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Piperine, a secondary metabolite compound, has a low solubility in water. In this study, through the formation of multicomponent crystals, glutamic acid is employed as a coformer to enhance the physicochemical characteristics and improve the dissolution rate of piperine. Solvent drop grinding was used to create multicomponent crystals using molar ratios of piperine and glutamic acid of 1:1 (F1), 1:2 (F2), and 2:1 (F3). Characterization of the solids' properties was performed using X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), and dissolution profiles in accordance with the United States Pharmacopoeia (USP), facilitating a comparison with the physical mixture and pure piperine. XRD results showed a decrease in intensity, and DSC showed a decrease in the endothermic peak transition temperature and significant decreases in enthalpy value. The FT-IR spectra showed a change in wave numbers, and no new functional groups were formed. SEM revealed changes in particle morphology forming new crystal habits. When contrasted with the physical mixture and pure piperine, the dissolution profiles of multicomponent crystals F1, F2, and F3 demonstrate increased dissolution rates, F2 exhibiting a 1.57-fold increase, followed by 1.44-fold for F1 and 1.49-fold for F3. Multicomponent crystals F1, F2, and F3 show a better dissolution profile than the physical mixture and pure piperine, with dissolved substance percentages of 63.60±6.56, 68.59±2.53, 65.25±12.10, 44.91±10.95, and 43.58±8.92, respectively, after 60 minutes at 37±0.5 °C. The multicomponent crystals produced using solvent drop grinding exhibited enhanced physicochemical features and an increased dissolution rate. [ABSTRACT FROM AUTHOR]

Multicomponent crystals have great scientific potential because of their amenability to crystal engineering in terms of composition and structure, and hence their properties can be easily modified. More and more research areas are employing the design of multicomponent materials to improve the known or induce novel physicochemical properties of crystals, and recently they have been explored as materials with abnormal pressure behaviour. The cocrystal of 1,2-bis(4′-pyridyl)ethane and fumaric acid (ETYFUM) exhibits a negative linear compressibility behaviour comparable to that of framework and metal-containing materials, but overcomes many of their deficiencies restricting their use. Herein ETYFUM was investigated at low temperature to reveal negative thermal expansion behaviour. Additionally, a cocrystal isostructural with ETYFUM, based on 1,2-bis(4′-pyridyl)ethane and succinic acid (ETYSUC), was exposed to high pressure and low temperature, showing that its behaviour is similar in nature to that of ETYFUM, but significantly differs in the magnitude of both effects. It was revealed that the minor structural difference between the acid molecules does not significantly affect the packing under ambient conditions, but has far-reaching consequences when it comes to the deformation of the structure when exposed to external stimuli.

Fenofibric acid (FA) is a class II biopharmaceutical system drug, a potential drug for antihyperlipidemic. FA lowers low-density lipoprotein (LDL) and triglyceride levels and increases high-density lipoprotein (HDL). Due to its low solubility, the bioavailability of FA is also low. To overcome the undesirable effects of these biopharmaceutical properties, this study focused on improving the solubility of FA in the form of FA multicomponent crystals with theobromine (TH) coformer using solvent drop grinding as the crystallisation method. Multicomponent crystals of FA with TH coformer named FA-TH were successfully prepared. Detailed structural studies of this new solid form were carried out using powder X-ray diffraction (PXRD), Fourier Transform Infrared (FT-IR), Differential Scanning Calorimetry (DSC), Scanning Electron Microscope (SEM), and hot-stage microscopy. The thermogram of the DSC test showed that the melting point of FA-TH multicomponent crystals was lower than the melting point of the forming compound. The X-ray diffraction exhibits diffraction peaks of FA-TH multicomponent crystal and superimposition between the diffraction peaks of FA and TH. Solubility of FA-TH multicomponent crystals showed improvement up 4.4-fold compared to pure FA. These results demonstrate the potential of this new solid form to improve the solubility of FA. [ABSTRACT FROM AUTHOR]

