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  • 1.
    Ahmed, Hamzah
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Shimpi, Manishkumar R.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Chemical Engineering.
    Velaga, Sitaram P.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol2017In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 1, p. 89-97Article in journal (Refereed)
    Abstract [en]

    Objectives were to study mechanical properties of various solid forms of paracetamol and relate to their crystal structures. Paracetamol Form I (PRA), its cocrystals with oxalic acid (PRA-OXA) and 4,4-bipyridine (PRA-BPY) and hydrochloride salt (PRA-HCL) were selected. Cocrystals and salt were scaled-up using rational crystallization methods. The resulting materials were subjected to differential scanning solid-state characterization. The powders were sieved and 90-360 µm sieve fraction was considered. These powders were examined by scanning electron microscopy (SEM) and densities were determined. Tablets were made at applied pressures of 35-180 MPa under controlled conditions and the tablet height, diameter and hardness were measured. Tensile strength and porosity of the tablets were estimated using well known models. Crystal structures of these systems were visualized and slips planed were identified. Cocrystal and salt of PRA were physically pure. Sieved powders had comparable morphologies and particle size. The apparent and theoretical densities of powders were similar but no clear trends were observed. The tensile strengths of these compacts were increased with increasing pressure whereas tabletability decreased in the order oxalic acid > PRA-HCL ≈ PRA-OXA > BPY > PRA-BPY. Tablet tensile strength decreases exponentially with increasing porosity with the exception of PRY-BPY and BPY. Slip plane prediction based on attachment energies may not be independently considered. However, it was possible to explain the improved mechanical properties of powders based on the crystal structure. Cocrystallization and salt formation have introduced structural features that are responsible for improved tableting properties of PRA.

  • 2. Alhalaweh, Amjad
    et al.
    Ali, Hassan
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media2014In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 14, no 2, p. 643-648Article in journal (Refereed)
    Abstract [en]

    Capturing solubility advantages of cocrystals is of great interest, and thus to understand the mechanism by which different excipients could maintain the supersaturation generated by cocrystals at the course of absorption in aqueous media is essential. To achieve this aim, the impact of different excipients on dissolution behavior of indomethacin-saccharin (IND-SAC) were monitored by measuring the concentrations of cocrystal components in the absence and presence of various concentration of excipients by HPLC, and solid phases were analyzed by differential scanning calorimetry after each experiment and the potential of Raman spectroscopy for monitoring phase transformations in situ was tested. No dissolution advantage was offered by cocrystals in the absence of any solution additive. The polymer and surfactant used in the study increased the solubility of IND but not SAC. This differential solubilization effect is believed to have stabilized the cocrystals for a relevant period for the absorption to take place. This could be attributed to either decreased gap between supersaturation and saturation of the drug or drug interaction with the additives. Understanding the effects of excipients type and concentration on the transformation profile is vital for designing enabling formulations for cocrystals. The eutectic constant may be useful in selecting excipients for stabilizing cocrystals.

  • 3.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Andersson, Staffan
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Preparation of Zolmitriptan-Chitosan microparticles by spray drying for nasal delivery2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 38, no 3, p. 206-214Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to use spray drying to prepare mucoadhesive dry powders of the antimigraine drug, zolmitriptan, in combination with the natural polymer, chitosan, for nasal administration. The effect of type, molecular weight, and proportion of chitosan on the powder and particle characteristics was also studied. Solutions containing different proportions of chitosans were prepared and spray dried. The chemical stability and content of the drug were determined by HPLC. The morphology and size range of the microparticles were also determined. Solid-state analysis was undertaken using thermal methods (DSC/MDSC and TGA), powder X-ray diffraction (PXRD), and Fourier transform infra-red spectroscopy (FT-IR). The drug release profiles were investigated and the time required to reach maximum solution concentrations (Tmax) was used for comparison. The drug was chemically stable, with a 93-105% loading in the microparticles. The microparticles were spherical with a narrow size distribution, irrespective of the formulation. Phase separation was observed for formulations containing less than 90% (w/w) chitosan, irrespective of the type. In contrast, in the formulation containing 90% (w/w) chitosan, the drug was molecularly dispersed. FT-IR studies showed that the bands corresponding to intermolecular hydrogen bonding were broader and more diffuse when zolmitriptan was amorphous. The formation of a hydrogen bond between drug and chitosans was also observed. Tmax increased as the proportion of chitosan decreased, and was proportional to the molecular weight of the chitosan in the formulation containing 90% (w/w) chitosan. Spray drying is a suitable technique for making mucoadhesive dry powders of zolmitriptan and chitosan for nasal application. The dispersion and release of the drug was affected by the properties and composition of the chitosan.

