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.
The document summarizes an undergraduate research fellowship investigating the crystal structures of various biologically significant molecules using X-ray diffraction. It describes research on chalcones, Schiff bases, Hantzsch 1,4-dihydropyridines, and pyrazolines, with several structures already published. The fellowship involves using industry standard software to analyze diffraction results and prepare final data for publication.
Ultra performance liquid chromatographic method for simultaneous quantificati...Ratnakaram Venkata Nadh
Plerixafor (PLX) injections are administered to patients with cancers of lymphocytes
(non-Hodgkin’s lymphoma) and plasma cells (multiple myeloma). The main
objective of the current study was to develop a short reverse phase chromatographic
method for the simultaneous quantification of PLX and its impurities, in an injection
formulation, to reduce the time required for these quality tests. Furthermore, the
present work describes the role of nonalkyl branched nonquaternary ion pair reagent
in improving the peak shape and reducing column equilibration time. The separation
of PLX and its related substances is pH dependent (optimum pH = 2.50) and was
achieved on an octadecylsilyl (C18) column. The method was validated for its intended
purpose in accordance with the current regulatory guidelines for validation. The
proposed method can be applied for quality control, release, and stability analyses of
active pharmaceutical ingredient, PLX, as well as finished products, PLX injections
Stable isotope labeled organic molecules have various applications in the pharmaceutical industry. Deuterium was discovered in 1932 and is used to study reaction mechanisms through kinetic isotope effects. Replacing hydrogen with deuterium in drug molecules can alter their metabolism and pharmacokinetics, potentially improving properties. Stable isotopes are also used as reference standards in mass spectrometry to improve quantification of drugs and metabolites. The global market for stable isotope labeled compounds was estimated at $220 million in 2013, with the pharmaceutical industry as the largest segment due to increasing clinical trials and quantification techniques. Challenges include high costs, but availability of resources in countries like India may allow for lower costs.
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.
Approaches for Bioequivalence Assessment of Topical Dermatological Formulations by Syed Arman Rabbani in Advancements in Bioequivalence & Bioavailability
https://crimsonpublishers.com/abb/fulltext/ABB.000503.php
Comparative Haematology and Urinary Analysis of Passive Inhalers of Petrol Fu...Erhunmwunsee Osazee
Exposure to petrol fumes was found to have hematotoxic effects on petrol station attendants in Benin City, Nigeria. Hematological analysis showed significant decreases in hemoglobin concentration, packed cell volume, red blood cell count, and white blood cell count in attendants compared to unexposed controls. These changes were more pronounced with longer exposure duration and indicate possible induction of anemia. Urinalysis revealed high levels of bilirubin, urobilinogen, and nitrites in attendants' urine, suggesting immune-depressing effects. The degree of changes depended on exposure duration, with four years of exposure showing the most significant effects. Overall, the study findings suggest that exposure to petrol fumes can negatively impact
Biochemical and molecular level screening system and their strategies ppd102U108
This document discusses screening methods for identifying microorganisms or compounds of interest from mixed populations. It describes chemical and biochemical screening approaches. Chemical screening involves developing a reliable bioassay, validating candidate compounds, and elucidating modes of action. Key considerations for screening include the source, substrates, and detection methods used. The document also discusses steps to design an effective chemical screening system, including assay development, hit selection, libraries, validation, and target identification. Overall, screening provides a way to select valuable microbes or compounds and remove those that are not as useful.
Crystal Engineering Applied to the Development of Novel Pharmaceutical Solid Forms with Improved Bioavailability: the Co Crystals Case by Javier Ellena in Advancements in Bioequivalence & Bioavailability
Pharmaceutical co crystal technology has emerged as a promising strategy to enhance bioavailability of poorly water soluble drugs. This mini review presents a brief overview of pharmaceutical co crystals with particular focus on co crystal design, characterization techniques and impacts on drug bioavailability.
https://crimsonpublishers.com/abb/fulltext/ABB.000514.php
The document summarizes an undergraduate research fellowship investigating the crystal structures of various biologically significant molecules using X-ray diffraction. It describes research on chalcones, Schiff bases, Hantzsch 1,4-dihydropyridines, and pyrazolines, with several structures already published. The fellowship involves using industry standard software to analyze diffraction results and prepare final data for publication.
Ultra performance liquid chromatographic method for simultaneous quantificati...Ratnakaram Venkata Nadh
Plerixafor (PLX) injections are administered to patients with cancers of lymphocytes
(non-Hodgkin’s lymphoma) and plasma cells (multiple myeloma). The main
objective of the current study was to develop a short reverse phase chromatographic
method for the simultaneous quantification of PLX and its impurities, in an injection
formulation, to reduce the time required for these quality tests. Furthermore, the
present work describes the role of nonalkyl branched nonquaternary ion pair reagent
in improving the peak shape and reducing column equilibration time. The separation
of PLX and its related substances is pH dependent (optimum pH = 2.50) and was
achieved on an octadecylsilyl (C18) column. The method was validated for its intended
purpose in accordance with the current regulatory guidelines for validation. The
proposed method can be applied for quality control, release, and stability analyses of
active pharmaceutical ingredient, PLX, as well as finished products, PLX injections
Stable isotope labeled organic molecules have various applications in the pharmaceutical industry. Deuterium was discovered in 1932 and is used to study reaction mechanisms through kinetic isotope effects. Replacing hydrogen with deuterium in drug molecules can alter their metabolism and pharmacokinetics, potentially improving properties. Stable isotopes are also used as reference standards in mass spectrometry to improve quantification of drugs and metabolites. The global market for stable isotope labeled compounds was estimated at $220 million in 2013, with the pharmaceutical industry as the largest segment due to increasing clinical trials and quantification techniques. Challenges include high costs, but availability of resources in countries like India may allow for lower costs.
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.
Approaches for Bioequivalence Assessment of Topical Dermatological Formulations by Syed Arman Rabbani in Advancements in Bioequivalence & Bioavailability
https://crimsonpublishers.com/abb/fulltext/ABB.000503.php
Comparative Haematology and Urinary Analysis of Passive Inhalers of Petrol Fu...Erhunmwunsee Osazee
Exposure to petrol fumes was found to have hematotoxic effects on petrol station attendants in Benin City, Nigeria. Hematological analysis showed significant decreases in hemoglobin concentration, packed cell volume, red blood cell count, and white blood cell count in attendants compared to unexposed controls. These changes were more pronounced with longer exposure duration and indicate possible induction of anemia. Urinalysis revealed high levels of bilirubin, urobilinogen, and nitrites in attendants' urine, suggesting immune-depressing effects. The degree of changes depended on exposure duration, with four years of exposure showing the most significant effects. Overall, the study findings suggest that exposure to petrol fumes can negatively impact
Biochemical and molecular level screening system and their strategies ppd102U108
This document discusses screening methods for identifying microorganisms or compounds of interest from mixed populations. It describes chemical and biochemical screening approaches. Chemical screening involves developing a reliable bioassay, validating candidate compounds, and elucidating modes of action. Key considerations for screening include the source, substrates, and detection methods used. The document also discusses steps to design an effective chemical screening system, including assay development, hit selection, libraries, validation, and target identification. Overall, screening provides a way to select valuable microbes or compounds and remove those that are not as useful.
Crystal Engineering Applied to the Development of Novel Pharmaceutical Solid Forms with Improved Bioavailability: the Co Crystals Case by Javier Ellena in Advancements in Bioequivalence & Bioavailability
Pharmaceutical co crystal technology has emerged as a promising strategy to enhance bioavailability of poorly water soluble drugs. This mini review presents a brief overview of pharmaceutical co crystals with particular focus on co crystal design, characterization techniques and impacts on drug bioavailability.
https://crimsonpublishers.com/abb/fulltext/ABB.000514.php
Preformulation studies characterize the physical and chemical properties of drug substances to aid in developing stable, safe, and effective drug formulations with high bioavailability. Key aspects of preformulation studies include characterizing the bulk properties, solubility, and stability of drugs. This involves investigating properties like crystallinity, polymorphism, particle size, density, and how these properties influence solubility, stability, and bioavailability when formulated into drug products. The goal is to obtain information early in development to guide decisions around formulation components, manufacturing processes, analytical methods, and dosage forms.
Dottor Ruszczak collagene per la somministrazione di antibioticiRobertoPalumbo12
In questo studio vengono riassunti alcuni sviluppi e applicazioni del collagene come sistema biologico di somministrazione di antibiotico, in particolare gentamicina.
Le principali applicazioni cliniche includono:
trattamento e profilassi delle infezioni delle ossa e dei tessuti molli, guarigione delle ferite, nonché trattamento oftalmico e parodontale.
Vengono discussi I vantaggi dell'applicazione locale e la logica dell'uso dei sistemi di somministrazione locale del farmaco.
Computer aided docking studies heterocyclic analogues of naproxen ijrpppharmaindexing
This document describes a study that used computer-aided molecular docking to design novel heterocyclic analogues of Naproxen, a nonsteroidal anti-inflammatory drug (NSAID). The goal was to develop analogues with greater selectivity for the COX-2 enzyme over COX-1 to reduce gastrointestinal (GI) toxicity, a common side effect of NSAIDs. Ten new ligands based on 1,3,4-oxadiazole analogues of Naproxen were designed and docked into the binding sites of COX-1 and COX-2 proteins. All the ligands showed greater selectivity for COX-2 and higher potency than Naproxen according to the docking results
The document summarizes a review by the European Food Safety Authority (EFSA) of a study published by Séralini et al. investigating the health effects of genetically modified maize and glyphosate formulations in rats. EFSA notes the study has unclear objectives and is inadequately reported, omitting many key details. EFSA concludes the study is of insufficient scientific quality for safety assessment. EFSA will provide the study authors an opportunity to provide further information, but sees no need at this time to reopen safety evaluations of the maize or glyphosate based on the published study.
Bioequivalence Study of the Two Products of Efavirenz by Validated Analytical...BRNSS Publication Hub
The aim of this study was to find whether the bioavailability of a 600 mg efavirenz capsule (E.F.600 capsule, test) produced by Macneil and Argus Pharmaceutical Ltd. was equivalent to the tablet EFAVIR produced by the Cipla Ltd. (reference preparation). The pharmacokinetic parameters assessed in this study were area under the plasma –concentration time curve 0–96 h (AUCt), area under the plasma concentration time curve from time 0 to ∞ (AUCinf), the peak plasma concentration of drug (Cmax), time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t½). This was a randomized, single-blind, two-period, crossover study which included 20 healthy adult male and female subjects under fasting conditions. In each of the two study periods (separated by a washout of 1 week), single dose of test or reference drug was administered. Blood samples were taken up to 96 h past dose, the plasma was separated, and the concentrations of efavirenz were determined by high-performance liquid chromatography -UV method. Bioavailability and bioequivalence studies play a key role during the phase of drug development for both innovator drugs and generic drugs and thus have gained a great attention over the past few decades. Bioequivalence study is used to introduce generic drugs of innovator drugs at a lower cost. Hence, a thorough understanding of these bioavailability/bioequivalence studies is required.
Co-fermentation of glucose, starch, and cellulose for mesophilic biohydrogen ...Preethi Velayutham
This study assessed the synergistic effects of co-fermenting glucose, starch, and cellulose for mesophilic biohydrogen production using anaerobic digester sludge. Batch experiments were conducted with glucose, starch, and cellulose individually and in combinations of two or three substrates. The hydrogen yields were on average 27% greater in co-substrate conditions compared to expected yields, indicating co-fermentation improved hydrogen production potential. Glucose addition favored acetate synthesis while cellulose degradation was associated with propionate synthesis. Microbial community analysis using 16S rRNA gene sequencing revealed that while some operational taxonomic units were common to mono- and co-substrate batches, others were unique to co-substrate conditions
Rahul Bhattacharya is a synthetic organic chemist currently working as a post-doctoral fellow at Johns Hopkins University School of Medicine. He has extensive experience in designing and synthesizing small molecule drug candidates for applications in metabolic glycoengineering and tissue engineering. Some of his accomplishments include developing a biopolymer-based drug delivery method for treating atherosclerosis and designing efficient synthesis routes for substituted pyrroles and hexopyranosides.
Acrylamide forms in foods when reducing sugars and asparagine are heated above 120°C through the Maillard reaction. It is found in various foods worldwide, especially those derived from carbohydrates like potatoes and cereals. While most epidemiological studies show no increased cancer risk from dietary acrylamide exposure, some cancer types warrant further study. Efforts to reduce acrylamide formation have met with some success for certain foods but complete elimination is likely not possible. A major toxicology study on acrylamide is ongoing but results have not yet been released. Current knowledge gaps remain around human health effects at low levels of dietary exposure.
Utilization of oriented crystal growth for screening of aromatic carboxylic a...Maciej Przybyłek
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.
Dr. Biswajit Chakraborty is a Senior Project Fellow at the Indian Institute of Chemical Biology in Kolkata, India. He received his Ph.D. in Chemistry from the same institution, where he studied the synthesis of analogues of natural products like Andrographolide and Betulinic acid and evaluated their anti-cancer potential. He has expertise in natural product isolation, organic synthesis, and analytical techniques. He has published 5 research papers on developing methods for synthesizing drug-like heterocyclic compounds and evaluating their biological activities.
Pharmacokinetic Properties of Biomass-extracted Substances Isolated by Green ...Michal Jablonsky
According to the literature, approximately 41 nutraceutical compounds have been isolated from different types of biomass using green solvents. It is important to collect information on the pharmacokinetic properties of the nutraceutical substances from biomass isolated according to the published papers. The pharmacokinetic properties of the bioactive substances extracted by green solvents, such as the molecular weight, logP, AlogP, H-bond acceptor, H-bond donor, total polar surface area, atom molar refractivity, number of rotatable bonds, number of atoms, rotatable bond count, number of rigid bonds, number of atom rings, and number of H-bonds, were calculated with a drug-likeness tool. In practical terms, the original and most well-known Lipinski's Rule of Five (Ro5) was applied to 28 substances, namely 3-hydroxytyrosol; apigenin; artemisinin; bergapten; bilobalide; biochanin A; caffeic Acid; caffeoylmalic acid; catechins; cinnamic acid; curcumin; daidzei; daidzin; epicatechin; gallic acid; genistein; ginkgolide A; ginkgolide B; levofloxacin; luteolin; naringenin; p-coumaric acid; protocatechuic acid; psoralen; quercetin; trans-ferulic acid; tyrosol, and vanillin.
