The possibility of molecular complex formation in the solid state of urea with benzoic acid analogues was measured directly on the crystallite films deposited on the glass surface using powder X-ray diffractometry (PXRD). Obtained solid mixtures were also analyzed using Fourier transform infrared spectroscopy (FTIR). The simple droplet evaporation method was found to be efficient, robust, fast and cost-preserving approach for first stage cocrystal screening. Additionally, the application of orientation effect to cocrystal screening simplifies the analysis due to damping of majority of diffraction signals coming from coformers. During validation phase the proposed approach successfully reproduced both positive cases of cocrystallization (urea:salicylic acid and urea:4-hydroxy benzoic acid) as well as pairs of co-formers immiscible in the solid state (urea:benzoic acid and urea:acetylsalicylic acids). Based on validated approach new cocrystals of urea were identified in complexes with 3-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid. In all cases formation of multicomponent crystal phase was confirmed by the appearance of new reflexes on the diffraction patterns and FTIR absorption band shifts of O–H and N–H groups.
This document summarizes literature on cocrystal systems published in 2011 that are of interest to pharmaceutical scientists. It begins with an introduction to cocrystal systems and relevant review articles. It then discusses general articles on cocrystal engineering principles and characterization methods. The majority of the document summarizes literature on preparation methods for cocrystal systems and specific pharmaceutical cocrystal systems that were reported. It concludes with a discussion of regulatory guidance on pharmaceutical cocrystals.
This document discusses co-crystals, which are crystalline materials composed of two or more components in the same crystal lattice. It outlines several advantages of co-crystals such as increased stability and solubility compared to amorphous forms. Common preparation methods include solution methods, grinding, and antisolvent techniques. Key characterization techniques are X-ray powder diffraction, infrared spectroscopy, and solubility analysis. Several marketed drug formulations utilizing co-crystals are also mentioned.
The document presents a research project on preparing and evaluating co-crystals of atorvastatin calcium with saccharin and urea. The objectives are to prepare the co-crystals using solvent drop grinding and solvent evaporation methods, characterize them using various techniques, and evaluate their solubility. The document outlines the materials, methods, results and discussion sections of the project including pre-formulation studies of atorvastatin calcium and the co-formers, characterization of the prepared co-crystals using FTIR, DSC and solubility testing, and evaluation of drug-excipient compatibility. The project aims to develop co-crystal formulations to improve the solubility and dissolution rate of the poorly soluble at
Exploring the cocrystallization potential of urea and benzamideMaciej Przybyłek
The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects. Intermolecular interactions of urea with para substituted benzoic acid analogues are stronger compared to those of benzamide. Also, the amount of charge transfer from amide to aromatic carboxylic acid and vice versa is more pronounced for urea. However, in both cases, the greater the electron withdrawing character of the substituent, the higher the binding energy, and the stronger the supermolecule polarization via the charge transfer mechanism.
This document summarizes metal-organic frameworks (MOFs), including their properties and applications. MOFs are highly porous materials formed by combining metal ions or metal clusters with organic ligands. They have extremely large surface areas, often exceeding 7,000 m2/g. Due to their tunable porous structures, MOFs show promise for applications such as gas storage, carbon capture, catalysis, and luminescence. While MOF research has advanced significantly in recent decades, further developing their potential applications and improving stability remains an active area of research.
This document is the thesis of Anna Shevchenko submitted for public examination at the University of Helsinki. It summarizes her research on discovering and characterizing new solid-state forms of weakly basic drug molecules. Specifically, it describes her work developing an approach for initial screening of polymorphism and solvatomorphism tendencies of drug candidates. Using this approach, she discovered three crystalline forms of a hydrochloric salt of a new drug candidate, including two anhydrous and one hemihydrate form. She also investigated cocrystals of the antifungal drug itraconazole with various dicarboxylic acids, discovering several new anhydrous and solvated cocrystal forms. Finally, she compared the properties
The document discusses co-crystals, which are crystalline materials composed of an active pharmaceutical ingredient and a co-crystal former. Co-crystals can improve properties like dissolution rate and stability. They are formed through hydrogen bonding, pi-stacking, or van der Waals forces between components. Common preparation methods include solution crystallization, grinding, and antisolvent crystallization. Co-crystals are characterized using techniques like infrared spectroscopy, X-ray crystallography, and thermal analysis. Examples of co-crystallized drugs discussed include itraconazole, caffeine, and carbamazepine.
This document discusses the co-crystal technique for enhancing the solubility of poorly water soluble drugs. It introduces co-crystals as crystalline materials comprised of an active pharmaceutical ingredient and one or more co-crystal formers. Co-crystals can improve solubility and bioavailability through interactions like hydrogen bonding and pi-stacking. The document outlines various methods for preparing co-crystals, including solution methods, grinding, and supercritical fluid technology. It also discusses selecting appropriate co-formers, solvents, and evaluation methods like powder X-ray diffraction and solubility analysis. Several marketed drug products incorporating co-crystal technology are presented as examples.
This document summarizes literature on cocrystal systems published in 2011 that are of interest to pharmaceutical scientists. It begins with an introduction to cocrystal systems and relevant review articles. It then discusses general articles on cocrystal engineering principles and characterization methods. The majority of the document summarizes literature on preparation methods for cocrystal systems and specific pharmaceutical cocrystal systems that were reported. It concludes with a discussion of regulatory guidance on pharmaceutical cocrystals.
This document discusses co-crystals, which are crystalline materials composed of two or more components in the same crystal lattice. It outlines several advantages of co-crystals such as increased stability and solubility compared to amorphous forms. Common preparation methods include solution methods, grinding, and antisolvent techniques. Key characterization techniques are X-ray powder diffraction, infrared spectroscopy, and solubility analysis. Several marketed drug formulations utilizing co-crystals are also mentioned.
The document presents a research project on preparing and evaluating co-crystals of atorvastatin calcium with saccharin and urea. The objectives are to prepare the co-crystals using solvent drop grinding and solvent evaporation methods, characterize them using various techniques, and evaluate their solubility. The document outlines the materials, methods, results and discussion sections of the project including pre-formulation studies of atorvastatin calcium and the co-formers, characterization of the prepared co-crystals using FTIR, DSC and solubility testing, and evaluation of drug-excipient compatibility. The project aims to develop co-crystal formulations to improve the solubility and dissolution rate of the poorly soluble at
Exploring the cocrystallization potential of urea and benzamideMaciej Przybyłek
The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects. Intermolecular interactions of urea with para substituted benzoic acid analogues are stronger compared to those of benzamide. Also, the amount of charge transfer from amide to aromatic carboxylic acid and vice versa is more pronounced for urea. However, in both cases, the greater the electron withdrawing character of the substituent, the higher the binding energy, and the stronger the supermolecule polarization via the charge transfer mechanism.
This document summarizes metal-organic frameworks (MOFs), including their properties and applications. MOFs are highly porous materials formed by combining metal ions or metal clusters with organic ligands. They have extremely large surface areas, often exceeding 7,000 m2/g. Due to their tunable porous structures, MOFs show promise for applications such as gas storage, carbon capture, catalysis, and luminescence. While MOF research has advanced significantly in recent decades, further developing their potential applications and improving stability remains an active area of research.
This document is the thesis of Anna Shevchenko submitted for public examination at the University of Helsinki. It summarizes her research on discovering and characterizing new solid-state forms of weakly basic drug molecules. Specifically, it describes her work developing an approach for initial screening of polymorphism and solvatomorphism tendencies of drug candidates. Using this approach, she discovered three crystalline forms of a hydrochloric salt of a new drug candidate, including two anhydrous and one hemihydrate form. She also investigated cocrystals of the antifungal drug itraconazole with various dicarboxylic acids, discovering several new anhydrous and solvated cocrystal forms. Finally, she compared the properties
The document discusses co-crystals, which are crystalline materials composed of an active pharmaceutical ingredient and a co-crystal former. Co-crystals can improve properties like dissolution rate and stability. They are formed through hydrogen bonding, pi-stacking, or van der Waals forces between components. Common preparation methods include solution crystallization, grinding, and antisolvent crystallization. Co-crystals are characterized using techniques like infrared spectroscopy, X-ray crystallography, and thermal analysis. Examples of co-crystallized drugs discussed include itraconazole, caffeine, and carbamazepine.
This document discusses the co-crystal technique for enhancing the solubility of poorly water soluble drugs. It introduces co-crystals as crystalline materials comprised of an active pharmaceutical ingredient and one or more co-crystal formers. Co-crystals can improve solubility and bioavailability through interactions like hydrogen bonding and pi-stacking. The document outlines various methods for preparing co-crystals, including solution methods, grinding, and supercritical fluid technology. It also discusses selecting appropriate co-formers, solvents, and evaluation methods like powder X-ray diffraction and solubility analysis. Several marketed drug products incorporating co-crystal technology are presented as examples.
This document summarizes the synthesis and characterization of a new thio-triazole ligand and its complexes with selected metals. A new ligand, thiocarboxyphenyl-4-allyl-5-phenyl-4H-1,2,4-triazole (L), was prepared and characterized using micro elemental analysis and infrared spectroscopy. This ligand was then reacted with Fe(III), Cu(II), Cd(II), Hg(II) and Au(III) to form new complexes. These complexes were identified through various techniques and their chemical formulas and geometries were suggested. The biological activity of the complexes against selected microorganisms was also examined.
This document discusses complex formation in pharmaceutical science. It defines complexes as molecules with some anomalous bonding structures that can be described by classical valence theories. There are several types of complexes discussed, including metal complexes where a metal ion interacts with ligands, organic molecular complexes held by weaker forces, and inclusion complexes where one component is trapped within another. Methods for analyzing complexes include determining stoichiometry and stability constants using techniques like continuous variation, spectroscopy, distribution methods, and protein binding studies. The document explores how complex formation can impact drug action.
This document summarizes high-resolution crystal structures of native cytochrome c peroxidase (CCP) and its oxidized reaction intermediate known as Compound I. Key findings include:
1) The 1.2 Å structure of native CCP and 1.3 Å structure of Compound I reveal subtle but important conformational changes that help stabilize the tryptophan 191 cation radical in Compound I.
2) In Compound I, the histidine-iron bond distance increases, iron moves into the porphyrin plane with shorter pyrrole-iron bonds, and the iron-oxygen bond distance is 1.87 Å, suggesting a single iron-oxygen bond.
3
This document summarizes three methods for preparing hollow metal-organic frameworks (MOFs): 1) the exterior-template method where templates are coated with MOF shells and then removed, 2) the self-template method where intermediate products or reactants act as sacrificial templates, and 3) the two-phase interface method using gas-liquid, liquid-liquid, or solid-liquid interfaces. It also discusses using hollow MOFs for drug delivery by loading drugs through immersion or one-pot synthesis and zinc-based MOFs for delivering 5-fluorouracil.
Seminar on "Crystal habit modification & it's industrial importance" prepared by Kishor Prajapati ( Final Year Chemical Engg. Student at Faculty of Technology & Engg.,M.S.University, Vadodara)
Polymorphism refers to a solid material existing in two or more crystalline forms with different arrangements in the crystal lattice. Over 50% of active pharmaceutical ingredients have more than one polymorphic form, which can exhibit different properties like solubility, dissolution rate, and stability. Methods to identify polymorphs include x-ray diffraction, differential scanning calorimetry, and thermal microscopy. The choice of polymorph is important for drug formulations, as the metastable form may have better bioavailability but convert to the stable form, impacting suspension stability or drug absorption. Case studies show certain polymorphs can be medically inactive or cause production issues if they convert dominant forms.
1) The document describes mathematical approaches to modeling drug release from hydrogel matrices. It discusses parameters like polymer volume fraction, molecular weight between crosslinks, and network mesh size that describe hydrogel structure.
2) The mechanisms that influence drug release from hydrogels include diffusion, swelling, erosion, and chemical reactions. Different geometries like thin films, spheres, and cylinders can impact release kinetics.
3) Mathematical models are described to predict drug release profiles from hydrogels. Models incorporate diffusion equations and consider different scenarios like reservoir systems, matrix systems, and whether the initial drug concentration is above or below solubility.
Mcq's of class 9 chapter IS MATTER AROUND US PUREthesaver
This document provides 16 multiple choice questions about class 9 science chapter 2 on matter. The questions test understanding of key concepts from the chapter including properties of pure substances, physical and chemical changes, mixtures and compounds. Sample questions ask about defining rusting, identifying homogeneous mixtures, and classifying substances and changes. The document also includes exercises to label elements and compounds, complete a crossword with science terms, and fill in blanks about colloids and separation techniques.
