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Pharmaceutical cocrystals offer a versatile approach to enhancing the properties of drug compounds, making them an important tool in drug formulation and development by improving the therapeutic performance and patient experience of pharmaceutical products. The prediction of cocrystals involves using computational and theoretical methods to identify potential cocrystal formers and understand the interactions between the active pharmaceutical ingredient and coformers. This process aims to predict whether two or more molecules can form a stable cocrystal structure before performing experimental synthesis, thus saving time and resources. In this review, the commonly used cocrystal prediction methods are first overviewed and then evaluated based on three criteria: efficiency, cost-effectiveness, and user-friendliness. Based on these considerations, we suggest to experimental researchers without strong computational experiences which methods and tools should be tested as a first step in the workflow of rational design of cocrystals. However, the optimal choice depends on specific needs and resources, and combining methods from different categories can be a more powerful approach. [ABSTRACT FROM AUTHOR]

Abstract Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline’s additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures. Graphical Abstract

Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline's additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective of this research work was to formulate crystal engineered multicomponent form of a BCS II drug, telmisartan (TEL) using crystal engineering approach to improve its aqueous solubility. Further, it was attempted to understand the co-crystallization specificity of TEL using a set of structurally similar coformers. Methods: Preliminary structural assessment and feasibility of cocrystal formation was done using Cambridge structural database (CSD) and molecular electrostatic surface potential (MESP). The formation of cocrystals was confirmed by different characterization techniques such as differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared spectroscopy (FTIR), and powder x-ray diffraction (PXRD). Solubility and dissolution studies were performed in phosphate buffer 7.5 and 0.1 N HCl. Results: TEL cocrystal with maleic acid (MA) was successfully obtained, and co-crystallization specificity was decoded at MESP. Cocrystal structure was also solved from PXRD data. A 4.27-fold and 2.8-fold improvement in the solubility was observed in phosphate buffer 7.5 and 0.1 N HCl. Conclusion: A significant improvement in the aqueous solubility and dissolution profile was observed for the prepared cocrystals over the pure TEL. The present study was a small initiative to serve as a guidance for the rationalized screening and preparation of novel multicomponent solids with desired properties. [ABSTRACT FROM AUTHOR]

Progesterone injection is oily because of its poor solubility. It is necessary to develop new dosage forms or delivery methods for Progesterone. Six cocrystals of Progesterone with nitrogen heterocyclic compounds (2,6-diaminopyridine, isonicotinamide, 4-aminopyridine, aminopyrazine, picolinamide and pyrazinamide) have been designed and prepared by ethyl acetate-assisted grinding, of which four cocrystals (2,6-diaminopyridine, isonicotinamide, 4-aminopyridine and aminopyrazine) had single crystal data in 1:1 stoichiometry. Metadynamics-genetic crossing was used to search and optimize various cluster structures to explain the reason the other two cocrystals could not be obtained with suitable size for single crystal X-ray diffraction. In contrast to the carboxyl group, the amide group and amino group were good substituents in the pyridine/pyrazine ring for cocrystallization with Progesterone, which meant inductive effect played an important role in nitrogen heterocyclic compounds containing reactive hydrogen. All cocrystals were more soluble than Progesterone in water, and Progesterone–pyrazinamide cocystal featured the best water solubility performance with an approximately six-fold increase over free Progesterone. This successful attempt provides an effective route for designing and manufacturing novel solid states of Progesterone. [ABSTRACT FROM AUTHOR]

X-ray powder diffraction is a vital analytical tool that is used in pharmaceutical science. It is increasingly used to establish the crystal structure of a new pharmaceutical substance, in particular, cocrystal or its polymorphic forms. This review begins with a brief discussion of the reliability of the structural parameters retrieved from powder patterns. Recent examples of the successful determination of crystal structures of pharmaceutical cocrystals and salts from powder diffraction data are discussed. These examples show the increased capabilities of laboratory X-ray powder diffractometers and modern software in solving actual problems of pharmaceutical science. [ABSTRACT FROM AUTHOR]