Dr. Biswajit Chakraborty is a Senior Project Fellow at the Structural Biology and Bioinformatics Division of the Indian Institute of Chemical Biology in Kolkata, India. He received his Ph.D. in Chemistry from the same institution, where his thesis focused on synthesizing analogues of biologically active natural products and evaluating their anti-cancer potential. His research experience includes isolating and characterizing natural products, synthesizing analog libraries, and evaluating compounds for anti-cancer activity. He has authored or co-authored 5 publications in peer-reviewed journals.
New Green Synthesis Approaches of Pharmacologically Active Heterocyclic Compo...ijtsrd
Green chemistry is a rapidly developing field providing a proactive avenue for the sustainable development of future science and technology. Green chemistry can be applied to the design of highly efficient, environmentally benign synthetic protocols to deliver life saving medicines, and to accelerate lead optimization processes in drug discovery, while minimizing environmental impact. It also offers enhanced chemical process economics, concomitant with a reduced environmental burden. There are relatively environmentally benign protocols for the synthesis of pharmaceutically active heterocycles that highlight the advantages of using green chemistry, for example, by proceeding under microwave irradiation or in aqueous reaction media. Chandra Prakash Gharu "New Green Synthesis Approaches of Pharmacologically Active Heterocyclic Compounds" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-5 , August 2022, URL: https://www.ijtsrd.com/papers/ijtsrd51793.pdf Paper URL: https://www.ijtsrd.com/chemistry/other/51793/new-green-synthesis-approaches-of-pharmacologically-active-heterocyclic-compounds/chandra-prakash-gharu
Development and characterization of anionic liposaccharides for enhanced oralAdel Abdelrahim, PhD
The document describes the development and characterization of novel anionic liposaccharide derivatives for enhancing oral drug delivery. Liposaccharides containing d-glucose and lipoamino acids were synthesized. Their critical aggregation concentration and thermodynamic profiles were determined using isothermal titration microcalorimetry. The liposaccharides were found to be non-toxic and did not cause hemolysis or reduce cell viability. When mixed with the model drug tobramycin, one of the liposaccharides formed aggregates around 200 nm and increased tobramycin's partitioning between n-octanol and water, suggesting it may enhance the oral absorption of hydrophilic drugs.
A STUDY TO EVALUATE THE IN VITRO ANTIMICROBIAL ACTIVITY AND ANTIANDROGENIC E...Dr. Pradeep mitharwal
The present paper deals with synthesis and characterization
of some new chromium (III) Schiff base complexes using microwave irradiation
technique as well as conventional heating. The S∩N donor benzothiazolines, 1-
(2-furanyl) ethanone benzothiazoline (Bzt1N
∩
SH), 1-(2-thienyl) ethanone
benzothiazoline (Bzt2N
∩
SH) and 1-(2-pyridyl) ethanone benzothiazoline
(Bzt3N
∩
SH) were prepared by the condensation of ortho-aminothiophenol with
respective ketones in ethanol.
Analytical Method Development and Validation of Prednisolone Sodium Phosphate...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Method development and validation of Sodium Cromoglycate sujatabhosale5
Here are the key steps in the sample preparation procedure for UV spectroscopy:
1. A standard stock solution of 100 μg/ml was prepared by dissolving 10 mg of drug in 100 ml of mobile phase (ACN:Water 80:20).
2. From the stock solution, 10 ml was pipetted and diluted to 100 ml with mobile phase to obtain a 10 μg/ml working standard solution.
3. Tablets/capsules were weighed and powdered. An amount of powder equivalent to 10 mg of drug was transferred to a 100 ml volumetric flask.
4. The powder was dissolved in mobile phase and sonicated for 15 minutes. The volume was made up to mark with mobile phase to obtain a
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).
Ramprasad Ghosh is seeking a research position in bioorganic/medicinal chemistry. He has a PhD in organic chemistry from the Indian Institute of Chemical Biology and has held three postdoctoral research positions. His research has focused on the synthesis of carbohydrates, nucleosides, and glycoconjugates for applications in drug delivery and enzyme inhibition. Currently he is working on synthesizing derivatives of glucosamine-6-phosphate to target bacterial riboswitches and develop new antibiotics.
This document describes the synthesis of 17 new 1,2,4-triazole derivatives and evaluates their antimicrobial and anticancer activities. The compounds showed the most potent antimicrobial activity against the fungus Aspergillus niger. Compound 14 was the most active. Compound 7 exhibited appreciable anticancer activity against colon cancer cells. Quantitative structure-activity relationship analysis identified topological and electronic properties important for the compounds' antimicrobial effects.
This document summarizes an editorial on recent advances in the clinical application of mass spectrometry. It discusses how liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma mass spectrometry (ICP-MS) have expanded the use of mass spectrometry in clinical chemistry testing over the past decade. The editorial notes that many clinical chemistry laboratories now use electrospray ionization LC-MS/MS and that external quality assurance programs include more analytes quantified by mass spectrometry methods. While mass spectrometry offers improvements in specificity and sensitivity, some debate remains around its use in clinical laboratories.
Preformulation studies characterize the physical and chemical properties of drug substances to aid in developing stable, safe, and effective drug formulations with high bioavailability. Key aspects of preformulation studies include characterizing the bulk properties, solubility, and stability of drugs. This involves investigating properties like crystallinity, polymorphism, particle size, density, and how these properties influence solubility, stability, and bioavailability when formulated into drug products. The goal is to obtain information early in development to guide decisions around formulation components, manufacturing processes, analytical methods, and dosage forms.
Dottor Ruszczak collagene per la somministrazione di antibioticiRobertoPalumbo12
In questo studio vengono riassunti alcuni sviluppi e applicazioni del collagene come sistema biologico di somministrazione di antibiotico, in particolare gentamicina.
Le principali applicazioni cliniche includono:
trattamento e profilassi delle infezioni delle ossa e dei tessuti molli, guarigione delle ferite, nonché trattamento oftalmico e parodontale.
Vengono discussi I vantaggi dell'applicazione locale e la logica dell'uso dei sistemi di somministrazione locale del farmaco.
Computer aided docking studies heterocyclic analogues of naproxen ijrpppharmaindexing
This document describes a study that used computer-aided molecular docking to design novel heterocyclic analogues of Naproxen, a nonsteroidal anti-inflammatory drug (NSAID). The goal was to develop analogues with greater selectivity for the COX-2 enzyme over COX-1 to reduce gastrointestinal (GI) toxicity, a common side effect of NSAIDs. Ten new ligands based on 1,3,4-oxadiazole analogues of Naproxen were designed and docked into the binding sites of COX-1 and COX-2 proteins. All the ligands showed greater selectivity for COX-2 and higher potency than Naproxen according to the docking results
The document summarizes a review by the European Food Safety Authority (EFSA) of a study published by Séralini et al. investigating the health effects of genetically modified maize and glyphosate formulations in rats. EFSA notes the study has unclear objectives and is inadequately reported, omitting many key details. EFSA concludes the study is of insufficient scientific quality for safety assessment. EFSA will provide the study authors an opportunity to provide further information, but sees no need at this time to reopen safety evaluations of the maize or glyphosate based on the published study.
Bioequivalence Study of the Two Products of Efavirenz by Validated Analytical...BRNSS Publication Hub
The aim of this study was to find whether the bioavailability of a 600 mg efavirenz capsule (E.F.600 capsule, test) produced by Macneil and Argus Pharmaceutical Ltd. was equivalent to the tablet EFAVIR produced by the Cipla Ltd. (reference preparation). The pharmacokinetic parameters assessed in this study were area under the plasma –concentration time curve 0–96 h (AUCt), area under the plasma concentration time curve from time 0 to ∞ (AUCinf), the peak plasma concentration of drug (Cmax), time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t½). This was a randomized, single-blind, two-period, crossover study which included 20 healthy adult male and female subjects under fasting conditions. In each of the two study periods (separated by a washout of 1 week), single dose of test or reference drug was administered. Blood samples were taken up to 96 h past dose, the plasma was separated, and the concentrations of efavirenz were determined by high-performance liquid chromatography -UV method. Bioavailability and bioequivalence studies play a key role during the phase of drug development for both innovator drugs and generic drugs and thus have gained a great attention over the past few decades. Bioequivalence study is used to introduce generic drugs of innovator drugs at a lower cost. Hence, a thorough understanding of these bioavailability/bioequivalence studies is required.
Co-fermentation of glucose, starch, and cellulose for mesophilic biohydrogen ...Preethi Velayutham
This study assessed the synergistic effects of co-fermenting glucose, starch, and cellulose for mesophilic biohydrogen production using anaerobic digester sludge. Batch experiments were conducted with glucose, starch, and cellulose individually and in combinations of two or three substrates. The hydrogen yields were on average 27% greater in co-substrate conditions compared to expected yields, indicating co-fermentation improved hydrogen production potential. Glucose addition favored acetate synthesis while cellulose degradation was associated with propionate synthesis. Microbial community analysis using 16S rRNA gene sequencing revealed that while some operational taxonomic units were common to mono- and co-substrate batches, others were unique to co-substrate conditions
Rahul Bhattacharya is a synthetic organic chemist currently working as a post-doctoral fellow at Johns Hopkins University School of Medicine. He has extensive experience in designing and synthesizing small molecule drug candidates for applications in metabolic glycoengineering and tissue engineering. Some of his accomplishments include developing a biopolymer-based drug delivery method for treating atherosclerosis and designing efficient synthesis routes for substituted pyrroles and hexopyranosides.
Acrylamide forms in foods when reducing sugars and asparagine are heated above 120°C through the Maillard reaction. It is found in various foods worldwide, especially those derived from carbohydrates like potatoes and cereals. While most epidemiological studies show no increased cancer risk from dietary acrylamide exposure, some cancer types warrant further study. Efforts to reduce acrylamide formation have met with some success for certain foods but complete elimination is likely not possible. A major toxicology study on acrylamide is ongoing but results have not yet been released. Current knowledge gaps remain around human health effects at low levels of dietary exposure.
Utilization of oriented crystal growth for screening of aromatic carboxylic a...Maciej Przybyłek
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.
Dr. Biswajit Chakraborty is a Senior Project Fellow at the Indian Institute of Chemical Biology in Kolkata, India. He received his Ph.D. in Chemistry from the same institution, where he studied the synthesis of analogues of natural products like Andrographolide and Betulinic acid and evaluated their anti-cancer potential. He has expertise in natural product isolation, organic synthesis, and analytical techniques. He has published 5 research papers on developing methods for synthesizing drug-like heterocyclic compounds and evaluating their biological activities.
Pharmacokinetic Properties of Biomass-extracted Substances Isolated by Green ...Michal Jablonsky
According to the literature, approximately 41 nutraceutical compounds have been isolated from different types of biomass using green solvents. It is important to collect information on the pharmacokinetic properties of the nutraceutical substances from biomass isolated according to the published papers. The pharmacokinetic properties of the bioactive substances extracted by green solvents, such as the molecular weight, logP, AlogP, H-bond acceptor, H-bond donor, total polar surface area, atom molar refractivity, number of rotatable bonds, number of atoms, rotatable bond count, number of rigid bonds, number of atom rings, and number of H-bonds, were calculated with a drug-likeness tool. In practical terms, the original and most well-known Lipinski's Rule of Five (Ro5) was applied to 28 substances, namely 3-hydroxytyrosol; apigenin; artemisinin; bergapten; bilobalide; biochanin A; caffeic Acid; caffeoylmalic acid; catechins; cinnamic acid; curcumin; daidzei; daidzin; epicatechin; gallic acid; genistein; ginkgolide A; ginkgolide B; levofloxacin; luteolin; naringenin; p-coumaric acid; protocatechuic acid; psoralen; quercetin; trans-ferulic acid; tyrosol, and vanillin.
Dr. Biswajit Chakraborty is a Senior Project Fellow at the Structural Biology and Bioinformatics Division of the Indian Institute of Chemical Biology in Kolkata, India. He received his Ph.D. in Chemistry from the same institution, where his thesis focused on synthesizing analogues of biologically active natural products and evaluating their anti-cancer potential. His research experience includes isolating and characterizing natural products, synthesizing analog libraries, and evaluating compounds for anti-cancer activity. He has authored or co-authored 5 publications in peer-reviewed journals.
New Green Synthesis Approaches of Pharmacologically Active Heterocyclic Compo...ijtsrd
Green chemistry is a rapidly developing field providing a proactive avenue for the sustainable development of future science and technology. Green chemistry can be applied to the design of highly efficient, environmentally benign synthetic protocols to deliver life saving medicines, and to accelerate lead optimization processes in drug discovery, while minimizing environmental impact. It also offers enhanced chemical process economics, concomitant with a reduced environmental burden. There are relatively environmentally benign protocols for the synthesis of pharmaceutically active heterocycles that highlight the advantages of using green chemistry, for example, by proceeding under microwave irradiation or in aqueous reaction media. Chandra Prakash Gharu "New Green Synthesis Approaches of Pharmacologically Active Heterocyclic Compounds" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-5 , August 2022, URL: https://www.ijtsrd.com/papers/ijtsrd51793.pdf Paper URL: https://www.ijtsrd.com/chemistry/other/51793/new-green-synthesis-approaches-of-pharmacologically-active-heterocyclic-compounds/chandra-prakash-gharu
Development and characterization of anionic liposaccharides for enhanced oralAdel Abdelrahim, PhD
The document describes the development and characterization of novel anionic liposaccharide derivatives for enhancing oral drug delivery. Liposaccharides containing d-glucose and lipoamino acids were synthesized. Their critical aggregation concentration and thermodynamic profiles were determined using isothermal titration microcalorimetry. The liposaccharides were found to be non-toxic and did not cause hemolysis or reduce cell viability. When mixed with the model drug tobramycin, one of the liposaccharides formed aggregates around 200 nm and increased tobramycin's partitioning between n-octanol and water, suggesting it may enhance the oral absorption of hydrophilic drugs.
A STUDY TO EVALUATE THE IN VITRO ANTIMICROBIAL ACTIVITY AND ANTIANDROGENIC E...Dr. Pradeep mitharwal
The present paper deals with synthesis and characterization
of some new chromium (III) Schiff base complexes using microwave irradiation
technique as well as conventional heating. The S∩N donor benzothiazolines, 1-
(2-furanyl) ethanone benzothiazoline (Bzt1N
∩
SH), 1-(2-thienyl) ethanone
benzothiazoline (Bzt2N
∩
SH) and 1-(2-pyridyl) ethanone benzothiazoline
(Bzt3N
∩
SH) were prepared by the condensation of ortho-aminothiophenol with
respective ketones in ethanol.