Introduction: The screening of multicomponent crystal system (MCC) is a key method for improving physicochemical properties of active pharmaceutical ingredients (APIs). The challenges associated with experimental salt screening include a large number of potential counterions and solvent systems and tendency to undergo disproportionation to produce free form during crystallization. These challenges may be mitigated by a combination of experimental and computational approaches to salt screening. The goal of this study is to evaluate performance of the counterion screening methods and propose and validate novel approaches to virtual solvent screening for MCC crystallization. Methods: The actual performance of the ΔpKa > 3 rule for counterion selection was validated using multiple screenings reports. Novel computational models for virtual solvent screening to avoid MCC incongruent crystallization were proposed. Using the ΔpKa rule, 10 acid counterions were selected for experimental aripiprazole (APZ) salt screening using 10 organic solvents. The experimental results were used to validate the proposed novel virtual solvent screen models. Results: Experimental APZ salt screening resulted in a total of eight MCCs which included glucuronate, mesylate, oxalate, tartrate, salicylate and mandelate. The new model to virtually screen solvents provided a general agreement with APZ experimental findings in terms of selecting the optimal solvent for MCC crystallization. Conclusion: The rational selection of counterions and organic solvents for MCC crystallization was presented using combined novel computational model as well as experimental studies. The current virtual solvent screen model was successfully implemented and validated which can be easily applied to newly discovered APIs. [ABSTRACT FROM AUTHOR]

Phthalocyanines (Pcs) are 18-electron π-conjugated macrocyclic ring systems with proven activities in diverse fields, including pharmaceuticals and catalysis. These demonstrated activities are often alluded to as their fascinating photophysical and photochemical dispositions, which are usually dependent on their molecular structures. However, many of these molecules suffer from aggregation due to π–π stacking and have limited insolubility in hydrophilic media, which limits their extensive utilisation in pharmaceutical applications. This review will explore the possibility of fine-tuning the physicochemical properties of phthalocyanines when designed as multicomponent crystals. Among the proven and SMART approaches that have been shown to enhance drug solubility without altering the molecular structure is co-crystallisation. This protocol involves the design and formation of non-covalent interactions between two or more molecular entities to create a supramolecular assembly and subsequently afford multicomponent crystals (MCCs). A systematic review of the Cambridge Structural Database repository yielded several single and multicomponent crystals of Pcs; however, most of them were either salts or solvates, with only a few reports on their co-crystals.

The alkaloid piperine is the main bioactive compound in black pepper (Piper nigrum L) and exhibits antihyperlipidemic activity. Piperine is a Biopharmaceutical Classification System (BCS) Class II compound, which has low water solubility, resulting in low bioavailability. This study aims to examine the effects of multicomponent nicotinic acid-piperine crystals on antihyperlipidemic activity in rats fed a high-fat diet. To increase the effectiveness of piperine, we prepared multicomponent crystals by the solvent-drop grinding method, using nicotinic acid as a co-former. The antihyperlipidemic activity of the preparation was estimated by measuring total cholesterol (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDLc), and high-density lipoprotein cholesterol (HDLc), using the enzymatic colorimetric method. Rats fed a high-fat diet exhibited an increase in plasma lipid levels. However, rats administered the multicomponent piperine-nicotinic acid crystals at a dose of 40 mg/kg/BW showed significantly (p<0.050) reduced plasma lipid levels. Compared with hyperlipidemic rats, multicomponent crystals of piperine-nicotinic acid decreased TC from 237.8±8.02 mg/dL to 174.53±7.07mg/dL, TG levels from 208.33±5.79 to 85.95±7.41mg/dL, and LDLc levels from 144.225±15.99 mg/dL to 88.55±10.83mg/dL but increased HDLc levels from 51.93±10.92mg/dL to 68.78±2.56 mg/dL. Thus, the results demonstrate that the multicomponent piperine-nicotinic acid crystals lowered TC, TG, and LDLc but increased HDLc. [ABSTRACT FROM AUTHOR]

This study exploits the polymorphism and multi-component crystal formation of γ-amino butanoic acid (GABA) and its pharmaceutically active derivative, gabapentin. Two polymorphs of GABA and both polymorphs of gabapentin are structurally revisited, together with gabapentin monohydrate. Hereby, GABA form II is only accessible under special conditions using additives, whereas gabapentin converts to the monohydrate even in the presence of trace amounts of water. Different accessibilities and phase stabilities of these phases are still not fully clarified. Thus, indicators of phase stability are discussed involving intermolecular interactions, molecular conformations, and crystallization environment. Calculated lattice energy differences for polymorphs reveal their similar stability. Quantification of the hydrogen bond strengths with the atoms-in-molecules (AIM) model in conjunction with non-covalent interaction (NCI) plots also shows similar hydrogen bond binding energy values for all polymorphs. We demonstrate that differences in the interacting modes, in an interplay with the intermolecular repulsion, allow the formation of the desired phase under different crystallization environments. Salts and co-crystals of GABA and gabapentin with fumaric as well as succinic acid further serve as models to highlight how strongly HBs act as the motif-directing force in the solid-phase GABA-analogs. Six novel multi-component entities were synthesized, and structural and computational analysis was performed: GABA fumarate (2:1); two gabapentin fumarates (2:1) and (1:1); two GABA succinates (2:1) and (1:1); and a gabapentin:succinic acid co-crystal. Energetically highly attractive carboxyl/carboxylate interaction overcomes other factors and dominates the multi-component phase formation. Decisive commonalities in the crystallization behavior of zwitterionic GABA-derivatives are discussed, which show how they can and should be understood as a whole for possible related future products. [ABSTRACT FROM AUTHOR]

