyclic hydrogen-bonded motifs with graph-set notation of R 2 2 (16), R 2 2 (10), R 3 2 (10), R 3 3 (10), R 2 2 (9), R 3 2 (8), and R 4 2 (8), to form different supramolecular homo- and hetero-synthons. In addition, in the crystal packing of 2, pairs of diaminopurinium ions display a strong anti-parallel π,π-stacking interaction, characterized by short inter-centroids and interplanar distances (3.39 and 3.24 Å, respectively) and a fairly tight angle (17.5°). These assemblies were further analyzed energetically using DFT calculations, MEP surface analysis, and QTAIM characterization. [ABSTRACT FROM AUTHOR]

Organic–inorganic halocuprates based on monovalent copper are promising luminescent compounds for optoelectronic applications; however, their relaxation processes in the excited electronic state are severely underexplored. In this contribution, we prepare thin films of bis(tetraethylammonium) di-µ-bromo-dibromodicuprate(I) [N(C2H5)4]2[Cu2Br4], abbreviated (TEA)2Cu2Br4, which features a "molecular salt" structure containing discrete [Cu2Br4]2− anions. This compound, which has an absorption peak at 283 nm, displays a blue, strongly Stokes-shifted emission with a peak at 467 nm. Transient photoluminescence (PL) experiments using broadband emission detection and time-correlated single-photon counting (TCSPC) both find an excited-state lifetime of 57 μs at 296 K. UV–Vis transient absorption experiments at 296 K covering time scales from femto- to microseconds provide evidence for the formation of the T1 state through intersystem crossing from S1 with a time constant of 184 ps. The triplet state subsequently decays to S0 predominantly by phosphorescence. In addition, the time constants for carrier–optical phonon scattering (1.8 ps) and acoustic phonon relaxation (8.3 ns and 465 ns) of (TEA)2Cu2Br4 are provided. [ABSTRACT FROM AUTHOR]

Organic acids (3-chlorobenzoic acid and 4-chlorobenzoic acid) were treated with 4-amino-2-chloropyridine and 2-amino-4-chloropyridine as coformers for cocrystallization. Acid/base pairs afforded a cocrystal (3-chlorobenzoic acid and 4-amino-2-chloropyridine, compound 1) and molecular salts (2-amino-4-chloropyridinium 3-chlorobenzoate, 2; 2-amino-4-chloropyridinium 4-chlorobenzoate, 3). The products were characterized with the help of FT-IR, UV/visible spectroscopy, PXRD, and SC-XRD. The position of the Cl-substituent on the phenyl ring was explored with respect to proton transfer between acid/base pairs, and its role in supramolecular chemistry is discussed in detail. The existence of supramolecular assemblies was further reproduced using DFT calculations. Further, frontier molecular orbital (FMO), molecular electrostatic potential (MEP), and noncovalent interaction index (NCI) analyses were performed to gain insight into the electronic properties and nature of noncovalent interactions. The prepared compounds were examined for their biological activities against selected Gram-positive and Gram-negative bacterial strains and were also tested as antioxidant agents (DPPH free radical scavenging). Structural parameters determined experimentally and theoretically are within the expected range, and the biological activities of the resultant compounds are moderate. [ABSTRACT FROM AUTHOR]

Drug–drug salts are a kind of pharmaceutical multicomponent solid in which the two co-existing components are active pharmaceutical ingredients (APIs) in their ionized forms. This novel approach has attracted great interest in the pharmaceutical industry since it not only allows concomitant formulations but also has proved potential to improve the pharmacokinetics of the involved APIs. This is especially interesting for those APIs that have relevant dose-dependent secondary effects, such as non-steroidal anti-inflammatory drugs (NSAIDs). In this work, six multidrug salts involving six different NSAIDs and the antibiotic ciprofloxacin are reported. The novel solids were synthesized using mechanochemical methods and comprehensively characterized in the solid state. Moreover, solubility and stability studies, as well as bacterial inhibition assays, were performed. Our results suggest that our drug–drug formulations enhanced the solubility of NSAIDs without affecting the antibiotic efficacy. [ABSTRACT FROM AUTHOR]

According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug is also highly hygroscopic, thus showing stability problems. Another kind of worldwide prescribed drug is the non-steroidal anti-inflammatory drug (NSAID). These latter, on the contrary, show a low solubility profile; therefore, they must be administered at high doses, which increases the probability of secondary effects. In this work, novel drug-drug pharmaceutical solids combining MTF-NSAIDs have been synthesized in solution or by mechanochemical methods. The aim of this concomitant treatment is to improve the physicochemical properties of the parent active pharmaceutical ingredients. After a careful solid-state characterization along with solubility and stability studies, it can be concluded that the new molecular salt formulations enhance not only the stability of MTF but also the solubility of NSAIDs, thus giving promising results regarding the development of these novel pharmaceutical multicomponent solids. [ABSTRACT FROM AUTHOR]