Analytical Method Development and Validation of Prednisolone Sodium Phosphate...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Method development and validation of Sodium Cromoglycate sujatabhosale5
Here are the key steps in the sample preparation procedure for UV spectroscopy:
1. A standard stock solution of 100 μg/ml was prepared by dissolving 10 mg of drug in 100 ml of mobile phase (ACN:Water 80:20).
2. From the stock solution, 10 ml was pipetted and diluted to 100 ml with mobile phase to obtain a 10 μg/ml working standard solution.
3. Tablets/capsules were weighed and powdered. An amount of powder equivalent to 10 mg of drug was transferred to a 100 ml volumetric flask.
4. The powder was dissolved in mobile phase and sonicated for 15 minutes. The volume was made up to mark with mobile phase to obtain a
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).
Ramprasad Ghosh is seeking a research position in bioorganic/medicinal chemistry. He has a PhD in organic chemistry from the Indian Institute of Chemical Biology and has held three postdoctoral research positions. His research has focused on the synthesis of carbohydrates, nucleosides, and glycoconjugates for applications in drug delivery and enzyme inhibition. Currently he is working on synthesizing derivatives of glucosamine-6-phosphate to target bacterial riboswitches and develop new antibiotics.
This document describes the synthesis of 17 new 1,2,4-triazole derivatives and evaluates their antimicrobial and anticancer activities. The compounds showed the most potent antimicrobial activity against the fungus Aspergillus niger. Compound 14 was the most active. Compound 7 exhibited appreciable anticancer activity against colon cancer cells. Quantitative structure-activity relationship analysis identified topological and electronic properties important for the compounds' antimicrobial effects.
This document summarizes an editorial on recent advances in the clinical application of mass spectrometry. It discusses how liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma mass spectrometry (ICP-MS) have expanded the use of mass spectrometry in clinical chemistry testing over the past decade. The editorial notes that many clinical chemistry laboratories now use electrospray ionization LC-MS/MS and that external quality assurance programs include more analytes quantified by mass spectrometry methods. While mass spectrometry offers improvements in specificity and sensitivity, some debate remains around its use in clinical laboratories.
Simultaneously and quantitatively analyze the heavy metals in Sargassum fusiforme by
laser-induced breakdown spectroscopy
Simultaneously and quantitatively analyze the heavy metals in Sargassum fusiforme by
laser-induced breakdown spectroscopy
Joseph Mwansa is a highly skilled MSci Pharmaceutical Science graduate with extensive practical expertise in organic chemistry and analytical techniques. He has research experience synthesizing complex molecules and publishing his work. His skills include independent research, critical analysis, teamwork, and strong communication abilities for presenting scientific findings. He is currently seeking opportunities where he can apply his expertise in organic synthesis and analytical skills.
1) Chalcones are α,β-unsaturated carbonyl compounds formed via the Claisen-Schmidt reaction between benzaldehyde and acetophenone. They contain two aromatic rings joined by an α,β unsaturated carbonyl group.
2) Chalcones exhibit various pharmacological activities including antioxidant, antibacterial, antifungal, anticancer, and antidepressant properties. Their activity is influenced by substitutions on the aromatic rings. Halogen and methoxy groups often enhance biological activity.
3) Studies have shown that chalcones can act as free radical scavengers and inhibit lipid peroxidation, demonstrating their antioxidant properties. Substitutions like hydroxyl and methoxy groups in
This document provides details of a thesis submitted for a Doctor of Philosophy degree in Chemistry. It describes the objectives of the thesis which are to synthesize and characterize N-phenyl succinimides, glutarimides, chalcones, pyrazoles, amino-pyrimidines and malononitriles and test their biological activities. It outlines the materials and methods used which involve synthesizing cyclic imides, chalcone derivatives from the imides, and then pyrazoles, amino-pyrimidines and malononitriles from the chalcones. It also provides an abstract that summarizes the key points of the thesis and introduces the topics to be covered.
A simple visible spectrophotometric method is proposed for the determination
of ulipristal acetate present in bulk and tablet formulation. The currently
proposed method is established based on MBTH oxidation by ferric ions to
form an active coupling species (electrophile), followed by its coupling with
the ulipristal in acidic medium to form high intensiϑied green colored chromophore
having max at 609 nm. Validated the method as per the current
guidelines of ICH. Beer’s law was obeyed in the concentration range of 6.25 –
37.50 g mL 1 with a high regression coefϑicient (r > 0.999). Reproducibility,
accuracy, and precision of the method are evident from the low values of R.S.D.
This method can be used in quality control laboratories for routine analysis of
ulipristal acetate in bulk drug and pharmaceutical dosage forms.
Similar to Propensity of salicylamide and ethenzamide cocrystallization with aromatic carboxylic acids (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.
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.
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
This research paper studied the use of natural deep eutectic solvents (NADES) to improve the solubility, stability, and delivery of curcumin. The study found that NADES composed of choline chloride and glycerol had the highest solubility for curcumin. This NADES system was also effective at extracting curcuminoids from turmeric and preventing degradation of curcumin when exposed to sunlight. Testing in simulated gastrointestinal fluids showed a significant increase in curcumin bioavailability in the small intestine. Quantum chemistry computations indicated that direct molecular interactions between curcumin and choline chloride or glycerol were responsible for enhancing curcumin's solubility in NADES, especially
Application of Multivariate Adaptive Regression Splines (MARSplines) for Pred...Maciej Przybyłek
A new method of Hansen solubility parameters (HSPs) prediction was developed by combining the multivariate adaptive regression splines (MARSplines) methodology with a simple multivariable regression involving 1D and 2D PaDEL molecular descriptors. In order to adopt the MARSplines approach to QSPR/QSAR problems, several optimization procedures were proposed and tested. The effectiveness of the obtained models was checked via standard QSPR/QSAR internal validation procedures provided by the QSARINS software and by predicting the solubility classification of polymers and drug-like solid solutes in collections of solvents. By utilizing information derived only from SMILES strings, the obtained models allow for computing all of the three Hansen solubility parameters including dispersion, polarization, and hydrogen bonding. Although several descriptors are required for proper parameters estimation, the proposed procedure is simple and straightforward and does not require a molecular geometry optimization. The obtained HSP values are highly correlated with experimental data, and their application for solving solubility problems leads to essentially the same quality as for the original parameters. Based on provided models, it is possible to characterize any solvent and liquid solute for which HSP data are unavailable.
Studies on the formation of formaldehyde during 2-ethylhexyl 4-(dimethylamino...Maciej Przybyłek
In order to protect the skin from UV radiation, personal care products (PCPS) often contain chemical UV-filters. These compounds can enter the environment causing serious consequences on the water ecosystems. The aim of this study was to examine, the effect of different factors, such as UV light, the presence of NaOCl and H2O2 on the formaldehyde formation during popular UV filter, 2-ethylhexyl 4-(dimethylamino)benzoate (ODPABA) demethylation. The concentration of formaldehyde was determined by VIS spectrophotometry after derivatization. The reaction mixtures were qualitatively analyzed using GC/MS chromatography. The highest concentration of formaldehyde was observed in the case of ODPABA/H2O2/UV reaction mixture. In order to describe two types of demethylation mechanisms, namely, radical and ionic, the experimental results were enriched with Fukui function analysis and thermodynamic calculations. In the case of non-irradiated system containing ODPABA and NaOCl, demethylation reaction probably proceeds via ionic mechanism. As it was established, amino nitrogen atom in the ODPABA molecule is the most susceptible site for the HOCl electrophilic attack, which is the first step of ionic demethylation mechanism. In the case of irradiated mixtures, the reaction is probably radical in nature. The results of thermodynamic calculations showed that abstraction of the hydrogen from N(CH3)2 group is more probable than from 2-ethylhexyl moiety, which indicates higher susceptibility of N(CH3)2 to the oxidation.
Reaction of aniline with ammonium persulphate and concentrated hydrochloric a...Maciej Przybyłek
In this paper, the reaction of aniline with ammonium persulphate and concentrated HCl was studied. As a result of our experimental studies, 2,4,6-trichlorophenylamine was identified as the main product. This shows that a high concentration of HCl does not favour oxidative polymerisation of phenylamine, even though the ammonium persulphate/HCl system is widely used in polyaniline synthesis. On the basis of the experimental data and density functional theory for reaction path modelling, we proposed a mechanism for oxidative chlorination of aniline. We assumed that this reaction proceeded in three cyclically repeated steps; protonation of aniline, formation of singlet ground state phenylnitrenium cation, and nucleophilic substitution. In order to confirm this mechanism, kinetic, thermochemical, and natural bond orbital population analyses were performed.
When I was asked to give a companion lecture in support of ‘The Philosophy of Science’ (https://shorturl.at/4pUXz) I decided not to walk through the detail of the many methodologies in order of use. Instead, I chose to employ a long standing, and ongoing, scientific development as an exemplar. And so, I chose the ever evolving story of Thermodynamics as a scientific investigation at its best.
Conducted over a period of >200 years, Thermodynamics R&D, and application, benefitted from the highest levels of professionalism, collaboration, and technical thoroughness. New layers of application, methodology, and practice were made possible by the progressive advance of technology. In turn, this has seen measurement and modelling accuracy continually improved at a micro and macro level.
Perhaps most importantly, Thermodynamics rapidly became a primary tool in the advance of applied science/engineering/technology, spanning micro-tech, to aerospace and cosmology. I can think of no better a story to illustrate the breadth of scientific methodologies and applications at their best.
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...AbdullaAlAsif1
The pygmy halfbeak Dermogenys colletei, is known for its viviparous nature, this presents an intriguing case of relatively low fecundity, raising questions about potential compensatory reproductive strategies employed by this species. Our study delves into the examination of fecundity and the Gonadosomatic Index (GSI) in the Pygmy Halfbeak, D. colletei (Meisner, 2001), an intriguing viviparous fish indigenous to Sarawak, Borneo. We hypothesize that the Pygmy halfbeak, D. colletei, may exhibit unique reproductive adaptations to offset its low fecundity, thus enhancing its survival and fitness. To address this, we conducted a comprehensive study utilizing 28 mature female specimens of D. colletei, carefully measuring fecundity and GSI to shed light on the reproductive adaptations of this species. Our findings reveal that D. colletei indeed exhibits low fecundity, with a mean of 16.76 ± 2.01, and a mean GSI of 12.83 ± 1.27, providing crucial insights into the reproductive mechanisms at play in this species. These results underscore the existence of unique reproductive strategies in D. colletei, enabling its adaptation and persistence in Borneo's diverse aquatic ecosystems, and call for further ecological research to elucidate these mechanisms. This study lends to a better understanding of viviparous fish in Borneo and contributes to the broader field of aquatic ecology, enhancing our knowledge of species adaptations to unique ecological challenges.
hematic appreciation test is a psychological assessment tool used to measure an individual's appreciation and understanding of specific themes or topics. This test helps to evaluate an individual's ability to connect different ideas and concepts within a given theme, as well as their overall comprehension and interpretation skills. The results of the test can provide valuable insights into an individual's cognitive abilities, creativity, and critical thinking skills
ESPP presentation to EU Waste Water Network, 4th June 2024 “EU policies driving nutrient removal and recycling
and the revised UWWTD (Urban Waste Water Treatment Directive)”
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
Current Ms word generated power point presentation covers major details about the micronuclei test. It's significance and assays to conduct it. It is used to detect the micronuclei formation inside the cells of nearly every multicellular organism. It's formation takes place during chromosomal sepration at metaphase.
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
The use of Nauplii and metanauplii artemia in aquaculture (brine shrimp).pptxMAGOTI ERNEST
Although Artemia has been known to man for centuries, its use as a food for the culture of larval organisms apparently began only in the 1930s, when several investigators found that it made an excellent food for newly hatched fish larvae (Litvinenko et al., 2023). As aquaculture developed in the 1960s and ‘70s, the use of Artemia also became more widespread, due both to its convenience and to its nutritional value for larval organisms (Arenas-Pardo et al., 2024). The fact that Artemia dormant cysts can be stored for long periods in cans, and then used as an off-the-shelf food requiring only 24 h of incubation makes them the most convenient, least labor-intensive, live food available for aquaculture (Sorgeloos & Roubach, 2021). The nutritional value of Artemia, especially for marine organisms, is not constant, but varies both geographically and temporally. During the last decade, however, both the causes of Artemia nutritional variability and methods to improve poorquality Artemia have been identified (Loufi et al., 2024).
Brine shrimp (Artemia spp.) are used in marine aquaculture worldwide. Annually, more than 2,000 metric tons of dry cysts are used for cultivation of fish, crustacean, and shellfish larva. Brine shrimp are important to aquaculture because newly hatched brine shrimp nauplii (larvae) provide a food source for many fish fry (Mozanzadeh et al., 2021). Culture and harvesting of brine shrimp eggs represents another aspect of the aquaculture industry. Nauplii and metanauplii of Artemia, commonly known as brine shrimp, play a crucial role in aquaculture due to their nutritional value and suitability as live feed for many aquatic species, particularly in larval stages (Sorgeloos & Roubach, 2021).