Crystals based on alkaline earth metal difluorides are widely used optical materials. In this study, in order to expand the range of optical matrices, multicomponent Pb1−x−yCdxSryF2 (0.27 < x < 0.55, 0.06 < y < 0.18) solid solution crystals with a fluorite structure (sp. gr. Fm-3m) were grown from melt using the vertical directional crystallization technique for the first time. The densities and refractive indices of the grown crystals vary depending on the quantitative content components (x and y) in the ranges of 6.6039(5)–7.5232(5) g/cm3 and 1.6403–1.7084, respectively. The optical transmission and electrochemical impedance spectra were studied. The homogenous composition regions of non-cellular crystallization of this ternary solid solution at a crystallization rate of 6 mm/h and an interface temperature gradient of 80 deg/cm were experimentally determined as 0.30 < x < 0.35, 0 < y < 0.6. These grown crystalline materials may be of interest as high-density highly refractive cubic isomorphic hosts and low-temperature ionic conductors (~2 × 10−5 S/cm at room temperature) for various applications. [ABSTRACT FROM AUTHOR]

Phthalocyanines (Pcs) are 18-electron π-conjugated macrocyclic ring systems with proven activities in diverse fields, including pharmaceuticals and catalysis. These demonstrated activities are often alluded to as their fascinating photophysical and photochemical dispositions, which are usually dependent on their molecular structures. However, many of these molecules suffer from aggregation due to π–π stacking and have limited insolubility in hydrophilic media, which limits their extensive utilisation in pharmaceutical applications. This review will explore the possibility of fine-tuning the physicochemical properties of phthalocyanines when designed as multicomponent crystals. Among the proven and SMART approaches that have been shown to enhance drug solubility without altering the molecular structure is co-crystallisation. This protocol involves the design and formation of non-covalent interactions between two or more molecular entities to create a supramolecular assembly and subsequently afford multicomponent crystals (MCCs). A systematic review of the Cambridge Structural Database repository yielded several single and multicomponent crystals of Pcs; however, most of them were either salts or solvates, with only a few reports on their co-crystals. [ABSTRACT FROM AUTHOR]

Developing multicomponent crystal forms, especially cocrystals and salts, is becoming a promising pathway to improve the solubility and bioavailability of drugs. Herein, new multicomponent crystals of SHR0302, a new generation of Janus Kinase (JAK) inhibitor that suffers from poor solubility, were developed based on a cooperative approach of computational and experimental coformer screenings. Virtual screening methods, including the conductor-like screening model for realistic solvents (COSMO-RS) and molecular complementary (MC) analysis, were employed to predict the binding affinity between SHR0302 and selected coformers. The developed screening method was capable of reducing the screening database to 30 coformers from a total of 42 proposed coformers. The proof-of-concept experimental screening study was performed to demonstrate the efficiency of computational screening, wherein three new multicomponent crystalline forms were found and fully characterized by powder X-ray diffraction, thermal analysis, and IR and 1H-NMR spectroscopy. Further, the measurements of the solubility property of these new multicomponent crystal forms reveal an apparent promotion compared with the drug alone. Finally, the receiver operator characteristic (ROC) curve was used to assess the prediction performance of the COSMO-RS model. It was found that the established screening model can effectively shorten the experimental screening time and efforts. [ABSTRACT FROM AUTHOR]

Crystals based on alkaline earth metal difluorides are widely used optical materials. In this study, in order to expand the range of optical matrices, multicomponent Pb1−x−yCdxSryF2 (0.27 < x < 0.55, 0.06 < y < 0.18) solid solution crystals with a fluorite structure (sp. gr. Fm-3m) were grown from melt using the vertical directional crystallization technique for the first time. The densities and refractive indices of the grown crystals vary depending on the quantitative content components (x and y) in the ranges of 6.6039(5)–7.5232(5) g/cm3 and 1.6403–1.7084, respectively. The optical transmission and electrochemical impedance spectra were studied. The homogenous composition regions of non-cellular crystallization of this ternary solid solution at a crystallization rate of 6 mm/h and an interface temperature gradient of 80 deg/cm were experimentally determined as 0.30 < x < 0.35, 0 < y < 0.6. These grown crystalline materials may be of interest as high-density highly refractive cubic isomorphic hosts and low-temperature ionic conductors (~2 × 10−5 S/cm at room temperature) for various applications.