Uday is a PhD student studying solid state chemistry in Dr. Simon Lawrence's research group. Solid state chemistry involves studying the synthesis, structure, and properties of materials in solid form. Over 80% of drugs are available as tablets or capsules, but 40% have issues with solubility and stability. Polymorphism, where compounds can exist in multiple solid forms, can impact properties and is important to drug development. Uday's current research focuses on using cocrystal technology to improve enantiopurity of organic compounds.
This document discusses polymorphism as part of a preformulation study seminar. It defines polymorphism as the ability of a substance to exist in two or more crystalline forms that have different molecular arrangements. The key points covered include:
- The need to study polymorphism to select the most stable and soluble form for formulations. Metastable forms often have better bioavailability.
- Various methods to identify and characterize polymorphs such as X-ray diffraction, thermal analysis techniques like DSC and TGA, and microscopy.
- Factors that can influence polymorphic transitions like temperature, humidity, solvents, grinding, and compression during tableting.
- The importance of understanding polymorphism for properties like
This document describes the synthesis and characterization of two new lanthanide-based metal-organic frameworks (MOFs) using pamoic acid as the organic ligand. Single crystal X-ray diffraction shows that the MOFs form three-dimensional frameworks with channels of different sizes depending on the lanthanide ion (Gd3+ or Dy3+). Magnetic measurements reveal one MOF acts as a cryogenic magnetic refrigerant while the other shows slow relaxation of magnetization. Adsorption studies show the MOFs selectively uptake CO2 over other gases and have high methanol vapor uptake. Photoluminescence properties indicate the MOFs are also photoluminescent materials.
Chromatography was first developed in 1906 by Russian scientist Tswett who used calcium carbonate to separate plant pigments in columns. It involves separating components of a mixture based on how they interact and bind to different phases, with one phase stationary and the other mobile. Chromatography can be classified based on the mechanism of separation (e.g. adsorption, partition), mobile phase used (liquid, gas), or method of holding the stationary phase (planar, columnar). It has both analytical uses like identification and quantification of mixtures, as well as preparative uses to obtain pure compounds.
This document discusses the use of a large-pore metal-organic framework (MOF) called MJ3' for sensing and discriminating explosives at variable concentrations. MJ3' showed good sensitivity and quenching of its fluorescence for a range of explosives like tetryl, TNT, RDX, PETN, and 2,4-DNT in solution. In particular, its large pore size allowed for interactions with PETN, one of the more difficult explosives to detect. Testing revealed concentration limits of detection in the ppm range, suggesting potential applications in homeland security and environmental monitoring. The document concludes that carefully designed MOFs with ultrahigh porosity and stability can enable interior functionalization for applications like
This document for Class 9 (CBSE), Chapter 2 - Is Matter Around Us Pure, includes MCQs, Match the following, True or False, Fill in the blanks and Very-Short-Answer Questions. Hope you like it.
This document discusses salt selection strategies in pharmaceutical product development. It begins by explaining the importance of salt formation in improving drug solubility, permeability, and dissolution. The key criteria for salt selection are discussed, including aqueous solubility, crystallinity, hygroscopicity, stability, and ease of synthesis. A multi-tiered approach is described for selecting the chemical form and physical form of the salt. A case study demonstrates evaluating different salt forms of a drug and selecting the optimal sulfate salt. The conclusion emphasizes that a multidisciplinary team approach and proper screening strategies are important for efficiently selecting the best salt form early in development.
Computationally Driven Characterization of Magnetism, Adsorption, and Reactiv...Joshua Borycz
Metal organic frameworks (MOFs) are a class of nanoporous materials that are com- posed of metal-containing nodes connected by organic linkers. The study of MOFs has grown in importance due to the wide range of possible node and linker combinations, which allow tailoring towards specific applications. This work demonstrates that the- ory can complement experiment in a way that advances the chemical understanding of MOFs. This thesis contains the results of several investigations on three different areas of MOF research: 1) magnetism, 2) CO2 adsorption, and 3) catalysis.
This document provides a summary of the education and experience of Prof. Dr Syeda Robina Gilani. It includes her positions, education history, research interests, publications, projects supervised, and other achievements. Some key details:
- She is currently the Chairperson of the Department of Chemistry at UET Lahore, Pakistan.
- Her education includes a Post Doc from Queen's University in 2008, a PhD from the University of Leicester in 1998, and an MSc from the University of Punjab in 1987-1989.
- Her research interests include environmental toxicology, coordination chemistry, functional food chemistry, and renewable energy.
- She has supervised several PhD, MPhil, and MSc the
This document discusses various preformulation techniques to enhance drug solubility, including solubilization, surfactants, temperature, pH, cosolvency, solid dispersion, and β-cyclodextrin drug dispersion. Key topics covered include the use of surfactants to increase solubility via micelle formation, the impact of pH on drug solubility through ionization, and the cosolvency technique of using water-miscible solvents to improve solubility. Solid dispersion and cyclodextrin drug dispersion are also introduced as methods to enhance solubility through formation of inclusion complexes.
On the origin of surface imposed anisotropic growth of salicylic and acetylsa...Maciej Przybyłek
In this paper droplet evaporative crystallization of salicylic acid (SA) and acetylsalicylic acid (ASA) crystals on different surfaces, such as glass, polyvinyl alcohol (PVA), and paraffin was studied. The obtained crystals were analyzed using powder X-ray diffraction (PXRD) technique. In order to better understand the effect of the surface on evaporative crystallization, crystals deposited on glass were scraped off. Moreover, evaporative crystallization of a large volume of solution was performed. As we found, paraffin which is non-polar surface promotes formation of crystals morphologically similar to those obtained via bulk evaporative crystallization. On the other hand, when crystallization is carried out on the polar surfaces (glass and PVA), there is a significant orientation effect. This phenomenon is manifested by the reduction of the number of peaks in PXRD spectrum recorded for deposited on the surface crystals. Noteworthy, reduction of PXRD signals is not observed for powder samples obtained after scraping crystals off the glass. In order to explain the mechanism of carboxylic crystals growth on the polar surfaces, quantum-chemical computations were performed. It has been found that crystal faces of the strongest orientation effect can be characterized by the highest surface densities of intermolecular interactions energy (IIE). In case of SA and ASA crystals formed on the polar surfaces the most dominant faces are characterized by the highest adhesive and cohesive properties. This suggests that the selection rules of the orientation effect comes directly from surface IIE densities.
On the origin of surfaces-dependent growth of benzoic acid crystal inferred t...Maciej Przybyłek
Crystal growth behavior of benzoic acid crystals on different surfaces was examined. The performed experiments documented the existence of very strong influence introduced by polar surfaces as glass, gelatin, and polyvinyl alcohol (PVA) on the growth of benzoic acid crystals. These surfaces impose strong orientation effect resulting in a dramatic reduction of number of faces seen with x-ray powder diffractions (XPRD). However, scrapping the crystal off the surface leads to a morphology that is similar to the one observed for bulk crystallization. The surfaces of low wettability (paraffin) seem to be useful for preparation of amorphous powders, even for well-crystallizable compounds. The performed quantum chemistry computations characterized energetic contributions to stabilization of morphology related faces. It has been demonstrated, that the dominant face (002) of benzoic acid crystal, growing on polar surfaces, is characterized by the highest densities of intermolecular interaction energies determining the highest cohesive properties among all studied faces. Additionally, the inter-layer interactions, which stand for adhesive properties, are also the strongest in the case of this face. Thus, quantum chemistry computations providing detailed description of energetic contributions can be successfully used for clarification of adhesive and cohesive nature of benzoic acids crystal faces.
This document summarizes the synthesis and characterization of a new thio-triazole ligand and its complexes with selected metals. A new ligand, thiocarboxyphenyl-4-allyl-5-phenyl-4H-1,2,4-triazole (L), was prepared and characterized using micro elemental analysis and infrared spectroscopy. This ligand was then reacted with Fe(III), Cu(II), Cd(II), Hg(II) and Au(III) to form new complexes. These complexes were identified through various techniques and their chemical formulas and geometries were suggested. The biological activity of the complexes against selected microorganisms was also examined.
This document discusses complex formation in pharmaceutical science. It defines complexes as molecules with some anomalous bonding structures that can be described by classical valence theories. There are several types of complexes discussed, including metal complexes where a metal ion interacts with ligands, organic molecular complexes held by weaker forces, and inclusion complexes where one component is trapped within another. Methods for analyzing complexes include determining stoichiometry and stability constants using techniques like continuous variation, spectroscopy, distribution methods, and protein binding studies. The document explores how complex formation can impact drug action.
This document summarizes high-resolution crystal structures of native cytochrome c peroxidase (CCP) and its oxidized reaction intermediate known as Compound I. Key findings include:
1) The 1.2 Å structure of native CCP and 1.3 Å structure of Compound I reveal subtle but important conformational changes that help stabilize the tryptophan 191 cation radical in Compound I.
2) In Compound I, the histidine-iron bond distance increases, iron moves into the porphyrin plane with shorter pyrrole-iron bonds, and the iron-oxygen bond distance is 1.87 Å, suggesting a single iron-oxygen bond.
3
This document summarizes three methods for preparing hollow metal-organic frameworks (MOFs): 1) the exterior-template method where templates are coated with MOF shells and then removed, 2) the self-template method where intermediate products or reactants act as sacrificial templates, and 3) the two-phase interface method using gas-liquid, liquid-liquid, or solid-liquid interfaces. It also discusses using hollow MOFs for drug delivery by loading drugs through immersion or one-pot synthesis and zinc-based MOFs for delivering 5-fluorouracil.
Seminar on "Crystal habit modification & it's industrial importance" prepared by Kishor Prajapati ( Final Year Chemical Engg. Student at Faculty of Technology & Engg.,M.S.University, Vadodara)
Polymorphism refers to a solid material existing in two or more crystalline forms with different arrangements in the crystal lattice. Over 50% of active pharmaceutical ingredients have more than one polymorphic form, which can exhibit different properties like solubility, dissolution rate, and stability. Methods to identify polymorphs include x-ray diffraction, differential scanning calorimetry, and thermal microscopy. The choice of polymorph is important for drug formulations, as the metastable form may have better bioavailability but convert to the stable form, impacting suspension stability or drug absorption. Case studies show certain polymorphs can be medically inactive or cause production issues if they convert dominant forms.
1) The document describes mathematical approaches to modeling drug release from hydrogel matrices. It discusses parameters like polymer volume fraction, molecular weight between crosslinks, and network mesh size that describe hydrogel structure.
2) The mechanisms that influence drug release from hydrogels include diffusion, swelling, erosion, and chemical reactions. Different geometries like thin films, spheres, and cylinders can impact release kinetics.
3) Mathematical models are described to predict drug release profiles from hydrogels. Models incorporate diffusion equations and consider different scenarios like reservoir systems, matrix systems, and whether the initial drug concentration is above or below solubility.
Mcq's of class 9 chapter IS MATTER AROUND US PUREthesaver
This document provides 16 multiple choice questions about class 9 science chapter 2 on matter. The questions test understanding of key concepts from the chapter including properties of pure substances, physical and chemical changes, mixtures and compounds. Sample questions ask about defining rusting, identifying homogeneous mixtures, and classifying substances and changes. The document also includes exercises to label elements and compounds, complete a crossword with science terms, and fill in blanks about colloids and separation techniques.
Uday is a PhD student studying solid state chemistry in Dr. Simon Lawrence's research group. Solid state chemistry involves studying the synthesis, structure, and properties of materials in solid form. Over 80% of drugs are available as tablets or capsules, but 40% have issues with solubility and stability. Polymorphism, where compounds can exist in multiple solid forms, can impact properties and is important to drug development. Uday's current research focuses on using cocrystal technology to improve enantiopurity of organic compounds.
This document discusses polymorphism as part of a preformulation study seminar. It defines polymorphism as the ability of a substance to exist in two or more crystalline forms that have different molecular arrangements. The key points covered include:
- The need to study polymorphism to select the most stable and soluble form for formulations. Metastable forms often have better bioavailability.
- Various methods to identify and characterize polymorphs such as X-ray diffraction, thermal analysis techniques like DSC and TGA, and microscopy.
- Factors that can influence polymorphic transitions like temperature, humidity, solvents, grinding, and compression during tableting.