2. broad categories depending on the cocrystal growth rate (Manin et al.,
2014a), namely fast kinetic methods and slow thermodynamic ap-
proaches. Both can be implemented on variety manners including sol-
vent evaporation (Hattori et al., 2015; Hiendrawan et al., 2015a; Lin
et al., 2013; Przybyłek et al., 2016; Rahman et al., 2011), spray drying
(Alhalaweh and Velaga, 2010; Alhalaweh et al., 2013; Patil et al.,
2014), neat and liquid assistant grinding (Hiendrawan et al., 2015a;
Karki et al., 2007; Sanphui et al., 2015; Sun and Hou, 2008), slurry
cocrystallization (Bučar et al., 2010; Kojima et al., 2010; Takata et al.,
2008), melting methods (Rahman et al., 2011; Repka et al., 2013; Yan
et al., 2015) and supercritical fluids techniques (Cuadra et al., 2016;
Hiendrawan et al., 2015b; Padrela et al., 2010, 2009). It is worth men-
tioning that many pharmaceutical cocrystals containing amides acting
either as API or excipients have been studied recently (Aitipamula
et al., 2015, 2012b, 2009; Cuadra et al., 2016; Furuta et al., 2015; Gryl
et al., 2008; Manin et al., 2014a, 2014b; Wang et al., 2013). The
compounds containing amino-carbonyl group including aromatic
amides, play many important roles in the medical applications. For
examples nicotinamide (vitamin B3), pyrazinamide (antitubercular
agent), vindesine (phytogenic and antineoplastic agent, tubulin modu-
lator), L-glutamine (nutritional supplement), cerulenin (antifungal
antibiotic), carbamazepine (anticonvulsant), nepafenac and the title
compounds (non-steroidal anti-inflammatory drugs) can be found
within DrugBank and WHO Collaborating Centre for Drug Statistics
Methodology (WHOCC) databases. On the other hand many drugs
acting as cyclooxygenase-2 (COX-2) inhibitors belong to the class of
carboxylic acids. For example salicylic acid, aspirin and ibuprofen
exhibit such activity. However, it was observed (Kalgutkar et al., 2000;
Qandil, 2012) that amide and ester derivatives of anti-inflammatory
agents have less gastric side effects. Another application of carboxylic
acids is pharmaceutical excipients (Rowe, 2009). Noteworthy, benzoic
acid and its derivatives have been often used as pharmaceutical
cocrystal formers (Berry et al., 2008; Caira et al., 1995; Lin et al., 2015;
Manin et al., 2014a, 2014b; Schultheiss and Newman, 2009;
Varughese et al., 2010). From pharmaceutical viewpoint particularly
important is the class of phenolic acids obtained after hydroxyl substit-
uents attachment to aromatic ring of benzoic acid. According to many
reports, these compounds reveal antioxidant activity (Piazzon et al.,
2012; Rice-Evans et al., 1996; Sroka and Cisowski, 2003) and possess
antimicrobial properties (Baskaran et al., 2013). Furthermore, the
phenolic acids are added to food, cosmetics and pharmaceutical
formulations to improve their stability (Ash and Ash, 2004; Jones
et al., 2006; Vangala et al., 2011).
The aim of this study is to examine the cocrystallization landscape of
two active pharmaceutical ingredients (API) namely salicylamide and
ethenzamide with aromatic carboxylic acids, including pharmaceutical-
ly relevant compounds such as acetylsalicylic acid, 4-acetamidobenzoic
acid (acedoben) as well as mono- and dihydroxybenzoic acids. For this
purpose a droplet evaporative crystallization (DEC) technique has been
applied. This fast and efficient method has been previously developed
(Cysewski et al., 2014; Przybyłek et al., 2015) and successfully applied
for cocrystal screening (Przybyłek et al., 2016). The experimental data
characterizing salicylamide and ethenzamide cocrystallization propen-
sities are also enriched by theoretical screening and detailed analysis
of R2
2
(8) heterosynthon properties.
2. Materials and methods
2.1. Materials
All chemicals were applied without purification, as received from
commercial suppliers. APIs considered in this study namely, salicylamide
(2-hydroxybenzamide, SMD) and ethenzamide (2-ethoxybenzamide,
EMD) were obtained from Avantor Performance Materials Poland S.A.
(Gliwice, Poland). Also the following compounds were taken from this
provider, namely methanol, benzoic acid (BA), 2-fluorobenzoic acid
(2FBA), 2-chlorobenzoic acid (2CBA), salicylic acid (SA), acetylsalicylic
acid (aspirin, ASA), 4-acetamidobenzoic acid (acedoben, 4ABA) 3-
hydroxybenzoic acid (3HBA), 2,6-dihydroxybenzoic acid (2,6DHBA),
2,5-dihydroxybenzoic acid (2,5DHBA) and 3,4-dihydroxybenzoic
acid (3,4DHBA). From Sigma-Aldrich (USA) there were purchased
the following chemicals 2,4-dihydroxybenzoic acid (2,4DHBA), 3,5-
dihydroxybenzoic acid (3,5DHBA), 4-hydroxybenzoic acid (4HBA), 2-
bromobenzoic acid (2BBA) and 2-iodobenzoic acid (2IBA).
2.2. Samples preparation procedure and measurements
The cocrystals screening was performed taking advantage of the
droplet evaporative crystallization (DEC) technique (Cysewski et al.,
2014; Przybyłek et al., 2016, 2015). This very simple, time and chemical
preserving approach, yet very efficient, was already validated and suc-
cessfully applied for new cocrystals preparation (Przybyłek et al.,
2016). In this technique the crystallite deposited on the glass surface
is analyzed based on the powder X-ray diffraction (PXRD) and Fourier
transform infrared-total attenuated reflectance techniques. The DEC
procedure consists of mixing methanolic solutions of SMD (0.7 M),
EMD (0.1 M) and potential cocrystal formers in 1:1 proportions and
allowing the fast drying of the 20 μL-droplets of these mixtures after
dropping on the glass surface. The cocrystal occurrence was confirmed
by comparison of PXRD and FTIR-ATR spectra of bi-component crystal-
lites with ones recorded for pure components under the same condi-
tions. In the case of low solubility of API the crystallite layers were
obtained after repeating of evaporation up to 5 times for obtaining the
PXRD diffraction patterns of sufficient quality.
The FTIR-ATR spectra reported in this study were recorded using
Bruker Alpha-PFT-IR spectrometer with diamond attenuated total
reflection (ATR) equipment. The PXRD patterns were performed using
PW3050/60 goniometer with Empyrean XRD tube Cu LFF DK303072
(5°–40° 2θ range, 0.02° step with). All diffraction patterns were
preprocessed in Reflex module of Accelrys Material Studio 8.0 (Accelrys,
San Diego, 2015) including Kα2 stripping, background subtraction,
curve smoothing and normalization.
2.3. Calculation details
2.3.1. Mixing enthalpy estimation
The excess thermodynamic functions characterizing components af-
finities in liquid state under super cooled conditions are often used as a
measure of cocrystallization propensities (Eckert and Klamt, 2014;
Loschen and Klamt, 2015). This post-quantum mechanical thermody-
namic analysis takes advantage of the Conductor like Screening Model
for Real Solvents model (COSMO-RS) (Klamt and Schüürmann, 1993;
Klamt, 2011) for sigma profiles generation at semiempirical AM1
(Dewar et al., 1985) level. Based on the statistical analysis offered by
COSMOtherm software (Eckert and Klamt, 2014) (parametrization
BP_SVP_AM1_C30_1501.ctd) it is possible to obtain the mixing enthal-
py. The negative enough values of mixing enthalpy are supposed to
indicate that the mixture is thermodynamically favored over the pure
component liquids. The miscibility under super cooled liquid is often
associated with miscibility in the solid state, hence documenting the
ability of cocrystallization (Loschen and Klamt, 2015). The geometries
of all amides and coformers were optimized using MOPAC2012 (Maia
et al., 2012; Stewart, 2016) both in the gas phase and in the condensed
phase modeled with and aid of the COSMO-RS approach.
2.3.2. Computations of the substituent effects on the heterosynthon
properties
The full gradient optimization was performed for 180 pairs
of para-substituted benzoic acid analogues with salicylamide or
enthenzamide using ΩB97XD density functional with 311++G**
basis set as implemented in GAUSSIAN package (Frisch et al., 2009).
The contributions to the pair stabilization energy were performed
133M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
3. based on the absolutely-localized orbitals method (ALMO) implement-
ed in QChem package (Shao et al., 2014). In this approach it is possible
to decompose the total intermolecular binding energy into several
contributions including the charge-transfer (CT) portion of the binding
energy (Krylov and Gill, 2013). Besides, the amount of bidirectional
charge transfer from and to monomers interacting via hydrogen bond-
ing can be quantified utilizing complementary occupied-virtual orbitals
formalism (Khaliullin et al., 2008). In order to obtain more accurate
results the basis set superposition error (BSSE) was included during in-
termolecular interactions energies calculations taking advantage of
counterpoise procedure (Boys and Bernardi, 1970; Simon et al., 1996).
3. Results and discussion
Focusing attention on cocrystal landscape of salicylamide (SMD) and
ethenzamide (EMD) is justified by their analgesic and antipyretic prop-
erties. Both SMD and EMD are non-prescription drugs belonging to non-
steroidal anti-inflammatory agents with medicinal uses similar to those
of aspirin. Typically they are administered in combination with other
components as acetaminophen, aspirin or caffeine in the over-the-
counter pain remedies. These drugs are poorly soluble in water and
cocrystallization with more soluble formers might be one of the remedy
to this limitation. The selected coformers belonging to the group of well
soluble aromatic carboxylic acids seem to be a rational choice especially
that many of them such as BA, SA, 3HBA, 4HBA, 2,4DHBA and 3,4DHBA
are known to be non-toxic and approved food additives. Hence, they
can be found on GRAS (Generally Recognized as Safe) or EAFUS (Every-
thing Added to Food in the United States) lists. In this paper the
cocrystallization landscapes of both SMD and EMD are studied experi-
mentally for limited number of coformers and further extended via
computational analysis. Finally, the R2
2
(8) heterosynthon responsible
for the major energetic contributions to the solid stabilization is charac-
terized in details based on quantum chemistry computations.
3.1. Experimental evidences of cocrystals formation
The solid state mixtures comprising salicylamide or ethenzamide
and one of 15 aromatic carboxylic acids were prepared and analyzed ac-
cording to previously described procedure (Przybyłek et al., 2016). The
complete documentation of experimental results for all analyzed sys-
tems is provided in the supporting materials in Fig. S1–S22. Here, in
the main text only exemplary cases are discussed. The identification of
the cocrystals formation can be confirmed by direct inspection of the
corresponding PXRD patterns. The fortunate circumstance of reducing
majority of signals obtained from oriented samples compared to bulk
crystallization allows for almost immediate identification of the new
peaks characterizing molecular complexes in the solid state. Additional
confirmation comes from FTIR spectra offering further proof by
documenting occurrence of band shifts related to alteration of intermo-
lecular interactions mainly due to changes in the hydrogen bonding pat-
terns. For example cocrystallization of both studied benzamides with
2,4-dihydroxybenzoic acid can be inferred from Fig. 1. In this case the
SMD-2,4HBA binary system is detectable by new small diffraction sig-
nals at 2θ = 6.8° and 26.8°, which cannot be assigned to pure compo-
nents and these signals most probably correspond to new cocrystal
phase. In the case of EMD-2,4HBA mixture a new intense PXRD peak
at 2θ = 18.9° appears as a consequence of cocrystal formation. Since it
is often observed overlapping of the reflexes coming from cocrystals
with peaks that might come from pure components additional confir-
mation is desirable and for this purpose the FTIR-ATR method is often
used. As it can be inferred from Fig. 1b and d there are significant chang-
es in the absorption bands shifts when comparing to vibrational spectra
recorded for mixtures with pure components. As it can be directly in-
ferred from Fig. 1b, formation of the SMD-2,4DHBA cocrystal leads to
the relatively small blue shift (from 3394 to 3412 cm−1
) of N–H
stretching mode absorption band, (NH) and significant red shift (from
3370 to 3303 cm−1
) of O–H stretching absorption band, v(OH). Changes
in the O–H stretching vibration mode regions of carboxylic acids
induced by new hydrogen bonds formation can be observed on spectra
recorded for other mixtures as well. However, in the majority of cases
the observed (NH) shifts are much more noticeable. Noteworthy, partic-
ularly significant blue shifts appeared in the case of EMD cocrystals
(Fig. 1d,supplementary Figs. S12, S13, S16, S20–S22). As we reported
in the previous work (Przybyłek et al., 2016), similar (NH) analogical
shifts were also observed for cocrystals of urea and carboxylic aromatic
acids. This regularity can be explained by the formation of a new NH⋯O
hydrogen bonding involving amide and carboxylic acid.
Similar analysis scrutinized using data provided in the supporting
materials allows for documenting the cocrystallization landscapes of
both studied here drugs. The conclusions drawn from performed
experiments were summarized in Table 1 proving identification of elev-
en new cocrystals that have not been previously reported. The content
of Table 1 was enriched by cocrystals identified by other authors includ-
ing records deposited in the Cambridge Structural Database. There are
positive and negative observations of drugs miscibility in the solid
state. Although in the former case the conclusion is definitive in the
case of lack of identification of cocrystal the inference is not the abso-
lute. The full confirmation of solids immiscibility can be obtained only
from full phase diagram and classification as simple eutectic system
(Berry et al., 2008; Cherukuvada and Guru Row, 2014; Prasad et al.,
2014; Yamashita et al., 2014, 2013) since successful cocrystallization
can depend on conditions of synthesis (Friščić et al., 2009; Gagnière
et al., 2009; Leyssens et al., 2012; Manin et al., 2014a, 2014b;
Schartman, 2009). However, DEC technique applied in this study was
found to be quite reliable tool for urea/aromatic carboxylic acids misci-
bility screening (Przybyłek et al., 2016). Noteworthy, formation of the
SMD-BA and the EMD-4HBA molecular complexes in the solid state
was confirmed also in the earlier studies (Aitipamula et al., 2012b;
Manin et al., 2014a). According to our observations, the SMD-BA
cocrystal formation can be evidenced by the appearance of an intense
peak at 2θ = 14.7° on the diffraction pattern and additionally by a char-
acteristic v(NH) blue shift from 3395 to 3406 cm−1
on the FTIR-ATR
spectra (supplementary Fig. S1). In the case of the EMD-4HBA system,
multicomponent crystal phase can be confirmed by overlapping of the
majority of PXRD peaks with diffraction pattern of EMD-4HBA mono-
crystal reported by Aitipamula et al. (2012b) (Fig. S20). The above ex-
amples demonstrate once again the reliability of DEC cocryslallization
procedure.
3.2. Extending of SMD and EMD cocrystallization landscapes
The data provided in Table 1 led to the conclusion that
cocrystallization is quite common for both studied benzamides. These
abilities of ethenzamide seem to be slightly broader compared to
salicylamide. Although the list of carboxylic acid used as coformers is
quite extended it would be interesting to analyze the cocrystallization
potential of SMD and EMD from much broader perspective. For this
purpose the CSD was searched against all carboxylic acids that were
used as coformers involved in any binary cocrystals. This led to the set
of great variety of aromatic carboxylic acids distinguishable by the
type, number and positions of the substituents attached to the aromatic
ring. The resulting set of 161 acids was then used as probe for
cocrystallization landscape of SMD and EMD. For this purpose the values
of mixing enthalpies (Hmix) were estimated using approach offered by
COMSOtherm program (Eckert and Klamt, 2014). It is worth mention-
ing that the post-quantum mechanical thermodynamic analysis based
on the Conductor like Screening Model for Real Solvents (COSMO-RS)
has been widely applied for pharmaceutics miscibility with different ad-
ditives and solubility evaluations (Abramov et al., 2012; Connelly et al.,
2015; Klamt, 2012, 2011; Klamt et al., 2002; Loschen and Klamt, 2015;
Pozarska et al., 2013). The dissemination of Hmix charactering all of con-
sidered here pairs is presented in Fig. 2 in the form of smoothed
134 M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
4. Fig. 1. PXRD and FTIR-ATR characteristics of salicylamide-2,4-dihydroxybenzoic acid (SMD-2,4HBA) (a, b) and ethenzamide-2,4-dihydroxybenzoic acid (EMD-2,4HBA) (c, d) crystallites
deposited on the glass surface. Our experimental PXRD data (black lines) were enriched with simulated diffraction patterns of coformers (gray lines). The polymorph I and II of 2,4-
dihydroxybenzoic acid are denoted by refcodes ZZZEEU08 and ZZZEEU04, respectively.