Organic acids (3-chlorobenzoic acid and 4-chlorobenzoic acid) were treated with 4-amino-2-chloropyridine and 2-amino-4-chloropyridine as coformers for cocrystallization. Acid/base pairs afforded a cocrystal (3-chlorobenzoic acid and 4-amino-2-chloropyridine, compound 1) and molecular salts (2-amino-4-chloropyridinium 3-chlorobenzoate, 2; 2-amino-4-chloropyridinium 4-chlorobenzoate, 3). The products were characterized with the help of FT-IR, UV/visible spectroscopy, PXRD, and SC-XRD. The position of the Cl-substituent on the phenyl ring was explored with respect to proton transfer between acid/base pairs, and its role in supramolecular chemistry is discussed in detail. The existence of supramolecular assemblies was further reproduced using DFT calculations. Further, frontier molecular orbital (FMO), molecular electrostatic potential (MEP), and noncovalent interaction index (NCI) analyses were performed to gain insight into the electronic properties and nature of noncovalent interactions. The prepared compounds were examined for their biological activities against selected Gram-positive and Gram-negative bacterial strains and were also tested as antioxidant agents (DPPH free radical scavenging). Structural parameters determined experimentally and theoretically are within the expected range, and the biological activities of the resultant compounds are moderate.

The synthesis and characterization of the multicomponent crystals formed by 2,2′-thiodiacetic acid (H2tda) and 2,6-diaminopurine (Hdap) or N9-(2-hydroxyethyl)adenine (9heade) are detailed in this report. These crystals exist in a salt rather than a co-crystal form, as confirmed by single crystal X-ray diffractometry, which reflects their ionic nature. This analysis confirmed proton transfer from the 2,2′-thiodiacetic acid to the basic groups of the coformers. The new multicomponent crystals have molecular formulas [(H9heade+)(Htda−)] 1 and [(H2dap+)2(tda2−)]·2H2O 2. These were also characterized using FTIR, 1H and 13C NMR and mass spectroscopies, elemental analysis, and thermogravimetric/differential scanning calorimetry (TG/DSC) analyses. In the crystal packing the ions interact with each other via O–H⋯N, O–H⋯O, N–H⋯O, and N–H⋯N hydrogen bonds, generating cyclic hydrogen-bonded motifs with graph-set notation of R22(16), R22(10), R32(10), R33(10), R22(9), R32(8), and R42(8), to form different supramolecular homo- and hetero-synthons. In addition, in the crystal packing of 2, pairs of diaminopurinium ions display a strong anti-parallel π,π-stacking interaction, characterized by short inter-centroids and interplanar distances (3.39 and 3.24 Å, respectively) and a fairly tight angle (17.5°). These assemblies were further analyzed energetically using DFT calculations, MEP surface analysis, and QTAIM characterization.

Organic–inorganic halocuprates based on monovalent copper are promising luminescent compounds for optoelectronic applications; however, their relaxation processes in the excited electronic state are severely underexplored. In this contribution, we prepare thin films of bis(tetraethylammonium) di-µ-bromo-dibromodicuprate(I) [N(C2H5)4]2[Cu2Br4], abbreviated (TEA)2Cu2Br4, which features a “molecular salt” structure containing discrete [Cu2Br4]2− anions. This compound, which has an absorption peak at 283 nm, displays a blue, strongly Stokes-shifted emission with a peak at 467 nm. Transient photoluminescence (PL) experiments using broadband emission detection and time-correlated single-photon counting (TCSPC) both find an excited-state lifetime of 57 μs at 296 K. UV–Vis transient absorption experiments at 296 K covering time scales from femto- to microseconds provide evidence for the formation of the T1 state through intersystem crossing from S1 with a time constant of 184 ps. The triplet state subsequently decays to S0 predominantly by phosphorescence. In addition, the time constants for carrier–optical phonon scattering (1.8 ps) and acoustic phonon relaxation (8.3 ns and 465 ns) of (TEA)2Cu2Br4 are provided.

Polymorphism/solid forms are acknowledged to have important implications in the pharmaceutical industry, hence regulating polymorph/solid forms formation is essential. 1H-Benzimidazole, 2-[4-(1,1-dimethylethyl)phenyl] (BDP) drug has been discovered as a transcriptional activator of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in certain metabolic tissues. Up to date, there is no solid forms of BDP have been reported. The purpose of this study was to see how changing solvent conditions and co-formers influenced the formation of distinct solid forms of BDP. The solvents were chosen based on their polarity, as different polarity solvents are anticipated to interact differently with APIs, impacting the creation of diverse solid forms. Similarly, two GRAS (Generally Recognized As Safe) co-formers, Oxalic Acid (OA) and Malonic Acid (MA), were employed to test the potential of various forms of BDP to form diverse supramolecular networks that might improve BDP's physicochemical qualities. The experimental finding reveals that one polymorph, two solvates and three molecular salts have been obtained by solvent evaporation (SE) and liquid assisted grinding (LAG) methods. Interestingly, BDP creates a similar channel structure in all the two solvates (acetone and isopropanol). Furthermore, different forms of BDP using the same co-former show different molecular assemblages, confirming the occurrence of multiple forms. PXRD, SCXRD, and thermal analyses were used to characterize all of the synthesized forms. The findings of this study indicate that solvent choice and synthesis process are important factors in polymorph screening and can influence the creation of diverse molecular forms.