Supramolecular chemistry under mechanochemical conditions has drawn attention because it can induce low‐solubility molecules to self‐assemble, although most of the reported examples have been limited to two‐component systems. We applied mechanochemical synthesis to achieve multimolecular self‐assembly in more challenging three‐component systems. The produced crystals showed multicolor solid‐state luminescence depending on the components when exposed to UV light. Optical outputs and X‐ray diffraction studies were used to examine the self‐assembling behavior in greater depth. Using synchrotron radiation, in situ X‐ray diffraction permitted direct observation of the milling process, which started the self‐assembly process within 1 min. This research emphasizes the importance of multicomponent molecules with optical functions and self‐assembling behavior and offers the possibility of developing more complicated multicomponent crystals and organic solid solutions for advanced materials. [ABSTRACT FROM AUTHOR]

Energy/enthalpy of intermolecular hydrogen bonds (H-bonds) in crystals have been calculated in many papers. Most of the theoretical works used non-periodic models. Their applicability for describing intermolecular H-bonds in solids is not obvious since the crystal environment can strongly change H-bond geometry and energy in comparison with non-periodic models. Periodic DFT computations provide a reasonable description of a number of relevant properties of molecular crystals. However, these methods are quite cumbersome and time-consuming compared to non-periodic calculations. Here, we present a fast quantum approach for estimating the energy/enthalpy of intermolecular H-bonds in crystals. It has been tested on a family of crystalline peroxosolvates in which the H∙∙∙O bond set fills evenly (i.e., without significant gaps) the range of H∙∙∙O distances from ~1.5 to ~2.1 Å typical for strong, moderate, and weak H-bonds. Four of these two-component crystals (peroxosolvates of macrocyclic ethers and creatine) were obtained and structurally characterized for the first time. A critical comparison of the approaches for estimating the energy of intermolecular H-bonds in organic crystals is carried out, and various sources of errors are clarified. [ABSTRACT FROM AUTHOR]

Two new multicomponent crystals consisting of 3,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (1) with 1,3-bis(4-methoxyphenyl)prop-2-en-1-one (2) and with dimethylformamide (DMF), both in 1:1 ratio, prepared and structurally characterized. The occurrence of 1 in different crystal structures enabled a comparison of hydrogen bonding contacts between the two structures as well as with the known structure of pure 1. The backbone of molecule 1 was similar in the structures but the orientation of the methoxy groups varied. Molecule 1 was involved in various combinations of the possible hydrogen bonding contacts, including N–H...O=C, N–H...OMe, and N–H...S. Both N–H hydrogens in the cocrystal (1–2) and the solvate (1-DMF) participated in hydrogen bonding but only one hydrogen atom took part in the structure of pure 1. The S atom accepted contacts in both the structures of pure 1 and cocrystal 1–2 but not in that of the 1-DMF solvate. The oxygen atoms of both methoxy groups acted as acceptors in the structure of pure 1, whereas one oxygen was involved in the 1-DMF solvate and none in cocrystal 1–2. [ABSTRACT FROM AUTHOR]

Developing multicomponent crystal forms, especially cocrystals and salts, is becoming a promising pathway to improve the solubility and bioavailability of drugs. Herein, new multicomponent crystals of SHR0302, a new generation of Janus Kinase (JAK) inhibitor that suffers from poor solubility, were developed based on a cooperative approach of computational and experimental coformer screenings. Virtual screening methods, including the conductor-like screening model for realistic solvents (COSMO-RS) and molecular complementary (MC) analysis, were employed to predict the binding affinity between SHR0302 and selected coformers. The developed screening method was capable of reducing the screening database to 30 coformers from a total of 42 proposed coformers. The proof-of-concept experimental screening study was performed to demonstrate the efficiency of computational screening, wherein three new multicomponent crystalline forms were found and fully characterized by powder X-ray diffraction, thermal analysis, and IR and 1H-NMR spectroscopy. Further, the measurements of the solubility property of these new multicomponent crystal forms reveal an apparent promotion compared with the drug alone. Finally, the receiver operator characteristic (ROC) curve was used to assess the prediction performance of the COSMO-RS model. It was found that the established screening model can effectively shorten the experimental screening time and efforts.