- The importance of understanding polymorphism for properties like
This document describes the synthesis and characterization of two new lanthanide-based metal-organic frameworks (MOFs) using pamoic acid as the organic ligand. Single crystal X-ray diffraction shows that the MOFs form three-dimensional frameworks with channels of different sizes depending on the lanthanide ion (Gd3+ or Dy3+). Magnetic measurements reveal one MOF acts as a cryogenic magnetic refrigerant while the other shows slow relaxation of magnetization. Adsorption studies show the MOFs selectively uptake CO2 over other gases and have high methanol vapor uptake. Photoluminescence properties indicate the MOFs are also photoluminescent materials.
Chromatography was first developed in 1906 by Russian scientist Tswett who used calcium carbonate to separate plant pigments in columns. It involves separating components of a mixture based on how they interact and bind to different phases, with one phase stationary and the other mobile. Chromatography can be classified based on the mechanism of separation (e.g. adsorption, partition), mobile phase used (liquid, gas), or method of holding the stationary phase (planar, columnar). It has both analytical uses like identification and quantification of mixtures, as well as preparative uses to obtain pure compounds.
This document discusses the use of a large-pore metal-organic framework (MOF) called MJ3' for sensing and discriminating explosives at variable concentrations. MJ3' showed good sensitivity and quenching of its fluorescence for a range of explosives like tetryl, TNT, RDX, PETN, and 2,4-DNT in solution. In particular, its large pore size allowed for interactions with PETN, one of the more difficult explosives to detect. Testing revealed concentration limits of detection in the ppm range, suggesting potential applications in homeland security and environmental monitoring. The document concludes that carefully designed MOFs with ultrahigh porosity and stability can enable interior functionalization for applications like
This document for Class 9 (CBSE), Chapter 2 - Is Matter Around Us Pure, includes MCQs, Match the following, True or False, Fill in the blanks and Very-Short-Answer Questions. Hope you like it.
This document discusses salt selection strategies in pharmaceutical product development. It begins by explaining the importance of salt formation in improving drug solubility, permeability, and dissolution. The key criteria for salt selection are discussed, including aqueous solubility, crystallinity, hygroscopicity, stability, and ease of synthesis. A multi-tiered approach is described for selecting the chemical form and physical form of the salt. A case study demonstrates evaluating different salt forms of a drug and selecting the optimal sulfate salt. The conclusion emphasizes that a multidisciplinary team approach and proper screening strategies are important for efficiently selecting the best salt form early in development.
Computationally Driven Characterization of Magnetism, Adsorption, and Reactiv...Joshua Borycz
Metal organic frameworks (MOFs) are a class of nanoporous materials that are com- posed of metal-containing nodes connected by organic linkers. The study of MOFs has grown in importance due to the wide range of possible node and linker combinations, which allow tailoring towards specific applications. This work demonstrates that the- ory can complement experiment in a way that advances the chemical understanding of MOFs. This thesis contains the results of several investigations on three different areas of MOF research: 1) magnetism, 2) CO2 adsorption, and 3) catalysis.
This document provides a summary of the education and experience of Prof. Dr Syeda Robina Gilani. It includes her positions, education history, research interests, publications, projects supervised, and other achievements. Some key details:
- She is currently the Chairperson of the Department of Chemistry at UET Lahore, Pakistan.
- Her education includes a Post Doc from Queen's University in 2008, a PhD from the University of Leicester in 1998, and an MSc from the University of Punjab in 1987-1989.
- Her research interests include environmental toxicology, coordination chemistry, functional food chemistry, and renewable energy.
- She has supervised several PhD, MPhil, and MSc the
This document discusses various preformulation techniques to enhance drug solubility, including solubilization, surfactants, temperature, pH, cosolvency, solid dispersion, and β-cyclodextrin drug dispersion. Key topics covered include the use of surfactants to increase solubility via micelle formation, the impact of pH on drug solubility through ionization, and the cosolvency technique of using water-miscible solvents to improve solubility. Solid dispersion and cyclodextrin drug dispersion are also introduced as methods to enhance solubility through formation of inclusion complexes.
On the origin of surface imposed anisotropic growth of salicylic and acetylsa...Maciej Przybyłek
In this paper droplet evaporative crystallization of salicylic acid (SA) and acetylsalicylic acid (ASA) crystals on different surfaces, such as glass, polyvinyl alcohol (PVA), and paraffin was studied. The obtained crystals were analyzed using powder X-ray diffraction (PXRD) technique. In order to better understand the effect of the surface on evaporative crystallization, crystals deposited on glass were scraped off. Moreover, evaporative crystallization of a large volume of solution was performed. As we found, paraffin which is non-polar surface promotes formation of crystals morphologically similar to those obtained via bulk evaporative crystallization. On the other hand, when crystallization is carried out on the polar surfaces (glass and PVA), there is a significant orientation effect. This phenomenon is manifested by the reduction of the number of peaks in PXRD spectrum recorded for deposited on the surface crystals. Noteworthy, reduction of PXRD signals is not observed for powder samples obtained after scraping crystals off the glass. In order to explain the mechanism of carboxylic crystals growth on the polar surfaces, quantum-chemical computations were performed. It has been found that crystal faces of the strongest orientation effect can be characterized by the highest surface densities of intermolecular interactions energy (IIE). In case of SA and ASA crystals formed on the polar surfaces the most dominant faces are characterized by the highest adhesive and cohesive properties. This suggests that the selection rules of the orientation effect comes directly from surface IIE densities.
On the origin of surfaces-dependent growth of benzoic acid crystal inferred t...Maciej Przybyłek
Crystal growth behavior of benzoic acid crystals on different surfaces was examined. The performed experiments documented the existence of very strong influence introduced by polar surfaces as glass, gelatin, and polyvinyl alcohol (PVA) on the growth of benzoic acid crystals. These surfaces impose strong orientation effect resulting in a dramatic reduction of number of faces seen with x-ray powder diffractions (XPRD). However, scrapping the crystal off the surface leads to a morphology that is similar to the one observed for bulk crystallization. The surfaces of low wettability (paraffin) seem to be useful for preparation of amorphous powders, even for well-crystallizable compounds. The performed quantum chemistry computations characterized energetic contributions to stabilization of morphology related faces. It has been demonstrated, that the dominant face (002) of benzoic acid crystal, growing on polar surfaces, is characterized by the highest densities of intermolecular interaction energies determining the highest cohesive properties among all studied faces. Additionally, the inter-layer interactions, which stand for adhesive properties, are also the strongest in the case of this face. Thus, quantum chemistry computations providing detailed description of energetic contributions can be successfully used for clarification of adhesive and cohesive nature of benzoic acids crystal faces.
Propensity of salicylamide and ethenzamide cocrystallization with aromatic ca...Maciej Przybyłek
The cocrystallization of salicylamide (2-hydroxybenzamide, SMD) and ethenzamide (2-ethoxybenzamide, EMD) with aromatic carboxylic acids was examined both experimentally and theoretically. The supramolecular synthesis taking advantage of the droplet evaporative crystallization (DEC) technique was combined with powder diffraction and vibrational spectroscopy as the analytical tools. This led to identification of eleven new cocrystals including pharmaceutically relevant coformers such as mono- and dihydroxybenzoic acids. The cocrystallization abilities of SMD and EMD with aromatic carboxylic acids were found to be unexpectedly divers despite high formal similarities of these two benzamides and ability of the R2,2(8) heterosynthon formation. The source of diversities of the cocrystallization landscapes is the difference in the stabilization of possible conformers by adopting alternative intramolecular hydrogen boding patterns. The stronger intramolecular hydrogen bonding the weaker affinity toward intermolecular complexation potential. The substituent effects on R2,2(8) heterosynthon properties are also discussed.
SiO2@FeSO4 nano composite: A recoverable nano-catalyst for eco-friendly synth...Iranian Chemical Society
Various aldoximes and ketoximes synthesis of corresponding aldehydes and ketones in the presence of SiO2@FeSO4 nano composite as recoverable nano catalyst and NH2OH·HCl. The SiO2@FeSO4 nano composite system was carried out between 10 to 15 min in oil bath (70-80 °C) under solvent-free condition in excellent yields in addition this protocol can be used for industrial scales. This method offers some advantages in term of clean reaction conditions, easy work-up procedure, short reaction time, applied to convert α-diketones to α-diketoximes (as longer than other carbonyl compounds), α,β-unsaturated aldehydes and ketones to corresponding oximes and suppression of any side product. So we think that NH2OH•HCl/SiO2@FeSO4 nano composite system could be considered a new and useful addition to the present methodologies in this area. Structure of products and nano composite elucidation was carried out by 1H NMR, 13C NMR, FT-IR, scanning electron microscopy (SEM).
This document summarizes research on synthesizing a hydrate cocrystal of the antitubercular drug isoniazid and the antioxidant protocatechuic acid in a 1:1 ratio. The cocrystal was characterized using Fourier transform infrared spectroscopy, single crystal X-ray diffraction, and differential scanning calorimetry. Solubility and stability studies showed the cocrystal was less soluble but more stable than isoniazid alone. Single crystal X-ray diffraction confirmed hydrogen bonding between the nitrogen of isoniazid's pyridine ring and the hydrogen of protocatechuic acid's carboxylic acid group. This cocrystal formation may improve isoniazid's tablet
Biocompatibility of Poly (L-Lactic Acid) Synthesized In Polymerization Unit B...IJERA Editor
The absorbable polyacid is one of the most used and studied materials in tissue engineering. This work
synthesized a poly (L-lactic acid) (PLLA) through ring-opening polymerization and produced nanofibers by the
electrospinning process. The PLLA was analyzed by FTIR and the cytotoxicity was evaluated by the MTT assay
and Live/Dead®. The hemocompatibility was tested by platelet adhesion and hemolytic activity assay. The tests
were performed in contact with human mesenchymal cells at varying times. The high rates of cell viability and
proliferation shown by MTT and Live/Dead® tests demonstrate that this PLLA is a non-toxic material and the
hemocompatibility assay revealed that the biomaterial was also biocompatible. It was achieved as well the
successful production of electrospinning nanofibers, which can be converted for specific biomedical applications
in the future
This document discusses the development of a catalytic Wittig reaction. The Wittig reaction is commonly used to construct alkene motifs but is stoichiometric and produces stoichiometric phosphine oxide waste. In 2009, a group developed a catalytic Wittig olefination where a phosphine oxide precatalyst is reduced by a silane to a phosphine catalyst. The document will address three aspects important for further developing the catalytic Wittig reaction: 1) recent understanding of the mechanism of the stoichiometric Wittig reaction, 2) suitable phosphine oxide precatalysts, and 3) appropriate reducing agents.
This document describes an approach to rapidly generate molecular diversity using photoassisted diversity-oriented synthesis. Linear photoprecursors containing amino ketone and unsaturated pendant groups are assembled using high-yielding coupling reactions. These precursors undergo efficient intramolecular photocyclizations upon irradiation to form polyheterocyclic scaffolds with increased saturation, reduced rotatable bonds, and new structural frameworks. The primary photoproducts contain reactive functional groups that allow for further post-photochemical modifications, growing molecular complexity and accessing elaborated three-dimensional structures. This modular approach aims to generate drug-like molecules with properties known to correlate with clinical success, overcoming limitations of traditional combinatorial chemistry methods.
Stability Indicating HPLC Method Development A Reviewijtsrd
High performance liquid chromatography is most powerful tools in analytical chemistry which assessing drug product stability. It is most accurate method for determining the qualitative and quantitative analysis of drug product. Forced degradation plays an important role in development of stability indicating analytical methodology. Stability indicating HPLC methods are used to separate various drug related impurities that are formed during the synthesis or manufacture of drug product. This article discusses the strategies and issues regarding the development of stability indicating HPLC system for drug substance. Forced degradation studies establish degradation pathways of drug substances and drug products. Forced degradation elucidate the possible degradation pathway of the drug substance or the active pharmaceutical ingredient in the drug product. At every stage of drug development practical recommendations are provided which will help to avoid failure. Rushikesh S Mulay | Rishikesh S Bachhav "Stability Indicating HPLC Method Development - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-6 , October 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46342.pdf Paper URL : https://www.ijtsrd.com/pharmacy/analytical-chemistry/46342/stability-indicating-hplc-method-development--a-review/rushikesh-s-mulay
J. Bukowczan - Various methods for one pot synthesis of triazoles from quinol...Jerzy_BN
This document describes various methods for synthesizing 1,2,3-triazoles from 4-amino-3-quinolinesulfonamides with a propargyl group. It discusses four reaction methods tried: (1) copper-catalyzed azide-alkyne cycloaddition, (2) phase transfer catalysis, (3) a two-step synthesis using an organic azide, and (4) a catalyst-free reaction in water. The copper-catalyzed and two-step methods produced the best yields of up to 99% and 82%, respectively. Thirteen new compounds were obtained and will be tested for potential anti-cancer activity, as the triazole, quin
Experimental and theoretical solubility advantage screening of bi-component s...Maciej Przybyłek
This document describes an experimental and theoretical study to screen potential solubilizers for curcumin. In the experimental phase, the solubility of curcumin was measured in binary mixtures with 24 excipients. The highest solubility enhancement was found with pyrogallol, caffeine, theophylline, and nicotinamide. A theoretical QSPR model was then developed using molecular descriptors to predict solubility. This model was applied to screen over 230,000 compounds and predict solubility for curcumin analogs and naturally occurring turmerones to identify new excipients.