This study aims at developing new multicomponent crystal forms of sulpiride, an antipsychotic drug. The main goal was to improve its solubility since it belongs to class IV of the BCS. Nine new adducts were obtained by combining the active pharmaceutical ingredient with acid coformers: a salt cocrystal and eight molecular salts. In addition, three novel co-drugs, of which two are molecular salts and one is a cocrystal, were also achieved. All samples were characterized in the solid state by complementary techniques (i.e., infrared spectroscopy, powder X-ray diffraction and solid-state NMR). For systems for which it was possible to obtain good-quality single crystals, the structure was solved by single crystal X-ray diffraction (SCXRD). SCXRD combined with solid-state NMR were used to evaluate the ionic or neutral character of the adducts. In vitro dissolution tests of the new crystal forms were performed and all the adducts display remarkable dissolution properties with respect to pure sulpiride. [ABSTRACT FROM AUTHOR]

Drug–drug salts are a kind of pharmaceutical multicomponent solid in which the two co-existing components are active pharmaceutical ingredients (APIs) in their ionized forms. This novel approach has attracted great interest in the pharmaceutical industry since it not only allows concomitant formulations but also has proved potential to improve the pharmacokinetics of the involved APIs. This is especially interesting for those APIs that have relevant dose-dependent secondary effects, such as non-steroidal anti-inflammatory drugs (NSAIDs). In this work, six multidrug salts involving six different NSAIDs and the antibiotic ciprofloxacin are reported. The novel solids were synthesized using mechanochemical methods and comprehensively characterized in the solid state. Moreover, solubility and stability studies, as well as bacterial inhibition assays, were performed. Our results suggest that our drug–drug formulations enhanced the solubility of NSAIDs without affecting the antibiotic efficacy.

According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug is also highly hygroscopic, thus showing stability problems. Another kind of worldwide prescribed drug is the non-steroidal anti-inflammatory drug (NSAID). These latter, on the contrary, show a low solubility profile; therefore, they must be administered at high doses, which increases the probability of secondary effects. In this work, novel drug-drug pharmaceutical solids combining MTF-NSAIDs have been synthesized in solution or by mechanochemical methods. The aim of this concomitant treatment is to improve the physicochemical properties of the parent active pharmaceutical ingredients. After a careful solid-state characterization along with solubility and stability studies, it can be concluded that the new molecular salt formulations enhance not only the stability of MTF but also the solubility of NSAIDs, thus giving promising results regarding the development of these novel pharmaceutical multicomponent solids.

This study aims at developing new multicomponent crystal forms of sulpiride, an antipsychotic drug. The main goal was to improve its solubility since it belongs to class IV of the BCS. Nine new adducts were obtained by combining the active pharmaceutical ingredient with acid coformers: a salt cocrystal and eight molecular salts. In addition, three novel co-drugs, of which two are molecular salts and one is a cocrystal, were also achieved. All samples were characterized in the solid state by complementary techniques (i.e., infrared spectroscopy, powder X-ray diffraction and solid-state NMR). For systems for which it was possible to obtain good-quality single crystals, the structure was solved by single crystal X-ray diffraction (SCXRD). SCXRD combined with solid-state NMR were used to evaluate the ionic or neutral character of the adducts. In vitro dissolution tests of the new crystal forms were performed and all the adducts display remarkable dissolution properties with respect to pure sulpiride.

Four molecular salts made from hexamethylenetetraminium and 2-chloro-4-nitrobenzoate have been synthesized and are reported, namely ammonium hexamethylenetetraminium bis(2-chloro-4-nitrobenzoate), NH4+·C6H13N4+·2C7H3ClNO4−, (I), hexamethylenetetraminium hydrogen bis(2-chloro-4-nitrobenzoate), 0.5C6H13N4+·C7H3.50ClNO4−, (II), hexamethylenetetraminium 2-chloro-4-nitrobenzoate, C6H13N4+·C7H3ClNO4−, (IIIa) and (IIIb). All four molecular salts show N+—H...O− hydrogen bonding. Salt (I) crystallized out with an NH4+ counter-ion which came from decomposition of 50% of the hexamethylenetetraminium cation in solution. (II) shows an unusual asymmetric unit, with both a hexamethylenetetraminium cation and a partially deprotonated 2-chloro-4-nitrobenzoate anion. Salts (IIIa) and (IIIb) are polymorphs of each other. This work shows that hexamethylenetetramine only protonates once, even in the presence of excess acid.