Cocrystallization is currently an attractive technique for tailoring the physicochemical properties of active pharmaceutical ingredients (APIs). Flavonoids are a large class of natural products with a wide range of beneficial properties, including anticancer, anti-inflammatory, antiviral and antioxidant properties, which makes them extensively studied. In order to improve the properties of flavonoids, such as solubility and bioavailability, the formation of cocrystals may be a feasible strategy. This review discusses in detail the possible hydrogen bond sites in the structure of APIs and the hydrogen bonding networks in the cocrystal structures, which will be beneficial for the targeted synthesis of flavonoid cocrystals. In addition, some successful studies that favorably alter the physicochemical properties of APIs through cocrystallization with coformers are also highlighted here. In addition to improving the solubility and bioavailability of flavonoids in most cases, flavonoid cocrystals may also alter their other properties, such as anti-inflammatory activity and photoluminescence properties. [ABSTRACT FROM AUTHOR]

As a low-risk, low-cost, but high-reward route, cocrystallization of drugs with appropriate coformers is applied to improve the physiochemical and biopharmaceutical properties of drugs. Currently, most researchers concentrate their efforts on the preparation, characterization, and improvement of physicochemical properties of pharmaceutical cocrystals. On the contrary, the biological study of pharmaceutical cocrystals has not attracted wide attention of researchers. In this review, we have focused on recent advances reporting the biological studies of pharmaceutical cocrystals. The covered areas consist of the solubility and permeability, the pharmacokinetics study, metabolism and distribution, pharmacodynamics research, and the toxicological evaluation of pharmaceutical cocrystals. Besides, discussions have been made on the in vivo–in vitro correlations for pharmaceutical cocrystals, the enhancement of efficiency and reduction of toxicity for pharmaceutical cocrystals, and the interaction between APIs and coformers in pharmaceutical cocrystals and marketed pharmaceutical cocrystals as well as their biological studies. At the same time, some problems such as the amount of animal samples, the number and distribution of blood sampling points, investigation on the pharmacokinetics of physical mixtures containing APIs and coformers, and the consideration of species differences should be taken into account. Although pharmaceutical cocrystals face some challenges in clarifying the characteristics of metabolism and distribution, revealing potential pharmacological mechanism, and evaluating safety, cocrystal engineering is still considered a green and promising approach to developing valuable new drugs. [ABSTRACT FROM AUTHOR]

Crystal engineering provides a unique approach to modulating the physicochemical properties of forming active drug molecules so nowadays pharmaceutical companies and researchers have shown interest in designing and building cocrystals. Creating new crystalline solid structures with altered physicochemical properties such as solubility, bioavailability, tabletability, melting point, stability, and so on. The intermolecular interactions of molecules in the crystal lattice are used to investigate these properties. Numbers of methods for crystallizing the drug are summarised and analyzed, pointing to the advantages and disadvantages that have been highlighted in the literature. This literature review discusses in detail the different types of cocrystals, their mechanisms, methods of cocrystals, applications of cocrystals, and their characterization. The main purpose of this article is to look at what has changed in this field in the last ten years and show what could be learned from better research on cocrystal formation and how it can be used. [ABSTRACT FROM AUTHOR]

The most favored approach for drug administration is the oral route. Several anticancer drugs come under this category and mostly lack solubility and oral bioavailability, which are the most common causes of inadequate clinical efficiency. Enhancing oral absorption of anticancer drugs with low aqueous solubility and drug impermeability is currently an effective area of research. Many scientists have looked into pharmaceutical cocrystals as a way to improve the physicochemical properties of several anticancer drugs. Benefits of pharmaceutical cocrystals over other solid forms may include improved solubility, bioavailability, and a reduced susceptibility for phase transition. Cocrystal strategy also stands as a green synthesis tool by using very limited organic solvents during its formulation. Having so many advantages, to date, the reported cocrystals and drug–drug cocrystals of anticancer drugs are limited. Here we review the pharmaceutical cocrystals and drug–drug cocrystals of the anticancer drugs reported in the last decade and their future in imaging, and also shed light on the opportunities and challenges for the development of anticancer drug cocrystals. [ABSTRACT FROM AUTHOR]