Two new multicomponent crystals consisting of 3,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (1) with 1,3-bis(4-methoxyphenyl)prop-2-en-1-one (2) and with dimethylformamide (DMF), both in 1:1 ratio, prepared and structurally characterized. The occurrence of 1 in different crystal structures enabled a comparison of hydrogen bonding contacts between the two structures as well as with the known structure of pure 1. The backbone of molecule 1 was similar in the structures but the orientation of the methoxy groups varied. Molecule 1 was involved in various combinations of the possible hydrogen bonding contacts, including N–H…O=C, N–H…OMe, and N–H…S. Both N–H hydrogens in the cocrystal (1–2) and the solvate (1-DMF) participated in hydrogen bonding but only one hydrogen atom took part in the structure of pure 1. The S atom accepted contacts in both the structures of pure 1 and cocrystal 1–2 but not in that of the 1-DMF solvate. The oxygen atoms of both methoxy groups acted as acceptors in the structure of pure 1, whereas one oxygen was involved in the 1-DMF solvate and none in cocrystal 1–2.

This study aims to improve the dissolution rate of ketoprofen by preparing multicomponent crystals with tromethamine. The multicomponent crystals (equimolar ratio) of ketoprofen and tromethamine were prepared by the solvent co-evaporation method. The solid-state properties of the resulting powder were characterized by powder X-ray diffraction, DSC thermal analysis, FT–IR spectroscopy, solubility, and in vitro dissolution rate. The crystal structure of the multicomponent crystal was determined by single-crystal X-ray diffraction analysis. The results showed that the powder X-ray diffraction pattern of the ketoprofen–tromethamine binary system was different from that of the starting materials. This difference indicates the formation of a new crystalline phase between ketoprofen and tromethamine (equimolar ratio). The DSC thermogram of the ketoprofen–tromethamine binary system exhibited a single and sharp endothermic peak at 128.67 °C, attributed to the melting point of a multicomponent crystal of ketoprofen–tromethamine. A single-crystal X-ray analysis revealed that ketoprofen–tromethamine formed a layered structure, salt-type multicomponent crystal. The solubility and dissolution rate of the multicomponent crystal were notably enhanced compared to the intact ketoprofen. The ketoprofen–tromethamine binary system forms salt-type multicomponent crystals, which can significantly increase the solubility and dissolution rate.

The aim of the study was to investigate the relationship between the melting point and the supramolecular structure of three multi-component crystals of aliphatic dicarboxylic acids with 2,2′-bipyridine and to investigate the conformations of 2,2′-bipyridine in published multi-component crystals. The crystals were prepared using the solvent evaporation method and were characterized using single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). The crystal structures were further analyzed using CrystalExplorer, and the results were correlated with the melting points. The results of the conformation analysis of the reported multi-component crystals of 2,2′-bipyridine are also presented.

Abstract In this review, we explain how pyrazine (hereafter as pz) leds to various structures spanning from multicomponent molecular crystals to coordination polymers. An important factor in the study of pz -based compounds is the crucial roles of the non-covalent interactions; we examined it with pz -based cocrystals and salts and also show that how purposeful selection of ligands with various functional groups can influence the physico-chemical property of the final structures. Furthermore, the CSD analysis revealed that due to the N , N ′- exo -bidentate nature of pz , the probability of polymeric compounds are much more than the dimers and monomers counterparts. We also showed that pz -based coordination polymers (CPs) can be categorized into two groups; i) CPs that expanding with only pz ligand into 1D to 3D structures. ii) CPs that are constituted from pz and some auxiliary ligands in which pz linked 2D layers and created porous extended CPs and metal organic frameworks (MOFs). We presented important applications of pz -based compounds in the spin crossover systems. Finally, this review summarized some structural features of pz ligand that are useful for the design and preparation of new materials, serving as a reference in learning more about this particular area which inspired new researchers. Graphical abstract Image 108 Highlights • Structural overview of pyrazine base compounds by CSD analysis. • Multicomponent structures of cocrystals and salts containing pyrazine. • Pyrazine base metal organic frameworks. • Important applications of pyrazine base Spin Crossover systems. [ABSTRACT FROM AUTHOR]