Table 1
Salicylamide (SMD) and 2-ethoxybenzamide (EMD) cocrystals screening results enriched with the examples taken from the literature and CSD. The experimental evidences of new mo-
lecular complexes reported in this study are given in supplementary materials as indicated by figure numbers.
Cocrystal former
Cocrystal identification
SMD Source EMD Source
Benzoic acid (BA) Yes Manin et al. (2014a), Fig. S1a
Yes Fig. S12a
2-Fluorobenzoic acid (2FBA) Yes Fig. S2a
Yes Fig. S13a
2-Chlorobenzoic acid (2CBA) No Fig. S3a
No Fig. S14a
2-Bromobenzoic acid (2BBA) No Fig. S4a
No Fig. S15a
2-Iodobenzoic acid (2IBA) No Fig. S5 Yes Fig. S16a
4-Acetamidobenzoic acid (4ABA) Yes Manin et al. (2014a, 2014b) No Fig. S17a
Acetylsalicylic acid (ASA) No Manin et al. (2014a) No Fig. S18a
Salicylic acid (SA) Yes Manin et al. (2014a) Yes REHSAAb
3-Hydroxybenzoic acid (3HBA) No Fig. S6a
No Fig. S19a
4-Hydroxybenzoic acid (4HBA) Yes Fig. S7a
Yes Aitipamula et al. (2012b), Fig. S20a
2,4-Dihydroxybenzoic acid (2,4DHBA) Yes Fig. 1 Yes Fig. 1
2,5-Dihydroxybenzoic acid (2,5DHBA) Yes Fig. S8a
Yes QULLUFb
2,6-Dihydroxybenzoic acid (2,6DHBA) Yes Fig. S9a
Yes GEQXEHb
3,4-Dihydroxybenzoic acid (3,4DHBA) No Fig. S10a
Yes Fig. S21a
3,5-Dihydroxybenzoic acid (3,5DHBA) No Fig. S11a
Yes Fig. S22a
a
This study experiment documented in supporting materials.
b
CSD refcode.
135M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
5. histograms. These curves confirm mentioned discrepancy in the
cocrystallization abilities between both of analyzed drugs. Indeed, the
majority of aromatic carboxylic acids seem to be freely miscible with
ethenzamide. The red line in Fig. 2 defines the critical value of Hmix
showing high probability of miscibility. In the case of EMD almost 99%
of mixtures with acids fall into this region. On the contrary the histo-
gram of salicylamide interactions with carboxylic acids is more shifted
toward higher values of Hmix, what results in reduction of miscible
pars down to about 76% cases. It is well known that urea is very good
cocrystal former (Przybyłek et al., 2016) being able to cocrystalize
with variety of compounds (Alhalaweh et al., 2013, 2010; Chang and
Lin, 2011; Deutsch and Bernstein, 2008; Martí-Rujas et al., 2011; Powell
et al., 2015; Tothadi, 2014; Videnova-Adrabińska, 1996). This is also
confirmed by corresponding plot in Fig. 2 documenting that about 99%
of aromatic carboxylic acids exhibit miscibility under super cooled
conditions what is regarded (Klamt, 2012) as sufficient condition for
cocrystallization. Thus, ethenzamide is more similar to urea than
benzamide, which is able to form the homogeneous mixtures with
94% of acids.
3.3. The R2
2
(8) heterosynthon properties
It is typical for cocrystals formed by benzamides with carboxylic
acids to adopt the hydrogen bonding motive classified by graph descrip-
tor as R2
2
(8) heterosynthon (Etter et al., 1990; Grell et al., 2000) in which
the carboxylic and amide groups are able to form 8-center ring stabi-
lized by two very strong hydrogen bonds. Both interacting components
are able to play the role of donor and acceptor, what forms two alterna-
tive channels allowing for electron density flow in both directions.
There is another interesting aspect related to conformations of studied
here benzamides, namely both molecules can benefit its stability from
intra-molecular hydrogen bonds formed between amide group and ox-
ygen atom of hydroxy- or ethoxy-substituent. As it is documented in
Scheme 1 there are two alternative types of such intramolecular stabili-
zation in the case and SMD only one for EMD. The intramolecular inter-
actions of salicylamide in the form A are much stronger if compared to B
conformer. As a consequence the estimated Boltzmann probability of A
isomer is five orders higher suggesting that this structure is predomi-
nant. In the case of EMD there is only one possibility of intramolecular
hydrogen bonding by adoption of form B and this configuration is sup-
posed to dominate over other isomers. Interestingly, formation of the
R2
2
(8) heterosynthon does not significantly alter these observations. Al-
though, small substituent effect can be observed as it is documented in
Fig. 3, for both benzamides the energy difference between conformers A
and B is promoted by the presence of electron withdrawing groups and
slightly reduced by the effect of electron donating groups. Thus, the
relative stability of conformers is not affected by intermolecular interac-
tions and formation of R2
2
(8) heterosynthon with aromatic carboxylic
acids.
Although, there are high structural similarities of both analyzed
drugs the attached substituent to the second position can alter donating
and accepting capabilities of the amide group. The precise quantification
of this phenomenon can be obtained by studying substituent effects on
the heterosynthon properties. For this purpose 180 para-substituted an-
alogues of benzoic acids were built by attachment of variety of substit-
uents in the para-position and used for pair preparation with either
SMD or EMD. The selected groups cover wide range of Hammett con-
stant values, σp, (Hansch et al., 1991) offering precise and complete in-
terpretation of the studied heterosynthon sensitivity to acids strength.
The first interesting property of such pairs is the energy of intermolecu-
lar interactions. For all optimized pairs the binding energy was
Fig. 2. The distributions of Hmix characterizing pairs of amides with either of 161 aromatic
carboxylic acids involved in binary systems deposited in CSD. Apart from data of SMD and
EMD also ones for benzamide (BMD) and urea (U) were provided. The percentages in the
legend denote population of pairs with high affinities of components defined by
Hmix ≤ −0.57 kcal/mol (Eckert and Klamt, 2014; Loschen and Klamt, 2015) and this
threshold was marked with the red line.
Scheme 1. The schematic representation of structures of ethenzamide (2-
ethoxybenzamide, EMD) and salicylamide (2-hydroxybenzamide, BMD).
Fig. 3. The substituent effect on relative stabilities of pairs formed by two alternative
conformations of SMD and EMD.
136 M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
6. estimated including the corrections for basis superposition error and
accounting also for the dispersion contributions. In Fig. 4 the presented
plots characterize the interactions of SMD and EMD with each of studied
para substituted carboxylic acids. Additionally, for comparison purposes
plots documenting similar effects on benzamide and urea were also pro-
vided. It is clearly noticeable that the stabilization energies of pairs
formed by each of these four amides with benzoic acids analogues are
fairly linear function of Hammett constant values. The attachment of
electron donating substituent weakens the interactions with considered
amides. On the contrary the more electron withdrawing nature of the
substituent the more stable pairs of such aromatic carboxylic acids
with all four amides. The distributions presented on both panels of
Fig. 4 clarify previously mentioned discrepancies in the cocrystallization
propensities between salicylamide and ethenzamide. The stabilization
contribution coming from the heterosynthon formation of the former
amide is significantly lower if compared to EMD. This trend is not affect-
ed by acid strength and that is why distributions of mixing enthalpies
are so divers for SMD and EMD. This observation is additionally con-
firmed by histograms provided in Fig. 4b. It is worth mentioning that
the origin of the observed discrepancies in intermolecular interactions
between studied benzamide is different orientation of substituent
adopted by both amides. This leads to the alternate patterns of intra-
molecular hydrogen bonds. In the case of salicylamide it is observed
the intramolecular bonding of O–H…O type, while for ethenzamide
the O…H–N type of hydrogen bond is formed. This has consequences
on the ability of intermolecular interactions and increase of intramolec-
ular stabilization of the R2
2
(8) heterosynthon. There are also other inter-
esting consequences of intra-stabilization effect. It is quite expected that
the presence of the electron withdrawing groups makes the synthon
more polar what can be quantified by amount of charge transfer from
benzamide to carboxylic acid (B → A) and vice versa (A → B). This prop-
erty expressed in terms of portion of electron charge dislocation is
presented in Fig. 5.
It is interesting to note that the stronger electron withdrawing char-
acter of the substituent the higher the charge transfer toward aromatic
acid from either of amides. However, SMD is less prone to this effect
compared to EMD, what in the light of mentioned intra-stability is
quite understandable. The channel formed by carbonyl oxygen center
is more affected by intramolecular hydrogen bonding in this case. The
lack of such intramolecular interaction in the case of benzamide and
urea results in much higher readiness to electron density outflow.
Thus, EMD is more similar in this aspect to benzamide than to
salicylamide. The stronger resistance of SMD to substituent effect on
B → A electron transfer can also be inferred from the slops of linear
trends presented in Fig. 5a. This value is about 30% lower for SMD com-
pared to EMD. The transfer of electron charge from amide toward acid is
also associated with opposite effect, what can be inferred from Fig. 5b.
This alternative channel of R2
2
(8) heterosynthon involves carbonyl
group on the acid side. However, the observed charge transfer is pro-
nounced in much lesser extend suggesting much stronger electron
withdrawing character of carboxylic group than amide fragment. The
observed absolute values of partial electron transfer are 3–5 times
smaller in the A → B way compared to opposite direction. Furthermore,
the absolute values of slopes are also 2–3 times smaller suggesting
much smaller substituent effect on this kind of synthon polarization.
Thus, taking into account both channels it is possible to conclude that
formation of the R2
2
(8) heterosynthon results in enrichment of the elec-
tron density on the acidic site irrespectively of the nature of the substit-
uent. This conclusion holds also for benzamide and urea. It is also
interesting to mention that apart from energetic and electronic effects
of substituent nature there are also numerous geometric consequences
on the R2
2
(8) heterosynthon structure. For example it is observed defor-
mation of the synthon geometry with the increase of electron with-
drawing character of the substituent leading to increase of skewness
of the system. This parameter defined as the mean value of so-called
Donohue angles (Donohue, 1968) can be used for description of the ge-
ometries of hydrogen bonds involved on synthon formation (Katrusiak,
1995, 1993). This is associated with systematic increase of O–H…O′ and
decrease of O…H′–O′ hydrogen bonds lengths with the rise of the elec-
tron withdrawing strength of the substituent. Here, the prime sign is
used for denoting centers located on carboxylic groups. This is consis-
tent for both studied here drugs.
4. Conclusions
The cocrystallization abilities of salicylamide and ethenzamide with
aromatic carboxylic acids are unexpectedly divers. Despite high formal
similarities of these two benzamides the propensities of cocrystal for-
mation explored both experimentally and theoretically revealed origin
of this fundamental difference. The formal analogy between SMD and
EMD comes from ability of the formation of the same intermolecular
pattern denoted by graph descriptor as R2
2
(8) heterosynthon. However,
difference in stabilization of possible conformers by adopting alterna-
tive intramolecular hydrogen boding patterns is the main source of
the observed difference in the cocrystallization landscape. Since
salicylamide (SMD) and ethenzamide (EMD) are efficient analgesic
and antipyretic drugs administered as non-prescription non-steroidal
anti-inflammatory agents in combination with other components
Fig. 4. The intermolecular interactions of pairs comprising salicylamide, ethenzamide, benzamide or urea with para-substituted benzoic acid analogues. On left panel (a) the absolute
values of binding energy are provided, while on the right side (b) the corresponding smoothed histograms of ΔEBSSE were collected.
137M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
7. their miscibility in the solid state is important aspect of pharmaceutical
relevance. Both APIs are poorly soluble in water and cocrystallization
with more soluble coformers seems to be one of the simplest way of
modulating their bio-availability. Particularly concentration on non-
toxic and much better soluble aromatic carboxylic acids as potential
coformers is rational also from the perspective of structural pattern rec-
ognition via R2
2
(8) heterosynthon.
The experiment observation of solid state miscibility of considered
herein APIs with a set of substituted benzoic acid derivatives was
assessed by means of supramolecular synthesis, taking advantage of
the efficient DEC technique combined with powder diffraction and vi-
brational spectroscopy as the analytical tools. As it was documented
above the phenolic acids turned out to be a good class of ethenzamide
cocrystals formers and since they can prevent drugs from degradation,
addition of these compounds to pharmaceutical formulations can po-
tentially improve also their shelf life. It is worth mentioning that
cocrystallization is an approach which gives the best dispersion of phar-
maceutical ingredients and hence the most effective interaction with
APIs. Finally the identification of eleven new cocrystals by means of
DEC experimental approach confirms its usefulness and extends it
applicability range.
Acknowledgments
This work utilized the COSMOtherm software kindly provided
by COSMOlogic. This research was supported in part by PL-Grid In-
frastructure (plgpiotrc2015b). The allocation of computational fa-
cilities of Academic Computer Centre “Cyfronet” AGH/Krakow/
POLAND is also acknowledged.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ejps.2016.02.010.
References
Aakeröy, C.B., Salmon, D.J., 2005. Building co-crystals with molecular sense and supramo-
lecular sensibility. CrystEngComm 7, 439.
Abramov, Y.A., Loschen, C., Klamt, A., 2012. Rational coformer or solvent selection for
pharmaceutical cocrystallization or desolvation. J. Pharm. Sci. 101, 3687–3697.
http://dx.doi.org/10.1002/jps.23227.
Aitipamula, S., Chow, P.S., Tan, R.B.H., 2009. Dimorphs of a 1:1 cocrystal of ethenzamide
and saccharin: solid-state grinding methods result in metastable polymorph.
CrystEngComm 11, 889.