As a result of triple condensation of malonodinitrile with benzaldehyde and ethyl 2-chloro-3-oxobutanoate a compound with 3-azabicyclo[3.1.0]hexane framework is formed whose crystal structure is determined by X-ray crystallography. In the crystal structure a layered character of the molecular packing is found. Molecules are linked in the layer by H bonds of N-H...O=C and C-H...O=C types and also a large number of atom-atom contacts whose energy corresponds to potential wells. [ABSTRACT FROM AUTHOR]

Three molecular adducts of the antituberculosis drug isoniazid (INH) are synthesized with γ-resorcylic acid (γRA), phloroglucinol (PG), and gallic acid (GA). The new solid phases are preliminarily characterized by the thermal analysis (DSC/TGA) and powder X-ray diffraction. The formation of new solid phases is confirmed by single crystal X-ray diffraction, infrared (FT-IR) and Raman spectroscopy. All three new solid crystalline forms are stabilized by various hydrogen bonding interactions such as N+···H-O-, N···H-O, O···H-O, and π-π stacking. The FT-IR analysis puts forward that the solid form of INH1 is a salt whereas the INH2 and INH3 molecular complexes are cocrystals. We have also investigated the density of states (DOS), band structure, and atomic orbit projected density of state (PDOS) of title compounds by adopting the density functional theory (DFT) technique in the local density approximation (LDA). The electronic structure calculations show that energy states are delocalized in the k-space due the hydrogen and covalent bonds in the crystals. The frontier molecular orbital (FMO) analysis reveals that charge transfer takes place within the compounds. The Hirshfeld analysis shows that H-H and N⋯H-O hydrogen bonding interactions are dominant in all three molecular adducts of INH. [ABSTRACT FROM AUTHOR]

This short review presents and highlights the work performed by the Lisbon Group on the mechanochemical synthesis of active pharmaceutical ingredients (APIs) multicomponent compounds. Here, we show some of our most relevant contributions on the synthesis of supramolecular derivatives of well-known commercial used drugs and the corresponding improvement on their physicochemical properties. The study reflects, not only our pursuit of using crystal engineering principles for the search of supramolecular entities, but also our aim to correlate them with the desired properties. The work also covers our results on polymorphic screening and describes our proposed alternatives to induce and maintain specific polymorphic forms, and our approach to avoid polymorphism using APIs as ionic liquids. We want to stress that all the work was performed using mechanochemistry, a green advantageous synthetic technique.

This article demonstrates 5,7-dimethyl-1,8-naphthyridine-2-amine based organic salts formation of crystalline solids 1 – 9 , in which the acidic units have been integrated via a variety of non-covalent bonds. Addition of equivalents of the acidic units to the solution of 5,7-dimethyl-1,8-naphthyridine-2-amine generates the single protonated species which direct the anions. The nine compounds crystallize as their salts with the acidic H transferred to the aromatic N of the 5,7-dimethyl-1,8-naphthyridine-2-amine. In 2 , 3 , 4 , and 7 the methyl substituted N-rings were protonated, while others were protonated at the NH 2 substituted N-ring. All salts have been characterized via IR, mp, EA and XRD technique. The major driving force for the salt formation is attributed to the classical H-bonds from 5,7-dimethyl-1,8-naphthyridine-2-amine and the acids. Other extensive intermolecular interactions also play great functions in space association of the molecular assemblies in the relevant crystals. The common R 2 2 (8) graph set has been observed in all salts due to the H-bonds and other intermolecular interactions, except 2 , 4 , and 6 . For the synergistic interactions of the various non-covalent bonds, all salts displayed 3D structures. [ABSTRACT FROM AUTHOR]

We report a novel 1:1 cocrystal of β‐alanine with dl‐tartaric acid, C3H7NO2·C4H6O6, (II), and three new molecular salts of dl‐tartaric acid with β‐alanine {3‐azaniumylpropanoic acid–3‐azaniumylpropanoate dl‐tartaric acid– dl‐tartrate, [H(C3H7NO2)2]+·[H(C4H5O6)2]−, (III)}, γ‐aminobutyric acid [3‐carboxypropanaminium dl‐tartrate, C4H10NO2+·C4H5O6−, (IV)] and dl‐α‐aminobutyric acid { dl‐2‐azaniumylbutanoic acid– dl‐2‐azaniumylbutanoate dl‐tartaric acid– dl‐tartrate, [H(C4H9NO2)2]+·[H(C4H5O6)2]−, (V)}. The crystal structures of binary crystals of dl‐tartaric acid with glycine, (I), β‐alanine, (II) and (III), GABA, (IV), and dl‐AABA, (V), have similar molecular packing and crystallographic motifs. The shortest amino acid (i.e. glycine) forms a cocrystal, (I), with dl‐tartaric acid, whereas the larger amino acids form molecular salts, viz. (IV) and (V). β‐Alanine is the only amino acid capable of forming both a cocrystal [i.e. (II)] and a molecular salt [i.e. (III)] with dl‐tartaric acid. The cocrystals of glycine and β‐alanine with dl‐tartaric acid, i.e. (I) and (II), respectively, contain chains of amino acid zwitterions, similar to the structure of pure glycine. In the structures of the molecular salts of amino acids, the amino acid cations form isolated dimers [of β‐alanine in (III), GABA in (IV) and dl‐AABA in (V)], which are linked by strong O—H…O hydrogen bonds. Moreover, the three crystal structures comprise different types of dimeric cations, i.e. (A…A)+ in (III) and (V), and A+…A+ in (IV). Molecular salts (IV) and (V) are the first examples of molecular salts of GABA and dl‐AABA that contain dimers of amino acid cations. The geometry of each investigated amino acid (except dl‐AABA) correlates with the melting point of its mixed crystal. [ABSTRACT FROM AUTHOR]