A novel multicomponent crystal (MC) of mefenamic acid (MA) and N-methyl- d -glucamine (MG) had been prepared to improve the physicochemical properties of poorly soluble drugs, and was characterized for its physicochemical properties by powder X-ray diffraction analysis, differential scanning calorimetry thermal analysis, FT-IR spectroscopy, in vitro dissolution rate, and physical stability. In addition, the crystal structure was determined by single-crystal X-ray diffraction analysis. The differential scanning calorimetry thermogram of the MA-MG binary system exhibits a single and sharp endothermic peak at 151.20°C, which was attributed to the melting point of a MC of MA-MG. FT-IR spectroscopy analysis showed the occurrence of solid-state interaction by involving proton transfer between MA and MG. The crystal structure analysis confirmed that MA-MG formed 1:1 ratio salt type MC. The formation of a MC of MA with MG significantly improved the dissolution rate of MA in compared to intact MA, and also the crystal demonstrated a good stability under a high relative humidity. These good properties would be attributed to the layer structure of MA and MG in the crystal. [ABSTRACT FROM AUTHOR]

New salt forms of the antioxidant drug emoxypine (EMX, 2‐ethyl‐6‐methylpyridin‐3‐ol) with pharmaceutically acceptable maleic (Mlt), malonic (Mln) and adipic (Adp) acids were obtained {emoxypinium maleate, C8H12NO+·C4H3O4−, [EMX+Mlt], emoxypinium malonate, C8H12NO+·C3H3O4−, [EMX+Mln], and emoxypinium adipate, C8H12NO+·C6H9O4−, [EMX+Adp]} and their crystal structures determined. The molecular packing in the three EMX salts was studied by means of solid‐state density functional theory (DFT), followed by QTAIMC (quantum theory of atoms in molecules and crystals) analysis. It was found that the major contribution to the packing energy comes from pyridine–carboxylate and hydroxy–carboxylate heterosynthons forming infinite one‐dimensional ribbons, with [EMX+Adp] additionally stabilized by hydrogen‐bonded C(9) chains of Adp− ions. The melting processes of the [EMX+Mlt] (1:1), [EMX+Mln] (1:1) and [EMX+Adp] (1:1) salts were studied and the fusion enthalpy was found to increase with the increase of the calculated lattice energy. The dissolution process of the EMX salts in buffer (pH 7.4) was also studied. It was found that the formation of binary crystals of EMX with dicarboxylic acids increases the EMX solubility by more than 30 times compared to its pure form. [ABSTRACT FROM AUTHOR]

• Metoprolol obtained six stable multicomponent crystals with para-hydroxybenzoic acid, 4-chlorobenzoic acid, 3,5-dinitrobenzoic acid, dihydrocaffeic acid, cinnamic acid, oxalic acid for the first time. • The multicomponent crystals were characterized by single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and fourier transform infrared technologies. • The stability of the six multicomponent crystals was significantly improved compared to metoprolol raw material. Crystal engineering is a crucial technology in improving the physicochemical properties of active pharmaceutical ingredients (APIs). To address the drawback of the instability and low melting point of metoprolol (MET), multi-component compounds of metoprolol were designed and synthesized to enhance their stability. Six stable multi-component crystals with dihydrocaffeic acid (DA), p-hydroxybenzoic acid (p-HA), 4-chlorobenzoic acid (4-CA), 3,5-dinitrobenzoic acid (3,5-DA), cinnamic acid (CA) and oxalic acid (OA) were obtained for the first time. Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) and thermogravimetric analysis (TG) techniques were used to characterize the novel multicomponent crystals. In addition, the stability of the solid drug forms was evaluated. The results indicate that the stability of all six multicomponent crystals was significantly higher than that of the raw materials. [Display omitted] Six MET multicomponent crystals with dihydrocaffeic acid, p-hydroxybenzoic acid, 4-chlorobenzoic acid, 3,5-dinitrobenzoic acid, cinnamic acid, and oxalic acid were synthesized for the first time to enhance stability. The result shows that a significant improvement in stability of the six multicomponent crystals when compared to the raw materials. [ABSTRACT FROM AUTHOR]

p-Coumaric acid (pCA) and trans-ferulic acid (TFA) were co-crystallised with 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP) producing organic salts of (pCA−)(2A4MP+) (1), (pCA̶ )(2A6MP+) (2) and (TFA̶ )(2A4MP+)·( 3 2 H2O) (3). For salt 3, water was included in the crystal structure fulfilling a bridging role. pCA formed a 1:1 salt with 2A4MP (Z’ = 1) and a 4:4 salt with 2A6MP (Z’ = 4). The thermal stability of the salts was determined using differential scanning calorimetry (DSC). Salt 2 had the highest thermal stability followed by salt 1 and salt 3. The salts were also characterised using Fourier transform infrared (FTIR) spectroscopy. Hirshfeld surface analysis was used to study the different intermolecular interactions in the three salts. Solvent-assisted grinding was also investigated in attempts to reproduce the salts.

