5053086
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
32471508
Effect of meloxicam on postoperative pain after abdominal hysterectomy.
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.
37937305
Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance
The anti-inflammatory, analgesic and antipyretic properties of the new non-steroidal anti-inflammatory agent, meloxicam, were investigated in a variety of animal models and compared with the properties of piroxicam, diclofenac, indomethacin and several other NSAIDs.With respect to the total effect of a single oral dose, the anti-exudative effect of meloxicam on carrageenaninduced oedema in the rat exceeded that of all the NSAIDs included in the comparison. Additionally, meloxicam showed the greatest potency of all the compounds examined with respect to adjuvant-induced arthritis in the rat, the granuloma pouch model and the cotton pellet test in the rat. Unlike indomethacin, in the carrageenan pleurisy model in the rat, meloxicam caused both a dose-dependent reduction in exudate volume and also inhibition of leucocyte migration.Meloxicam showed a strong and lasting effect on inflammatory pain in the rat. Like other NSAIDs, but unlike dipyrone, meloxicam had no effect in the hot plate and tail clamp tests, which are used to identify weak central analgesic effects. Unlike dipyrone and like indomethacin, meloxicam had no effect in a model of visceral distention pain.In common with other NSAIDs, meloxicam had no influence on the body temperature of normothermic rats in the anti-inflammatory dose range, but did reduce yeastinduced fever in the rat in a dose-dependent manner. Like piroxicam, meloxicam had a uricosuric effect on rats treated with oxonic acid.Low-dose meloxicam inhibited both bradykinin-induced and PAF-induced bronchospasm in the guinea-pig, but had no effect on acetylcholine-induced bronchospasm.Piroxicam had greater ulcerogenic effects in the rat stomach than meloxicam.The therapeutic range of meloxicam in the rat, with regard to inhibition of adjuvant arthritis, was several times greater than that of piroxicam, indomethacin, diclofenac and naproxen.
12788793
Evaluation of a short duration behaviour‐based post‐operative pain scoring system in rats
We have recently demonstrated dose‐related analgesic‐induced reductions in the occurrence of 7 behavioural activities following midline laparotomy in rats. For these behaviours to be useful in evaluating pain in laboratory rats they must be shown to occur after different types of surgery, and frequently enough to allow rapid scoring of animals. Here, the relevant behaviours were used to test the analgesic efficacy of meloxicam with a variation of our previous laparotomy model. As part of an unrelated project, 57 male Fischer rats were divided into groups to receive either saline (0.2 ml/100 g s/c), meloxicam (0.5, 1 or 2 mg/kg s/c) or carprofen (2.5, 5, or 10 mg/kg s/c) 1 h before surgery. Behaviour data were collected for 10 min following 25 min of recovery from isoflurane anaesthesia. The cumulative frequencies of back arching, fall/stagger, writhe and poor gait were used to compute a composite behaviour score. Irrespective of whether analyses included only 5 or all 10 min of the observation period, the relevant behaviours occurred significantly more often in rats given saline or low dose meloxicam than in those given 1 or 2 mg/kg of meloxicam, or any dose of carprofen. We conclude that this technique of quantifying post‐surgery behaviour is an effective pain scoring method following abdominal surgery in rats, and that 1 mg/kg meloxicam significantly attenuates laparotomy induced pain. Since only a short observation period is required, this approach represents an important practical advance in assessing abdominal pain severity and clinical drug potency.
98764194
Structure and physicochemical properties of meloxicam, a new NSAID
Abstract The physicochemical properties of meloxicam, a new NSAID, were investigated. Dependent on pH and solvents used, X-ray crystallography showed that meloxicam crystallized in four different prototropic forms; the anion, the acidic enol, the zwitterion and the cation forms. As determined by 1H- and 13C-NMR, meloxicam in neutral or weakly basic solution exists in the anion form. An equilibrium between the enol and zwitterion forms, dependent upon solvent polarity, was indicated. Meloxicam was soluble at neutral pH but became rapidly insoluble with decreasing pH. At very low pH its solubility increased, indicating a second pKa value and the existen of a cation species. The very low solubility of meloxicam in acidic environments suggests it may cause few local gastrointestinal adverse events. The n-octanol-water partition coefficients (log P values) of meloxicam and other NSAIDs were estimated. At low pH meloxicam was more lipophilic than piroxicam or tenoxicam and similar to ketoprofen and naproxen.
