Intermolecular interaction as a direct measure of water solubility advantage of meloxicam cocrystalized with carboxylic acids

AbstractThe solubility advantage (SA) of meloxicam cocrystalized with mono- and dicarboxylic acids was expressed in terms of equilibrium constants involving active pharmaceutical ingredient and coformer in aqueous solutions. It is argued that SA can be quantified by concentration of pairs formed in water. The pH and concentration of dissolved components is included explicitly in the model. The alternative behavior of mono- and dicarboxylic acids was emphasized and addressed to different structural motifs. The structural and energetic properties of meloxicam and its complexes with carboxylic acids were characterized, including tautmerism and dissociation in aqueous media. In particular, performed in silico modeling confirmed experimental observation that meloxicam dissolved in water or modest acidic solutions is expected to be a mixture of anionic form in equilibrium with at least five neutral isomers. Tautomer-related diversity of pairs formation and the possibility of salt formation is also discussed.
 Graphical abstractTwo types of motifs found in meloxicam cocrystals reveal two sources of solubility advantage

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title: Effect of meloxicam on postoperative pain after abdominal hysterectomy.
abstract: We studied 36 patients, allocated randomly to receive meloxicam 15 mg rectally (n = 18) or placebo suppository (n = 18) before total abdominal hysterectomy in a double-blind study. Visual analogue scores for pain at rest (P < 0.005), on movement (P < 0.05) and on coughing (P < 0.05) were significantly decreased in the meloxicam group during the first 24 h after surgery. Mean 24-h PCA morphine requirements were 33.2 (SD 16.9) mg and 38.2 (20.8) mg in the meloxicam and placebo groups, respectively (ns). There was no difference in the incidence of nausea, vomiting or sedation between groups.

title: Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance
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title: Evaluation of a short duration behaviour‐based post‐operative pain scoring system in rats
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title: Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy
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title: Solubility Product and Solubility of Cyclodextrin Inclusion Complex Precipitates in an Aqueous Medium
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title: Findings of the Challenge To Predict Aqueous Solubility
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title: Major Source of Error in QSPR Prediction of Intrinsic Thermodynamic Solubility of Drugs: Solid vs Nonsolid State Contributions?
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title: Is experimental data quality the limiting factor in predicting the aqueous solubility of druglike molecules?
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title: Physicochemical characterization, in vitro dissolution behavior, and pharmacodynamic studies of rofecoxib-cyclodextrin inclusion compounds. Preparation and properties of rofecoxib hydroxypropyl β-cyclodextrin inclusion complex: A technical note
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title: Physicochemical characterization and dissolution properties of meloxicam-cyclodextrin binary systems.
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title: Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Edition.
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title: Formulation and evaluation of meloxicam orally dispersible capsules
abstract: Meloxicam is a non-steroidal anti-inflammatory drug with highly variable bioavailability due to its poor aqueous solubility and dissolution. This work aimed to improve meloxicam bioavailability by formulating it in orodispersible capsules containing a soluble complex of the drug with beta-cyclodextrin.  Complexes were prepared by different methods and characterized by differential scanning calorimetry, X-ray diffraction, infrared spectroscopy and dissolution efficiency studies. Orodispersible capsule shells were prepared from conventional hard gelatin capsule shells by freeze-drying and evaluated by image analysis microscopy and moisture content estimation. Formulae containing the freeze-dried complex and different fillers were prepared and characterized for their flowability, moisture content and moisture absorption behavior. The orodispersible capsules were evaluated in-vitro and in-vivo in comparison with meloxicam commercial tablets (Mobic TM).  Inclusion complexes between meloxicam and beta-cyclodextrin were formed and the dissolution efficiency was greatly enhanced by the freeze-dried product. The formulations containing mannitol or anhydrous lactose as fillers were superior and disintegrated within 23 s. The dissolution efficiency after 60 min exceeded 98% for the orodispersible capsules while its value was only 79% for Mobic TM. In comparison with Mobic TM, the tested orodispersible capsules showed a 1.7-fold increase in the average Cmax, a 0.5-fold decrease in the average tmax and a 1.4-fold increase in the average AUC0-4� of meloxicam.  Orodispersible capsules containing meloxicam/beta-cyclodextrin freeze-dried complex markedly improve meloxicam bioavailability.

