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Purpose: Rebamipide (REB) a potent anti-ulcer agent, has not been exploited to its full potential, owing to it extremely poor solubility, leading to highly diminutive bioavailability (<10%). The purpose is to carry out its solid-state modification. Method: Cocrystallisation was done with three GRAS coformers namely citric acid (CA), 3,4-dihydroxybenzoic acid (DHBA) and oxalic acid (OXA) employing the liquid-assisted grinding method. Cocrystal formation was based upon amide-carboxyl and amide-hydroxyl supramolecular synthons. Characterization of novel cocrystals i.e. RCA, RDHBA and ROXA was carried out by DSC, PXRD and additionally by FT-IR spectroscopy. Chemical structures have been determined utilizing the PXRD pattern by Material Studio®. Furthermore, cocrystals were subjected to solubility and intrinsic dissolution rate (IDR) evaluation. Also, pharmacodynamic and pharmacokinetic studies were performed and compared with pure rebamipide. Result: The appearances of a single sharp melting endotherm in DSC, along with novel characteristic peaks in PXRD infer the existence of a new crystalline form. Shifting in characteristic vibrations in FT-IR spectroscopy supports the establishment of distinct hydrogen-bonded networks. Structural determination revealed that RCA crystallizes in 'Bb2b' space groups whereas RDHBA in 'P1' and ROXA crystallize out in the 'P-1' space group. All the cocrystals exhibited superior apparent solubility and almost 7-13 folds increase in IDR. Furthermore, 1.6-2.5 folds enhancement in relative bioavailability and remarkable amplification in anti-ulcer, anti-inflammatory and the antioxidant potential of these cocrystals were observed. Conclusion: The study ascertains the advantages of cocrystallization, with RCA showing greatest potential and suggests a viable alternative approach for improved formulation of rebamipide. [ABSTRACT FROM AUTHOR]

The present work highlights a novel polymorph (form II) of ambrisentan (AMT), a selective endothelin type A (ETA) receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH). Form II was isolated by solution crystallization and characterised by differential scanning calorimetry, powder X-ray diffraction, solution calorimetry and aqueous solubility. The single crystal X-ray diffraction shows that it crystallizes in monoclinic system with space group P21/c different from the form I (commercial form). Form II was found to be enantiotropically related to form I. Apparent solubility of form II was performed in 0.1 N HCl (pH 1.2) was found to be higher (1.5 fold) than of form I. Solution mediated and stress-induced phase transformation studies revealed conversion of form II to form I. Accelerated stability studies (40 °C & 75% RH) also reveal that form II converted to form I after one month. However, this does not belittle the improved solubility of a new solid form. [ABSTRACT FROM AUTHOR]

Context: To characterize a new conformation of hydrochlorothiazide (HCT) with better solubility and establishing its relationship with previously reported form I, obtained during attempted crystallization experiments. Objective: The aim of present investigation is to unveil a new conformational polymorph (form IA) having a higher solubility compared to commercially available form I. Materials and methods: New form (IA) was obtained from slow evaporation as well as by solvent–antisolvent method and was then characterized by DSC, FTIR, PXRD and SCXRD. Equilibrium solubility profile shows that it is more soluble than form I. Results: Appearance of phase transition endotherm at 215.87 °C in DSC spectra indicated the existence of new polymorph which was further confirmed by FTIR and PXRD. Single crystal study showed significant difference in various bond angles and torsion angles of the two forms. The solubility exhibited by form IA was (938 µg/mL) compared to form I (791 µg/mL) in water. Discussion: Complete structural analysis and molecular arrangements in the unit cell along with the DSC and FTIR data confirm the existence of new conformer of HCT. Conclusion: This study reveals the existence of a new conformational polymorph of HCT molecule having higher solubility could prove to be promising in pre-formulation. [ABSTRACT FROM AUTHOR]

The present study involves the exploration of the cocrystallization technique for the amelioration of the biopharmaceutical parameters of gliclazide (GL), a poorly water soluble antidiabetic agent, using GRAS status coformers: succinic acid (GL–SA) and malic acid (GL–MA). Cocrystals were prepared by liquid-assisted grinding and characterized by thermoanalytical and vibrational spectroscopic techniques. The crystal structure was determined from PXRD data using BIOVIA Materials Studio software and further assessed for its solubility, intrinsic dissolution and in vivo profile. An almost 2-fold improvement was observed in the solubility and intrinsic dissolution. Pharmacodynamic and pharmacokinetic studies evidenced a remarkable reduction in glucose level and higher Cmax in comparison to GL, respectively. The new solid entities thus formed have the potential to be developed as a new formulation of GL and can be commercialized. [ABSTRACT FROM AUTHOR]