21085622
A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability
A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating invivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which noin vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.
68559668
Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy
This unique text helps students and healthcare professionals master the fundamentals of pharmacokinetics and pharmacodynamics. Written by distinguished international experts, it provides readers with an introduction to the basic principles underlying the establishment and individualization of dosage regimens and their optimal use in drug therapy. Up-to-date examples featuring currently prescribed drugs illustrate how pharmacokinetics and pharmacodynamics relate to contemporary drug therapy. Study problems at the end of each chapter help students and professionals gain a firm grasp of the material covered within the text.
94559444
Handbook of aqueous solubility data
Introduction Solubility Data References Index 1: Molecular formulae Index 2: Names and Synonyms Index 3: Chemical Abstracts Service Registry Numbers
95805065
Thermodynamics of the encapsulation by cyclodextrins
Molecular encapsulation on a molecular basis can be performed by cyclodextrins. The inclusion of organic molecules into the interior changes the properties of these molecules, which may be used for a broad variety of applications. The affinity of guest molecules for the cavities of various cyclodextrins depends on the stereochemistry and on the interaction forces of the molecules involved. Calculations of the thermodynamic parameters show that the reaction entropy is highly important for the inclusion reaction. Completely different reaction mechanisms are observed for various types of cyclodextrins as some of these reactions show enthalpy–entropy compensation. Others are supported by the reaction entropy or are even entropically controlled. Protonation and deprotonation reactions contribute significantly to the inclusion reaction, as first of all the solubility of the compounds in water is strongly influenced by the acidity of the solution, and, moreover, all tautomeric forms of the compounds show different affinities to various cyclodextrins. Copyright © 2006 Society of Chemical Industry
98684505
Solubility Product and Solubility of Cyclodextrin Inclusion Complex Precipitates in an Aqueous Medium
Cyclodextrins (CyD’s) have been precipitated as inclusion complexes with guest hydrocarbons from an aqueous medium, in which the guest hydrocarbon of interest was present in various concentrations. The solubility product constant of the CyD precipitate at 25 °C was determined by measuring the CyD concentration in the supernatant aqueous solution. Five model hydrocarbons were used as guests: hexane, cyclohexane, benzene, naphthalene, and biphenyl. The solubility products and the solubility in water of α-, β-, and γ-CyD inclusion complex precipitates with 36 varieties of guests were calculated based on the solubility of the guest hydrocarbon in water and the concentration of free CyD in the supernatant aqueous medium.
36430170
Findings of the Challenge To Predict Aqueous Solubility
The Solubility Challenge is based upon intrinsic solubility data measured in one laboratory for a set of biologically relevant compounds. More than 100 entries to the Solubility Challenge have been received. In several cases multiple entries came from the same person or group. In addition, more than 5% of the prediction sheet entries were incomplete in that predictions were not reported for all 32 compounds of the prediction set. These incomplete entries are not included in the overall findings given here, but the submitted prediction sheets, like those of all other entries, have been scored and will be returned by email to the contestants along with a copy of this report. Overall, 99 completed entries were scored and are reported here.
28941409
Major Source of Error in QSPR Prediction of Intrinsic Thermodynamic Solubility of Drugs: Solid vs Nonsolid State Contributions?