title: The effect of meloxicam/ethanolamine salt formation on percutaneous absorption of meloxicam
abstract: This study was undertaken to prepare meloxicam-ethanolamine salts (MX-EAs) that enhance the transdermal delivery of meloxicam. The physicochemical properties of MX-EAs were investigated by solubility measurements, Differential Scanning Calorimetry (DSC), and Infrared Spectroscopy (FT-IR). The DSC thermogram and FTIR spectra indicated that meloxicam formed salts with ethanolamines. The effects of various vehicles on the percutaneous absorption of meloxicam and of its salts across hairless mouse skin were evaluated using a flow-through diffusion cell system at 37°C. Salt formation lowered the melting point of meloxicam and slightly reduced its octanol/water partition coefficient. Meloxicam-monoethanolamine salt (MX-MEA) and meloxicam-diethanolamine salt (MX-DEA) had greater solubilities and trans-dermal permeation rates across hairless mouse skin than meloxicam alone in various vehicles. Moreover, although the solubility of meloxicam-triethanolamine salt (MX-TEA) was generally lower than that of meloxicam, its permeation rate across the skin was higher. The fluxes of meloxicam and its salts were generally lower than those of piroxicam.

title: Tablet formulation containing meloxicam and β-cyclodextrin: Mechanical characterization and bioavailability evaluation
abstract: The purpose of this research was to evaluate β-cyclodextrin (β-CD) as a vehicle, either singly or in blends with lactose (spray-dried or monohydrate), for preparing a meloxicam tablet. Aqueous solubility of meloxicam in presence of β-CD was investigated. The tablets were prepared by direct compression and wet granulation techniques. The powder blends and the granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, disintegration time, and in vitro dissolution studies. The effect of β-CD on the bioavailability of meloxicam was also investigated in human volunteers using a balanced 2-way crossover study. Phase-solubility studies indicated an AL-type diagram with inclusion complex of 1∶1 molar ratio. The powder blends and granules of all formulations showed satisfactory flow properties, compressibility, and drug content. All tablet formations prepared by direct compression or wet granulation showed acceptable mechanical properties. The dissolution rate of meloxicam was significantly enhanced by inclusion of β-CD in the formulations up to 30%. The mean pharmacokinetic parameters (Cmax, Ke, and area under the curve [AUC]0−∞) were significantly increased in presence of β-CD. These results suggest that β-CD would facilitate the preparation of meloxicam tablets with acceptable mechanical properties using the direct compression technique as there is no important difference between tablets prepared by direct compression and those prepared by wet granulation. Also, β-CD is particularly useful for improving the oral bioavailablity of meloxicam.

title: Solubility enhancement of cox-2 inhibitors using various solvent systems
abstract: This study examined the solubility enhancement of 4 cox-2 inhibitors, celecoxib, rofecoxib, meloxicam, and nimesulide, using a series of pure solvents and solvent mixtures. Water, alcohols, glycols, glycerol, and polyethylene glycol 400 (PEG 400) were used as solvents and water-ethanol, glycerol-ethanol, and polyethylene glycol-ethanol were used as mixed-solvent systems. A pH-solubility profile of drugs was obtained in the pH range 7.0 to 10.9 using 0.05M glycine-sodium hydroxide buffer solutions. Lower alcohols, higher glycols, and PEG 400 were found to be good solvents for these drugs. The aqueous solubility of celecoxib, rofecoxib, and nimesulide could be enhanced significantly by using ethanol as the second solvent. Among the mixed-solvent systems, PEG 400-ethanol system had highest solubilization potential. In the case of meloxicam and nimesulide, solubility increased significantly with increase in pH value. Physico-chemical properties of the solvent such as polarity, intermolecular interactions, and the ability of the solvent to form a hydrogen bond with the drug molecules were found to be the major factors involved in the dissolution of drugs by pure solvents. The greater the difference in the polarity of the 2 solvents in a given mixed solvent, the greater was the solubilization power. However, in a given mixed-solvent system, the solubilization power could not be related to the polarity of the drugs. Significance of the solubility data in relation to the development of formulations has also been discussed in this study.

title: Micronization of meloxicam using a supercritical fluids process
abstract: A pre-filtration rapid expansion of a supercritical solution (PF-RESS) technique was developed to reduce particle size and to increase drug solubility. Carbon dioxide was used as the supercritical fluid and meloxicam was employed as the model drug. The meloxicam content was measured using high-performance liquid chromatography (HPLC). The physicochemical properties of the micronized meloxicam were assessed using scanning electron and optical microscopy, laser light scattering, and powder X-ray diffraction. No aggregation occurred and no polymorphism was observed in the micronized drug. The morphology of the micronized drug was irregular in shape, with a uniform particle size between 0.5 and 2 μm. The micronized meloxicam solubility in water (7.9 μg/mL) and the solubility rate (0.19 μg/mL/min) after a period of 30 min were faster than non-micronized meloxicam (3.6 μg/mL and 0.02 μg/mL/min, respectively). Although no significant change in dissolution rate at pH 1.2 was observed between the micronized and non-micronized meloxicam, when the pH was increased to 5.0–7.4, the micronized meloxicam showed a significant increase in dissolution rate after a period of 180 min. Our results provide an alternative methodology for improving the solubility of poorly soluble drugs, and show this methodology's great potential in oral drug delivery systems.