  • 4.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    George, Sumod
    Basavoju, Srinivas
    Childs, S.L.
    Renovo Research, Atlanta, GA.
    Rizvi, S.A.A.
    College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical cocrystals of nitrofurantoin: Screening, characterization and crystal structure analysis2012In: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 14, no 15, p. 5078-5088Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), l-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons.

  • 5.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    George, Sumod
    Boström, Dan
    Department of Energy Technology and Thermal Process Chemistry, Umea University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    1:1 and 2:1 urea-succinic acid cocrystals: structural diversity, solution chemistry, and thermodynamic stability2010In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 10, no 11, p. 4847-4855Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to study the crystal structures of 1:1 and 2:1 urea-succinic acid (U-SA) cocrystals and to investigate the role of solution chemistry in the formation and stability of different stoichiometric cocrystals. The structural diversity of other urea-dicarboxylic acid cocrystals is also discussed. The 1:1 U-SA cocrystal was stabilized by an acid-amide heterosynthon while acid-amide heterosynthons and amide-amide homosynthons stabilized the 2:1 cocrystals. The hydrogen bonding motifs in 1:1 and 2:1 U-SA cocrystals were consistent with other urea-dicarboxylic acid systems with similar stoichiometries. The 1:1 cocrystals were transformed to 2:1 cocrystals upon slurrying in various solvents at 25 °C. The phase solubility diagram was used to define the stability regions of different solid phases in 2-propanol at 25 °C. While no phase stability region for 1:1 cocrystal could be found, the stable regions for the 2:1 cocrystals and their pure components were defined by eutectic points. The solubility of the 2:1 cocrystals was dependent on the concentration of the ligand in the solution and explained by the solubility product and 1:1 solution complexation. The mathematical models predicting the solubility of the 2:1 cocrystals were evaluated and found to fit the experimental data

  • 6.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Kaialy, Waseem
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Buckton, Graham
    Department of Pharmaceutics, School of Pharmacy, University College London.
    Gill, Hardyal
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Nokhodchi, Ali
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Theophylline cocrystals prepared by spray drying: physicochemical properties and aerosolization performance2013In: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 14, no 1, p. 265-276Article in journal (Refereed)
    Abstract [en]

    The purpose of this work was to characterize theophylline (THF) cocrystals prepared by spray drying in terms of the physicochemical properties and inhalation performance when aerosolized from a dry powder inhaler. Cocrystals of theophylline with urea (THF-URE), saccharin (THF-SAC) and nicotinamide (THF-NIC) were prepared by spray drying. Milled THF and THF-SAC cocrystals were also used for comparison. The physical purity, particle size, particle morphology and surface energy of the materials were determined. The in vitro aerosol performance of the spray-dried cocrystals, drug-alone and a drug-carrier aerosol, was assessed. The spray-dried particles had different size distributions, morphologies and surface energies. The milled samples had higher surface energy than those prepared by spray drying. Good agreement was observed between multi-stage liquid impinger and next-generation impactor in terms of assessing spray-dried THF particles. The fine particle fractions of both formulations were similar for THF, but drug-alone formulations outperformed drug-carrier formulations for the THF cocrystals. The aerosolization performance of different THF cocrystals was within the following rank order as obtained from both drug-alone and drug-carrier formulations: THF-NIC > THF-URE > THF-SAC. It was proposed that micromeritic properties dominate over particle surface energy in terms of determining the aerosol performance of THF cocrystals. Spray drying could be a potential technique for preparing cocrystals with modified physical properties.