Sulfamethoxazole is a sulphonamide bacteriostatic antibiotic having poor solubility, resulting in a high prescribed dose of 800 mg/day. Accordingly, these high doses relate to an increased risk of adverse effects. In this contribution, a novel cocrystal of sulfamethoxazole-succinimide was prepared by mechanochemical synthesis to modulate the physicochemical properties. X-ray diffraction, thermal, and spectroscopic analyses were used to characterize the cocrystal thoroughly. Also, to gain an insight into the optimized structural geometry, important functional frequencies, and electronic properties, the density functional theory was used. The contribution of auxiliary interactions and intermolecular interactions have been investigated by Hirshfeld surface analysis. Solubility and powder dissolution studies were performed to investigate the changes in the physicochemical properties. The cocrystal demonstrated an improvement in the solubility profile in aqueous media and an enhanced dissolution rate in the recommended dissolution media. Furthermore, accelerated stability studies under stress conditions were performed, where the cocrystal showed no indication of dissociation. The study demonstrates the significance of mechanochemical cocrystallization to modulate the physicochemical properties of an API, along with an insight into spectroscopic, electronic and chemical conformation. [Display omitted] • Sulfamethoxazole-Succinimide cocrystal was prepared by mechanochemical synthesis. • Characterization was done by X-ray diffraction, thermal, and spectroscopic analyses. • DFT calculation was applied to reveal the optimized structural geometry of cocrystal. • Cocrystallization modulated the physicochemical properties. [ABSTRACT FROM AUTHOR]

Pharmaceutical cocrystals are multicomponent systems in which at least one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable ingredients. Cocrystallization of a drug substance with a coformer is a promising and emerging approach to improve the performance of pharmaceuticals, such as solubility, dissolution profile, pharmacokinetics and stability. This review article presents a comprehensive overview of pharmaceutical cocrystals, including preparation methods, physicochemical properties, and applications. Furthermore, some examples of drug cocrystals are highlighted to illustrate the effect of crystal structures on the various aspects of active pharmaceutical ingredients, such as physical stability, chemical stability, mechanical properties, optical properties, bioavailability, sustained release and therapeutic effect. This review will provide guidance for more efficient design and manufacture of pharmaceutical cocrystals with desired physicochemical properties and applications.

Cocrystals can be defined as crystalline solids composed of at least two compounds in a stoichiometric ratio which interact nonionically. While one of the components is an active pharmaceutical ingredient (API) the term ‘pharmaceutical cocrystal’ could be applied. These are the subject of interest in academic and industrial research as they offer better control over physicochemical, mechanical and pharmacokinetic properties of API while its therapeutic activity remains intact. Commercial success of this approach can be confirmed by the number of marketed pharmaceutical cocrystal drug forms. Despite the range of cocrystallization methods introduced, it is challenging to propose a technique meeting industrial requirements such as scalability or continuousness of the process with respect to ‘green chemistry’ principles being reduction of solvents use. This paper covers the criteria of cocrystallization method selection and presents techniques potentially applicable for large-scale purposes such as Hot Melt Extrusion, Matrix Assisted Cocrystallization and spray congealing with advantages and limitations of those. Within mechanochemical methods of obtaining cocrystals, Matrix Assisted Cocrystallization (MAC) is a promising candidate for industrial-scale use as it is a continuous, one-step, solvent-free technique offering high control over process parameters (e.g. temperature, feed rate, screw speed, screw configuration, extruder type) in order to increase the efficiency of the synthesis and provide high quality product. The addition of polymer facilitates the extrusion and enables conducting the process at lower temperature to prevent degradation of thermolabile substances. Furthermore, cocrystals embedded in polymeric matrix can exhibit the improvement of dissolution rate or compressibility. Additionally, the MAC can be coupled with Process Analytical Technology (PAT) tools to provide real-time data for manufacturing process monitoring and control of product quality.