Aitipamula, S., Banerjee, R., Bansal, A.K., Biradha, K., Cheney, M.L., Choudhury, A.R.,
Desiraju, G.R., Dikundwar, A.G., Dubey, R., Duggirala, N., Ghogale, P.P., Ghosh, S.,
Goswami, P.K., Goud, N.R., Jetti, R.R.K.R., Karpinski, P., Kaushik, P., Kumar, D., Kumar,
V., Moulton, B., Mukherjee, A., Mukherjee, G., Myerson, A.S., Puri, V., Ramanan, A.,
Rajamannar, T., Reddy, C.M., Rodriguez-Hornedo, N., Rogers, R.D., Row, T.N.G.,
Sanphui, P., Shan, N., Shete, G., Singh, A., Sun, C.C., Swift, J.A., Thaimattam, R.,
Thakur, T.S., Kumar Thaper, R., Thomas, S.P., Tothadi, S., Vangala, V.R., Variankaval,
N., Vishweshwar, P., Weyna, D.R., Zaworotko, M.J., 2012a. Polymorphs, salts, and
cocrystals: what's in a name? Cryst. Growth Des. 12, 2147–2152.
Aitipamula, S., Wong, A.B.H., Chow, P.S., Tan, R.B.H., 2012b. Pharmaceutical cocrystals of
ethenzamide: structural, solubility and dissolution studies. CrystEngComm 14,
8515. http://dx.doi.org/10.1039/c2ce26325d.
Aitipamula, S., Mapp, L.K., Wong, A.B.H., Chow, P.S., Tan, R.B.H., 2015. Novel pharmaceuti-
cal cocrystals of triflusal: crystal engineering and physicochemical characterization.
CrystEngComm 17, 9323–9335.
Alhalaweh, A., Velaga, S.P., 2010. Formation of cocrystals from stoichiometric solutions of
incongruently saturating systems by spray drying. Cryst. Growth Des. 10, 3302–3305.
http://dx.doi.org/10.1021/cg100451q.
Alhalaweh, A., George, S., Boström, D., Velaga, S.P., 2010. 1:1 and 2:1 urea–succinic acid
cocrystals: structural diversity, solution chemistry, and thermodynamic stability.
Cryst. Growth Des. 10, 4847–4855. http://dx.doi.org/10.1021/cg100823p.
Alhalaweh, A., Kaialy, W., Buckton, G., Gill, H., Nokhodchi, A., Velaga, S.P., 2013. Theophyl-
line cocrystals prepared by spray drying: physicochemical properties and aerosoliza-
tion performance. AAPS PharmSciTech 14, 265–276. http://dx.doi.org/10.1208/
s12249-012-9883-3.
Ash, M., Ash, I., 2004. Handbook of Preservatives (Synapse Info Resources).
Baskaran, S.A., Upadhyay, A., Kollanoor-Johny, A., Upadhyaya, I., Mooyottu, S., Roshni
Amalaradjou, M.A., Schreiber, D., Venkitanarayanan, K., 2013. Efficacy of plant-derived
antimicrobials as antimicrobial wash treatments for reducing enterohemorrhagic
Escherichia coli O157:H7 on apples. J. Food Sci. 78, M1399–M1404.
Berry, D.J., Seaton, C.C., Clegg, W., Harrington, R.W., Coles, S.J., Horton, P.N., Hursthouse,
M.B., Storey, R., Jones, W., Friščić, T., Blagden, N., 2008. Applying hot-stage microscopy
to co-crystal screening: a study of nicotinamide with seven active pharmaceutical in-
gredients. Cryst. Growth Des. 8, 1697–1712. http://dx.doi.org/10.1021/cg800035w.
Bhogala, B.R., Nangia, A., 2008. Ternary and quaternary co-crystals of 1,3-cis,5-cis-
cyclohexanetricarboxylic acid and 4,4′-bipyridines. New J. Chem. 32, 800.
Boys, S.F., Bernardi, F., 1970. The calculation of small molecular interactions by the differ-
ences of separate total energies. Some procedures with reduced errors. Mol. Phys. 19,
553–566.
Bučar, D.-K., Henry, R.F., Duerst, R.W., Lou, X., MacGillivray, L.R., Zhang, G.G.Z., 2010. A 1:1
cocrystal of caffeine and 2-hydroxy-1-naphthoic acid obtained via a slurry screening
method. J. Chem. Crystallogr. 40, 933–939. http://dx.doi.org/10.1007/s10870-010-
9766-y.
Caira, M.R., Nassimbeni, L.R., Wildervanck, A.F., 1995. Selective formation of hydrogen
bonded cocrystals between a sulfonamide and aromatic carboxylic acids in the
solid state. J. Chem. Soc. Perkin Trans. 2, 2213.
Chang, H.-S., Lin, J.-L., 2011. Urea–adipic acid (2/1). Acta Crystallogr. Sect. E: Struct. Rep.
Online 67, o1317. http://dx.doi.org/10.1107/S1600536811015273.
Cherukuvada, S., Guru Row, T.N., 2014. Comprehending the formation of eutectics and
cocrystals in terms of design and their structural interrelationships. Cryst. Growth
Des. 14, 4187–4198. http://dx.doi.org/10.1021/cg500790q.
Childs, S.L., Kandi, P., Lingireddy, S.R., 2013. Formulation of a danazol cocrystal with con-
trolled supersaturation plays an essential role in improving bioavailability. Mol.
Pharm. 10, 3112–3127.
Connelly, P.R., Snyder, P.W., Zhang, Y., McClain, B., Quinn, B.P., Johnston, S., Medek, A.,
Tanoury, J., Griffith, J., Patrick Walters, W., Dokou, E., Knezic, D., Bransford, P., 2015.
The potency-insolubility conundrum in pharmaceuticals: mechanism and solution
for hepatitis C protease inhibitors. Biophys. Chem. 196, 100–108. http://dx.doi.org/
10.1016/j.bpc.2014.08.008.
Cuadra, I.A., Cabañas, A., Cheda, J.A.R., Martínez-Casado, F.J., Pando, C., 2016. Pharmaceu-
tical co-crystals of the anti-inflammatory drug diflunisal and nicotinamide obtained
Fig. 5. The substituent effect on charge transfer between constituents of C2
2(8) heterosynthon, where B denotes amide and A stands for acid.
138 M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
8. using supercritical CO2 as an antisolvent. J. CO₂ Util. 13, 29–37. http://dx.doi.org/10.
1016/j.jcou.2015.11.006.
Cysewski, P., Przybyłek, M., Miernik, T., Kobierski, M., Ziółkowska, D., 2014. On the origin
of surfaces-dependent growth of benzoic acid crystal inferred through the droplet
evaporation method. Struct. Chem. 26, 705–712. http://dx.doi.org/10.1007/s11224-
014-0528-x.
Deutsch, Z., Bernstein, J., 2008. Cocrystal of urea and imidazolidone: formation of an un-
expected 1-D substructure in a plausibly predictable cocrystal. Cryst. Growth Des. 8,
3537–3542. http://dx.doi.org/10.1021/cg070569c.
Dewar, M.J.S., Zoebisch, E.G., Healy, E.F., Stewart, J.J.P., 1985. Development and use of
quantum mechanical molecular models. 76. AM1: a new general purpose quantum
mechanical molecular model. J. Am. Chem. Soc. 107, 3902–3909.
Donohue, J., 1968. Selected topics in hydrogen bonding. In: Rich, A., Davison, N. (Eds.),
Structural Chemistry and Molecular Biology. Freeman, San Francisco, pp. 443–465.
Eckert, F., Klamt, A., 2014. COSMOtherm, Version C3.0, Release 15.01. COSMOlogic Gm bH
& Co.KG, Leverkusen.
Etter, M.C., MacDonald, J.C., Bernstein, J., 1990. Graph-set analysis of hydrogen-bond pat-
terns in organic crystals. Acta Crystallogr. Sect. B: Struct. Sci. 46, 256–262.
Fernandes, C.M., Carvalho, R.A., Pereira da Costa, S., Veiga, F.J., 2003. Multimodal molecu-
lar encapsulation of nicardipine hydrochloride by β-cyclodextrin, hydroxypropyl-β-
cyclodextrin and triacetyl-β-cyclodextrin in solution. Structural studies by 1H NMR
and ROESY experiments. Eur. J. Pharm. Sci. 18, 285–296.
Frisch, M.J., et al., 2009. Gaussian 09, Revision A.02 (Gaussian 09, Revis. A.02).
Friščić, T., Childs, S.L., Rizvi, S.A.A., Jones, W., 2009. The role of solvent in mechanochemical
and sonochemical cocrystal formation: a solubility-based approach for predicting
cocrystallisation outcome. CrystEngComm http://dx.doi.org/10.1039/b815174a.
Furuta, H., Mori, S., Yoshihashi, Y., Yonemochi, E., Uekusa, H., Sugano, K., Terada, K., 2015.
Physicochemical and crystal structure analysis of pranlukast pseudo-polymorphs II:
solvate and cocrystal. J. Pharm. Biomed. Anal. 111, 44–50.
Gagnière, E., Mangin, D., Puel, F., Rivoire, A., Monnier, O., Garcia, E., Klein, J.P., 2009. Forma-
tion of co-crystals: kinetic and thermodynamic aspects. J. Cryst. Growth 311,
2689–2695. http://dx.doi.org/10.1016/j.jcrysgro.2009.02.040.
Good, D.J., Rodríguez-Hornedo, N., 2009. Solubility advantage of pharmaceutical
cocrystals. Cryst. Growth Des. 9, 2252–2264. http://dx.doi.org/10.1021/cg801039j.
Grell, J., Bernstein, J., Tinhofer, G., 2000. Graph-set analysis of hydrogen-bond patterns:
some mathematical concepts. Acta Crystallogr. B 56 (Pt 1), 1029–1043.
Grifasi, F., Chierotti, M.R., Gaglioti, K., Gobetto, R., Maini, L., Braga, D., Dichiarante, E., Curzi,
M., 2015. Using salt cocrystals to improve the solubility of niclosamide. Cryst. Growth
Des. 15, 1939–1948. http://dx.doi.org/10.1021/acs.cgd.5b00106.
Gryl, M., Krawczuk, A., Stadnicka, K., 2008. Polymorphism of urea–barbituric acid co-
crystals. Acta Crystallogr. B 64, 623–632.
Hansch, C., Leo, A., Taft, R.W., 1991. A survey of Hammett substituent constants and
resonance and field parameters. Chem. Rev. 91, 165–195.
Hattori, Y., Sato, M., Otsuka, M., 2015. Initial dissolution kinetics of cocrystal of carbamaz-
epine with nicotinamide. J. Pharm. Pharmacol. 67, 1512–1518.
Hiendrawan, S., Veriansyah, B., Widjojokusumo, E., Soewandhi, S.N., Wikarsa, S.,
Tjandrawinata, R.R., 2015a. Physicochemical and mechanical properties of paraceta-
mol cocrystal with 5-nitroisophthalic acid. Int. J. Pharm. 497, 106–113. http://dx.
doi.org/10.1016/j.ijpharm.2015.12.001.
Hiendrawan, S., Veriansyah, B., Widjojokusumo, E., Soewandhi, S.N., Wikarsa, S.,
Tjandrawinata, R.R., 2015b. Simultaneous cocrystallization and micronization of para-
cetamol-dipicolinic acid cocrystal by supercritical antisolvent (SAS). Int. J. Pharm.
Pharm. Sci.
Jones, P.S., Thigpen, D., Morrison, J.L., Richardson, A.P., 2006. p-Hydroxybenzoic acid esters
as preservatives III. The physiological disposition of p-Hydroxybenzoic acid and its es-
ters. J. Am. Pharm. Assoc. 45, 268–273.
Jones, W., Motherwell, W.D.S., Trask, A.V., 2011. Pharmaceutical cocrystals: an emerging
approach to physical property enhancement. MRS Bull. 31, 875–879.
Jug, M., Bećirević-Laćan, M., 2004. Influence of hydroxypropyl-β-cyclodextrin complexa-
tion on piroxicam release from buccoadhesive tablets. Eur. J. Pharm. Sci. 21, 251–260.
Kalgutkar, A.S., Marnett, A.B., Crews, B.C., Remmel, R.P., Marnett, L.J., 2000. Ester and
amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selec-
tive cyclooxygenase-2 inhibitors. J. Med. Chem. 43, 2860–2870.
Karki, S., Friščić, T., Jones, W., Motherwell, W.D.S., 2007. Screening for pharmaceutical
cocrystal hydrates via neat and liquid-assisted grinding. Mol. Pharm. 4, 347–354.
http://dx.doi.org/10.1021/mp0700054.
Karki, S., Friščić, T., Fabián, L., Laity, P.R., Day, G.M., Jones, W., 2009. Improving mechanical
properties of crystalline solids by cocrystal formation: new compressible forms of
paracetamol. Adv. Mater. 21, 3905–3909.
Katrusiak, A., 1993. Geometric effects of H-atom disordering in hydrogen-bonded
ferroelectrics. Phys. Rev. B 48, 2992–3002.
Katrusiak, A., 1995. Coupling of displacive and order–disorder transformations in
hydrogen-bonded ferroelectrics. Phys. Rev. B 51, 589–592.
Khaliullin, R.Z., Bell, A.T., Head-Gordon, M., 2008. Analysis of charge transfer effects in mo-
lecular complexes based on absolutely localized molecular orbitals. J. Chem. Phys.
128, 184112.
Klamt, A., 2011. The COSMO and COSMO-RS solvation models. Wiley Interdiscip. Rev.:
Comput. Mol. Sci. 1, 699–709. http://dx.doi.org/10.1002/wcms.56.
Klamt, A., 2012. Solvent-screening and co-crystal screening for drug development with
COSMO-RS. J. Cheminf. http://dx.doi.org/10.1186/1758-2946-4-S1-O14.
Klamt, A., Schüürmann, G., 1993. COSMO: a new approach to dielectric screening in sol-
vents with explicit expressions for the screening energy and its gradient. J. Chem.
Soc. Perkin Trans. 2, 799. http://dx.doi.org/10.1039/p29930000799.
Klamt, A., Eckert, F., Hornig, M., Beck, M.E., Bürger, T., 2002. Prediction of aqueous solubil-
ity of drugs and pesticides with COSMO-RS. J. Comput. Chem. 23, 275–281. http://dx.
doi.org/10.1002/jcc.1168.
Kojima, T., Tsutsumi, S., Yamamoto, K., Ikeda, Y., Moriwaki, T., 2010. High-throughput
cocrystal slurry screening by use of in situ Raman microscopy and multi-well plate.