  • 7.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Roy, Lilly
    Department of Pharmaceutical Sciences, University of Michigan.
    Rodriguez-Hornedo, Nair
    Department of Pharmaceutical Sciences, University of Michigan.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    pH-dependent solubility of indomethacin-saccharin and carbamazepine-saccharin cocrystals in aqueous media2012In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 9, p. 2605-2612Article in journal (Refereed)
    Abstract [en]

    Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.

  • 8.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Sokolowski, Anders
    Department of Pharmaceutical Chemistry, Uppsala University.
    Rodriguez-Hornedo, Nair
    Department of Pharmaceutical Sciences, University of Michigan.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Solubility behavior and solution chemistry of indomethacin cocrystals in organic solvents2011In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 11, no 9, p. 3923-3929Article in journal (Refereed)
    Abstract [en]

    The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin-saccharin (IND-SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND-SAC cocrystals was compared with that of indomethacin-nicotinamide (IND-NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND-SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND-SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND-NIC cocrystals were more soluble than the IND-SAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior

  • 9.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Formation of cocrystals by spray drying2010In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 62, no 10 - Special issue, p. 1332-1333Article in journal (Other academic)
    Abstract [en]

    Spray drying is a widely used technique for material processing and scale-up. The cocrystals formation by spray drying is studied. In contrast to solvent evaporation method, spray drying of stiochiometric solutions of incongruently saturating cocrystals had generated pure cocrystals. The formation phenomena in spray drying could be kinetically controlled or mediated by glassy state.

  • 10.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying2010In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 10, no 8, p. 3302-3305Article in journal (Refereed)
    Abstract [en]

    Spray drying is a well established technique for material processing and scale-up. This study investigated the formation of pharmaceutical cocrystals by spray drying. The cocrystal formation mechanisms in spray-drying and solution methods, based on triangular phase diagrams, are discussed. The solvent evaporation of stoichiometric solutions of incongruently saturating cocrystals resulted in a mixture of phases, as dictated by the thermodynamic phase diagram. In contrast, spray drying of similar solutions of incongruently saturating systems generated pure cocrystals. It is thus suggested that the formation of cocrystals by spray drying could be kinetically controlled and/or mediated by the glassy state of the material.

  • 11.
    Alhalaweh, Amjad
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Vilinska, Annamaria
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Gavini, Elisabetta
    University of Sassari.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Rassu, Giovanna
    University of Sassari.
    Surface thermodynamics of mucoadhesive dry powder formulation of zolmitriptan2011In: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 12, no 4, p. 1186-1192Article in journal (Refereed)
    Abstract [en]

    Microparticle powders for nasal delivery were formulated to contain the model drug, zolmitriptan, and varying proportions of different polymers. The objective of the study was to investigate the effects of these formulative parameters on the surface chemistry of the spray-dried microparticles and their potential for adhesion to the tested substrates, porcine mucin, and nasal tissue. The polymers used were chitosans of varying ionization states and molecular weights and hydroxypropyl methyl cellulose. The surface energies of the surfaces of the microparticles were determined using contact angle measurements and the van Oss model. The theory of surface thermodynamics was applied to determine the theoretical potential for the different materials to adhere to the substrates. It was found that the drug or polymers alone, as well as the various formulations, were more likely to adhere to mucin than to nasal tissue. Further, there was a trend for higher molecular weight chitosans to adhere better to the substrates than lower molecular weight chitosans. Similarly, adhesion was improved for formulations with a higher content of polymers. These theoretical predictions may be compared with further experimental results and be of use in making informed decisions on the choice of formulations for future expensive bio-studies.