Progesterone injection is oily because of its poor solubility. It is necessary to develop new dosage forms or delivery methods for Progesterone. Six cocrystals of Progesterone with nitrogen heterocyclic compounds (2,6-diaminopyridine, isonicotinamide, 4-aminopyridine, aminopyrazine, picolinamide and pyrazinamide) have been designed and prepared by ethyl acetate-assisted grinding, of which four cocrystals (2,6-diaminopyridine, isonicotinamide, 4-aminopyridine and aminopyrazine) had single crystal data in 1:1 stoichiometry. Metadynamics-genetic crossing was used to search and optimize various cluster structures to explain the reason the other two cocrystals could not be obtained with suitable size for single crystal X-ray diffraction. In contrast to the carboxyl group, the amide group and amino group were good substituents in the pyridine/pyrazine ring for cocrystallization with Progesterone, which meant inductive effect played an important role in nitrogen heterocyclic compounds containing reactive hydrogen. All cocrystals were more soluble than Progesterone in water, and Progesterone–pyrazinamide cocystal featured the best water solubility performance with an approximately six-fold increase over free Progesterone. This successful attempt provides an effective route for designing and manufacturing novel solid states of Progesterone.

X-ray powder diffraction is a vital analytical tool that is used in pharmaceutical science. It is increasingly used to establish the crystal structure of a new pharmaceutical substance, in particular, cocrystal or its polymorphic forms. This review begins with a brief discussion of the reliability of the structural parameters retrieved from powder patterns. Recent examples of the successful determination of crystal structures of pharmaceutical cocrystals and salts from powder diffraction data are discussed. These examples show the increased capabilities of laboratory X-ray powder diffractometers and modern software in solving actual problems of pharmaceutical science.

Cocrystallization is currently an attractive technique for tailoring the physicochemical properties of active pharmaceutical ingredients (APIs). Flavonoids are a large class of natural products with a wide range of beneficial properties, including anticancer, anti-inflammatory, antiviral and antioxidant properties, which makes them extensively studied. In order to improve the properties of flavonoids, such as solubility and bioavailability, the formation of cocrystals may be a feasible strategy. This review discusses in detail the possible hydrogen bond sites in the structure of APIs and the hydrogen bonding networks in the cocrystal structures, which will be beneficial for the targeted synthesis of flavonoid cocrystals. In addition, some successful studies that favorably alter the physicochemical properties of APIs through cocrystallization with coformers are also highlighted here. In addition to improving the solubility and bioavailability of flavonoids in most cases, flavonoid cocrystals may also alter their other properties, such as anti-inflammatory activity and photoluminescence properties.

In recent years, the design of pharmaceutical cocrystals has garnered significant attention. The process of cocrystallization offers a remarkable opportunity to develop drug products with enhanced properties such as improved stability, solubility, hygroscopicity, dissolution rate, and bioavailability. This detailed review delves into this evolving area, thereby exploring its relevance in pharmaceutical formulation by defining cocrystals and their practical applications and also by discussing methods for their preparation as well as characterization. It also contrasts traditional and innovative techniques for cocrystal formation. Historically, cocrystals have been synthesized using methods like solvent evaporation, grinding, and slurry techniques; however, each has its own set of limitations under specific conditions. The latest trends in cocrystal formation lean toward more advanced approaches such as spray-drying, hot melt extrusion, and supercritical fluid technology, as well as the cutting-edge technique of laser irradiation. The aim behind developing new methods is not just to address the limitations of traditional cocrystallization techniques but also to streamline the process by introducing simpler steps and enabling a continuous production workflow for cocrystal products. In general, this full-length review article offers a report on various techniques available for the creation of pharmaceutical cocrystals, along with the methods for their evaluation. Moreover, it includes reporting developments and diverse applications of cocrystals along with the commercially available cocrystals in the pharmaceutical as well as medical domains., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Chavan et al.)

Environmental impacts of the industrial revolution necessitate adoption of sustainable practices in all areas of development. The pharmaceutical industry faces increasing pressure to minimize its ecological footprint due to its significant contribution to environmental pollution. Over the past two decades, pharmaceutical cocrystals have received immense popularity due to their ability to optimize the critical attributes of active pharmaceutical ingredients and presented an avenue to bring improved drug products to the market. This review explores the potential of pharmaceutical cocrystals as an ecofriendly alternative to traditional solid forms, offering a sustainable approach to drug development. From reducing the number of required doses to improving the stability of actives, from eliminating synthetic operations to using pharmaceutically approved chemicals, from the use of continuous and solvent-free manufacturing methods to leveraging published data on the safety and toxicology, the cocrystallization approach contributes to sustainability of drug development. The latest trends suggest a promising role of pharmaceutical cocrystals in bringing novel and improved medicines to the market, which has been further fuelled by the recent guidance from the major regulatory agencies.