title: Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam.
abstract: The rate of dissolution of drugs remains one of the most challenging aspects in formulation development of poorly water-soluble drugs. The meloxicam, a low molecular analgetic for oral administration, exhibits a slow dissolution. To improve the dissolution rate, the drug was formulated in a nanosuspension by using an emulsion-diffusion method, high-pressure homogenization or sonication. Optimization of the technological parameters (organic solvents, stabilizers, homogenization procedure and recovery of particles) allowed the formation of nanosuspensions with a particle size of 200-900 nm. SEM imaging confirmed the nanosized drug particles. Use of an SMCR method on the XRPD patterns of the nanosuspensions revealed the crystalline form of the drug and the strong interaction between meloxicam and the stabilizer. The rate of dissolution of the dried meloxicam nanosuspension was enhanced (90% in 5 min), relative to that of raw meloxicam (15% in 5 min), mainly due to the formation of nanosized particles. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate, and thus possibly enhance fast onset of therapeutic drug effect.

title: Enhanced anti-inflammatory activity of carbopol loaded meloxicam nanoethosomes gel.
abstract: The aim of the current investigation is to develop nanoethosomes for transdermal meloxicam delivery. The ethosomes were prepared by varying the variables such as concentrations of phospholipids 90G, ethanol, and sonication time while entrapment efficiency, vesicle size and transdermal flux were the chosen responses. Results indicate that the nanoethosomes of meloxicam provides lesser vesicles size, better entrapment efficiency and improved flux for transdermal delivery as compared to rigid liposomes. The optimized formulation (MCEF-OPT) obtained was further evaluated for an in vivo anti-inflammatory activity in rats. Optimized nanoethosomal formulation with vesicles size of 142.3nm showed 78.25% entrapment efficiency and achieved transdermal flux of 10.42μg/cm(2)/h. Nanoethosomes proved to be significantly superior in terms of, amount of drug permeated into the skin, with an enhancement ratio of 3.77 when compared to rigid liposomes. In vivo pharmacodynamic study of carbopol(®) loaded nanoethosomal gel showed significant higher percent inhibition of rat paw edema compared with oral administration of meloxicam. Our results suggest that nanoethosomes are an efficient carrier for transdermal delivery of meloxicam.

title: Development of nanocrystal formulation of meloxicam with improved dissolution and pharmacokinetic behaviors.
abstract: The present study aimed to develop nanocrystal formulations of meloxicam (MEL) in order to enhance its biopharmaceutical properties and provide a rapid onset of action. Nanocrystal formulations were prepared by wet-milling and lyophilization with hydrophilic polymers used as aggregation inhibitors. Aggregation inhibitors were selected based on high-throughput screening of crystal growth inhibition in supersaturated MEL solution. Supersaturation of MEL was observed in PVP K-30, HPC-SSL, and POVACOAT Type F solution. Although the particle size distributions of pulverized MEL with PVP K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and POVACOAT Type F (MEL/POVA) were in the nanometer range following lyophilization, increases in micron-sized aggregates were observed after storage at 60°C for 21 days. The order of increased amount of aggregates was MEL/POVA≫MEL/HPC>MEL/PVP. These findings showed that hydrophilic polymers that inhibited crystal growth in supersaturated MEL solutions tended to prevent aggregation. The dissolution behavior of all nanocrystal formulations tested was markedly enhanced compared with that of unpulverized MEL. Oral administration of MEL/PVP showed a 2.0h shortened Tmax and a 5.0-fold increase in bioavailability compared with unpulverized MEL. These findings showed that the MEL/PVP mixture was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration.