  • 12.
    Al-Hayali, Amani Ibraheem Younis
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Tavelin, Staffan
    Umeå university.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Dissolution and precipitation behavior of ternary solid dispersions of Ezetimibe in biorelevant media: AAPS annual meeting and Exposition2014 USA2014Conference paper (Other academic)
    Abstract [en]

    PurposeTo prepare ternary solid dispersions of Ezetimibe (EZ) and investigate their powder dissolution and precipitation behavior(supersaturation) in simulated gastric and intestinal fluidsMethodsTernary solid dispersions of EZ were prepared with PVPK30 and Poloxamer 188 at different ratios. Spray drying and meltquenching methods were used for the preparation of these solid dispersions. The solid dispersions were characterized bybasic to advanced solid-state tools including Modulated differential scanning calorimetry (MDSC), Powder X-ray diffractionand Fourier transform infrared spectroscopy .Biorelevant simulated media (FaSSIF pH 6.5 and FaSSGF pH1.6) were used tostudy the supersaturating solubility of the ternary solid dispersions. HPLC was used to determine the drug concentrationsResultsTernary solid dispersions were successfully prepared by spray drying and melt quench methods. All prepared soliddispersions showed broadening of the XRD peaks indicating amorphous nature. MDSC analysis revealed disappearance ofthe melting peak of Ezetimibe indicating that molecular dispersion of the drug in polymer matrix. The solid dispersions withhigher PVPK30 content showed single Tg at 158.54 °C (spray drying) and 169.32 °C (melt quench). About 10 folds increasein the apparent solubility was observed for solid dispersions prepared by both methods. However, melt quenched soliddispersions had maintained the supersaturation solubility in FaSSIF longer than spray dried solid dispersions. Dissolutionstudies in FaSSGF are ongoingConclusionAmorphous ternary solid dispersions of Ezetimibe containing PVP K30 and Poloxamer 188 could be prepared by spraydrying and melt quenching methods. These solid dispersions showed improved solubility and prolonged supersaturation inbiorelevant media

  • 13.
    Al-Hayali, Amani Ibraheem Younis
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Tavellin, Staffan
    Departments of Pharmacology and Clinical Neuroscience, Umeå university.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media2017In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 1, p. 79-88Article in journal (Refereed)
    Abstract [en]

    The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25˚C and 37˚C) were investigated in this work. Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry, modulated differential scanning calorimetry, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions. All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25˚C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried solid (SD) dispersions and supersaturation was maintained. However, at 37˚C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures. Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25˚C may not predict the supersaturation behavior at physiologically relevant temperatures.  

  • 14.
    AlHayali, Amani
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Selo, Mohammed Ali
    School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College, Dublin. Faculty of Pharmacy, University of Kufa, Al-Najaf, Iraq.
    Ehrhardt, Carsten
    School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College, Dublin.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 117, p. 147-153Article in journal (Refereed)
    Abstract [en]

    The interplay between supersaturation, precipitation and permeation characteristics of the poorly water-soluble drug ezetimibe (EZ) was investigated. Supersaturation and precipitation characteristics of EZ in the presence of Caco-2 cells were compared to those in a cell-free environment. The effect of the water-soluble polymer polyvinyl pyrrolidone (PVP-K30) on the supersaturation, precipitation and transport of EZ was also investigated and the amount of drug taken up by Caco-2 cells was quantified.

    A one-compartment setup without Caco-2 cells (i.e. in the wells of cell-culture plates) was used to mimic a non-sink in vitro dissolution chamber. The two-compartment Caco-2 cell monolayer setup (with apical and basolateral compartments) was used to investigate how the absorption of EZ affects supersaturation. EZ in varying degrees of supersaturation (DS; 10, 20, 30 and 40) was introduced into the one-compartment setup or the apical chamber of the two-compartment setup. Samples were collected at specific times to determine supersaturation, precipitation and permeation. At the end of the study, Caco-2 cells were lysed and the intracellular amount of EZ was quantified.