Molecular salts, often observed as cocrystals, play an important role in the fields of pharmaceutics and materials science, where salt formation is used to tune the properties of active pharmaceutical ingredients (APIs) and improve the stability of solid-state materials. Salt formation via a proton-transfer reaction typically alters hydrogen-bonding motifs and influences supramolecular assembly patterns. We report here the molecular salts formed by the pyridyl bis-urea macrocycle 3,5,13,15,21,22-hexaazatricyclo[15.3.1.17,11]docosa-1(21),7(22),8,10,17,19-hexaene-4,14-dione, ( 1), and naphthalene-1,5-disulfonic acid (H2NDS) as two salt cocrystal solvates, namely 4,14-dioxo-3,5,13,15,21,22-hexaazatricyclo[15.3.1.17,11]docosa-1(21),7(22),8,10,17,19-hexaene-21,22-diium naphthalene-1,5-disulfonate dimethyl sulfoxide disolvate, C16H20N6O22+·C10H6O6S22−·2C2H6OS, ( 2), and the corresponding monosolvate, C16H20N6O22+·C10H6O6S22−·C2H6OS, ( 3). This follows the Δp Ka rule such that there is a proton transfer from H2NDS to ( 1), forming the reported molecular salts through hydrogen bonding. Prior to salt formation, ( 1) is relatively planar and assembles into columnar structures. The salt cocrystal solvates were obtained upon slow cooling of dimethyl sulfoxide-acetonitrile solutions of the molecular components from two temperatures (363 and 393 K). The proton transfer to ( 1) significantly alters the conformation of the macrocycle, changing the formerly planar macrocycle into a step-shaped conformation with trans- cis urea groups in ( 2) or into a bowl-shape conformation with trans- trans urea groups in ( 3). [ABSTRACT FROM AUTHOR]

Four mol­ecular salts made from hexa­methyl­ene­tetra­minium and 2-chloro-4-nitro­benzoate have been synthesized and are reported, namely ammonium hexa­methyl­ene­tetra­minium bis­(2-chloro-4-nitro­benzoate), NH4+·C6H13N4+·2C7H3ClNO4−, (I), hexa­methyl­ene­tetra­minium hydrogen bis­(2-chloro-4-nitro­benzoate), 0.5C6H13N4+·C7H3.50ClNO4−, (II), hexa­methyl­ene­tetra­minium 2-chloro-4-nitro­benzoate, C6H13N4+·C7H3ClNO4−, (IIIa) and (IIIb). All four mol­ecular salts show N+—HO− hydrogen bonding. Salt (I) crystallized out with an NH4+ counter-ion which came from decomposition of 50% of the hexa­methyl­ene­tetra­minium cation in solution. (II) shows an unusual asymmetric unit, with both a hexa­methyl­ene­tetra­minium cation and a partially deproton­ated 2-chloro-4-nitro­benzoate anion. Salts (IIIa) and (IIIb) are polymorphs of each other. This work shows that hexamethylenetetramine only protonates once, even in the presence of excess acid. [ABSTRACT FROM AUTHOR]

In the present study, two molecular complexes of 2,6-DHB with pharmaceutically active nutraceuticals i.e. nicotinic acid (NA) and nicotinamide (NIC) have been synthesized and preliminarily characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and FT-IR spectroscopy. Finally the crystal structures were solved by single crystal X-ray diffraction and the structures were analyzed in terms of supramolecular interactions. The salt 1 crystallizes in the monoclinic space group Cc , with a = 10.1503(1) Å, b = 12.3821(1) Å, c = 9.5291(1) Å, β = 94.343(1)°, V = 1194.20(2) Å 3 , Z = 4. The salt 2 crystallizes in monoclinic space group P 2 1 / n , with a = 7.0098 (1) Å, b = 12.5495 (1) Å, c = 13.4048 (1) Å, β = 92.746 (1)°, V = 1177.86 (2) Å 3 , Z = 4. The molecular packing of both salts are stabilized by N + –H⋯O − , O–H⋯O − , N–H⋯O and O–H⋯O hydrogen bonding interactions. DFT calculations substantiate the features of crystal structures. The Hirshfeld surfaces and the associated 2D fingerprint plots were investigated which revealed that more than two-third of close contacts were associated with relatively weak H⋯H, C⋯H and H⋯C interactions. The use of 3-D Hirshfeld surfaces in combination with 2-D fingerprint plots revealed that these weak interactions play major role in molecular crystal packing. [ABSTRACT FROM AUTHOR]