Carbohydrates can be used to create nanoparticles for biomedical applications. They are one of the major classes of biomolecules and comprise over 80% of biomass. Carbohydrates can be classified as monosaccharides, oligosaccharides, or polysaccharides. They have recently been shown to play regulatory roles in biological processes. Carbohydrate nanoparticles have potential uses in drug delivery, vaccines, tissue engineering, and imaging through carbohydrate-protein interactions and coating on other nanoparticles and surfaces. Specific carbohydrates like cyclodextrins and cellulose have shown promise for medical uses including drug encapsulation and scaffolding. Detection of cancer cells and pathogens is another application being researched using carbohydrate-coated nanoparticles.
Applications of click chemistry in drug discoveryrita martin
his article focus mainly on click chemistry mechanisms and its applications, click chemistry is an easy way to generate substances quickly and reliably by joining small units together, with this ease of use mechanism, click chemistry as found its applications in various technologies especially in drug discovery ,medicinal chemistry, enzyme activity, chemistry natural products, material science, polymers, nanotechnology and bioconjugation
Predicting sulfanilamide solubility in the binary mixtures using a reference ...Maciej Przybyłek
Background. Solubility is a fundamental physicochemical property of active pharmaceutical ingredients. The optimization of a dissolution medium aims not only to increase solubility and other aspects are to be included such as environmental impact, toxicity degree, availability, and costs. Obtaining comprehensive solubility characteristics of chemical compounds is a non-trivial and demanding process. Therefore, support from theoretical approaches is of practical importance.
Objectives. This study aims to examine the accuracy of the reference solubility approach in the case of sulfanilamide dissolution in a variety of binary solvents. This pharmaceutically active substance has been extensively studied, and a substantial amount of solubility data is available. Unfortunately, using this set of data directly for theoretical modeling is impeded by noticeable inconsistencies in the published solubility data. Hence, this aspect is addressed by data curation using theoretical and experimental confirmations.
Materials and methods. In the experimental part of our study, the popular shake-flask method combined with ultraviolet (UV) spectrophotometric measurements was applied for solubility determination. The computational phase utilized the conductor-like screening model for real solvents (COSMO-RS) approach.
Results. The analysis of the results of solubility calculations for sulfonamide in binary solvents revealed abnormally high error values for acetone-ethyl acetate mixtures, which were further confirmed with experimental measurements. Additional confirmation was obtained by extending the solubility measurements to a series of homologous acetate esters.
Conclusions. Our study addresses the crucial issue of coherence of solubility data used for many theoretical inquiries, including parameter fitting of semi-empirical models, in-depth thermodynamic interpretations and application of machine learning protocols. The effectiveness of the proposed methodology for dataset curation was demonstrated for sulfanilamide solubility in binary mixtures. This approach enabled not only the formulation of a consistent dataset of sulfanilamide solubility binary solvent mixtures, but also its implementation as a qualitative tool guiding rationale solvent selection for experimental solubility screening.
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open acc...Austin Publishing Group
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open access journal publishes manuscripts in the following areas but not limited to structures, synthesis, kinetics, organic synthesis, physical organic chemistry, supramolecular chemistry and chemical biology.
Austin Journal of Bioorganic & Organic Chemistry accepts original research articles, review articles, commentaries, Letters, perspectives, and rapid communication on all the aspects of Bioorganic & Organic Chemistry.
Radiolytic Modification of Basic Amino Acid Residues in Peptides : Probes for...Keiji Takamoto
This document discusses using hydroxyl radical mediated protein footprinting coupled with mass spectrometry to map protein structure and examine protein-protein interactions. It specifically examines the radiolytic oxidation of histidine, lysine, and arginine residues in model peptides. Arginine was found to be very sensitive to radiolytic oxidation, producing a characteristic product. Histidine generated a mixture of oxidation products involving rupture and addition to its imidazole ring. Lysine was converted to hydroxylysine or carbonylysine. Examining the reactivity of these basic amino acids expands the utility of protein footprinting techniques.
This document describes the synthesis of novel spirooxindole derivatives via a three-component 1,3-dipolar cycloaddition reaction. Various spirooxindole-spiropiperidinone-pyrrolidine and spirooxindole-spiropiperidinone-pyrrolizine derivatives were synthesized in good yields from isatin, sarcosine or L-proline, and Knoevenagel adducts under optimized reaction conditions. The antimicrobial activities of the synthesized compounds were evaluated, with some compounds exhibiting excellent activity against bacteria and fungi, comparable or superior to standard antimicrobial drugs.
This document summarizes an article that appeared in a journal published by Elsevier. The attached copy is for the author's internal non-commercial use, including instruction and sharing with colleagues. Other uses like reproduction, distribution, selling or posting to websites are prohibited without permission. Authors are allowed to post their version of the article to their personal or institutional websites or repositories, with some restrictions on commercial use. The document provides a link to Elsevier's full copyright and archiving policies.
Group5.the influence of phosphorus precursors on the synthesis and bioactivit...Roy Rodriguez Solano
This document summarizes a study that investigated the influence of different phosphorus precursors on the synthesis and bioactivity of sol-gel derived SiO2-CaO-P2O5 bioactive glasses and glass-ceramics. Three phosphorus precursors were used - triethylphosphate, phosphoric acid, and a solution of phosphorus oxide in ethanol. The different precursors affected the gel formation time and crystallization behavior during heat treatment. Samples prepared with phosphoric acid had a lower crystallization onset temperature and higher resistance to devitrification. However, all resulting materials were bioactive. Bioactivity decreased with increasing heat treatment temperature and was favored in crystallized samples containing wollastonite and tricalcium phosphate
This document is a thesis submitted by Christos A. Ilioudis for the degree of Doctor of Philosophy at King's College London in 2003. The thesis focuses on synthesizing polyaza-macrocycles and macrobicycles and studying their ability to bind inorganic anions. Key findings include determining the crystal structures of various macrocycles and their complexes with halide ions. pH titrations and potentiometric studies showed high binding constants for fluoride and chloride by one of the macrobicycles. The thesis provides an overview of the synthesis methods used and characterization of the resulting compounds.
Similar to Utilization of oriented crystal growth for screening of aromatic carboxylic acids cocrystallization with urea (20)
Experimental and Machine-Learning-Assisted Design of Pharmaceutically Accepta...Maciej Przybyłek
Deep eutectic solvents (DESs) are commonly used in pharmaceutical applications as excellent solubilizers of active substances. This study investigated the tuning of ibuprofen and ketoprofen solubility utilizing DESs containing choline chloride or betaine as hydrogen bond acceptors and various polyols (ethylene glycol, diethylene glycol, triethylene glycol, glycerol, 1,2-propanediol, 1,3-butanediol) as hydrogen bond donors. Experimental solubility data were collected for all DES systems. A machine learning model was developed using COSMO-RS molecular descriptors to predict solubility. All studied DESs exhibited a cosolvency effect, increasing drug solubility at modest concentrations of water. The model accurately predicted solubility for ibuprofen, ketoprofen, and related analogs (flurbiprofen, felbinac, phenylacetic acid, diphenylacetic acid). A machine learning approach utilizing COSMO-RS descriptors enables the rational design and solubility prediction of DES formulations for improved pharmaceutical applications.
Effect of Nanohydroxyapatite on Silk Fibroin–Chitosan Interactions—Molecular ...Maciej Przybyłek
Fibroin–chitosan composites, especially those containing nanohydroxyapatite, show potential for bone tissue regeneration. The physicochemical properties of these biocomposites depend on the compatibility between their components. In this study, the intermolecular interactions of fibroin and chitosan were analyzed using a molecular dynamics approach. Two types of systems were investigated: one containing acetic acid and the other containing calcium (Ca2+) and hydrogen phosphate (HPO₄2−) ions mimicking hydroxyapatite conditions. After obtaining the optimal equilibrium structures, the distributions of several types of interactions, including hydrogen bonds, ionic contacts, and hydrophobic contacts, along with structural and energetical features, were examined. The calculated binding energy values for the fibroin–chitosan complexes confirm their remarkable stability. The high affinity of fibroin for chitosan can be explained by the formation of a dense network of interactions between the considered biopolymers. These interactions were found to primarily be hydrogen bonds and ionic contacts involving ALA, ARG, ASN, ASP, GLN, GLU, GLY, LEU, PRO, SER, THR, TYR, and VAL residues. As established, the complexation of fibroin with chitosan maintains the β-sheet conformation of the peptide. β-Sheet fragments in fibroin are involved in the formation of a significant number of hydrogen bonds and ionic contacts with chitosan.
Experimental and Theoretical Insights into the Intermolecular Interactions in...Maciej Przybyłek
Solubility is not only a crucial physicochemical property for laboratory practice but also provides valuable insight into the mechanism of saturated system organization, as a measure of the interplay between various intermolecular interactions. The importance of these data cannot be overstated, particularly when dealing with active pharmaceutical ingredients (APIs), such as dapsone. It is a commonly used anti-inflammatory and antimicrobial agent. However, its low solubility hampers its efficient applications. In this project, deep eutectic solvents (DESs) were used as solubilizing agents for dapsone as an alternative to traditional solvents. DESs were composed of choline chloride and one of six polyols. Additionally, water–DES mixtures were studied as a type of ternary solvents. The solubility of dapsone in these systems was determined spectrophotometrically. This study also analyzed the intermolecular interactions, not only in the studied eutectic systems, but also in a wide range of systems found in the literature, determined using the COSMO-RS framework. The intermolecular interactions were quantified as affinity values, which correspond to the Gibbs free energy of pair formation of dapsone molecules with constituents of regular solvents and choline chloride-based deep eutectic solvents. The patterns of solute–solute, solute–solvent, and solvent–solvent interactions that affect solubility were recognized using Orange data mining software (version 3.36.2). Finally, the computed affinity values were used to provide useful descriptors for machine learning purposes. The impact of intermolecular interactions on dapsone solubility in neat solvents, binary organic solvent mixtures, and deep eutectic solvents was analyzed and highlighted, underscoring the crucial role of dapsone self-association and providing valuable insights into complex solubility phenomena. Also the importance of solvent–solvent diversity was highlighted as a factor determining dapsone solubility. The Non-Linear Support Vector Regression (NuSVR) model, in conjunction with unique molecular descriptors, revealed exceptional predictive accuracy. Overall, this study underscores the potency of computed molecular characteristics and machine learning models in unraveling complex molecular interactions, thereby advancing our understanding of solubility phenomena within the scientific community.
Deep Eutectic Solvents as Agents for Improving the Solubility of Edaravone: E...Maciej Przybyłek
In this study, both practical and theoretical aspects of the solubility of edaravone (EDA) in Deep Eutectic Solvents (DESs) were considered. The solubility of edaravone in some media, including water, can be limited, which creates the need for new efficient and environmentally safe solvents. The solubility of EDA was measured spectrophotometrically and the complex intermolecular interactions within the systems were studied with the COSMO-RS framework. Of the four studied DES systems, three outperformed the most efficient classical organic solvent, namely dichloromethane, with the DES comprising choline chloride and triethylene glycol, acting as hydrogen bond donor (HBD), in a 1:2 molar proportion yielding the highest solubility of EDA. Interestingly, the addition of a specific amount of water further increased EDA solubility. Theoretical analysis revealed that in pure water or solutions with high water content, EDA stacking is responsible for self-aggregation and lower solubility. On the other hand, the presence of HBDs leads to the formation of intermolecular clusters with EDA, reducing self-aggregation. However, in the presence of a stoichiometric amount of water, a three-molecular EDA–HBD–water complex is formed, which explains why water can also act as a co-solvent. The high probability of formation of this type of complexes is related to the high affinity of the components, which exceeds all other possible complexes.