Highlights: [•] The effect of M-β-CD and Tween 80 (0.5%, v/v) on solubility and biological performance of valsartan has been evaluated. [•] The mode of interaction, stoichiometry and other binding parameters has been determined by molecular modelling, NMR and solution calorimetry studies. [•] The VAL:M-β-CD:Tween 80 (0.5%, v/v) complex showed enhanced biological activity in comparison to drug alone. [ABSTRACT FROM AUTHOR]

Oxcarbazepine (OXCBZ) is an antiepileptic drug with lowaqueoussolubility, and its dissolution is the rate limiting step for absorption.The present work investigates three muticomponent solid forms of OXCBZwith water-soluble coformers with an aim to enhance its solubilityand in vivo performance. The experiments based on the solution methodyielded two cocrystals, with succinic acid (1) and saccharin(2) and a solvate with acetic acid (3).Compound 1was identified by single crystal X-ray diffraction(XRD) as a solvated cocrystal involving eight molecules of OXCBZ,four molecules of succinic acid, and four molecules of chloroformin the unit cell. The structural changes upon desolvation of cocrystal 1have also been examined. Single crystals of compounds 2and 3could not be obtained in a size suitablefor single crystal X-ray analysis and thus was studied by differentialscanning calorimetry, thermogravimetric analysis, hot stage microscopy,powder XRD, Fourier-transform infrared spectroscopy, and solid-statenuclear magnetic resonance spectroscopy. Furthermore, the powder dissolutionof compounds 1(desolvated form), 2, 3, and OXCBZ was performed in an acidic aqueous medium andanalyzed by high performance liquid chromatography. Their physicalstability was also assessed. The cocrystal with saccharin showed asignificant improvement in the solubility of OXCBZ in aqueous conditionsand exhibited a lower ED50value as compared to pure OXCBZ. [ABSTRACT FROM AUTHOR]

The work is undertaken to evaluate the effect of Tween 80 on the complexing ability of β-cyclodextrins to encapsulate the poorly soluble antiretroviral agent, nevirapine. The phase solubility diagram indicates 1:1 stoichiometry and is supported by electronspray ionization mass spectrometry. The complexes were characterized by DSC, FT-IR, and XRD in the solid state. The ternary systems were autoclaved before being lyophilized for the best results. Proton NMR suggests that the methyl pyridine ring of the drug is involved in inclusion and enters from the wider side of the cavity which was confirmed by COESY NMR. Solution calorimetry, a direct method to determine the thermodynamic parameters, was used to determine the complexation constant ( K) and other thermodynamic properties. The process is associated with negative ∆ H and positive ∆ S indicating a stable inclusion complex. The value of K follows the order β-CD < HP-β-CD < M-β-CD. The molar enthalpy of solution in autoclaved solid formulation is less endothermic as compared to additive molar enthalpy of solution obtained by summation of enthalpy of solution of individual components suggesting synergistic interaction between the drug and its constituents. A threefold increase of the in vitro permeability flux was observed for binary systems which was elevated to fourfold for autoclaved ternary complexes. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate and characterize different crystal forms of arteether, a rapidly acting, highly potent antimalarial drug for the treatment of acute Plasmodium falciparum malaria. Six different crystal forms were prepared utilizing various polar and non-polar solvents. Scanning electron microscopy (SEM) revealed differences in the surface characteristics of the six forms from those of a commercial sample. Differential scanning calorimetry (DSC) revealed the absence of a desolvation endotherm indicating that the forms were neither hydrates nor solvates. Powder X-ray diffraction (PXRD) patterns of the forms showed much weaker major peaks than in the commercial sample indicating them to be less crystalline. Solubility and dissolution studies showed that the most amorphous form was the most soluble and possessed the highest antimalarial activity. [Copyright &y& Elsevier]