The main purpose of this study is to define the major limiting factor in the accuracy of the quantitative structure-property relationship (QSPR) models of the thermodynamic intrinsic aqueous solubility of the drug-like compounds. For doing this, the thermodynamic intrinsic aqueous solubility property was suggested to be indirectly "measured" from the contributions of solid state, ΔGfus, and nonsolid state, ΔGmix, properties, which are estimated by the corresponding QSPR models. The QSPR models of ΔGfus and ΔGmix properties were built based on a set of drug-like compounds with available accurate measurements of fusion and thermodynamic solubility properties. For consistency ΔGfus and ΔGmix models were developed using similar algorithms and descriptor sets, and validated against the similar test compounds. Analysis of the relative performances of these two QSPR models clearly demonstrates that it is the solid state contribution which is the limiting factor in the accuracy and predictive power of the QSPR models of the thermodynamic intrinsic solubility. The performed analysis outlines a necessity of development of new descriptor sets for an accurate description of the long-range order (periodicity) phenomenon in the crystalline state. The proposed approach to the analysis of limitations and suggestions for improvement of QSPR-type models may be generalized to other applications in the pharmaceutical industry.
10064221
Is experimental data quality the limiting factor in predicting the aqueous solubility of druglike molecules?
We report the results of testing quantitative structure-property relationships (QSPR) that were trained upon the same druglike molecules but two different sets of solubility data: (i) data extracted from several different sources from the published literature, for which the experimental uncertainty is estimated to be 0.6-0.7 log S units (referred to mol/L); (ii) data measured by a single accurate experimental method (CheqSol), for which experimental uncertainty is typically <0.05 log S units. Contrary to what might be expected, the models derived from the CheqSol experimental data are not more accurate than those derived from the "noisy" literature data. The results suggest that, at the present time, it is the deficiency of QSPR methods (algorithms and/or descriptor sets), and not, as is commonly quoted, the uncertainty in the experimental measurements, which is the limiting factor in accurately predicting aqueous solubility for pharmaceutical molecules.
8353290
The Cambridge Structural Database: a quarter of a million crystal structures and rising.
The Cambridge Structural Database (CSD) now contains data for more than a quarter of a million small-molecule crystal structures. The information content of the CSD, together with methods for data acquisition, processing and validation, are summarized, with particular emphasis on the chemical information added by CSD editors. Nearly 80% of new structural data arrives electronically, mostly in CIF format, and the CCDC acts as the official crystal structure data depository for 51 major journals. The CCDC now maintains both a CIF archive (more than 73,000 CIFs dating from 1996), as well as the distributed binary CSD archive; the availability of data in both archives is discussed. A statistical survey of the CSD is also presented and projections concerning future accession rates indicate that the CSD will contain at least 500,000 crystal structures by the year 2010.
26175977
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
ConclusionAn inclusion complex of rofecoxib and HPβ-CD was prepared successfully by the spray-drying method in a molar ratio of 1∶1. The inclusion complex was found to have improved in vitro drug release compared with the pure drug. The solubility profile of complexes of rofecoxib prepared using HPβ-CD as the complexing agent in a molar ratio of 1∶1 by the spray-drying method in pH 1.2 and pH 7.4 indicated that the acid solubility of rofecoxib was enhanced considerably by formation of an inclusion complex with HPβ-CD. The above results also clearly demonstrated a significant decrease in the gastric ulcerogenic activity of rofecoxib through complexation with cyclodextrins. Even though the physical mixture of rofecoxib with cyclodextrins reduced ulcer formation, it was the spray-dried complex formation approach that minimized gastric ulceration. These findings are extremely important from a commercial point of view as the prepared complex removes a major drawback for rofecoxib in therapy.
30354006
Physicochemical characterization and dissolution properties of meloxicam-cyclodextrin binary systems.
The objective of the work is physicochemical characterization of meloxicam (ME)-cyclodextrin (CD) binary systems both in solution and solid states and to improve the dissolution properties of meloxicam via complexation with alpha-, beta- and gamma-cyclodextrins. Detection of inclusion complexation was done in solution state by means of phase solubility analysis, mass spectrometry and 1H nuclear magnetic resonance (NMR) studies, and in solid state using differential scanning calorimetry (DSC), powder X-ray diffractometry, and in vitro dissolution studies. Phase solubility, mass spectrometry and 1H NMR studies in solution state revealed 1:1M complexation of meloxicam with all CDs. A true inclusion of ME with gamma-CD at 1:1 and 1:2M in solid state was confirmed by DSC, powder XRD and scanning electron microscopy (SEM) studies. Dissolution properties of ME-CDs binary systems were superior when compared to pure ME.