Molecular dynamics simulations of the affinity of chitin and chitosan for col...Maciej Przybyłek
Chitosan and chitin are promising biopolymers used in many areas including biomedical applications, such as tissue engineering and viscosupplementation. Chitosan shares similar properties with hyaluronan, a natural component of synovial fluid, making it a good candidate for joint disease treatment. The structural and energetic consequences of intermolecular interactions are crucial for understanding the biolubrication phenomenon and other important biomedical features. However, the properties of biopolymers, including their complexation abilities, are influenced by the nature of the aqueous medium with which they interact. In this study, we employed molecular dynamics simulations to describe the effect of pH and the presence of sodium and calcium cations on the stability of molecular complexes formed by collagen type II with chitin and chitosan oligosaccharides. Based on Gibbs free energy of binding, all considered complexes are thermodynamically stable over the entire pH range. The affinity between chitosan oligosaccharide and collagen is highly influenced by pH, while oligomeric chitin shows no pH-dependent effect on the stability of molecular assemblies with collagen. On the other hand, the presence of sodium and calcium cations has a negligible effect on the affinity of chitin and chitosan for collagen.
Intermolecular Interactions as a Measure of Dapsone Solubility in Neat Solven...Maciej Przybyłek
Dapsone is an effective antibacterial drug used to treat a variety of conditions. However, the aqueous solubility of this drug is limited, as is its permeability. This study expands the available solubility data pool for dapsone by measuring its solubility in several pure organic solvents: N-methyl-2-pyrrolidone (CAS: 872-50-4), dimethyl sulfoxide (CAS: 67-68-5), 4-formylmorpholine (CAS: 4394-85-8), tetraethylene pentamine (CAS: 112-57-2), and diethylene glycol bis(3-aminopropyl) ether (CAS: 4246-51-9). Furthermore, the study proposes the use of intermolecular interactions as molecular descriptors to predict the solubility of dapsone in neat solvents and binary mixtures using machine learning models. An ensemble of regressors was used, including support vector machines, random forests, gradient boosting, and neural networks. Affinities of dapsone to solvent molecules were calculated using COSMO-RS and used as input for model training. Due to the polymorphic nature of dapsone, fusion data are not available, which prohibits the direct use of COSMO-RS for solubility calculations. Therefore, a consonance solvent approach was tested, which allows an indirect estimation of the fusion properties. Unfortunately, the resulting accuracy is unsatisfactory. In contrast, the developed regressors showed high predictive potential. This work documents that intermolecular interactions characterized by solute–solvent contacts can be considered valuable molecular descriptors for solubility modeling and that the wealth of encoded information is sufficient for solubility predictions for new systems, including those for which experimental measurements of thermodynamic properties are unavailable.
Finding the Right Solvent: A Novel Screening Protocol for Identifying Environ...Maciej Przybyłek
This study investigated the solubility of benzenesulfonamide (BSA) as a model compound using experimental and computational methods. New experimental solubility data were collected in the solvents DMSO, DMF, 4FM, and their binary mixtures with water. The predictive model was constructed based on the best-performing regression models trained on available experimental data, and their hyperparameters were optimized using a newly developed Python code. To evaluate the models, a novel scoring function was formulated, considering not only the accuracy but also the bias–variance tradeoff through a learning curve analysis. An ensemble approach was adopted by selecting the top-performing regression models for test and validation subsets. The obtained model accurately back-calculated the experimental data and was used to predict the solubility of BSA in 2067 potential solvents. The analysis of the entire solvent space focused on the identification of solvents with high solubility, a low environmental impact, and affordability, leading to a refined list of potential candidates that meet all three requirements. The proposed procedure has general applicability and can significantly improve the quality and speed of experimental solvent screening.
Intermolecular Interactions of Edaravone in Aqueous Solutions of Ethaline and...Maciej Przybyłek
Edaravone, acting as a cerebral protective agent, is administered to treat acute brain infarction. Its poor solubility is addressed here by means of optimizing the composition of the aqueous choline chloride (ChCl)-based eutectic solvents prepared with ethylene glycol (EG) or glycerol (GL) in the three different designed solvents compositions. The slurry method was used for spectroscopic solubility determination in temperatures between 298.15 K and 313.15 K. Measurements confirmed that ethaline (ETA = ChCl:EG = 1:2) and glyceline (GLE = ChCl:GL = 1:2) are very effective solvents for edaravone. The solubility at 298.15 K in the optimal compositions was found to be equal xE = 0.158 (cE = 302.96 mg/mL) and xE = 0.105 (cE = 191.06 mg/mL) for glyceline and ethaline, respectively. In addition, it was documented that wetting of neat eutectic mixtures increases edaravone solubility which is a fortunate circumstance not only from the perspective of a solubility advantage but also addresses high hygroscopicity of eutectic mixtures. The aqueous mixture with 0.6 mole fraction of the optimal composition yielded solubility values at 298.15 K equal to xE = 0.193 (cE = 459.69 mg/mL) and xE = 0.145 (cE = 344.22 mg/mL) for glyceline and ethaline, respectively. Since GLE is a pharmaceutically acceptable solvent, it is possible to consider this as a potential new liquid form of this drug with a tunable dosage. In fact, the recommended amount of edaravone administered to patients can be easily achieved using the studied systems. The observed high solubility is interpreted in terms of intermolecular interactions computed using the Conductor-like Screening Model for Real Solvents (COSMO-RS) approach and corrected for accounting of electron correlation, zero-point vibrational energy and basis set superposition errors. Extensive conformational search allowed for identifying the most probable contacts, the thermodynamic and geometric features of which were collected and discussed. It was documented that edaravone can form stable dimers stabilized via stacking interactions between five-membered heterocyclic rings. In addition, edaravone can act as a hydrogen bond acceptor with all components of the studied systems with the highest affinities to ion pairs of ETA and GLE. Finally, the linear regression model was formulated, which can accurately estimate edaravone solubility utilizing molecular descriptors obtained from COSMO-RS computations. This enables the screening of new eutectic solvents for finding greener replacers of designed solvents. The theoretical analysis of tautomeric equilibria confirmed that keto-isomer edaravone is predominant in the bulk liquid phase of all considered deep eutectic solvents (DES).
Collagen Type II—Chitosan Interactions as Dependent on Hydroxylation and Acet...Maciej Przybyłek
Chitosan–collagen blends have been widely applied in tissue engineering, joints diseases treatment, and many other biomedical fields. Understanding the affinity between chitosan and collagen type II is particularly relevant in the context of mechanical properties modulation, which is closely associated with designing biomaterials suitable for cartilage and synovial fluid regeneration. However, many structural features influence chitosan’s affinity for collagen. One of the most important ones is the deacetylation degree (DD) in chitosan and the hydroxylation degree (HD) of proline (PRO) moieties in collagen. In this paper, combinations of both factors were analyzed using a very efficient molecular dynamics approach. It was found that DD and HD modifications significantly affect the structural features of the complex related to considered types of interactions, namely hydrogen bonds, hydrophobic, and ionic contacts. In the case of hydrogen bonds both direct and indirect (water bridges) contacts were examined. In case of the most collagen analogues, a very good correlation between binding free energy and DD was observed.
Solubility Characteristics of Acetaminophen and Phenacetin in Binary Mixtures...Maciej Przybyłek
The solubility of active pharmaceutical ingredients is a mandatory physicochemical characteristic in pharmaceutical practice. However, the number of potential solvents and their mixtures prevents direct measurements of all possible combinations for finding environmentally friendly, operational and cost-effective solubilizers. That is why support from theoretical screening seems to be valuable. Here, a collection of acetaminophen and phenacetin solubility data in neat and binary solvent mixtures was used for the development of a nonlinear deep machine learning model using new intuitive molecular descriptors derived from COSMO-RS computations. The literature dataset was augmented with results of new measurements in aqueous binary mixtures of 4-formylmorpholine, DMSO and DMF. The solubility values back-computed with the developed ensemble of neural networks are in perfect agreement with the experimental data, which enables the extensive screening of many combinations of solvents not studied experimentally within the applicability domain of the trained model. The final predictions were presented not only in the form of the set of optimal hyperparameters but also in a more intuitive way by the set of parameters of the Jouyban–Acree equation often used in the co-solvency domain. This new and effective approach is easily extendible to other systems, enabling the fast and reliable selection of candidates for new solvents and directing the experimental solubility screening of active pharmaceutical ingredients.
Application of COSMO-RS-DARE as a Tool for Testing Consistency of Solubility ...Maciej Przybyłek
This study examined the solubility of coumarin, a naturally occurring compound, in various alcohols using experimental and computational methods. Inconsistencies were found in literature solubility data for coumarin. The study developed a theoretical approach using COSMO-RS-DARE modeling to test solubility data consistency and identify outliers. Experimentally measured solubility data for coumarin in a series of alcohols matched the back-calculated COSMO-RS-DARE values, validating the theoretical approach. Linear regressions were also developed to correlate COSMO-RS-DARE integration parameters with molecular descriptors.
Albumin–Hyaluronan Interactions: Influence of Ionic Composition Probed by Mol...Maciej Przybyłek
The lubrication mechanism in synovial fluid and joints is not yet fully understood. Nevertheless,
intermolecular interactions between various neutral and ionic species including large
macromolecular systems and simple inorganic ions are the key to understanding the excellent lubrication
performance. An important tool for characterizing the intermolecular forces and their
structural consequences is molecular dynamics. Albumin is one of the major components in synovial
fluid. Its electrostatic properties, including the ability to form molecular complexes, are closely
related to pH, solvation, and the presence of ions. In the context of synovial fluid, it is relevant to
describe the possible interactions between albumin and hyaluronate, taking into account solution
composition effects. In this study, the influence of Na+, Mg2+, and Ca2+ ions on human serum
albumin–hyaluronan interactions were examined using molecular dynamics tools. It was established
that the presence of divalent cations, and especially Ca2+, contributes mostly to the increase of
the affinity between hyaluronan and albumin, which is associated with charge compensation in
negatively charged hyaluronan and albumin. Furthermore, the most probable binding sites were
structurally and energetically characterized. The indicated moieties exhibit a locally positive charge
which enables hyaluronate binding (direct and water mediated).
Effect of Chitosan Deacetylation on Its Affinity to Type III Collagen: A Mole...Maciej Przybyłek
The ability to form strong intermolecular interactions by linear glucosamine polysaccharides with collagen is strictly related to their nonlinear dynamic behavior and hence bio-lubricating features. Type III collagen plays a crucial role in tissue regeneration, and its presence in the articular cartilage affects its bio-technical features. In this study, the molecular dynamics methodology was applied to evaluate the effect of deacetylation degree on the chitosan affinity to type III collagen. The computational procedure employed docking and geometry optimizations of different chitosan structures characterized by randomly distributed deacetylated groups. The eight different degrees of deacetylation from 12.5% to 100% were taken into account. We found an increasing linear trend (R2 = 0.97) between deacetylation degree and the collagen-chitosan interaction energy. This can be explained by replacing weak hydrophobic contacts with more stable hydrogen bonds involving amino groups in N-deacetylated chitosan moieties. In this study, the properties of chitosan were compared with hyaluronic acid, which is a natural component of synovial fluid and cartilage. As we found, when the degree of deacetylation of chitosan was greater than 0.4, it exhibited a higher affinity for collagen than in the case of hyaluronic acid.
New Screening Protocol for Effective Green Solvents Selection of Benzamide, S...Maciej Przybyłek
New protocol for screening efficient and environmentally friendly solvents was proposed and experimentally verified. The guidance for solvent selection comes from computed solubility via COSMO-RS approach. Furthermore, solute-solvent affinities computed using advanced quantum chemistry level were used as a rationale for observed solvents ranking. The screening protocol pointed out that 4-formylomorpholine (4FM) is an attractive solubilizer compared to commonly used aprotic solvents such as DMSO and DMF. This was tested experimentally by measuring the solubility of the title compounds in aqueous binary mixtures in the temperature range between 298.15 K and 313.15 K. Additional measurements were also performed for aqueous binary mixtures of DMSO and DMF. It has been found that the solubility of studied aromatic amides is very high and quite similar in all three aprotic solvents. For most aqueous binary mixtures, a significant decrease in solubility with a decrease in the organic fraction is observed, indicating that all systems can be regarded as efficient solvent-anti-solvent pairs. In the case of salicylamide dissolved in aqueous-4FM binary mixtures, a strong synergistic effect has been found leading to the highest solubility for 0.6 mole fraction of 4-FM.