title: Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics.
abstract: Meloxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility and high permeability. Because of its low solubility under acidic conditions (e.g., pH 1-5), it can take more than 2 h for meloxicam to reach its therapeutic concentration in humans. Although the slow onset of meloxicam does not necessarily impact the current label indications, the slow onset does prevent meloxicam from its potential application for the relief of mild-to-medium-level acute pain. Pharmaceutical cocrystallization of meloxicam, which represents a promising approach to generate diverse novel crystal forms, could be used to improve the aqueous solubility and accelerate the onset of action. In this contribution, we describe how a novel method can be used for coformer selection to enable the efficient and effective development of a pharmaceutical cocrystal with desired physicochemical and pharmacokinetic properties. Aspirin was selected as the coformer for meloxicam based upon this alternative route, which combines the supramolecular synthon approach with findings in the previous pharmacological and toxicological studies of meloxicam. The resulting cocrystal of meloxicam and aspirin exhibited superior kinetic solubility and possessed the potential to significantly decrease the time required to reach the human therapeutic concentration compared with the parent drug, meloxicam.

title: Supramolecular Architectures of Meloxicam Carboxylic Acid Cocrystals, a Crystal Engineering Case Study
abstract: Meloxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility and high permeability prescribed for indications of arthritis, primary dysmenorrhea, fever, and pain. In this contribution, we apply crystal engineering and the supramolecular synthon approach to prepare novel meloxicam cocrystal forms with various pharmaceutically acceptable or toxicologically qualified carboxylic acids. As a result, 19 pharmaceutical cocrystals including one cocrystal of a salt are synthesized by solid-state and solution methods. All resulting cocrystals are characterized by X-ray diffraction, infrared, and thermal analyses. In particular, crystal structures of six meloxicam cocrystals are determined and reported, namely, meloxicam·1-hydroxy-2-naphthoic acid cocrystal (1), meloxicam·glutaric acid cocrystal (2), meloxicam·l-malic acid cocrystal of a salt (3), meloxicam·salicylic acid cocrystal form III (4), meloxicam·fumaric acid cocrystal (5), and meloxicam·succinic acid cocrystal (6). The supramolecular asse...

title: Improving solubility and pharmacokinetics of meloxicam via multiple-component crystal formation.
abstract: Meloxicam is a nonsteroidal anti-inflammatory drug prescribed for rheumatoid arthritis, osteoarthritis, postoperative pain and fever. Meloxicam exhibits low solubility in acidic aqueous media and a slow onset of action in biological subjects. An oral dosage form of meloxicam with enhanced aqueous solubility is desired to enable a faster onset of action and its use for mild-to-medium-level acute pain relief. With this in mind, we examine the solubility and pharmacokinetics of 12 meloxicam cocrystals with carboxylic acids. Dissolution studies of meloxicam and its cocrystals were performed in pH 6.5 phosphate buffer solutions at 37 °C. In addition, pharmacokinetic profiles over four hours were acquired after oral administration of a 10 mg/kg (meloxicam equivalent) solid suspension in rats. The majority of meloxicam cocrystals were found to achieve higher meloxicam concentrations in dissolution media and enhanced oral absorption compared to that of pure meloxicam. All meloxicam cocrystals were converted to meloxicam form I when the slurry reached equilibrium. To better understand how cocrystallization impacts the absorption of meloxicam after oral administration, correlations between the in vitro and in vivo data were explored. The results suggest that the meloxicam cocrystals with a faster dissolution rate would exhibit increased oral absorption and an earlier onset of action.

title: Preparation and studies of the co-crystals of meloxicam with carboxylic acids
abstract: Mechanical treatment with addition of some liquid, crystallization from solutions, and heating of the mixture components preliminary subjected to mechanical treatment were the methods used for the preparation of the co-crystals of 4-hydroxy-2-methyl-N-(5-methylthiazol-2-yl)-2H-1,2-benzothiazin-3-carboxamide 1,1-dioxide (meloxicam) with carboxylic acids. It was shown that preliminary mechanical treatment plays significant role for the synthesis, whereas the addition of small amounts of solvents accelerates the process. The co-crystals were obtained for 17 mixtures of meloxicam—carboxylic acid. The use of the co-crystals of meloxicam in the compositions of improved pharmaceutical forms was found promising, which was attributable to the fact that the dissolution rate and the solubility of the co-crystals of meloxicam with the carboxylic acids under study are higher than those for meloxicam itself.

title: The COSMO and COSMO‐RS solvation models
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title: COSMO : a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient
abstract: Starting from the screening in conductors, an algorithm for the accurate calculation of dielectric screening effects in solvents is presented, which leads to rather simple explicit expressions for the screening energy and its analytic gradient with respect to the solute coordinates. Thus geometry optimization of a solute within a realistic dielectric continuum model becomes practicable for the first time. The algorithm is suited for molecular mechanics as well as for any molecular orbital algorithm. The implementation into MOPAC and some example applications are reported.