    In the one-compartment setup, a high DS was associated with rapid precipitation. Supersaturation was maintained for longer time periods and precipitation was lower in the presence of Caco-2 cells. There were no significant differences in the absorption rate of the drug, even at high concentrations on the apical side. Permeability coefficients for all supersaturated solutions (i.e. DS 10–40) were significantly (p < 0.05) different from those when EZ was present in crystalline form. Both concentrations of PVP-K30 (i.e. 0.05% and 0.1% w/v) improved solubility and supersaturation of EZ when added to the apical side, however, the increase in absorption at the higher concentration was not proportional. The amount of intracellular EZ increased with increasing DS in the apical side, until the saturation limit was reached in the cells (i.e. at DS 30 and higher).

    This study demonstrated that precipitation of EZ could be overestimated when supersaturation was investigated without the implementation of an absorption compartment in vitro, both in the absence and in the presence of polymer.

  • 15.
    Al-Hayali, Amani
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Selo, Mohammed Ali
    School of Pharmacy and Pharmaceutical Sciences , Trinity College Dublin .
    Ehrhardt, Carsten
    School of Pharmacy and Pharmaceutical Sciences , Trinity College Dublin .
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Investigation of supersaturation and permeation of a poorly water soluble drug Ezetimibe: Systems approaches to drug discovery, development and clinical usage2017In: Future Medicines For One World, 2017Conference paper (Refereed)
  • 16.
    AlHayali, Amani
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science. College of Pharmacy, University of Mosul, Mosul, Iraq.
    Vuddanda, Parameswara Rao
    Research Centre for Topical Drug Delivery and Toxicology, Department of Clinical and Pharmaceutical Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Silodosin oral films: Development, physico-mechanical properties and in vitro dissolution studies in simulated saliva2019In: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, article id 101122Article in journal (Refereed)
    Abstract [en]

    Sublingual film dosage forms for drugs used for fast symptomatic treatment have promise because they allow a rapid onset of action. The aim of this study was to prepare films of silodosin intended for sublingual administration for the symptomatic treatment of benign prostatic hyperplasia in men. Hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were used as film-forming polymers. The effects of the polymers and the surfactant tocopherol polyethylene glycol succinate (TPGS) on the physico-mechanical properties and dissolution behavior of the films in simulated saliva were investigated. The eight silodosin oral films developed (F1–F8) contained 8 mg silodosin per 6 cm2 film and HPMC or HPMC-AS in drug:polymer ratios of 1:5 or 1:3, while four also contained TPGS (0.5% w/w). The films were characterized using DSC, TGA, SEM, and PXRD and the mechanical properties were investigated by measuring tensile strength, elongation at break and Young's modulus. The mechanical properties of the films were dependent on the ratio of polymer used. The in vitro dissolution and drug release studies indicated that HPMC-AS films disintegrated more quickly than HPMC films. Silodosin was shown to be dispersed within the polymers. Despite silodosin being submicronized in the HPMC films, the dissolution and drug release rate (time for 80% release) from HPMC films was significantly faster than from HPMC-AS films. TPGS increased the drug release rate to a greater extent with HPMC than with HPMC-AS. The degree of saturation of formulation F4 was >1, which shows potential for improving oral absorption of silodosin.

  • 17.
    Ali, Hassan
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Mendes, N.F.C.
    Ribeiro-Claro, Paulo
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Solid-state vibrational spectroscopic investigation of cocrystals and salt of indomethacin2012In: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 14, no 20, p. 6665-6674Article in journal (Refereed)
    Abstract [en]

    Knowledge and control of the solid forms of active pharmaceutical ingredients are important aspects of drug development in the pharmaceutical industry. In this paper, the process of the molecular self-assembly of saccharin cocrystals and the 2-amino-5-methylpyridine salt of indomethacin, in terms of the hydrogen bonding patterns, has been studied in the solid-state using vibrational spectroscopy (Raman and infrared). Interaction patterns in the respective crystalline states were obtained from the single crystal data. The effects of cocrystal and salt formation on the frequencies of the vibrational modes of motion were explained by vibrational spectroscopy and supported by quantum chemical calculations at the density functional theory level, leading to unambiguous assignment of the vibrational spectra of the starting materials and their respective products. Both Raman and infrared spectroscopies were useful, reliable tools for characterizing and distinguishing the indomethacin cocrystals and salt.