Predicting Value of Binding Constants of Organic Ligands to Beta-Cyclodextrin...Maciej Przybyłek
The quantitative structure–activity relationship (QSPR) model was formulated to quantify values of the binding constant (lnK) of a series of ligands to beta–cyclodextrin (β-CD). For this purpose, the multivariate adaptive regression splines (MARSplines) methodology was adopted with molecular descriptors derived from the simplified molecular input line entry specification (SMILES) strings. This approach allows discovery of regression equations consisting of new non-linear components (basis functions) being combinations of molecular descriptors. The model was subjected to the standard internal and external validation procedures, which indicated its high predictive power. The appearance of polarity-related descriptors, such as XlogP, confirms the hydrophobic nature of the cyclodextrin cavity. The model can be used for predicting the affinity of new ligands to β-CD. However, a non-standard application was also proposed for classification into Biopharmaceutical Classification System (BCS) drug types. It was found that a single parameter, which is the estimated value of lnK, is sufficient to distinguish highly permeable drugs (BCS class I and II) from low permeable ones (BCS class II and IV). In general, it was found that drugs of the former group exhibit higher affinity to β-CD then the latter group (class III and IV).
Natural Deep Eutectic Solvents as Agents for Improving Solubility, Stability ...Maciej Przybyłek
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Or: Beyond linear.
Abstract: Equivariant neural networks are neural networks that incorporate symmetries. The nonlinear activation functions in these networks result in interesting nonlinear equivariant maps between simple representations, and motivate the key player of this talk: piecewise linear representation theory.
Disclaimer: No one is perfect, so please mind that there might be mistakes and typos.
dtubbenhauer@gmail.com
Corrected slides: dtubbenhauer.com/talks.html
The ability to recreate computational results with minimal effort and actionable metrics provides a solid foundation for scientific research and software development. When people can replicate an analysis at the touch of a button using open-source software, open data, and methods to assess and compare proposals, it significantly eases verification of results, engagement with a diverse range of contributors, and progress. However, we have yet to fully achieve this; there are still many sociotechnical frictions.
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3D Hybrid PIC simulation of the plasma expansion (ISSS-14)
Utilization of oriented crystal growth for screening of aromatic carboxylic acids cocrystallization with urea
1. Utilization of oriented crystal growth for screening of aromatic
carboxylic acids cocrystallization with urea
Maciej Przybyłek a
, Dorota Ziółkowska b
, Mirosław Kobierski c
, Karina Mroczyńska d
,
Piotr Cysewski a,n
a
Department of Physical Chemistry, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-950 Bydgoszcz, Poland
b
University of Technology and Life Sciences in Bydgoszcz, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland
c
University of Technology And Life Sciences in Bydgoszcz, Faculty of Agriculture and Biotechnology, Department of Soil Science and Soil Protection,
Bernardyńska 6, 85-029 Bydgoszcz, Poland
d
Research Laboratory, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland
a r t i c l e i n f o
Article history:
Received 25 June 2015
Received in revised form
1 October 2015
Accepted 19 October 2015
Available online 27 October 2015
Keywords:
A1 Crystallites
A1 Surfaces
A1 X-ray diffraction
B1 Acids
B1 Aromatic compounds
a b s t r a c t
The possibility of molecular complex formation in the solid state of urea with benzoic acid analogues was
measured directly on the crystallite films deposited on the glass surface using powder X-ray dif-
fractometry (PXRD). Obtained solid mixtures were also analyzed using Fourier transform infrared
spectroscopy (FTIR). The simple droplet evaporation method was found to be efficient, robust, fast and
cost-preserving approach for first stage cocrystal screening. Additionally, the application of orientation
effect to cocrystal screening simplifies the analysis due to damping of majority of diffraction signals
coming from coformers. During validation phase the proposed approach successfully reproduced both
positive cases of cocrystallization (urea:salicylic acid and urea:4-hydroxy benzoic acid) as well as pairs of
co-formers immiscible in the solid state (urea:benzoic acid and urea:acetylsalicylic acids). Based on
validated approach new cocrystals of urea were identified in complexes with 3-hydroxybenzoic acid, 2,4-
dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid and 3,5-dihydroxybenzoic
acid. In all cases formation of multicomponent crystal phase was confirmed by the appearance of new
reflexes on the diffraction patterns and FTIR absorption band shifts of O–H and N–H groups.
& 2015 Elsevier B.V. All rights reserved.
1. Introduction
According to widely accepted definition [1] a cocrystal is a
homogeneous crystalline solid that contains stoichiometric
amounts of discrete neutral molecular species, which are solids
under ambient conditions. These kind of solution differ from other
dispersions as eutectic or monotectic systems by congruent
melting and a molecular complex formation of a definite propor-
tions of interaction components [2–4]. The practical application of
organic solid alloys encompassing variety industries as pharma-
ceutical, textile, paper, chemical processing, photographic, pro-
pellants or electronics [5] stimulated growth of accumulated
knowledge and diversity of obtained materials. This explosion of
interests resulted in 7688 structures of binary cocrystals solved so
far [6] not counting hydrates, solvates, clathrates nor organome-
tallic species. The change of physicochemical properties of
cocrystals with respect of the coformers is especially useful and
important in the case of active pharmaceutical ingredients (API).
There are many examples of significant improving of API behaviors
both in vivo and in vitro [7–12]. The advantages of cocrystalliza-
tion for pharmaceutical industry are not only related to bioavail-
ability enhancement but also to the increase of stability [13],
hygroscopicity decrease [14], mechanical properties improvement
[15] and also due to intellectual property issues [16].
Urea is a quite common former of cocrystals and in the Cam-
bridge Structural Database (CSD) [6]. One can find more than 100
records documenting its involvement in multicomponent com-
pounds. One of the reason of so common occurrence of urea is the
diversity of possible interactions offered by two amino groups.
Although, the pure urea crystal is deposited 18-times in the CSD
corresponding to measurements at different temperatures but only
one polymorphic form is reported, which adopts tetragonal system
of P421m symmetry. Urea molecule can form strong intermolecular
hydrogen bonds and can act both as acceptor and donor. Indeed, the
carbonyl group is very strong acceptor center interacting with three
neighboring urea molecules via four hydrogen bonds. The bi-center
interactions with amino groups lead to formation of 1D columns
each surrounded by four identical chains. The stabilization of
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/jcrysgro
Journal of Crystal Growth
http://dx.doi.org/10.1016/j.jcrysgro.2015.10.015
0022-0248/& 2015 Elsevier B.V. All rights reserved.
n
Corresponding author.
E-mail address: piotr.cysewski@cm.umk.pl (P. Cysewski).
Journal of Crystal Growth 433 (2016) 128–138
2. resulting perpendicular 2D sheets is gained via hydrogen bonds
formed with amino groups [17–24]. This ability of divers hydrogen
bonding is the source of observed variety of cocrystals structures of
urea since it can cocrystalize with polar coformers as for example
with salicylic acid (SLCADC) but also with non-polar species as for
instance with 1,10-phenanthroline (AMILUD). The other interesting
feature of the cocrystals formed by urea is significant diversity of
stoichiometry of complexes found in the solid phase. Although the
1:1 ratio predominates in cocrystals but one can find as high as 10:1
proportion in the case of urea-2,12-tridecanedione (MISNOR). Also
many drugs can cocrystalize with urea as for example barbital
(BARBUR) – a hypnotic and sedative agent also used in veterinary
practice for central nervous system depression, febuxostat (HIQ-
QUV) – inhibiting xanthine oxidase, nitrofurantoin (ORUXUV) – an
antibiotic usually used for treatment of urinary tract infections or
betonicin (REGKUK) – a psychoactive agent. On the other hand there
are many drugs that have not been cocrystalized with urea as for
example aspirin (acetylsalicylic acid) – a common prototypical
analgesic having anti-inflammatory and antipyretic properties.
However, structurally very similar salicylic acid used as analgesics
was successfully cocrystalized with urea (SLCADC). Besides, urea in
some case can form eutectic or monotectic mixtures with organic
compounds for example with 4-chloronitrobenzene [25]. There is
remarkably small data about cocrystallization of urea with other
aromatic carboxylic acids. Apart from salicylic acid also 3,5-dini-
trosalicylic acid (NUHYAQ), 1,1-binaphthyl-2,20
-dicarboxylic acid
(ROGKOO), trimesic acid (benzene-1,3,5-tricarboxylic acid) (CEKSIU)
and 4-hydroxycarboxylic acid (JOZZIH) cocrystalize with urea in the
monoclinic system. The orthorhombic crystal system is typical for 4-
aminobenzoic acid:urea cocrystal (NUHYEU). Finally the triclinic
system is observed in the case of o-phthalic acid (NUHYIY,
NUHYIY01) and 5-nitrosalicylic acid (NUHXUJ) cocrystals with urea.
It is slightly surprising that no more structures of urea cocrystals
with other aromatic carboxylic acid were determined, despite the
fact that stabilization of such potential systems might be gained
from quite common R-COOH Á Á Á H2NCO-R heterosynthon of
C2
2(8) type. These observations suggest that predicting of the ability
of cocrystal formation of urea with other coformers is not straight-
forward and non-trivial task. This is the starting point of our
investigations. There are many ways of cocrystal preparation and
among them the mechanochemical approach [26] is commonly
used. In fact, this method was applied for obtaining the very first
cocrystal of quinone and hydroquinone [27]. Besides, many alter-
native methods were adopted for cocrystallization purposes [28] as
for example sonication [29], melting [30] including direct phase
transition observations under thermal microscopy [31] and many
other techniques. Generally speaking, two basic categories of
cocrystals screening methods can be distinguished: thermodynamic
(slow crystal growth) and kinetic (fast crystallization) [32–34]. Par-
ticularly noteworthy are the latter methods relying on the fast
solution evaporation like spray drying [35], spin coating [36],
microwave-accelerated evaporative crystallization [37–39] and dro-
plet evaporation [40–46]. Hence, they are routinely utilized for
cocrystals synthesis [47–49]. One of the form of such crystallization
are preparation of oriented samples. As we reported previously
[45,46] the crystallization on the polar surfaces leads to interesting
effect of reducing number of peaks on PXRD spectra if measure-
ments are performed directly on thin layer deposits. The origin of
this phenomena is the orientation effect of exposed faces toward
solution which exhibits both the highest adhesive and cohesive
properties [45,46]. It is worth noting that, PXRD measurements of
so-called oriented samples is commonly used in geology and soil
science [50–53]. Noteworthy, preparation of oriented phenzaine–
chloranilic acid cocrystal thin films using sublimation method was
reported by Thompson et al. [54]. The main advantage of oriented
samples measurements is enhancing the intensity of certain
diffraction signals and diminishing majority of the rest. Therefore, it
is interesting to see if oriented samples measurements can be useful
in identification of cocrystal formation what stands for the purpose
of this paper. Below, the verification of proposed methodology of
identification of known cocrystals of urea with aromatic carboxylic
acids is followed by screening of urea cocrystallization landscape for
finding new homogeneous bi-component solids that were not-
reported in the literature so far.
2. Materials and methods
2.1. Chemicals
All analytical grade chemicals were purchased from commercial
suppliers and used without further purification. Urea (U, CAS:
57-13-6), benzoic acid (BA, CAS: 65-85-0), salicylic acid (SA, CAS:
69-72-7), acetylsalicylic acid (ASA, CAS: 50-78-2), 3-hydroxybenzoic
acid (3HBA, CAS: 99-06-9), 2,5-dihydroxybenzoic acid (2,5DHBA,
gentisic acid, CAS: 490-79-9), 2,6-dihydroxybenzoic acid (2,6DHBA,
γ-resorcylic acid, CAS: 303-07-1) and methanol (CAS: 67-56-1)
were obtained from POCH (Poland). Other compounds namely,
4-hydroxybenzoic acid (4HBA, CAS: 99-96-7), 2,4-dihydroxybenzoic
acid (2,4DHBA, β-resorcylic acid, CAS: 89-86-1), 3,5-dihydrox-
ybenzoic acid (3,5DHBA, CAS: 99-10-5) were purchased from Sigma-
Aldrich (USA). Structures of used dicarboxylic acids were presented
on Scheme 1.