68440294
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Edition.
The eighth edition of Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems has a significant change to its title. The text now bears the name of its original author, Howard Ansel. In the academia field of pharmaceutics, the text has always been known as just Ansel's. The text now entitled Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems is a fitting tribute to the author who pioneered this educational work over 30 years ago. Another change is that the first author is now Dr. Loyd Allen who, in conjunction with Dr. Ansel and Dr. Popovich, has rewritten several sections of the eighth edition while expanding the text with the introduction of case studies related to manufacturing pharmaceutics topics and concepts as well as clinical patient care.
138008447
Formulation and evaluation of meloxicam orally dispersible capsules
Purpose: 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. Methods: 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). Results: 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. Conclusion: Orodispersible capsules containing meloxicam/beta-cyclodextrin freeze-dried complex markedly improve meloxicam bioavailability.
37837434
The effect of meloxicam/ethanolamine salt formation on percutaneous absorption of meloxicam
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.
27849103
Tablet formulation containing meloxicam and β-cyclodextrin: Mechanical characterization and bioavailability evaluation
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.
28868200
Solubility enhancement of cox-2 inhibitors using various solvent systems
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.
93721816
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.
30706809
Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam.
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.
38482403
Enhanced anti-inflammatory activity of carbopol loaded meloxicam nanoethosomes gel.
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.
24502606
Development of nanocrystal formulation of meloxicam with improved dissolution and pharmacokinetic behaviors.
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.
5212237
Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics.
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.
94947744
Supramolecular Architectures of Meloxicam Carboxylic Acid Cocrystals, a Crystal Engineering Case Study
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...
34311399
Improving solubility and pharmacokinetics of meloxicam via multiple-component crystal formation.
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.
96968003
Preparation and studies of the co-crystals of meloxicam with carboxylic acids
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.
102942338
The COSMO and COSMO‐RS solvation models
The conductor‐like screening model COSMO, a variant of the dielectric continuum solvation models, has become very popular due to its algorithmic simplicity, numerical stability, and its great insensitivity with respect to outlying charge errors. The advanced model COSMO‐RS, i.e., COSMO for realistic solvation, is a statistical thermodynamics theory based on COSMO polarization charge densities, which overcomes many of the limitations and theoretical shortcomings of dielectric continuum models. Due to its ability to treat mixtures at variable temperatures, it has become very popular in chemical engineering and in wide areas of physical and medicinal chemistry. COSMO‐RS may currently be considered the most accurate model for the prediction of solvation energies. This article provides a short description of the basic concepts of both models, of the differences with other solvation models, and of their application areas. Finally, Direct‐COSMO‐RS, a recent direct integration of the COSMO‐RS concept into quantum chemical calculations, is briefly described. WIREs Comput Mol Sci 2018, 8:e1338. doi: 10.1002/wcms.1338
97207810
COSMO : a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient
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.
10884174
TmoleX—A graphical user interface for TURBOMOLE
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. © 2010 Wiley Periodicals, Inc. J Comput Chem 2010
83711468
Spectroscopic studies of microenvironment dictated structural forms of piroxicam and meloxicam
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.
97799983
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.
96797595
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.
95093242
Are meloxicam dimers really the structure-forming units in the ‘meloxicam–carboxylic acid’ co-crystals family? Relation between crystal structures and dissolution behaviour
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., Cryst. Growth Des. 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.
97929821
Polymorphs, Salts, and Cocrystals: What’s in a Name?
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...