  • 18.
    Ali, Hassan
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin2013In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 39, no 5, p. 625-634Article in journal (Refereed)
    Abstract [en]

    Context:Identification of optimal solid form of an active pharmaceutical ingredient and form control are very important in drug development. Thus, the structural information of these forms and in-depth insight on the modes of molecular interactions are necessary, and vibrational spectroscopic methods are well suited for this purpose.Objective:In-depth structural analysis of different solid forms of indomethacin (IND) using Raman and infrared (IR) spectroscopy is the objective. We have investigated the modes of molecular interactions in polymorphs (α and γ), amorphous and discovered cocrystals of IND with nicotinamide (NIC) and trans-cinnamic acid (CIN) coformers.Materials and methods: The solid forms of IND have been prepared; their purity has been verified by differential scanning calorimetry and powder X-ray diffractometry and then studied in the solid-state by Raman and IR spectroscopy. The modes of the interactions were closely investigated from the vibrational data.Results: The key vibrational features of IND solid forms have been specified. The IR (C=O) band at 1713 cm−1 attributed to cyclic acid dimer of γ IND has disappeared in IND–NIC/CIN whilst retained in IND–SAC cocrystal.Discussion:IND cocrystallizes in different conformations and crystal lattices with different coformers. The cyclic acid dimer of IND has been kept on its cocrystallization with saccharin and it could have been broken with NIC and CIN.Conclusions: The complementary nature of Raman and IR spectroscopy allowed unambiguous investigation of the chemical composition of pharmaceutical materials which is of particular importance in the absence of detailed structural information, as in the case of IND–NIC and IND–CIN.

  • 19.
    Alleso, Morten
    et al.
    Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, and Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Cornett, Claus
    Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, and Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Rasmussen, Morten A.
    Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Berg, Frans van den
    Department of Food Science, Faculty of Life Sciences, University of Copenhagen.
    Diego, Heidi Lopez de
    Analytical R and D, H. Lundbeck A/S.
    Rantanen, Jukka
    Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen.
    Near-infrared spectroscopy for cocrystal screening: a comparative study with Raman spectroscopy2008In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 80, no 20, p. 7755-7764Article in journal (Refereed)
    Abstract [en]

    Near-infrared (NIR) spectroscopy is a well-established technique for solid-state analysis, providing fast, noninvasive measurements. The use of NIR spectroscopy for polymorph screening and the associated advantages have recently been demonstrated. The objective of this work was to evaluate the analytical potential of NIR spectroscopy for cocrystal screening using Raman spectroscopy as a comparative method. Indomethacin was used as the parent molecule, while saccharin and L-aspartic acid were chosen as guest molecules. Molar ratios of 1:1 for each system were subjected to two types of preparative methods. In the case of saccharin, liquid-assisted cogrinding as well as cocrystallization from solution resulted in a stable 1:1 cocrystalline phase termed IND-SAC cocrystal. For L-aspartic acid, the solution-based method resulted in a polymorphic transition of indomethacin into the metastable a form retained in a physical mixture with the guest molecule, while liquid-assisted cogrinding did not induce any changes in the crystal lattice. The good chemical peak selectivity of Raman spectroscopy allowed a straightforward interpretation of sample data by analyzing peak positions and comparing to those of pure references. In addition, Raman spectroscopy provided additional information on the crystal structure of the IND-SAC cocrystal. The broad spectral line shapes of NIR spectra make visual interpretation of the spectra difficult, and consequently, multivariate modeling by principal component analysis (PCA) was applied. Successful use of NIR/PCA was possible only through the inclusion of a set of reference mixtures of parent and guest molecules representing possible solid-state outcomes from the cocrystal screening. The practical hurdle related to the need for reference mixtures seems to restrict the applicability of NIR spectroscopy in cocrystal screening.