2.2. Crystallization and samples preparation procedures
First, 0.724 M methanolic solutions of coformers were prepared
and mixed together to obtain urea/carboxylic acid solutions at
unimolar composition. Then, such mixtures and the pure compo-
nents solutions were used for preparing of crystallite layers
according to previously described procedure [45,46]. This method
involves placing of 20 ml of the solution on glass microscope slide
and letting for fast evaporation at 43 °C under atmospheric
pressure.
Additional cocrystallization experiments were performed for
all new cocrystals (2,4DHBA, 2,5DHBA, 2,6DHBA, 3,5DHBA and
3HBA) for alternative verifications. The PXRD patterns recorded for
oriented crystallites were compared with diffractograms of pow-
der samples obtained using mechanochemical method and bulk
evaporation approach. In the case of the mechanochemical
method, coformers crystals were mixed in the 1:1 M proportion
and ground in the mortar for an hour. The bulk evaporation
cocrystallization 30 ml of methanolic solutions were evaporated in
a glass beaker at 43 °C under atmospheric pressure.
2.3. Measurements
The Fourier transform infrared (FTIR) spectra were recorded on
a Bruker Alpha-PFT-IR spectrometer (Bruker, Germany) with a
diamond attenuated total reflection (ATR) crystal. Powder X-ray
diffraction (PXRD) patterns were recorded with the use of Goni-
ometer PW3050/60 armed with Empyrean XRD tube Cu LFF
DK303072. Diffraction data were collected in the range of 2θ
between 5° and 40° with 0.001° step width. The patterns were
processed in Reflex module of Accelrys Material Studio 8.0 [55] by
Kα2 stripping, background computation and subtraction followed
by curve smoothing and normalization.
3. Results and discussion
In this study, the possibilities of binary homogeneous mixture
formation of urea in solid state with nine aromatic carboxylic acids
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138 129
3. were examined. In the first part the interest was focused on such
pairs, where structures are known. This step ensures the reliability
of cocrystallization on the glass surface and allows for demon-
stration of usefulness of sample orientation for cocrystal screening.
After validation of proposed procedure by positive examples
additional verification was performed for such coformers that are
known to be able to form simple eutectic systems instead of
molecular complex in the solid state. In the third part the results of
actual seeking of new cocrystals are documented.
3.1. Validation of cocrystal screening method
The efficacy of cocrystal identification after deposition on the
glass film is demonstrated in Fig. 1, where the experimental PXRD
spectra of coformers and U–SA cocrystal are presented. Addition-
ally, plots were augmented with simulated spectra obtained using
CIF-content deposited in CSD. First of all the strong orientation
effect is visible both for urea and salicylic acid. In the former case
the most dominant signal characterizing crystallites deposited on
glass is positioned at 2θ¼22.2° what corresponds to (110) Miller
plane. This is not surprising since on the single crystals XRD
spectra of urea this signal is also the most intense. The orientation
effect is especially pronounced in the case of salicylic acid, what
has already been documented [46]. The formation of U–SA
cocrystal on the surface is indisputable since direct comparison
with SLCAD01 signals confirms overlapping of all the most sig-
nificant peaks. The orientation effect is not so spectacular as for
monomers, but still identification of cocrystal is straightforward.
Besides, the analysis of FTIR spectra shows evidences of new
hydrogen bonding pattern. The consequence of molecular complex
formation in the case of amides and carboxylic acids is shifting of
N–H and O–H stretching vibrations in comparison to pure cofor-
mers [56–59]. It is worth mentioning that U–SA cocrystal has
already been studied by means of vibrational spectroscopy [60].
Our measurements agree with reported spectra of U–SA and sev-
eral absorption bands characteristic for intermolecular interac-
tions between urea and salicylic acid can be identified. First of all,
there is a broad and intense band located at 1898 cmÀ1
. This signal
corresponds to a stretching vibration of carboxylic group forming
intermolecular C(O)OH∙∙∙O¼C(NH2)2 hydrogen bond. For com-
parison in the case of pure salicylic acid crystallites O–H stretching
bands are located in the range from 3236 cmÀ1
to 2539 cmÀ1
. Our
observation agrees with reported IR spectra [61] and confirms
existence of two distinct types of N–H vibrational modes, namely
out-of-phase stretching (asymmetric, νas(NH)) and in-phase
stretching (symmetric, νs(NH)) vibrations. As it is shown in
Fig. 1, the νas(NH) vibration is located at 3431 cmÀ1
and
3471 cmÀ1
for pure urea and urea–salicylic acid molecular com-
plex, respectively. This indicates that formation of NH∙∙∙O inter-
action results in blue-shift of out-of-phase NH stretching absorp-
tion band. On the other hand in the case of N–H in-phase
stretching mode, a significant red-shift from 3260 down to
3215 cmÀ1
can be observed.
The second example of positive cocrystallization of urea with
aromatic carboxylic acids is the case of 4HBA. Although the U–
4HBA cocrystal has already been solved and discussed [62] but
FIGURES
Scheme 1. The schematic representation of hydroxycarboxylic acids structures used for cocrystals synthesis.
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138130
4. neither structure nor XRD spectra were deposited in CDS. It is
reported however, that the 2:1 complex of urea and 4HBA crys-
tallizes as triclinic system in the P1 space group. As one can infer
from Fig. 2 the crystallization on glass surfaces also leads to
molecular complex. Formation of a new multicomponent crystal
can be evidenced by a new signal located at 2θ¼13.5°. Further-
more, cocrystal formation can be confirmed by means of FTIR
spectroscopy. However, in this case the shift of absorption bands is
less pronounced than in the case of U–SA cocrystal. As a con-
sequence of U–4HBA molecular complex formation the three
bands located in the O–H stretching region are shifted from
2548 cmÀ1
, 2664 cmÀ1
and 2825 cmÀ1
to 2559 cmÀ1
, 2690 cmÀ1
and 2817 cmÀ1
, respectively.
Presented analysis of successful identification of cocrystalliza-
tion on the glass surfaces is a promising circumstance, suggesting
usefulness of adopted screening method for further applications.
However, before seeking of new cocrystals, also negative cases
should be considered. For this purpose there were considered two
structurally very similar compounds such as benzoic acid and
acetylsalicylic acid. The lack of structures of these cocrystals in CSD
[6] is not accidental. As it was revealed by thermomicroscopic
measurements the U–BA [63] and U–ASA [64] binary systems
exhibit simple eutectic behavior. The thaw melt method [65] as
very useful in detailed analysis of miscibility of solid and liquid
mixtures proved the lack of molecular complex formation in the
entire range of concentrations. In both cases the single invariant
point the for either of systems was identified. The characteristic
melting temperature of eutectic mixture was measured. Further-
more, the direct inspection of binary phase diagrams shows neg-
ligible formation of solid solutions or molecular compounds. The
lack of clustering of coformers and consequently solidification of
two distinct phases is also confirmed by excess thermodynamic
functions. Interestingly, our experiments on crystallization of
these two pairs on glass surface also failed to identify cocrystal
formation. Indeed, as it is presented in supporting materials (see
Fig. S1 and S2) the lack of cocrystal is directly provable since
complete overlapping of single component PXRD patterns with
signals measured for 1:1 mixtures of urea with benzoic or acet-
ylsalicylic acids was observed. Inspection of FTIR spectra, showed
that absorption bands corresponding to N–H and O–H in U–BA and
U–ASA mixtures are not shifted when compared to signals of pure
co-formers. However in the case of FTIR spectra of U–ASA mixture
two new absorption bands located at 2850 cmÀ1
and 2919 cmÀ1
might be noticed. Appearance of these characteristic sharp signals
corresponding to CH stretching vibrational modes is typical for
adsorbed or occluded methanol [66–70]. This is understandable,
since methanol was used as a solvent in the evaporative crystal-
lization procedure.
3.2. New cocrystals of urea with aromatic carboxylic acids
The usefulness of glass surfaces for cocrystal screening relying
on the orientation effect is documented in the case of such
hydroxycarboxylic aromatic acids as 2,4DHBA, 2,5DHBA, 2,6DHBA,
3,5DHBA and 3HBA. These compounds were selected since to our
best knowledge there are no reports on their cocrystallization with
urea. The possibility of molecular complexes formation was eval-
uated by inspection of both PXRD and FTIR spectra recorded for
crystallite layers. The FTIR analysis omitted dactyloscopic region
and absorption bands in the regions corresponding to O–H and N–
H stretching vibrational modes were taken into account.
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
SA (glass)
SA (SALIAC)
U-SA (glass)
U−SA (SLCADC01)
U(UREAXX23)
0.2
0.4
0.6
0.8
1.0
1700 2200 2700 3200 3700 4200
normalizedtransmitance
wave number [cm-1
]
U-SA
SA
U
°
Fig. 1. The measured PXRD and FTIR patterns of urea (U), salicylic acid (SA) and cocrystal (U–SA) deposited on the glass surface. The diffraction plots were augmented with
the simulated spectra of single component crystals and U–SA cocrystal. Codes represent deposits found in CSD [6].
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138 131
5. 3.2.1. Cocrystallization of 2,4-dihydroxybenzoic acid with urea
The 2,4-dihydroxybenzoic acid can crystallize in three distinct
polymorphic forms (I: ZZZEEU08, II: from ZZZEEU01 to ZZZEEU07,
III: ZZZEEU) [71–74]. Unfortunately the latter was not solved and
neither space group nor structure factors are available. On the
other hand computational studied suggest that only two poly-
morph are to be considered as the most stable at room tempera-
ture [71]. Our measurements of PXRD spectra of single compo-
nents crystal deposited on glass surface demonstrated very strong
orientation effect of 2,4DHBA since only one diffraction peak can
be observed at 2θ¼13.7°. This signal is associated with (021)
Miller plane, what suggests existence on the glass surface exclu-
sively polymorph II. This is quite expected since it is thermo-
dynamically the most stable polymorphic form at room tempera-
ture [71]. Interestingly, β-resorcylic acid, as many other hydro-
xybenzoic acids, can readily form solvates [71,75–80]. The struc-
ture of 2,4-dihydroxybenzoic acid hemihydrate has been solved
[76] (QIVTUK) and corresponding diffractogram was also supplied
in Fig. 3. It is practically impossible to distinguish hydrate from dry
crystal due to strong overlapping of registered signals. Thus, traces
of water in air or methanol might also have influence the solid
formation on glass surfaces. The ability of formation of a multi-
component crystal with urea can be confirmed by the appearance
of two intense diffraction peaks at 2θ¼8.4° and 2θ¼9.7°. Fur-
thermore, in the case of U–2,4DHBA cocrystal, there is a significant
shift of N–H stretching bands from 3260 cmÀ1
to 3312 cmÀ1
and
from 3431 cmÀ1
to 3461 cmÀ1
(Fig. 3). Also shift of the O–H
stretching vibrations from 2559 cmÀ1
to 2594 cmÀ1
can be
observed as a consequence of complex formation in the solid state.
3.2.2. Cocrystallization of 2,5-dihydroxybenzoic acid with urea
The gentisic acid acting as analgesic, antirheumatic and anti-
arthritic agent can adopt two polymorphic forms, namely I: BES-
KAL01 and II: BESKAL, from BESKAL02 to BESKAL14 [73,81–82].
According to literature, 2,5-dihydroxybenzoic acid does not form
hydrate and also no hydrate structure was found in the CSD [6,83].
The most stable from the thermodynamic point of view [73] is the
polymorph crystallizing in monoclinic system (Pa space group). As
it is documented in Fig. 4 the same polymorph is also present on
the glass surface. The most intense reflexes observed on the PXRD
spectra of 2,5DHBA are located at 2θ¼15.8°, 2θ¼17.5° and
2θ¼30.9°. They correspond to (200), (210) and (311) Miller planes,
respectively. The formation of U–2,5DHBA cocrystal can be infer-
red from the most intense signal placed at 2θ¼12.9°, which is
typical for cocrystal rather than for coformers. The PXRD signals of
U–2,5DHBA cocrystal possess additional two signals located at
2θ¼15.6° and 2θ¼18.8°. However, only latter can be used for
additional confirmation of cocrystal occurrence since the former
corresponds to the (200) crystal face of 2,5DHBA. In the case of U–
2,5DHBA complex the characteristic broad absorption band with a
maximum at 1864 cmÀ1
appears on the FTIR spectra. It is worth
mentioning that similar band was observed also in the case of SA–
U complex (Fig. 1). Moreover, the presence of C(O)OH∙∙∙O¼C
(NH2)2 hydrogen bond can be confirmed by observed red-shift of
O–H stretching band from 3260 cmÀ1
to 3115 cmÀ1
along with
shifts in the N–H stretching region.