The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products. [ABSTRACT FROM AUTHOR]

The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products.

Pharmaceutical cocrystals are multicomponent systems in which at least one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable ingredients. Cocrystallization of a drug substance with a coformer is a promising and emerging approach to improve the performance of pharmaceuticals, such as solubility, dissolution profile, pharmacokinetics and stability. This review article presents a comprehensive overview of pharmaceutical cocrystals, including preparation methods, physicochemical properties, and applications. Furthermore, some examples of drug cocrystals are highlighted to illustrate the effect of crystal structures on the various aspects of active pharmaceutical ingredients, such as physical stability, chemical stability, mechanical properties, optical properties, bioavailability, sustained release and therapeutic effect. This review will provide guidance for more efficient design and manufacture of pharmaceutical cocrystals with desired physicochemical properties and applications. Pharmaceutical cocrystals is a promising and emerging approach to modulate the performance of pharmaceuticals, including physical stability, chemical stability, mechanical properties, optical properties, release profiles, bioavailability and therapeutic effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Several key topics in solubility measurement and interpretation are briefly summarized and illustrated with case studies drawing on published solubility determinations as a function of pH. Featured are examples of ionizable molecules that exhibit solubility-pH curve distortion from that predicted by the traditionally used Henderson-Hasselbalch equation and possible interpretations for these distortions are provided. The scope is not exhaustive; rather it is focused on detailed descriptions of a few cases. Topics discussed are limitations of kinetic solubility, ‘brick-dust and grease-balls,’ applications of simulated and human intestinal fluids, supersaturation and the relevance of pre-nucleation clusters and sub-micellar aggregates in the formation of solids, drug-buffer/excipient complexation, hydrotropic solubilization, acid-base ‘supersolubilization,’ cocrystal route to supersaturation, as well as data quality assessment and solubility prediction. The goal is to highlight principles of solution equilibria – graphically more than mathematically – that could invite better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids. The value of solid state characterizations is stressed but not covered explicitly in this mini-review.

The most favored approach for drug administration is the oral route. Several anticancer drugs come under this category and mostly lack solubility and oral bioavailability, which are the most common causes of inadequate clinical efficiency. Enhancing oral absorption of anticancer drugs with low aqueous solubility and drug impermeability is currently an effective area of research. Many scientists have looked into pharmaceutical cocrystals as a way to improve the physicochemical properties of several anticancer drugs. Benefits of pharmaceutical cocrystals over other solid forms may include improved solubility, bioavailability, and a reduced susceptibility for phase transition. Cocrystal strategy also stands as a green synthesis tool by using very limited organic solvents during its formulation. Having so many advantages, to date, the reported cocrystals and drug–drug cocrystals of anticancer drugs are limited. Here we review the pharmaceutical cocrystals and drug–drug cocrystals of the anticancer drugs reported in the last decade and their future in imaging, and also shed light on the opportunities and challenges for the development of anticancer drug cocrystals.

Mechanochemistry is considered an alternative attractive greener approach to prepare diverse molecular compounds and has become an important synthetic tool in different fields (e.g., physics, chemistry, and material science) since is considered an ecofriendly procedure that can be carried out under solvent free conditions or in the presence of minimal quantities of solvent (catalytic amounts). Being able to substitute, in many cases, classical solution reactions often requiring significant amounts of solvents. These sustainable methods have had an enormous impact on a great variety of chemistry fields, including catalysis, organic synthesis, metal complexes formation, preparation of multicomponent pharmaceutical solid forms, etc. In this sense, we are interested in highlighting the advantages of mechanochemical methods on the obtaining of pharmaceutical cocrystals. Hence, in this review, we describe and discuss the relevance of mechanochemical procedures in the formation of multicomponent solid forms focusing on pharmaceutical cocrystals. Additionally, at the end of this paper, we collect a chronological survey of the most representative scientific papers reporting the mechanochemical synthesis of cocrystals.