title: TmoleX—A graphical user interface for TURBOMOLE
abstract: We herein present the graphical user interface (GUI) TmoleX for the quantum chemical program package TURBOMOLE. TmoleX allows users to execute the complete workflow of a quantum chemical investigation from the initial building of a structure to the visualization of the results in a user friendly graphical front end. The purpose of TmoleX is to make TURBOMOLE easy to use and to provide a high degree of flexibility. Hence, it should be a valuable tool for most users from beginners to experts. The program is developed in Java and runs on Linux, Windows, and Mac platforms. It can be used to run calculations on local desktops as well as on remote computers.

title: Spectroscopic studies of microenvironment dictated structural forms of piroxicam and meloxicam
abstract: Long acting non-steroidal anti-inflammatory drugs (NSAIDs) belonging to the oxicam group have attracted special interest because of their diverse biological functions. In this study we present the influence of microenvironment on the spectral properties of two oxicam drugs viz. piroxicam and meloxicam. For the two drugs, a high energy shift of the UV absorption maxima was observed with increasing drug concentrations both in protic solvent like ethanol and aprotic solvent like dimethyl sulfoxide (DMSO). Studies involving variation of percentage volume of water as well as pH, using absorption and steady state fluorescence spectroscopy, allow us to identify the principal species present at different concentrations of the drugs. It is found that even trace quantity of water present in the solvent becomes significant at low concentration of the drug making the water/drug ratio sufficiently large to support the formation of anion. As the concentration of the drug increases, the number of water molecules available per drug molecule decreases and most of the drug molecules face a relatively apolar environment in which zwitterionic/neutral species become predominant. This results in a concentration-dependent high-energy shift of the absorption maximum. This study demonstrates how microenvironments of these drugs guide the nature of the predominant form present in solution.

title: Solubility and preferential solvation of meloxicam in ethanol + water mixtures
abstract: The solubilities of the analgesic drug meloxicam (MEL) in ethanol + water cosolvent mixtures were determined at several temperatures from 293.15 to 313.15 K. The Gibbs energy, enthalpy, and entropy of solution and of mixing were obtained from these solubility data. The solubility was maximal in 0.85 mass fraction of ethanol at several temperatures and very low in pure water at all the temperatures studied. A non-linear plot of Δ H soln 0 vs. Δ G soln 0 with negative slope from pure water up to 0.85 mass fraction of ethanol and positive beyond this composition up to neat ethanol was obtained. Accordingly, the driving mechanism for MEL solubility in almost all mixtures is the entropy, probably due to water-structure loss around the drug non-polar moieties caused by the ethanol. The preferential solvation of MEL by the components of the solvent was estimated by means of the quasi-lattice quasi-chemical and by the inverse Kirkwood–Buff integral method, showing the preferential solvation of MEL by ethanol except at very low water contents, where water preferentially solvates the drug.

title: Solubility and preferential solvation of meloxicam in methanol+water mixtures at 298.15K
abstract: The equilibrium solubility of meloxicam in methanol + water binary mixtures at 298.15 K was determined and the preferential solvation parameters were derived from their thermodynamic solution properties by means of the inverse Kirkwood–Buff integrals method. From solvent effect studies, it is found that this drug is sensitive to specific solvation effects. The preferential solvation parameter by methanol δx 1,3 , is negative in water-rich mixtures but positive in compositions from 0.30 in mole fraction of methanol to pure methanol. It is conjecturable that in the former case the hydrophobic hydration around aromatic rings and/or methyl groups plays a relevant role in the solvation. The more solvation by methanol in mixtures of similar co-solvent compositions and in methanol-rich mixtures could be explained in terms of the bigger basic behavior of the co-solvent interacting with hydrogen-donor groups of the drug.