• The synthesis and crystal structures of AP−PHBA and AP−NA are illustrated. • Molecular salts are characterized by Single crystal XRD, PXRD, FTIR, UV-Vis, NMR and computational methods. • Hydrogen bonding assembly is described with the help of graph set notations. • Intermolecular interactions are analyzed through Hirshfeld surfaces. Herein, synthesis, analytical and structural characterization of two new molecular salts (AP − PHBA and AP − NA) of 2 − aminopyridine (AP) using GRAS molecules i.e, p − hydroxybenzoic acid (PHBA) and nicotinic acid (NA) has been envisaged. The TGA/DSC revealed that both molecular salts were thermally more stable than the AP molecule. In the UV-Vis spectrum of AP − PHBA there observed a bathochromic shift (λ max 298 nm to 305 nm) caused by extended conjugation due to the hydroxy group at the para position of PHBA which might influence the photophysical property and no such shift was observed in AP − NA (λ max =298 nm). Both the salts were found to be dominated by the two − point charge assisted acid − pyridine heterosynthonic ring motif with graph set notation R 2 2 (8). This was held via N+ − H···O− and N − H···O linkages that formed between the 2 − aminopyridinium cation and carboxylate anions. In both crystals, a ribbon synthon linking the ring synthon via N2 A —H2 AB / AC ···O3 B hydrogen bonds was noted with the chain motifs C 2 1 (6) and C 2 2 (6). Furthermore, the C1 A —H1 AA ···N1 B and N2 A —H2 AC ···O3 B networks were associated to build a large tetramer with R 4 4 (22) was seen in the AP − NA salt system. From Hirshfeld surfaces analysis, it was noteworthy that the variation in the percentage contribution of O···H (20.8% in AP − PHBA and 15.8% in AP − NA) and N···H (1.9% in AP − PHBA and 12.1% in AP − NA) interconnects signify the importance of hydroxy group (PHBA) and pyridine N (NA) in stabilizing the crystal systems. Hence, a complete analysis of crystal structure and supramolecular packing of the two molecular salts AP − PHBA and AP − NA was presented. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Poly nitro aromatic compounds are high energy density materials. Carbon-bonded anionic sigma complexes derived from them have remarkable thermal stability. At present there is a strong requirement for thermally stable insensitive high energy density materials (IHEDMs) in the energetic field which necessitates the present investigation. Results: Three new carbon-bonded anionic sigma complexes were synthesized from 2-chloro-1,3,5-trinitrobenzene, 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (1,3-dimethylbarbituric acid) and bases such as triethanolamine, pyridine and N,N-diethylaniline, characterized by UV-VIS, IR, 1H NMR, 13C NMR and elemental analysis data. Their molecular structures were further ascertained through single crystal X-ray diffraction studies. TGA/DTA testings were undertaken at four different heating rates (5, 10, 20 and 40 K/min) and energy of activation was determined employing Ozawa and Kissinger plots. Conclusions: The reported carbon-bonded anionic sigma complexes were prepared through single pot synthesis in good yield with high purity. These complexes are molecular salts comprise of cation and anion moieties. Because of the salt-like nature, they are highly stable upto 300°C and decompose in two stages on further heating. They are stable towards impact of 2 kg mass hammer upto height limit (160 cm) of the instrument. The delocalization of the negative charge and various hydrogen bonds noticed in their crystals are the added factors of their thermal stability. The new insensitive high energy density materials of the present findings may receive attention in the field of energetics in future. [ABSTRACT FROM AUTHOR]

Aspirin is one of the most widely used analgesic, antipyretic, and anti-inflammatory drugs. Herein we disclose a way to transform aspirin into novel multicomponent crystal forms of salicylic acid, also a long-known analgesic with anti-inflammatory properties, among others, covering a broad spectrum of applications, including skin care products. A salicylic acid:salicylate ammonium salt and a salicylate:2-methyl-4-oxopentan-2-aminium molecular salt are concomitantly formed in acetone/ammonia solutions, resulting from aspirin decomposition. Furthermore the 2-methyl-4-oxopentan-2-aminium cation results from a sequence of in situ reactions: (i) imine formation, in which acetone is known to undergo under basic pH conditions; (ii) nucleophilic attack of α-carbon of the deprotonated acetone to the imine yielding 4-amino-4-methylpentan-2-one; and (iii) protonation of 4-amino-4-methylpentan-2-one. In the structures obtained for the novel multicomponent crystal forms, the strong charge-assisted N-H···O/O hydrogen bonds between the drug molecule and the co-former play a key function in the supramolecular arrangement. The typical $${\mathbf{R}}_{{\mathbf{2}}}^{{\mathbf{2}}} ({\mathbf{8}})$$ carboxylic···carboxylic homosynthon observed in salicylic acid was inhibited by the salt formation. These results are in agreement with the results of a careful survey on the Cambridge Structural Database. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