Two, well defined binary crystals with 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide (HIMO) as coformer and thiobarbituric acid (TBA) as well barbituric acid (BA) as Active Pharmaceutical Ingredients (APIs) were obtained by cocrystallization (from methanol) or mechanochemically by grinding. The progress of cocrystal formation in a ball mill was monitored by means of high-resolution, solid state NMR spectroscopy. The 13C CP/MAS, 15N CP/MAS and 1H Very Fast (VF) MAS NMR procedures were employed to inspect the tautomeric forms of the APIs, structure elucidation of the coformer and the obtained cocrystals. Single crystal X-ray studies allowed us to define the molecular structure and crystal packing for the coformer as well as the TBA/HIMO and BA/HIMO cocrystals. The intermolecular hydrogen bonding, π–π interactions and CH-π contacts responsible for higher order organization of supramolecular structures were determined. Biological studies of HIMO and the obtained cocrystals suggest that these complexes are not cytotoxic and can potentially be considered as therapeutic materials.

The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide–lactam cocrystals (SO2NH2...CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N—H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthon C21(4) chain motif, synthon 2: dimer–cyclic ring synthon R22(8)R42(8) motifs, and synthon 3: dimer–catemer synthon of R22(8)C11(4)D notation. These heterosynthons of the cocrystals observed in this study are compared with the N—H...O dimer R22(8) ring and C(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide–lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.

Crystal engineering approaches have been found to increase the possibility of discovering the new solid forms. Cocrystals are solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates/hydrates nor simple salts. Cocrystals may be binary, ternary and quaternary based on the number of components present and may be ionic or polymorphic in nature because of the presence of components (i.e. ions or polymorphs) in the crystalline structure. Cocrystals offer a unique advantage of preserving the pharmacological properties of the Active Pharmaceutical Ingredient (API), and strive to add the improved physicochemical properties of the coformers. The main challenging step during the design of pharmaceutical cocrystals is the screening of coformers which are suitable with the API. In the development process of cocrystal, one of the approaches for coformer selection is based on trial and error. Many researchers have used some theoretical and experimental approaches for the selection of effective coformers in crystal engineering, for the design of pharmaceutical cocrystals. This review article briefly explains various types of cocrystals reported in the literature and crystal design approaches (such as hydrogen bonding propensity, pKa Rule, Cambridge structure database (CSD), Fabian's method and Hansen solubility parameters, with examples) for the selection of coformers which may be more selective, time-efficient and cost-effective. [ABSTRACT FROM AUTHOR]

Two mixed crystals were obtained by crystallizing the active pharmaceutical ingredient pyridoxine [systematic name: 4,5-bis(hydroxymethyl)-2-methylpyridin-3-ol, PN] with ( E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid (ferulic acid) and 4-hydroxy-3,5-dimethoxybenzoic acid (syringic acid). PN and the coformers crystallize in the form of pharmaceutical salts in a 1:1 stoichiometric ratio, namely 3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridin-1-ium ( E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoate, C8H12NO3+·C9H9O5−, and 3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridin-1-ium 4-hydroxy-3,5-dimethoxybenzoate monohydrate, C8H12NO3+·C10H11O5−·H2O, the proton exchange between PN and the acidic partner being supported by the differences of the p Ka values of the two components and by the C-O bond lengths of the carboxylate groups. Besides complex hydrogen-bonding networks, π-π interactions between aromatic moieties have been found to be important for the packing architecture in both crystals. Hirshfeld surface analysis was used to explore the intermolecular interactions in detail and compare them with the interactions found in similar pyridoxine/carboxylic acid salts. [ABSTRACT FROM AUTHOR]

4,5,6,7-Tetrabromo-1H-benzotriazole (TBBT) is still considered a reference inhibitor of casein kinase II (CK2), a valuable target for anticancer therapy, even though the poor solubility in water of this active pharmaceutical ingredient (API) has prevented its implementation in therapy. We decided to explore the interactions preferentially formed by TBBT in crystalline solids in order to obtain information helpful for the development of new TBBT cocrystals possibly endowed with improved bioavailability. In this paper, we describe the synthesis and the structural characterization of the TBBT methanol solvate and of the TBBT salt with N,N,N',N'-tetramethylethylenediamine. It is shown that TBBT can give rise to several competing interactions. This API is clearly a good halogen bond (XB) donor, with bromine atoms adjacent to the triazole ring possibly better donors than the two others. TBBT is also a good hydrogen bond (HB) donor, with the triazole hydrogen forming an HB with the acceptor or being transferred to it. Interestingly, one of the triazole nitrogens was proven to be able to work as a hydrogen bond acceptor. [ABSTRACT FROM AUTHOR]