3.2.3. Cocrystallization of 2,6-dihydroxybenzoic acid with urea
The γ-resorcylic acid has been found to form two distinct
polymorphs [79,84]. The first one crystallizes in the orthorhombic
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
4HBA (glass)
4HBA (JOZZIH)
U-4HBA (glass)
U (UREAXX23)
0.0
0.2
0.4
0.6
0.8
1.0
1740 2240 2740 3240 3740
normalizedtransmitance
wave number [cm-1]
U-4HBA
4-HBA
U
°
Fig. 2. The measured PXRD and FTIR patterns of urea (U), 4-hydroxybenzoic acid (4HBA) and cocrystal (U–U–4HBA) deposited on glass surfaces. The diffraction plots were
augmented with the simulated spectra of single component crystals. Codes represent deposits found in CSD [6].
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138132
6. system (LEZJAB) and the other one as monoclinic crystal (LEZ-
JAB01). Besides, 2,6DHBA can form monohydrate, which structure
was deposited in CSD under code LEZJEF. After inspection of PXRD
spectra provided in Fig. 5 one can directly conclude that γ-
resorcylic acid crystallizes on glass surface as mixture of dry and
monohydrate solids. This is probable caused by the moisture
sorption. Both crystals show strong orientation effect and on the
glass surface only one polymorph of 2,6DHBA is to be expected.
From the perspective of this project the most interesting is the
documentation of U–2,6DHBA occurrence. As shown on Fig. 5 the
crystallization of binary mixture on glass surface leads to forma-
tion of single component urea crystals, what is suggested by
strongest signal located at 2θ¼22.3°. However, this is not the only
solid appearing on the surface. The diffraction peak placed at
2θ¼12.9° suggests presence of new crystal phase. The inspection
of FTIR spectra confirms this suggestion. There is clearly visible
broad absorption band located at 1805 cmÀ1
, which is character-
istic for hydrogen bonding between urea and carboxylic acid.
Furthermore, formation of cocrystal can be also evidenced by
several shifts of absorption bands at the O–H and N–H stretching
regions making spectra of U–2,6DHBA distinct from pure compo-
nents patterns.
3.2.4. Cocrystallization of 3,5-dihydroxybenzoic acid with urea
The next studied case focuses on 3,5-dihydroxybenzoic acid.
This compound is known to exist in solid state as one of two
polymorphs (I: WUYPOW and II: WUYPOW01) both sharing the
same space group in triclinic system [75]. Also it is known the
hemihydrate of the α-resorcylic acid [85], which structure is
available in CSD under code OKEMAT. As it is presented in Fig. 6
these three solids have quite distinct diffraction characteristics. It
appears that on glass surface the hemihydrate predominates and
its grow has strong oriented. There is observed single and intense
peak located at 2θ¼26.9° what enables straightforward identifi-
cation of the form present in thin films. Interestingly, the α-
resorcylic acid can form molecular complex with urea what can be
directly documented after inspection of the PXRD spectra. The
most significant signal is located at 2θ¼10.8°, which seems to
unique for U-3,5DHBA cocrystal. There are also other peaks on
PXRD plots, but they overlap with hydrate or dry 3,5-dihydrox-
ybenzoic acid solids. Additional confirmation of existence of U-
35DHBA system can be inferred from FTIR spectra. As it is visible in
Fig. 6 significant shifts of small N–H absorption band from
3260 cmÀ1
to 3394 cmÀ1
can be observed.
3.2.5. Cocrystallization of 3-hydroxybenzoic acid with urea
The last considered here carboxylic acid was 3-hydroxybenzoic
acid, which is known to be produced in the gut microflora as one
of the three main metabolites formed from the catechin diet. The
3-HBA solids can adopt two distinct polymorphic form crystalizing
either in monoclinic (BIDLOP) or orthorhombic (BIDLOP01,
BIDLOP02) crystallographic systems [86,87]. No hydrate structure
is available in CSD. The PXRD spectra of 3-HBA presented in Fig. 7
suggests that both of orthorhombic forms might be present on the
glass crystallites. The signals cannot be univocally separated and in
this case the orientation effect is not useful in the identification of
polymorphic forms. As it is presented in Fig. 7 formation of the
cocrystal phase can be evidenced by the new reflex on the dif-
fraction pattern located at 2θ¼5.5°. However, the most intense
diffraction peak comes from pure urea suggesting a non uni-molar
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
2,4DHBA (glass)
2,4DHBA
(ZZZEEU08)
U-2,4DHBA (glass)
U (UREAXX23)
2,4DHBA
(ZZZEEU04)
2,4DHBA hydrate
(QIVTUK)
U-2,4DHBA (grinding)
U-2,4DHBA (bulk)
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500 4000
normalizedtransmitance
wave number [cm-1 ]
U-2,4DHBA
2,4DHBA
U
°
Fig. 3. The measured PXRD and FTIR patterns of urea (U), 2,4-hydroxybenzoic acid (2,4HBA) and cocrystal (U–2,4HBA) crystallite deposited on glass surfaces. Additionally,
diffraction plots were augmented with the simulated spectra based on data deposited in CSD [6] and cocrystallization via two alternative methods.
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138 133
7. 5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
2,5DHBA (glass)
2,5DHBA
(BESKAL01)
U-2,5DHBA (glass)
U (UREAXX23)
2,5DHBA
(BESKAL08)
U-2,5DHBA (grinding)
U-2,5DHBA (bulk)
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1700 2200 2700 3200 3700
normalizedtransmitance
wave number [cm-1
]
U-2,5DBA
2,5DHBA
U
°
Fig. 4. The measured PXRD and FTIR patterns of urea (U), 2,5-hydroxybenzoic acid (2,5HBA) and cocrystal (U–2,5HBA) crystallite deposited on glass surfaces. Additionally,
diffraction plots were augmented with the simulated spectra based on data deposited in CSD [6] and cocrystallization via two alternative methods.
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
2,6DHBA (glass)
U-2,6DHBA (glass)
U (UREAXX23)
2,6DHBA
(LEZJAB)
2,6DHBA hydrate
(LEZJEF)
2,6DHBA
(LEZJAB01)
U-2,6DHBA (grinding)
U-2,6DHBA bulk)
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1700 2200 2700 3200 3700
normalizedtransmitance
wave number [cm-1]
U-2,6DHBA
2,6DHBA
U
°
Fig. 5. The measured PXRD and FTIR patterns of urea (U), 2,6-hydroxybenzoic acid (2,6HBA) and cocrystal (U–2,6HBA) crystallite deposited on glass surfaces. Additionally,
diffraction plots were augmented with the simulated spectra based on data deposited in CSD [6] and cocrystallization via two alternative methods.
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138134
8. 5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
3,5DHBA (glass)
U (UREAXX23)
U-3,5DHBA (glass)
3,5DHBA (WUYPOW)
3,5DHBA (WUYPOW01)
3,5DHBA hydrate
(OKEMAT)
U-3,5DHBA (grinding)
U-3,5DHBA (bulk)
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1750 2250 2750 3250 3750
normalizedtransmitance
wave number [cm-1]
U-3,5DHBA
3,5DHBA
U
°
Fig. 6. The measured PXRD and FTIR patterns of urea (U), 3,5-hydroxybenzoic acid (3,5HBA) and cocrystal (U-3,5HBA) crystallite deposited on glass surfaces. Additionally,
diffraction plots were augmented with the simulated spectra based on data deposited in CSD [6] and cocrystallization via two alternative methods.
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
3HBA (glass)
3HBA (BIDLOP01)
3HBA (BIDLOP)
U-3HBA (glass)
U (UREAXX23)
U-3HBA (grinding)
U-3HBA (bulk)
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
2000 2500 3000 3500 4000
relativetransmitance
wave number [cm-1]
U-3HBA
3HBA
U
°
Fig. 7. The measured PXRD and FTIR patterns of urea (U), 3-hydroxybenzoic acid (3HBA) and cocrystal (U-3HBA) crystallite deposited on glass surfaces. Additionally,
diffraction plots were augmented with the simulated spectra based on data deposited in CSD [6] and cocrystallization via two alternative methods.
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138 135
9. complexation. Furthermore, the FTIR spectra shown in Fig. 7
confirms occurrence of the hydrogen bond between U and 3HBA.
The intermolecular interactions in U-3HBA molecular complex
differ from coformers what can be evidenced by the blue-shifts of
OH stretching bands from 2842 cmÀ1
to 2971 cmÀ1
and from
3083 cmÀ1
to 3151 cmÀ1
.
4. Conclusions
As it was reported in our previous studies [45,46], anisotropic
crystal growth during droplet evaporation on the polar surfaces
depends on the adhesive and cohesive properties of crystal faces.
The role of intermolecular interactions on the orientation effect
was also described in case of thin layers obtained using sublima-
tion method [88]. Moreover, according to Schweicher et al.,
orientation of terthiophene crystal thin films obtained during
directional thermal gradient crystallization can be explained
within the framework of equilibrium crystal morphology calcula-
tion, which is based on the crystal faces energetics analysis [89].
Since the lattice energy calculations showed that multicomponent
crystals are generally more energetically stable than pure com-
ponents crystals [90–92], it is understandable that cocrystals faces
growth on the surface under oriented crystallization conditions is
favorable and hence the appearance of diffraction peaks corre-
sponding to cocrystal is highly probable. Therefore, despite of the
fact that orientation effect leads to significant reduction of PXRD
peaks, new cocrystal phase can be identified. In this study, the
ability of molecular complex formation in the solid state was
documented for series of aromatic carboxylic acids with urea. For
this purpose the cocrystallization was performed on glass surfaces
using simple drop evaporate method. The direct measurements of
obtained deposits were done using both PXRD and FTIR techni-
ques. The comparison of signals characterizing single component
with those observed for binary mixtures of urea with several
aromatic carboxylic acids allows for identification of several new
cocrystals. Although, this method is unsuitable for crystal structure
solution due to significant reduction of peaks number in diffrac-
tion spectra but is useful as the first stage tool in the cocrystal
screening. The strong orientation effect on surfaces dampens many
signals in PXRD spectra and distinguishing of cocrystal from
coformers is much simpler. Before application the procedure to
new cocrystal finding the validation stage successfully identified
cases of both cocrystallization and pairs of coformers not being
able to cocrystalize. Indeed, two positive cases known in the lit-
erature were confirmed, namely U–SA and U–4HBA. Additionally,
two binary mixtures of eutectic character also pointed out efficacy
of utilized technique for identification of such negative examples.
The pairs comprising urea and either benzoic acid or aspirin is
known as simple eutectic mixture. In both cases, the measured
signals of crystallites deposited on surfaces obtained from 1:1
stoichiometric solutions were substantially indistinguishable from
single components signals. The proposed method seems to be
suited as preliminary tool for cocrystal screening and offers several
advantages worth emphasizing. First of all this is very simple, time
saving technique enabling for robust screening without sophisti-
cated equipment. Due to small volume of the solution the eva-
poration process takes seconds and several samples on the glass
plates can be prepared at the same time. Furthermore, the PXRD
measurements can be fasten due to the fact that the most sig-
nificant analytical signals belong to low 2θ region and rarely
reaching 30°. The method is very cheap since microliters of solu-
tion are used for measurements. That is why proposed approach
seems to be especially valuable in cocrystal screening of active
pharmaceutical ingredients. What is also worth mentioning, the
protocol can be applied for cases of low solubility by scanning the
film several times and accumulating even small intensity signals.
Of course there is practical limit due to possible noise, which is
especially disturbing in the cases of high contribution from
amorphous phase. However, in reported cases this was not a ser-
ious issue. If additive measuring is not sufficient one can repeat
several times the procedure of dropping and evaporating. This
results in thicker crystallite. However this reduces the orientation
effect and spectra are more similar to the bulk crystallization. After
identification of positive cocrystallization pairs one can apply
traditional methods for cocrystal formation as for example
mechanochemical approach restricting synthesis only to such
cases, which were pre-screened on glass surfaces. In studied bin-
ary mixtures the 1:1 M ratio of coformers was used, but in general
one can study other proportions for identification of stoichiometry
of molecular complex formation in the cocrystal, what will be the
subject of further investigations.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.bios.2014.05.063.
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