The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.

Single-crystal X-ray diffraction and quantum mechanical theories were used to examine in detail the subtle nature of non-covalent interactions in the [2:1:1] multicomponent crystal of 1,1-aminocyclopentanecarboxylic acid:oxalic acid:water. The crystal, which is a hydrate salt of the amino acid with the hydrogen-oxalate ion, also contains the zwitterion of the amino acid in equal proportions. It was found that a dimeric cation [Acc5(Z)...Acc5(C)]+ bonded by an O-H...O hydrogen bond exists due to a charge transfer between acid and carboxylate groups. The three-dimensional crystal is built by blocks stacked along the [101] direction by dispersion interactions, with each block growing along two directions: a hydrogen oxalate HOX−...HOX− catameric supramolecular structure along the [010] direction; and double ...HOX−- W-[Acc5(Z)... Acc5(C)]+... chains related by inversion centers along the direction. A PBE-DFT optimization, under periodic boundary conditions, was carried out. The fully optimized structure obtained was used to extract the coordinates to calculate the stabilization energy between the dimers under the crystal field, employing the M062X/aug-cc-pVTZ level of theory. The non-covalent index isosurfaces employed here allow the visualization of where the hydrogen bond and dispersion interactions contribute within the crystal. The crystal atomic arrangements are analyzed by employing the Atoms in Molecules and electron localization function theories. Within this context, the presence of density bond critical points is employed as a criterion for proving the existence of the hydrogen bond and it was found that these results agree with those rendered by the crystallographic geometrical analysis, with only three exceptions, for which bond critical points were not found. [ABSTRACT FROM AUTHOR]

As small molecule drugs become harder to develop and less cost effective for patient use, efficient strategies for their property improvement become increasingly important to global health initiatives. Improvements in the physical properties of Active Pharmaceutical Ingredients (APIs), without changes in the covalent chemistry, have long been possible through the application of binary component solids. This was first achieved through the use of pharmaceutical salts, within the last 10–15 years with cocrystals and more recently coamorphous systems have also been consciously applied to this problem. In order to rationally discover the best multicomponent phase for drug development, intermolecular interactions need to be considered at all stages of the process. This review highlights the current thinking in this area and the state of the art in: pharmaceutical multicomponent phase design, the intermolecular interactions in these phases, the implications of these interactions on the material properties and the pharmacokinetics in a patient. [ABSTRACT FROM AUTHOR]

Objectives In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients ( APIs). The different strategies will be addressed, and successful examples will be given. Key findings This overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics. It discusses some of the latest progresses. Summary We want to present, in a brief overview, what recently has been done to improve the discovery of innovative methods of using well-known APIs, and improve their efficiency. Multicomponent crystal forms have shown to be the most promising achievements to accomplish these aims, by altering API physico-chemical properties, such as solubility, thermal stability, shelf life, dissolution rate and compressibility. API-ionic liquids ( ILs) and their advantages will be briefly referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-organic frameworks ( BioMOFs) will also be addressed. [ABSTRACT FROM AUTHOR]

Colloidal crystals are interesting materials owing to their customizable photonic properties, high surface area, and analogy to chemical structures. The flexibility of these materials has been greatly enhanced through mixing particles with varying sizes, compositions, and surface charges. In this way, distinctive patterns or analogies to chemical stoichiometries are produced; however, to date, this body of research is limited to particles with nanoscale dimensions. A simple method is now presented for bottom-up assembly of non-Brownian particle mixtures to create a new class of hierarchically-ordered materials that mimic those found in nature (both in pore distribution as well as stoichiometry). Additionally, these crystals serve as a template to create particle-based inverted crystalline structures with customizable properties. [ABSTRACT FROM AUTHOR]