Poor aqueous solubility and low oral bioavailability of an active pharmaceutical ingredient are the major constraints during the development of new product. Various approaches have been used for enhancement of solubility of poorly aqueous soluble drugs, but success of these approaches depends on physical and chemical nature of molecules being developed. Cocrystallization of drug substances offers a great opportunity for the development of new drug products with superior physicochemical such as melting point, tabletability, solubility, stability, bioavailability and permeability, while preserving the pharmacological properties of the active pharmaceutical ingredient. Cocrystals are multicomponent systems in which two components, an active pharmaceutical ingredient and a coformer were present in stoichiometric ratio and bonded together with non-covalent interactions in the crystal lattice. This review article presents a systematic overview of pharmaceutical cocrystals. Differences between cocrystals with salts, solvates and hydrates are summarized along with the advantages of cocrystals with examples. The theoretical parameters underlying the selection of coformers and screening of cocrystals have been summarized and different methods of cocrystal formation and evaluation have been explained. [ABSTRACT FROM AUTHOR]

We report herein quantitative in situ monitoring by simultaneous PXRD and Raman spectroscopy of the mechanochemical reaction between benzoic acid and nicotinamide, affording a rich polymorphic system with four new cocrystal polymorphs, multiple phase transformations, and a variety of reaction pathways. After observing polymorphs by in situ monitoring, we were able to isolate and characterize three of the four polymorphs, most of which are not accessible from solution. Relative stabilities among the isolated polymorphs at ambient conditions were established by slurry experiments. Using two complementary methods for in situ monitoring enabled quantitative assessment and kinetic analysis of each studied mechanochemical reaction, even when involving unknown crystal structures, and short-lived intermediates. In situ Raman monitoring was introduced here also as a standalone laboratory technique for quantitative assessment of mechanochemical reactions and understanding of mechanochemical reactivity. Our results provide an important step toward a complete and high-throughput quantitative approach to mechanochemical reaction kinetics and mechanisms, necessary for the development of the mechanistic framework of milling reactions. [ABSTRACT FROM AUTHOR]

New theoretical screening procedure was proposed for appropriate selection of potential cocrystal formers possessing the ability of enhancing dissolution rates of drugs. The procedure relies on the training set comprising 102 positive and 17 negative cases of cocrystals found in the literature. Despite the fact that the only available data were of qualitative character, performed statistical analysis using binary classification allowed to formulate quantitative criterions. Among considered 3679 molecular descriptors the relative value of lipoaffinity index, expressed as the difference between values calculated for active compound and excipient, has been found as the most appropriate measure suited for discrimination of positive and negative cases. Assuming 5% precision, the applied classification criterion led to inclusion of 70% positive cases in the final prediction. Since lipoaffinity index is a molecular descriptor computed using only 2D information about a chemical structure, its estimation is straightforward and computationally inexpensive. The inclusion of an additional criterion quantifying the cocrystallization probability leads to the following conjunction criterions H mix < − 0.18 and ΔLA > 3.61, allowing for identification of dissolution rate enhancers. The screening procedure was applied for finding the most promising coformers of such drugs as Iloperidone, Ritonavir, Carbamazepine and Enthenzamide. [ABSTRACT FROM AUTHOR]

A recurrent problem faced by the pharmaceutical industry when formulating drug products concerns poorly soluble drugs, which, despite having desirable pharmacological activity, present limited bioavailability. Cocrystallization is growing up as a possible approach to tackle this problem. Cocrystals are crystalline materials comprising at least two components, solid at room temperature, and held together by non-covalent bonds. The increasing interest in these compounds is steadily demanding faster, simpler, and more reliable methods for the task of screening new cocrystals. This work aims at comparing the performance of three vibrational spectroscopy techniques (mid infrared, near infrared, and Raman spectroscopy) for cocrystals screening. Presented results are based on hydrochlorothiazide, a poorly soluble drug belonging to class IV of the Biopharmaceutical Classification System. The implemented cocrystal screening procedure tested six coformers (all considered safe for human administration) added according to a drug:coformer ratio of 1:1 and 1:2 and seven solvents with different polarity. The screening method chosen was based on slurry cocrystallization performed by sonication (ultrasound assisted) in a 96-well plate. Results show that all evaluated vibrational spectroscopy techniques provided important information regarding cocrystal formation, including information on the groups involved in the cocrystallization and purity, and can be used for the screening task.