New molecular salts have been synthesized from chloronitroaromatic compounds, 1,3-disubstituted pyrimidine-2,4,6(1H,3H,5H)-trione and amines. Structures of these molecular salts have been established by elemental analysis and spectroscopic techniques (UV-Vis, FT-IR, H NMR and C NMR). The structures of all these molecular salts have also been ascertained through single crystal X-ray diffraction studies. They crystallize either in the monoclinic or triclinic system. A number of O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds stabilize the crystal lattice. Disorder has been observed in the cation moiety of these molecular salts. TGA/DTA studies of these molecular salts have also been undertaken at four different heating rates (5, 10, 20 and 40 K/min) and energy of activation has been determined by employing Ozawa and Kissinger plots. Impact sensitivity test and activation energies imply that the synthesized molecular salts are insensitive high energy density materials. Graphical Abstract: Essence of the paper: The article focuses on the formation of new molecular salts with good thermal stability which may be used as the insensitive high energy density materials (IHEDMS). A figure of the most important structure:[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The structures of two neutral and 17 salt forms of the base (1 R, 2 S)-(−)-ephedrine are reported. These structures are discussed in the light of the conformers of the ephedrine moiety, the existence of bilayers and the structure determining role of the counterions. Overall, most of the salt structures are essentially derived from the observed packing of the neutral base and are dominated by the amphiphilic nature of the ephedrine molecular structure. In a few cases the size and hydrophobicity of the counterion disrupts this behaviour. [ABSTRACT FROM AUTHOR]

Synthesis, crystal structure of two new ABTS (2,2-azinobis-3-ethyl benzothiazoline-6-sulfonate) hybrid organic–inorganic salts containing Fe3+ or Cu2+ cations is described. Electrochemical oxidation of the diammonium salt (ABTS)(NH4)2·2H2O in presence of FeSO4·7H2O or CuSO4·5H2O in aqueous solutions yields to black single crystals of Fe2O(ABTS)2(H2O)16 and Cu(ABTS)2·(H2O)8. Due to the low thermal stability of three water molecules intercalated in the network, crystal structures were solved at 200 K using a STOE IPDS diffractometer. Cell parameters are: a=8.5635(7) A˚, b=8.69236(6) A˚, c=20.336(2) A˚, α=84.69(1)°, β=82.10(1)°, γ=81.767(9)°, space group P-1 for the iron complex and a=15.691(3) A˚, b=14.474(3) A˚, c=21.552(4) A˚, β=94.60(3)°, space group P21/c for the copper complex. Transition metal cations are in an octahedral coordination with a different condensation, corner-sharing octahedra Fe2O11 dimmers or CuO6 octahedra. Taking in account these structural results, the chemical formula must be written: [Fe2O(H2O)10][ABTS]2·6H2O and [Cu(H2O)5][ABTS]2·3H2O. The crystalline networks are also different; the iron complex salt presents a bidimensional character and the copper one can be considered as a one-dimensional network. Values obtained from bond valence calculations correspond to iron Fe3+ and copper Cu2+. A Mossbauer study shows that iron is in a high spin 3+ oxidation state without any magnetic ordering even at 4 K (isomer shift δ=0.62 mm s−1 and quadrupole splitting ΔE=1.64 mm s−1). [Copyright &y& Elsevier]

• Molecular salts of N-heterocyclic bases with salicylic and benzoic acid were obtained as crystals. • Molecular structure of three salts was determined by X-ray diffraction. • Non-covalent interactions in synthons have been discussed in details. • The AIM analysis of non-covalent interactions was carried out. • The O∙∙∙O, O∙∙∙S, Cl∙∙∙Cl, etc. collaborate to direct the supramolecular arrangements. Reaction between 2-amino-3-methylpyridine, 2-amino-4-methylbenzothiazole with salicylic acid, and 2-amino-5-chloropyridine with 3-chlorobenzoic acid were carried out and respective molecular salts 1–3 were obtained. During reactions, proton transfer from acid to endocyclic N of the base was observed. Structural elucidation of all compounds was carried out with the help of FT-IR and X-ray Diffraction for single crystals. The acid/base pairs in a molecular salt are held together with the help of H- and charge-assisted bonding and additional non-covalent bonding extend the supramolecular structure. All hydrogen bonds and secondary interactions have been discussed and a detailed comparison of experimental data with theoretical calculations through AIM, NBO and Wiberg bond index analysis has been made. The non-covalent character was mainly typified by positive values of Laplacian of electronic density. The theoretical studies demonstrate that other than classical H-bonds, the non-classical and secondary non-covalent interactions are very important to direct supramolecular structure of the respective molecular salt. The DFT calculations with solvent model SMD proved a good alternative to deduce the molecular salt formation when the 0>ΔpKa>3. Moreover, global reactivity descriptors (GRD) have been calculated utilizing the energies of FMOs. The calculated values for HOMO of compounds 1–3 , -5.469, -5.642 and -6.435, respectively indicate that the compounds adopt the numerical order in terms of electron donation/Lewis basicity. The molecular salt formation is more feasible for heterosynthon 1 and least for 3. Reaction between 2-amino-3-methylpyridine, 2-amino-4-methylbenzothiazole with salicylic acid, and 2-amino-5-chloropyridine with 3-chlorobenzoic acid were carried out and respective heterosynthons 1–3 were isolated. Structural elucidation of all compounds was carried out with the help of FT-IR and X-ray Diffraction for single crystals. Experimental data was validated by DFT and noncovalent interactions are discussed in full detail. Image, graphical abstract [ABSTRACT FROM AUTHOR]