Int. J. Pharm. 399, 52–59. http://dx.doi.org/10.1016/j.ijpharm.2010.07.055.
Krylov, A.I., Gill, P.M.W., 2013. Q-Chem: an engine for innovation. Wiley Interdiscip. Rev.:
Comput. Mol. Sci. 3, 317–326.
Leyssens, T., Springuel, G., Montis, R., Candoni, N., Veesler, S., 2012. Importance of solvent
selection for stoichiometrically diverse cocrystal systems: caffeine/maleic acid 1:1
and 2:1 cocrystals. Cryst. Growth Des. 12, 1520–1530. http://dx.doi.org/10.1021/
cg201581z.
Lin, H.-L., Hsu, P.-C., Lin, S.-Y., 2013. Theophylline–citric acid co-crystals easily induced by
DSC–FTIR microspectroscopy or different storage conditions. Asian J. Pharm. Sci. 8,
19–27.
Lin, R.-Z., Sun, P.-J., Tao, Q., Yao, J., Chen, J.-M., Lu, T.-B., 2015. Mechanism study on stability
enhancement of adefovir dipivoxil by cocrystallization: degradation kinetics and
structure-stability correlation. Eur. J. Pharm. Sci. http://dx.doi.org/10.1016/j.ejps.
2015.10.006.
Loschen, C., Klamt, A., 2015. Solubility prediction, solvate and cocrystal screening as tools
for rational crystal engineering. J. Pharm. Pharmacol. 67, 803–811. http://dx.doi.org/
10.1111/jphp.12376.
Maia, J.D.C., Urquiza Carvalho, G.A., Mangueira, C.P., Santana, S.R., Cabral, L.A.F., Rocha,
G.B., 2012. GPU linear algebra libraries and GPGPU programming for accelerating
MOPAC semiempirical quantum chemistry calculations. J. Chem. Theory Comput. 8,
3072–3081.
Manin, A.N., Voronin, A.P., Drozd, K.V., Manin, N.G., Bauer-Brandl, A., Perlovich, G.L.,
2014a. Cocrystal screening of hydroxybenzamides with benzoic acid derivatives: a
comparative study of thermal and solution-based methods. Eur. J. Pharm. Sci. 65,
56–64. http://dx.doi.org/10.1016/j.ejps.2014.09.003.
Manin, A.N., Voronin, A.P., Manin, N.G., Vener, M.V., Shishkina, A.V., Lermontov, A.S.,
Perlovich, G.L., 2014b. Salicylamide cocrystals: screening, crystal structure, sublima-
tion thermodynamics, dissolution, and solid-state DFT calculations. J. Phys. Chem. B
118, 6803–6814. http://dx.doi.org/10.1021/jp5032898.
Martí-Rujas, J., Kariuki, B.M., Hughes, C.E., Morte-Ródenas, A., Guo, F., Glavcheva-Laleva, Z.,
Taştemür, K., Ooi, L., Yeo, L., Harris, K.D.M., 2011. Structural diversity, but no polymor-
phism, in a homologous family of co-crystals of urea and α,Ω-dihydroxyalkanes. New
J. Chem. 35, 1515. http://dx.doi.org/10.1039/c1nj20040b.
McNamara, D.P., Childs, S.L., Giordano, J., Iarriccio, A., Cassidy, J., Shet, M.S., Mannion, R.,
O'Donnell, E., Park, A., 2006. Use of a glutaric acid cocrystal to improve oral bioavail-
ability of a low solubility API. Pharm. Res. 23, 1888–1897. http://dx.doi.org/10.1007/
s11095-006-9032-3.
Musumeci, D., Hunter, C.A., Prohens, R., Scuderi, S., McCabe, J.F., 2011. Virtual cocrystal
screening. Chem. Sci. 2, 883. http://dx.doi.org/10.1039/c0sc00555j.
Padrela, L., Rodrigues, M.A., Velaga, S.P., Matos, H.A., de Azevedo, E.G., 2009. Formation of
indomethacin-saccharin cocrystals using supercritical fluid technology. Eur. J. Pharm.
Sci. 38, 9–17.
Padrela, L., Rodrigues, M.A., Velaga, S.P., Fernandes, A.C., Matos, H.A., de Azevedo, E.G.,
2010. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced
atomization process. J. Supercrit. Fluids 53, 156–164.
Patil, S.P., Modi, S.R., Bansal, A.K., 2014. Generation of 1:1 carbamazepine: nicotinamide
cocrystals by spray drying. Eur. J. Pharm. Sci. 62, 251–257. http://dx.doi.org/10.
1016/j.ejps.2014.06.001.
Piazzon, A., Vrhovsek, U., Masuero, D., Mattivi, F., Mandoj, F., Nardini, M., 2012. Antioxi-
dant activity of phenolic acids and their metabolites: synthesis and antioxidant
properties of the sulfate derivatives of ferulic and caffeic acids and of the acyl glucu-
ronide of ferulic acid. J. Agric. Food Chem. 60, 12312–12323. http://dx.doi.org/10.
1021/jf304076z.
Powell, K.A., Bartolini, G., Wittering, K.E., Saleemi, A.N., Wilson, C.C., Rielly, C.D., Nagy, Z.K.,
2015. Toward continuous crystallization of urea–barbituric acid: a polymorphic co-
crystal system. Cryst. Growth Des. 15, 4821–4836. http://dx.doi.org/10.1021/acs.
cgd.5b00599.
Pozarska, A., da Costa Mathews, C., Wong, M., Pencheva, K., 2013. Application of COSMO-
RS as an excipient ranking tool in early formulation development. Eur. J. Pharm. Sci.
49, 505–511. http://dx.doi.org/10.1016/j.ejps.2013.04.021.
Prasad, K.D., Cherukuvada, S., Devaraj Stephen, L., Guru Row, T.N., 2014. Effect of
inductive effect on the formation of cocrystals and eutectics. CrystEngComm 16,
9930–9938.
Przybyłek, M., Cysewski, P., Pawelec, M., Ziółkowska, D., Kobierski, M., 2015. On the origin
of surface imposed anisotropic growth of salicylic and acetylsalicylic acids crystals
during droplet evaporation. J. Mol. Model. 21, 49.
Przybyłek, M., Ziółkowska, D., Kobierski, M., Mroczyńska, K., Cysewski, P., 2016. Utilization
of oriented crystal growth for screening of aromatic carboxylic acids cocrystallization
with urea. J. Cryst. Growth 433, 128–138. http://dx.doi.org/10.1016/j.jcrysgro.2015.
10.015.
Qandil, A.M., 2012. Prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs), more
than meets the eye: a critical review. Int. J. Mol. Sci. 13, 17244–17274.
Rahman, Z., Agarabi, C., Zidan, A.S., Khan, S.R., Khan, M.A., 2011. Physico-mechanical
and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS
PharmSciTech 12, 693–704.
Repka, M.A., Langley, N., DiNunzio, J., 2013. Melt Extrusion: Materials, Technology and
Drug Product Design. Springer Science & Business Media.
Rice-Evans, C.A., Miller, N.J., Paganga, G., 1996. Structure-antioxidant activity relationships
of flavonoids and phenolic acids. Free Radic. Biol. Med. 20, 933–956. http://dx.doi.org/
10.1016/0891-5849(95)02227-9.
Rowe, R.C., 2009. Handbook of Pharmaceutical Excipients.
Salameh, A.K., Taylor, L.S., 2006. Physical stability of crystal hydrates and their anhydrates
in the presence of excipients. J. Pharm. Sci. 95, 446–461. http://dx.doi.org/10.1002/
jps.20532.
139M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
9. Sanphui, P., Mishra, M.K., Ramamurty, U., Desiraju, G.R., 2015. Tuning mechanical
properties of pharmaceutical crystals with multicomponent crystals: voriconazole
as a case study. Mol. Pharm. 12, 889–897.
Schartman, R.R., 2009. On the thermodynamics of cocrystal formation. Int. J. Pharm. 365,
77–80. http://dx.doi.org/10.1016/j.ijpharm.2008.08.029.
Schultheiss, N., Newman, A., 2009. Pharmaceutical cocrystals and their physicochemical
properties. Cryst. Growth Des. 9, 2950–2967.
Shan, N., Zaworotko, M.J., 2008. The role of cocrystals in pharmaceutical science. Drug
Discov. Today 13, 440–446.
Shao, Y., Gan, Z., Epifanovsky, E., Gilbert, A.T.B., Wormit, M., Kussmann, J., Lange, A.W.,
Behn, A., Deng, J., Feng, X., Ghosh, D., Goldey, M., Horn, P.R., Jacobson, L.D., Kaliman,
I., Khaliullin, R.Z., Kuś, T., Landau, A., Liu, J., Proynov, E.I., Rhee, Y.M., Richard, R.M.,
Rohrdanz, M.A., Steele, R.P., Sundstrom, E.J., Woodcock, H.L., Zimmerman, P.M.,
Zuev, D., Albrecht, B., Alguire, E., Austin, B., Beran, G.J.O., Bernard, Y.A., Berquist, E.,
Brandhorst, K., Bravaya, K.B., Brown, S.T., Casanova, D., Chang, C.-M., Chen, Y., Chien,
S.H., Closser, K.D., Crittenden, D.L., Diedenhofen, M., DiStasio, R.A., Do, H., Dutoi,
A.D., Edgar, R.G., Fatehi, S., Fusti-Molnar, L., Ghysels, A., Golubeva-Zadorozhnaya, A.,
Gomes, J., Hanson-Heine, M.W.D., Harbach, P.H.P., Hauser, A.W., Hohenstein, E.G.,
Holden, Z.C., Jagau, T.-C., Ji, H., Kaduk, B., Khistyaev, K., Kim, J., Kim, J., King, R.A.,
Klunzinger, P., Kosenkov, D., Kowalczyk, T., Krauter, C.M., Lao, K.U., Laurent, A.D.,
Lawler, K.V., Levchenko, S.V., Lin, C.Y., Liu, F., Livshits, E., Lochan, R.C., Luenser, A.,
Manohar, P., Manzer, S.F., Mao, S.-P., Mardirossian, N., Marenich, A.V., Maurer, S.A.,
Mayhall, N.J., Neuscamman, E., Oana, C.M., Olivares-Amaya, R., O'Neill, D.P., Parkhill,
J.A., Perrine, T.M., Peverati, R., Prociuk, A., Rehn, D.R., Rosta, E., Russ, N.J., Sharada,
S.M., Sharma, S., Small, D.W., Sodt, A., Stein, T., Stück, D., Su, Y.-C., Thom, A.J.W.,
Tsuchimochi, T., Vanovschi, V., Vogt, L., Vydrov, O., Wang, T., Watson, M.A., Wenzel,
J., White, A., Williams, C.F., Yang, J., Yeganeh, S., Yost, S.R., You, Z.-Q., Zhang, I.Y.,
Zhang, X., Zhao, Y., Brooks, B.R., Chan, G.K.L., Chipman, D.M., Cramer, C.J., Goddard,
W.A., Gordon, M.S., Hehre, W.J., Klamt, A., Schaefer, H.F., Schmidt, M.W., Sherrill,
C.D., Truhlar, D.G., Warshel, A., Xu, X., Aspuru-Guzik, A., Baer, R., Bell, A.T., Besley,
N.A., Chai, J.-D., Dreuw, A., Dunietz, B.D., Furlani, T.R., Gwaltney, S.R., Hsu, C.-P.,
Jung, Y., Kong, J., Lambrecht, D.S., Liang, W., Ochsenfeld, C., Rassolov, V.A., Slipchenko,
L.V., Subotnik, J.E., Van Voorhis, T., Herbert, J.M., Krylov, A.I., Gill, P.M.W., Head-
Gordon, M., 2014. Advances in molecular quantum chemistry contained in the
Q-Chem 4 program package. Mol. Phys. 113, 184–215.
Simon, S., Duran, M., Dannenberg, J.J., 1996. How does basis set superposition error
change the potential surfaces for hydrogen-bonded dimers? J. Chem. Phys. 105,
11024. http://dx.doi.org/10.1063/1.472902.
Sroka, Z., Cisowski, W., 2003. Hydrogen peroxide scavenging, antioxidant and anti-radical
activity of some phenolic acids. Food Chem. Toxicol. 41, 753–758.
Steed, J.W., 2013. The role of co-crystals in pharmaceutical design. Trends Pharmacol. Sci.
34, 185–193. http://dx.doi.org/10.1016/j.tips.2012.12.003.
Stewart, J.J.P., 2016. MOPAC2012, Version 15.089W. Fujitsu Limited, Tokyo, Japan.
Sun, C.C., Hou, H., 2008. Improving mechanical properties of caffeine and methyl gallate
crystals by cocrystallization. Cryst. Growth Des. 8, 1575–1579. http://dx.doi.org/10.
1021/cg700843s.
Takata, N., Shiraki, K., Takano, R., Hayashi, Y., Terada, K., 2008. Cocrystal screening of
stanolone and mestanolone using slurry crystallization. Cryst. Growth Des. 8,
3032–3037. http://dx.doi.org/10.1021/cg800156k.
Thakuria, R., Delori, A., Jones, W., Lipert, M.P., Roy, L., Rodríguez-Hornedo, N., 2013.
Pharmaceutical cocrystals and poorly soluble drugs. Int. J. Pharm. 453, 101–125.
Tothadi, S., 2014. Polymorphism in cocrystals of urea:4,4′-bipyridine and salicylic acid:
4,4′-bipyridine. CrystEngComm 16, 7587. http://dx.doi.org/10.1039/C4CE00866A.
Vangala, V.R., Chow, P.S., Tan, R.B.H., 2011. Characterization, physicochemical and
photo-stability of a co-crystal involving an antibiotic drug, nitrofurantoin,
and 4-hydroxybenzoic acid. CrystEngComm 13, 759–762.
Varughese, S., Azim, Y., Desiraju, G.R., 2010. Molecular complexes of alprazolam with car-
boxylic acids, boric acid, boronic acids, and phenols. Evaluation of supramolecular
heterosynthons mediated by a triazole ring. J. Pharm. Sci. 99, 3743–3753. http://dx.
doi.org/10.1002/jps.22117.
Videnova-Adrabińska, V., 1996. Symmetry constraints, molecular recognition and crystal
engineering. Comparative structural studies of urea–butanedioic and urea–E-
butanedioic acid (2:1) cocrystals. Acta Crystallogr. Sect. B: Struct. Sci. 52,
1048–1056. http://dx.doi.org/10.1107/S0108768196005216.