Pharmaceutical cocrystals are used as a strategy to overcome poor physicochemical properties of drugs. The use of cocrystals in the pharmaceutical industry remains to be fully exploited due, in part, to the scarcity of suitable large-scale production methods and lack of robust and cost-effective processes. To overcome these challenges, spray congealing was used for the first time in the preparation of cocrystals. The work considered a feasibility study, followed by a design of experiments to assess the impact of varying atomization and cooling-related process parameters on cocrystal formation, purity, particle size, shape and bulk powder flow properties. It was demonstrated that spray congealing could be used to produce cocrystals. The thermal analysis and X-ray results of the spray-congealed products were different from the pure components or physical mixtures and were aligned with those reported for the same cocrystals systems produced by other techniques. Cocrystal particles were compact and spherical consisting of aggregates of individual cocrystals entangled or adhered with each other. From the design of experiments, the results demonstrated that varying the process parameters did not influence cocrystal formation, but had an impact on cocrystal purity. Moreover, it was demonstrated that cocrystal particle properties can be adjusted, in situ , by varying atomization and cooling efficiency, in order to produce particles more suited for incorporation in final dosage forms such as tablets. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

4,5,6,7-Tetrabromo-1H-benzotriazole (TBBT) is still considered a reference inhibitor of casein kinase II (CK2), a valuable target for anticancer therapy, even though the poor solubility in water of this active pharmaceutical ingredient (API) has prevented its implementation in therapy. We decided to explore the interactions preferentially formed by TBBT in crystalline solids in order to obtain information helpful for the development of new TBBT cocrystals possibly endowed with improved bioavailability. In this paper, we describe the synthesis and the structural characterization of the TBBT methanol solvate and of the TBBT salt with N,N,N’,N’-tetramethylethylenediamine. It is shown that TBBT can give rise to several competing interactions. This API is clearly a good halogen bond (XB) donor, with bromine atoms adjacent to the triazole ring possibly better donors than the two others. TBBT is also a good hydrogen bond (HB) donor, with the triazole hydrogen forming an HB with the acceptor or being transferred to it. Interestingly, one of the triazole nitrogens was proven to be able to work as a hydrogen bond acceptor.

Many solids crystallize as microcrystalline powders, thus precluding the application of single crystal X-Ray diffraction in structural elucidation. In such cases, a joint use of high-resolution solid-state NMR and crystal structure prediction (CSP) calculations can be successful. However, for molecules showing significant conformational freedom, the CSP-NMR protocol can meet serious obstacles, including ambiguities in NMR signal assignment and too wide conformational search space to be covered by computational methods in reasonable time. Here, we demonstrate a possible way of avoiding these obstacles and making as much use of the two methods as possible in difficult circumstances. In a simple case, our experiments led to crystal structure elucidation of a cocrystal of linezolid (LIN), a wide-range antibiotic, with 2,3-dihydroxybenzoic acid, while a significantly more challenging case of a cocrystal of LIN with 2,4-dihydroxybenzoic acid led to the identification of the most probable conformations of LIN inside the crystal. Having four rotatable bonds, some of which can assume many discreet values, LIN molecule poses a challenge in establishing its conformation in a solid phase. In our work, a set of 27 conformations were used in CSP calculations to yield model crystal structures to be examined against experimental solid-state NMR data, leading to a reliable identification of the most probable molecular arrangements. [Display omitted] • SsNMR and CSP were used to determine crystal structure of LIN:2,3-DHBA cocrystal. • SsNMR data indicated the most probable conformation of LIN in LIN:2,4-DHBA cocrystal. • Optimization of only atomic positions is not enough to yield reliable NMR data. [ABSTRACT FROM AUTHOR]