title: Are meloxicam dimers really the structure-forming units in the ‘meloxicam–carboxylic acid’ co-crystals family? Relation between crystal structures and dissolution behaviour
abstract: We compare the packing of meloxicam in all the meloxicam-containing crystal structures known up to now, with a special emphasis on meloxicam and its co-crystals with carboxylic acids, two of which, with adipic and terephthalic acids, have not been reported before. We argue that it is not the meloxicam dimers, as was claimed in Cheney et al.,  2010, 10, 4401–4413, but a fragment containing two molecules of meloxicam linked via a carboxylic acid molecule that is the primary structure-forming element in all the known 2 : 1 meloxicam : carboxylic acid co-crystals. Meloxicam molecules form H-bonded dimers in the crystals of meloxicam, but these dimers are no longer present in any of the known meloxicam co-crystals. The molecules of meloxicam in some of its co-crystal structures can be occasionally close to each other as a consequence of a certain steric relation defined by the size of the carboxylic acid molecules. However, these molecular pairs termed “dimers” by Cheney et al. are different from the dimers in the crystals of meloxicam and can be held together by weak H-bonds only (if any), therefore they can hardly be considered as a structure-forming unit. An improved dissolution of meloxicam co-crystals as compared to poorly soluble meloxicam is supposed to be related to the presence of meloxicam dimers linked by relatively strong H-bonds in the crystals of meloxicam and to the absence of these dimers in its co-crystals.

title: Polymorphs, Salts, and Cocrystals: What’s in a Name?
abstract: The December 2011 release of a draft United States Food and Drug Administration (FDA) guidance concerning regulatory classification of pharmaceutical cocrystals of active pharmaceutical ingredients (APIs) addressed two matters of topical interest to the crystal engineering and pharmaceutical science communities: (1) a proposed definition of cocrystals; (2) a proposed classification of pharmaceutical cocrystals as dissociable “API-excipient” molecular complexes. The Indo–U.S. Bilateral Meeting sponsored by the Indo–U.S. Science and Technology Forum titled The Evolving Role of Solid State Chemistry in Pharmaceutical Science was held in Manesar near Delhi, India, from February 2–4, 2012. A session of the meeting was devoted to discussion of the FDA guidance draft. The debate generated strong consensus on the need to define cocrystals more broadly and to classify them like salts. It was also concluded that the diversity of API crystal forms makes it difficult to classify solid forms into three categories that...

title: Organic crystal engineering : frontiers in crystal engineering
abstract: List of Contributors. Preface. 1 The Role of the Cambridge Structural Database in Crystal Engineering ( Andrew D. Bond ).  1.2 Organisation and Management of Crystallographic Information. 1.3 Organisation of Crystallographic Information for Crystal Engineering. 1.4 New Tools for Database Research. 1.5 Search for Functional Group Exchanges: GRX. 1.6 Search for Solvated and Unsolvated Structures: Solvates. 1.7 Clustering and Classifying CSD Search Results: dSNAP.  The PXRD Profile as a Structural Descriptor. 1.9 Identifying Supramolecular Constructs: XPac. 1.10 Concluding Remarks: the Future Role of Crystallographic Databases.  Towards In Silico Solid Form Screening ( Graeme M. Day ).  2.2 Methods used to Predict Crystal Structures. 2.3 Current Capabilities of Crystal Structure Prediction. 2.4 Exploration of Crystal Forms.  Carbamazepine. 2.5 Summary. Acknowledgments.  Two-component Structures Containing Secondary Amides and Pyridine Derivatives. 7.7 Triamidopyridine Derivatives.  Acknowledgements. References. 8 Urea/Thiourea-Anion Host Lattices, Stabilization of Labile Species, and Designed Construction of Rosette Ribbon and Layers ( Thomas C. W. Mak, Chi-Keung Lam, Jie Han, Qi Li and Feng Xue ).  8.2 Inclusion Compounds with Urea/Thiourea-Anion Host Lattices. 8.3 Stabilization of Cyclic Oxocarbon Dianions by Hydrogen Bonding with Urea/Thiourea. 8.4 Supramolecular Assembly Based on the Rosette Motif.

title: Spring and parachute: How cocrystals enhance solubility
abstract: This article is intended to combine literature on cocrystallization – a tool for enhancing the solubility and for improving the physicochemical properties of an API (an API is the molecule which is responsible for providing the therapeutic effect) with special emphasis on the mechanism responsible for the same. The pharmaceutical industries are witnessing a developing crisis in the process of drug development due to the increasing cost of their R&D departments, the failure of some blockbuster drug candidates exhibiting poor aqueous solubility and the unavailability of newer molecules because of patent limitations. Cocrystallization is an emerging approach to improve solubility, dissolution profile, bioavailability, and other physicochemical and mechanical properties of an API. A pharmaceutical cocrystal is now a new epitome which enables the use of a wide range of active pharmaceutical ingredients without the need to form or break the covalent bonds. The prime focus of this review article is the mechanism on how cocrystals have a solubility advantage over the amorphous form. This review also provides a brief introduction to the nature of cocrystals, their role, principles of crystal engineering and also highlights the nature of supramolecular synthons which are present in cocrystals.