92867176
Organic crystal engineering : frontiers in crystal engineering
List of Contributors. Preface. 1 The Role of the Cambridge Structural Database in Crystal Engineering ( Andrew D. Bond ). 1.1 Introduction. 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. 1.8 The PXRD Profile as a Structural Descriptor. 1.9 Identifying Supramolecular Constructs: XPac. 1.10 Concluding Remarks: the Future Role of Crystallographic Databases. References. 2 Computational Crystal Structure Prediction: Towards In Silico Solid Form Screening ( Graeme M. Day ). 2.1 Introduction. 2.2 Methods used to Predict Crystal Structures. 2.3 Current Capabilities of Crystal Structure Prediction. 2.4 Exploration of Crystal Forms. A Case Study: Carbamazepine. 2.5 Summary. Acknowledgments. References. 3 Multi-component Pharmaceutical Crystalline Phases: Engineering for Performance ( Matthew L. Peterson, Edwin A. Collier, Magali B. Hickey, Hector Guzman and Orn Almarsson ). 3.1 Introduction. 3.2 Exploring Crystal Form Diversity. 3.3 High-throughput Experimentation. 3.4 Examples of 'Form and Formulation'. 3.5 AMG517 and Celecoxib - 'Spring and Parachute' Approach. 3.6 Carbamazepine - Stabilization Against a Hydrate. 3.7 Theophylline:Phenobarbital - Two is Better Than One. 3.8 Delaviridine Mesylate - Material Misbehavior. 3.9 Summary and Outlook. References. 4 Complex Formation of Surfactants with Aromatic Compounds and their Pharmaceutical Applications ( Yuji Ohashi, Keiju Sawada and Nahoko Iimura ). 4.1 Introduction. 4.2 Structures of the Complexes Formed Between Surfactants and Aromatic Compounds. 4.3 Complex Formation of Aromatic Compounds Containing an Hetero Ring. 4.4 Complex Formation of Biphenyl with Cationic Surfactants. 4.5 Complex Formation of Odd-Number Surfactants with Biphenyl. 4.6 Common Packing Mode in the Complexes. 4.7 Complex Formation by Grinding in a Mortar. 4.8 C-H... p interactions. 4.9 Complex Formation of Anionic Surfactants with Aromatic Compounds. 4.10 Increased Solubility of Insoluble Drugs. 4.11 Enhanced Thermal Stability of Perfumes. 4.12 Complex Formation with Surfactants other than Quaternary Alkylammonium Salts. 4.13 Hydroquinone Complexes. 4.14 Application to Whitening Agents. Acknowledgments. References. 5 Hydrogen Bonding and Molecular Packing in Multi-Functional Crystal Structures ( Ashwini Nangia ). 5.1 Introduction. 5.2 Hydrogen Bonding in Ureas and Amides. 5.3 Pyridyl Ureas and Amides. 5.4 Nitrophenyl Ureas and Amides. 5.5 Molecular Conformation and Hydrogen Bonding. 5.6 Supramolecular HSAB Interactions. 5.7 gem -alkynols. 5.8 Conclusions. Acknowledgments. References. 6 Persistence of N-H...S Hydrogen Bonding in Thiocarbamide Structures ( Edward R. T. Tiekink ). 6.1 Introduction. 6.2 Supramolecular Aggregation Patterns in the Thiocarbamides. 6.3 Conclusions. References. 7 Crystal Engineering with the Molecules Containing Amide and Pyridine Functionalities ( Kumar Biradha and Lalit Rajput ). 7.1 Introduction. 7.2 Primary Amides Containing the Pyridine Moiety. 7.3 Co-crystals with Primary Amidopyridines. 7.4 Secondary Amides Containing a Pyridine Moiety. 7.5 Bis-Amidopyridine Derivatives. 7.6 Two-component Structures Containing Secondary Amides and Pyridine Derivatives. 7.7 Triamidopyridine Derivatives. 7.8 Conclusions. 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 ). 8.1 Introduction. 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. 8.5 Conclusion and Outlook. Acknowledgments. References. Index.
99519843
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.