Vishweshwar, P., McMahon, J.A., Bis, J.A., Zaworotko, M.J., 2006. Pharmaceutical co-
crystals. J. Pharm. Sci. 95, 499–516.
Wang, L., Tan, B., Zhang, H., Deng, Z., 2013. Pharmaceutical cocrystals of diflunisal with
nicotinamide or isonicotinamide. Org. Process. Res. Dev. 17, 1413–1418. http://dx.
doi.org/10.1021/op400182k.
Xu, Y., Jiang, L., Huang, Y., Wang, J.-R., Mei, X., 2014. Solid-state characterization and
transformation of various creatine phosphate sodium hydrates. J. Pharm. Sci. 103,
3688–3695.
Yamashita, H., Hirakura, Y., Yuda, M., Teramura, T., Terada, K., 2013. Detection of cocrystal
formation based on binary phase diagrams using thermal analysis. Pharm. Res. 30,
70–80.
Yamashita, H., Hirakura, Y., Yuda, M., Terada, K., 2014. Coformer screening using thermal
analysis based on binary phase diagrams. Pharm. Res. 31, 1946–1957.
Yan, Y., Chen, J.-M., Lu, T.-B., 2015. Thermodynamics and preliminary pharmaceutical
characterization of a melatonin–pimelic acid cocrystal prepared by a melt crystalliza-
tion method. CrystEngComm 17, 612–620. http://dx.doi.org/10.1039/C4CE01921K.
Zhang, T.-T., Wang, H.-T., Jia, J.-T., Cui, X.-Q., Li, Q., Zhu, G.-S., 2014. Syntheses and pharma-
cokinetics properties of an iloperidone pharmaceutical cocrystal. Inorg. Chem.
Commun. 39, 144–146.
140 M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140
10. Supplementary materials
Propensity of salicylamide and ethenzamide cocrystallization with aromatic carboxylic
acids
Maciej Przybyłek1
, Dorota Ziółkowska2
, Karina Mroczyńska3
, Piotr Cysewski1*
1
Chair and Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz,
Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-950 Bydgoszcz, Poland,
piotr.cysewski@cm.umk.pl
2
University of Technology and Life Sciences in Bydgoszcz, Faculty of Chemical Technology and
Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland;
3
Research Laboratory, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326
Bydgoszcz
List of figures
1. PXRD and FTIR-ATR characteristics of salicylamide-carboxylic acid mixtures
Fig. S1. PXRD and FTIR-ATR characteristics of salicylamide-benzoic acid (SMD-BA) crystallite layers
deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with simulated
diffraction patterns of coformers (grey lines).
Fig. S2. PXRD and FTIR-ATR characteristics of salicylamide-2-fluorobenzoic acid (SMD-2FBA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
Fig. S3. PXRD and FTIR-ATR characteristics of salicylamide-2-chloroobenzoic acid (SMD-2CBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S4. PXRD and FTIR-ATR characteristics of salicylamide-2-bromobenzoic acid (SMD-2BBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S5. PXRD and FTIR-ATR characteristics of salicylamide-2-iodobenzoic acid (SMD-2IBA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
Fig. S6. PXRD and FTIR-ATR characteristics of salicylamide-3-hydroxybenzoic acid (SMD-3HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines). The monoclinic and orthorhombic
polymorphs of 3-hydroxybenzoic acid are denoted by refcodes BIDLOP and BIDLOP02, respectively.
Fig. S7. PXRD and FTIR-ATR characteristics of salicylamide-4-hydroxybenzoic acid (SMD-4HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S8. PXRD and FTIR-ATR characteristics of salicylamide-2,5-dihydroxybenzoic acid (SMD-2,5DHBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S9. PXRD and FTIR-ATR characteristics of salicylamide-2,6-dihydroxybenzoic acid (SMD-2,6DHBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines). The orthorhombic and monoclinic
polymorphs of 2,6-dihydroxybenzoic acid and hydrate (dotted line) are denoted by refcodes LEZJAB,
LEZJAB01 and LEZJEF, respectively.
Fig. S10. PXRD and FTIR-ATR characteristics of salicylamide-3,4-dihydroxybenzoic acid (SMD-
3,4DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines).
11. Fig. S11. PXRD and FTIR-ATR characteristics of salicylamide-3,5-dihydroxybenzoic acid (SMD-
3,5DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines). The polymorph I and II of
3,5-dihydroxybenzoic acid are denoted by refcodes WUYPOW and WUYPOW01, respectively.
2. PXRD and FTIR-ATR characteristics of ethenzamide-carboxylic acid mixtures
Fig. S12. PXRD and FTIR-ATR characteristics of ethenzamide-benzoic acid (EMD-BA) crystallite layers
deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with simulated
diffraction patterns of coformers (grey lines).
Fig. S13. PXRD and FTIR-ATR characteristics of ethenzamide-2-fluorobenzoic acid (EMD-2FBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S14. PXRD and FTIR-ATR characteristics of ethenzamide-2-chlorobenzoic acid (EMD-2CBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S15. PXRD and FTIR-ATR characteristics of ethenzamide-2-bromobenzoic acid (EMD-2BBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S16. PXRD and FTIR-ATR characteristics of ethenzamide-2-iodobenzoic acid (EMD-2IBA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
Fig. S17. PXRD and FTIR-ATR characteristics of ethenzamide-4-acetamidobenzoic acid (EMD-4ABA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S18. PXRD and FTIR-ATR characteristics of ethenzamide-acetylsalicylic acid (EMD-ASA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
Fig. S19. PXRD and FTIR-ATR characteristics of ethenzamide-3-hydroxybenzoic acid (EMD-3HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines). The monoclinic and orthorhombic
polymorphs of 3-hydroxybenzoic acid are denoted by refcodes BIDLOP and BIDLOP02, respectively.
Fig. S20. PXRD and FTIR-ATR characteristics of ethenzamide-4-hydroxybenzoic acid (EMD-4HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers and cocrystal (grey lines). Cocrystal formation was
confirmed by Aitipamula et al. (2012b).
Fig. S21. PXRD and FTIR-ATR characteristics of ethenzamide-3,4-dihydroxybenzoic acid (EMD-
3,4DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines).
Fig. S22. PXRD and FTIR-ATR characteristics of ethenzamide-3,5-dihydroxybenzoic acid (EMD-
3,5DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines). The polymorph I and II of
3,5-dihydroxybenzoic acid are denoted by refcodes WUYPOW and WUYPOW01, respectively.
12. 1. PXRD and FTIR-ATR characteristics of salicylamide-carboxylic acid mixtures
Fig. S1. PXRD and FTIR-ATR characteristics of salicylamide-benzoic acid (SMD-BA) crystallite layers
deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with simulated
diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
BA
BA (BENZAC02)
SMD-BA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
SMD-BA
BA
SMD
13. Fig. S2. PXRD and FTIR-ATR characteristics of salicylamide-2-fluorobenzoic acid (SMD-2FBA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
5 15 25 35
relativeintensity
2[]
SMD
2FBA
2FBA (FBENZA)
SMD-2FBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
SMD-2FBA
2FBA
SMD
14. Fig. S3. PXRD and FTIR-ATR characteristics of salicylamide-2-chloroobenzoic acid (SMD-2CBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 15 25 35
relativeintensity
2[]
SMD
2CBA
2CBA (CLBZAC)
SMD-2CBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
SMD-2CBA
2CBA
SMD
15. Fig. S4. PXRD and FTIR-ATR characteristics of salicylamide-2-bromobenzoic acid (SMD-2BBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
2BBA
2BBA (BRBZAC)
SMD-2BBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
SMD-2BBA
2BBA
SMD
16. Fig. S5. PXRD and FTIR-ATR characteristics of salicylamide-2-iodobenzoic acid (SMD-2IBA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
2IBA
2IBA (OIBZAC)
SMD-2IBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
1800 2300 2800 3300
normalizedtransmitance
wave number [cm-1]
SMD-2IBA
2IBA
SMD
17. Fig. S6. PXRD and FTIR-ATR characteristics of salicylamide-3-hydroxybenzoic acid (SMD-3HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines). The monoclinic and orthorhombic
polymorphs of 3-hydroxybenzoic acid are denoted by refcodes BIDLOP and BIDLOP02, respectively.
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
3HBA
3HBA (BIDLOP02)
3HBA (BIDLOP)
SMD-3HBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
normalizedtransmitance
wave number [cm-1]
SMD-3HBA
3HBA
SMD
18. Fig. S7. PXRD and FTIR-ATR characteristics of salicylamide-4-hydroxybenzoic acid (SMD-4HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
4HBA
4HBA (JOZZIH)
SMD-4HBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
SMD-4HBA
4HBA
SMD
19. Fig. S8. PXRD and FTIR-ATR characteristics of salicylamide-2,5-dihydroxybenzoic acid (SMD-2,5DHBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
2,5DHBA
2,5DHBA
(BESKAL01)
SMD-2,5DHBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
normalizedtransmitance
wave number [cm-1]
SMD-2,5DHBA
2,5DHBA
SMD
20. Fig. S9. PXRD and FTIR-ATR characteristics of salicylamide-2,6-dihydroxybenzoic acid (SMD-2,6DHBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines). The orthorhombic and monoclinic
polymorphs of 2,6-dihydroxybenzoic acid and hydrate (dotted line) are denoted by refcodes LEZJAB,
LEZJAB01 and LEZJEF, respectively.
5 15 25 35
relativeintensity
2[]
SMD
2,6DHBA
SMD-2,6DHBA
SMD (SALMID01)
2,6DHBA
(LEZJAB)
2,6DHBA hydrate
(LEZJEF)
2,6DHBA
(LEZJAB01)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
normalizedtransmitance
wave number [cm-1]
SMD-2,6DHBA
2,6DHBA
SMD
21. Fig. S10. PXRD and FTIR-ATR characteristics of salicylamide-3,4-dihydroxybenzoic acid (SMD-
3,4DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
3,4DHBA
SMD (SALMID01)
SMD-3,4DHBA
3,4DHBA (WUYNUA)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
SMD-3,4DHBA
3,4DHBA
SMD
22. Fig. S11. PXRD and FTIR-ATR characteristics of salicylamide-3,5-dihydroxybenzoic acid (SMD-
3,5DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines). The polymorph I and II of
3,5-dihydroxybenzoic acid are denoted by refcodes WUYPOW and WUYPOW01, respectively.
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
3,5DHBA
SMD (SALMID01)
SMD-3,5DHBA
3,5DHBA
(WUYPOW01)
3,5DHBA
(WUYPOW)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
normalizedtransmitance
wave number [cm-1]
SMD-3,5DHBA
3,5DHBA
SMD
23. 2. PXRD and FTIR-ATR characteristics of ethenzamide-carboxylic acid mixtures.
Fig. S12. PXRD and FTIR-ATR characteristics of ethenzamide-benzoic acid (EMD-BA) crystallite layers
deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with simulated
diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
BA
BA (BENZAC02)
EMD-BA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-BA
BA
EMD
24. Fig. S13. PXRD and FTIR-ATR characteristics of ethenzamide-2-fluorobenzoic acid (EMD-2FBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
2FBA
2FBA (FBENZA)
EMD-2FBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-2FBA
2FBA
EMD
25. Fig. S14. PXRD and FTIR-ATR characteristics of ethenzamide-2-chlorobenzoic acid (EMD-2CBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 15 25 35
relativeintensity
2[]
EMD
2CBA
2CBA (CLBZAC)
EMD-2CBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-2CBA
2CBA
EMD
26. Fig. S15. PXRD and FTIR-ATR characteristics of ethenzamide-2-bromobenzoic acid (EMD-2BBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 15 25 35
relativeintensity
2[]
EMD
2BBA
2BBA (BRBZAC)
EMD-2BBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-2BBA
2BBA
EMD
27. Fig. S16. PXRD and FTIR-ATR characteristics of ethenzamide-2-iodobenzoic acid (EMD-2IBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 15 25 35
relativeintensity
2[]
EMD
2IBA
2IBA (OIBZAC)
EMD-2IBA
2EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-2IBA
2IBA
EMD
28. Fig. S17. PXRD and FTIR-ATR characteristics of ethenzamide-4-acetamidobenzoic acid (EMD-4ABA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
4ABA
4ABA (DIXFAR)
EMD-4ABA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-4ABA
4ABA
EMD
29. Fig. S18. PXRD and FTIR-ATR characteristics of ethenzamide-acetylsalicylic acid (EMD-ASA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
ASA
ASA (ACSALA01)
EMD-ASA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-ASA
ASA
EMD
30. Fig. S19. PXRD and FTIR-ATR characteristics of ethenzamide-3-hydroxybenzoic acid (EMD-3HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines). The monoclinic and orthorhombic
polymorphs of 3-hydroxybenzoic acid are denoted by refcodes BIDLOP and BIDLOP02, respectively.
5 15 25 35
relativeintensity
2[]
EMD
3HBA
3HBA (BIDLOP02)
3HBA (BIDLOP)
EMD-3HBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
normalizedtransmitance
wave number [cm-1]
EMD-3HBA
3HBA
EMD
31. Fig. S20. PXRD and FTIR-ATR characteristics of ethenzamide-4-hydroxybenzoic acid (EMD-4HBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers and cocrystal (grey lines). Cocrystal formation was
confirmed by Aitipamula et al. (2012b).
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
4HBA
4HBA (JOZZIH)
EMD-4HBA
EMD (DUKXAJ)
EMD-4HBA
(Aitipamula et al. 2012b)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-4HBA
4HBA
EMD
32. Fig. S21. PXRD and FTIR-ATR characteristics of ethenzamide-3,4-dihydroxybenzoic acid (EMD-
3,4DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines).
5 15 25 35
relativeintensity
2[]
EMD
3,4DHBA
EMD (DUKXAJ)
EMD-3,4DHBA
3,4DHBA (WUYNUA)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
EMD-3,4DHBA
3,4DHBA
EMD
33. Fig. S22. PXRD and FTIR-ATR characteristics of ethenzamide-3,5-dihydroxybenzoic acid (EMD-
3,5DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines). The polymorph I and II of
3,5-dihydroxybenzoic acid are denoted by refcodes WUYPOW and WUYPOW01, respectively.
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
3,5DHBA
EMD (DUKXAJ)
EMD-3,5DHBA
3,5DHBA
(WUYPOW01)
3,5DHBA
(WUYPOW)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
normalizedtransmitance
wave number [cm-1]
EMD-3,5DHBA
3,5DHBA
EMD