This short review presents and highlights the work performed by the Lisbon Group on the mechanochemical synthesis of active pharmaceutical ingredients (APIs) multicomponent compounds. Here, we show some of our most relevant contributions on the synthesis of supramolecular derivatives of well-known commercial used drugs and the corresponding improvement on their physicochemical properties. The study reflects, not only our pursuit of using crystal engineering principles for the search of supramolecular entities, but also our aim to correlate them with the desired properties. The work also covers our results on polymorphic screening and describes our proposed alternatives to induce and maintain specific polymorphic forms, and our approach to avoid polymorphism using APIs as ionic liquids. We want to stress that all the work was performed using mechanochemistry, a green advantageous synthetic technique. [ABSTRACT FROM AUTHOR]

Molecular salts of terephthalic acid (TA) with 2-amino-4-chloropyridine (ACP), 2-amino-6-methylpyridine (AMP), 2-aminothiazole (AT) and 2-amino-5-methylthiazole (AMT), were prepared with an intent to get new crystalline materials with improved physical properties. Crystals of the desired compounds were obtained through slow evaporation technique. The solid state structures reveal that proton transfer from acid to aromatic nitrogen of the base occurs, thus affording molecular salts of general representation AT-TA-AT (1), AMT-TA-AMT (2), AMP-TA-AMP (3) and ACP-TA-ACP (4). The NH 2 group at position 2 of each amino base is still available to interact with C O to afford planar fragment. The COOH functional groups in TA at para position with respect to each other accommodated the respective base in a 1:2 M ratio (acid:base, respectively) to give almost planar Base-Acid-Base (BAB) fragments. The resultant molecular salts were structurally characterized with the help of FT-IR and X-ray diffraction. The antimicrobial (selected strains), antioxidant (2,2-DiPheny-1-Picry-l-Hydrazyl, DPPH and 2,2′-Azino- Bis (3-ethylbenzoThiazoline-6-Sulphonic acid, ABTS) and enzyme inhibition (AChE, BChE and AGS) potencies of the synthesized Base-Acid-Base type, molecular salts were explored. In addition to improved physical properties, all molecular salts showed promising biological activities. The optimization, natural bonding orbitals (NBOs) and FT-IR analysis of the molecular salts were carried out by DFT/B3LYP/6-311G (d,p) level in PCM model with ethanol solvent. However, frontier molecular orbitals (FMOs) analysis was performed utilizing TD-DFT/B3LYP/6-311G (d,p) level. A comparative analysis reveals that consistency is found between the experimental and theoretical findings of geometric parameters and vibrational frequencies. The inter-molecular hydrogen bond (IHB) and hyper conjugative interactions are characterized by NBO analysis. The chemical stability of molecules is evaluated by FMOs. The energies of FMOs are also used to calculate the global reactivity descriptor parameters. The obtained high softness values indicated that entitled compounds might be biologically active. 2-Aminopyrazole and 2-Aminopyridine derivatives possess N-nucleophilic centers which were used for establishment of non-covalent interactions between these species and terephthalic acid. The behaviour of both N centers in a base coformer was different, the endocyclic N, being stronger nucleophile was capable to abstract a proton from the acid and exocyclic N participated in conventional H-bonding. Thus both the oxygen centers of an acid functionality and both N-centers of the base/coformer were linked to each other thereby affording molecular salts. Four salts were obtained in crystalline form, were structurally characterized with the help of FT-IR, X-ray Diffraction and experimental data pertaining to these salts were calculated by DFT. Image 1 • Terephthalic acid, a dioic acid, 2-aminopyrazole and 2-aminopyradine derivatives were treated together. • Proton abstraction/transfer was observed from acid to endocyclic N of the base coformer. • Four molecular salts were isolated and their structure was confirmed by single crystal X-ray diffraction. • All structural parameters and spectroscopic data were calculated by using TD-DFT/B3LYP/6-311G (d,p) level. • Solid state (experimental) and solution state (theoretical) data were compared and found in close agreement with each other. [ABSTRACT FROM AUTHOR]