Cocrystal screening of hesperetin with certain countermolecules generated highly soluble noncovalent derivatives in the form of eutectics, instead of expected cocrystals. As adhesive forces established by complimentary functional groups on hesperetin and coformers were unable to overcome the stress due to size shape mismatch of component molecules, thus, eutectics were formed. Hesperetin, a polyphenolic antioxidant with potent anticancer and cardioprotective effects, has an underdeveloped role in modern therapeutics on account of its critically low aqueous solubility resulting in stunted bioavailability. The liquid-assisted cogrinding of hesperetin and coformers generated binary-phase eutectics in fixed stoichiometry with theophylline (1:1.5), adenine (2:1), gallic acid (1.5:1), and theobromine (2:1). Primarily characterized by lower melting endotherm in differential scanning calorimetry, the eutectics showed complete melting in hot-stage microscopy. Apart from characteristic V-shaped binary-phase diagram, no discernible changes in the FTIR and powder X-ray diffraction spectra further confirm eutectic formation. The morphological differences were analyzed by SEM measurements. A 2 to 4 times enhanced dissolution profile of the eutectics measured in pH 7.4 aqueous buffer was coupled with the in vitro (1,1-diphenyl-2-picryl hydroxyl free radical antioxidant assay and RBC antihemolytic assay) studies to present a complete preliminary data on the improved bioavailability of hesperetin eutectics. [ABSTRACT FROM AUTHOR]

Famotidine (FMT) an anti-ulcer drug, recently being repurposed in COVID-19 treatment, suffers from poor aqueous solubility and restricted bioavailability (<40%). To conquer the limitations endured by this potent anti-ulcer agent, two novel 1:1 cocrystals of FMT, namely Famotidine-Sorbic Acid (FSOR) and Famotidine-Syringic Acid (FSY), were synthesized using the liquid-assisted grinding method and evaluated. Distinct DSC thermograms and PXRD patterns advocate the existence of a new crystalline form. The unique organization of the hydrogen-bonded network, in the prepared cocrystals, is inferred by variation in characteristic vibrational frequencies in FT-IR spectroscopic analysis and supported by crystal structure determination. FSOR cocrystallize in orthorhombic PNCB and FSY in triclinic P 1 crystal system. Further, a significant amplification in the solubility (9 to 5-fold) and dissolution (8 to 5-fold) of FMT in cocrystalline form, with simultaneous augmentation in peak plasma concentration (2 to 1.5-fold higher) and relative bioavailability (approx. 200% to 135%). This is associated with the remarkable increment in their anti-ulcer and anti-oxidant potential. Thus, the study illustrates that cocrystallization as a worthy approach in the efficient delivery of neutral compounds suffering from inadequate solubility crisis. [Display omitted] • Famotidine a poorly aqueous soluble anti-ulcer agent has recently been repurposed for treatment in COVID-19 patients. • Solubility, dissolution and bioavailability enhancement of this supremely useful agent was achieved via cocrystallisation. • Tremendously functionalized structure of Famotidine with a high capacity to establish hydrogen bonds yielded two worthy cocrystals Famotidine-Sorbic acid (FSOR) and Famotidine-Syringic acid (FSY). • Both the cocrystals possesses superior biopharmaceutical parameters and improved efficacy over pure Famotidine. [ABSTRACT FROM AUTHOR]

• Norfloxacin a poorly aqueous soluble, synthetic fluoroquinolone molecule discovered in 1986 for the treatment of urinary tract infections. • Immensely valuable agent's enhanced bioavailability, solubility, and dissolution were all made possible through co-crystallization. • NF was shown to be in a hydrogen bond with the complimentary functional groups of the NIC, CIN, and SA in all three conditions. • The prepared co-crystals (NF-NIC, NF-CIN, NF-SA) possess improved biopharmaceutical parameters over pure API (Norfloxacin). The study aims to enhance the biopharmaceutical properties of norfloxacin, a water-insoluble antibacterial antibiotic by synthesizing its co-crystals. Co-crystallization technique resulted in the formation of three co-crystals (NF-NIC, NF-CIN, and NF-SA using three co-formers: nicotinamide, cinnamic acid, and sorbic acid, and employing liquid-assisted grinding approach. Newly prepared co-crystals were characterised using different analytical techniques and crystalline identity was revealed by the PXRD studies, which were further used to determine the crystal structure using Material studio Software. Co-crystals were sustained by hydroxyl-‑carbonyl, amide–carbonyl, and amide‑hydroxyl hydrogen bond network. Novel solid forms were assessed for their physicochemical properties, pharmacokinetics parameters and in vitro antimicrobial activity. Present study provided us with NF in co crystalline forms with significant improvement in the solubility (8 to 3-fold) and dissolution (6 to 2-fold) with simultaneous augmentation in peak plasma concentration (2 to 1.5-fold higher). [Display omitted] [ABSTRACT FROM AUTHOR]