Four new ternary crystalline molecular complexes have been synthesised from a common 3,5-dinitrobenzoic acid (3,5-dnda) and 4,4′-bipyridine (bipy) pairing with a series of amino-substituted aromatic compounds (4-aminobenzoic acid (4-aba), 4-( N, N-dimethylamino)benzoic acid (4-dmaba), 4-aminosalicylic acid (4-asa) and sulfanilamide (saa)). The ternary crystals were created through the application of complementary charge transfer and hydrogen-bonding interactions. For these systems a dimer was created through a charge-transfer interaction between two of the components, while hydrogen bonding between the third molecule and this dimer completed the construction of the ternary co-crystal. All resulting structures display the same acid ⋅⋅⋅pyridine interaction between 3,5-dnba and bipy. However, changing the third component causes the proton of this bond to shift from neutral OH ⋅⋅⋅N to a salt form, O− ⋅⋅⋅HN+, as the nature of the group hydrogen bonding to the carboxylic acid was changed. This highlights the role of the crystal environment on the level of proton transfer and the utility of ternary systems for the study of this process. [ABSTRACT FROM AUTHOR]

Tetraarylpyrene H that typifies a host system with three distinct domains for guest inclusion in the solid state is found to include different aromatic guests in the lattice and crystallize as a multicomponent molecular crystal. It is found to exhibit site-selective inclusion of the guests in that the large-sized guests such as biphenyl, anthracene, [2.2]paracyclophane, fluorene and pyrene are included selectively in the trough region, whereas small-sized benzene guest is bound in concave and/or basin regions. These results are of particular importance from the point of view of creating multicomponent molecular crystals based on rational design of the host structure. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the relationship between the melting point and the supramolecular structure of three multi-component crystals of aliphatic dicarboxylic acids with 2,2′-bipyridine and to investigate the conformations of 2,2′-bipyridine in published multi-component crystals. The crystals were prepared using the solvent evaporation method and were characterized using single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). The crystal structures were further analyzed using CrystalExplorer, and the results were correlated with the melting points. The results of the conformation analysis of the reported multi-component crystals of 2,2′-bipyridine are also presented. [ABSTRACT FROM AUTHOR]

Development of novel drug for manipulating the physicochemical properties of the API by obtaining their multicomponent forms is a challenging task in the pharmaceutical industry. Novel multicomponent crystal forms of gallic acid with three hydroxypyridines have been prepared by liquid assisted grinding and slow evaporation of the solvent. Preliminary PXRD and FTIR characterizations were carried out to confirm the interactions between the components, then the three dimensional molecular structures were confirmed through single crystal X-ray diffraction method. Structural studies clearly revealed the three distinct molecular crystal forms of gallic acid with hydroxypyridines. The molecular structures exhibit O–H⋯O, N–H⋯O and C–H⋯O intermolecular hydrogen bond interactions, which results different supramolecular motifs. Further, intermolecular interactions were quantified through Hirshfeld surface analysis, which revealed the dominance of O⋯H and H⋯H interactions. Computation of interaction energies between the molecules and analysis of three dimensional energy frameworks quantifies the molecular packing. The density functional theory calculations were employed to optimize the structural coordinates, which substantiate the experimental results. Low value of HOMO-LUMO energy gap signifies the promising electronic properties of the molecules. The chemical reactive sites were further identified on the molecular electrostatic potential surface. Finally, thermal properties of the crystals were studied using thermogravimetric analysis. Image 1 • Gallic acid-hydroxypyridine multicomponent crystals were successfully obtained. • Multicomponent crystals were characterized and structures were confirmed by XRD method. • The molecular structures exhibit various intermolecular hydrogen bond interactions, which results in supramolecular motifs. • Hirshfeld surface analysis establishes interaction energies and various intermolecular interactions. • DFT calculations revealed the lowering in the HOMO-LUMO energy gap. [ABSTRACT FROM AUTHOR]

p-Coumaric acid (pCA) and trans-ferulic acid (TFA) were co-crystallised with 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP) producing organic salts of (pCA−)(2A4MP+) (1), (pCA̶)(2A6MP+) (2) and (TFA̶)(2A4MP+)·( 3 2 H2O) (3). For salt 3, water was included in the crystal structure fulfilling a bridging role. pCA formed a 1:1 salt with 2A4MP (Z' = 1) and a 4:4 salt with 2A6MP (Z' = 4). The thermal stability of the salts was determined using differential scanning calorimetry (DSC). Salt 2 had the highest thermal stability followed by salt 1 and salt 3. The salts were also characterised using Fourier transform infrared (FTIR) spectroscopy. Hirshfeld surface analysis was used to study the different intermolecular interactions in the three salts. Solvent-assisted grinding was also investigated in attempts to reproduce the salts. [ABSTRACT FROM AUTHOR]

The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others. [ABSTRACT FROM AUTHOR]