  • 20.
    Alomari, Mustafa
    et al.
    UCL School of Pharmacy, University College London.
    Vuddanda, Parameswara Rao
    Luleå University of Technology, Department of Health Sciences, Medical Science. UCL School of Pharmacy, University College London.
    Trenfield, Sarah J.
    UCL School of Pharmacy, University College London.
    Dodoo, Cornelius C.
    UCL School of Pharmacy, University College London.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Basit, Abdul W.
    UCL School of Pharmacy, University College London.
    Gaisford, Simon
    UCL School of Pharmacy, University College London.
    Printing of T3 and T4 Oral Drug Combinations as a Novel Strategy for Hypothyroidism2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 363-369Article in journal (Refereed)
    Abstract [en]

    Hypothyroidism is a chronic and debilitating disease that is estimated to affect 3% of the general population. Clinical experience has highlighted the synergistic value of combining triiodothyronine (T3) and thyroxine (T4) for persistent or recurrent symptoms. However, thus far a platform that enables the simultaneous and independent dosing of more than one drug for oral administration has not been developed. Thermal inkjet (TIJ) printing is a potential solution to enable the dual deposition of T3 and T4 onto orodispersible films (ODFs) for therapy personalisation. In this study, a two-cartridge TIJ printer was modified such that it could print separate solutions of T3 and T4. Dose adjustments were achieved by printing solutions adjacent to each other, enabling therapeutic T3 (15–50 μg) and T4 dosages (60–180 μg) to be successfully printed. Excellent linearity was observed between the theoretical and measured dose for both T3 and T4 (R2 = 0.982 and 0.985, respectively) by changing the length of the print objective (Y-value). Rapid disintegration of the ODFs was achieved (< 45 seconds). As such, this study for the first time demonstrates the ability to produce personalised dose combinations by TIJ printing T3 and T4 onto the same substrate for oral administration.

  • 21.
    Andersen, Anders J.
    et al.
    PolyPeptide Laboratories.
    Frokjaer, Sven
    Danish University of Pharmaceutical Sciences.
    Weert, Marco van de
    Danish University of Pharmaceutical Sciences.
    Yang, Mingshi
    Danish University of Pharmaceutical Sciences.
    Fomsgaard, Jens
    PolyPeptide Laboratories.
    Hovgaard, Lars
    Danish University of Pharmaceutical Sciences.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Characterization of salmon calcitonin in spray-dried powder for inhalation: effect of formulation and process variables2006In: 2006 AAPS Annual Meeting and Exposition, American Association of Pharmaceutical Scientists , 2006Conference paper (Refereed)
    Abstract [en]

    To characterize physicochemical properties of salmon calcitonin in spray-dried powder for inhalation and understand the interplay between stability, formulation and process parametersSalmon calcitonin (sCT) was spray-dried together with mannitol and chitosan that acts as stabiliser and absorption enhancer, respectively. Two process variables, i.e. inlet temperature and atomizing air volumetric flow rate, were investigated. Solid state properties of the spray-dried powders were characterized using SEM, TGA, XRPD and DSC. The physicochemical stability of salmon calcitonin in the dry powder was investigated by FTIR, HPLC and LC-MS techniques.A high yield of up to 80 % spray-dried powder was obtained with an improved cyclone assembled with B-290 Mini Spray Drier. Nevertheless, the yield was markedly reduced when addition of chitosan exceeded a certain proportion in spray drying formulation. XRPD and DSC results indicated that crystallinity of mannitol was inhibited with an increase of chitosan in the formulation. Residual moisture levels in the spray dried powders were 1-2%. As indicated by FTIR analysis, sCT retained its structural integrity under the spray drying conditions studied, i.e. 100-180 ºC inlet temperature and 357-742 L/h atomizing air volumetric flow rate. Addition of mannitol and chitosan in the spray drying formulation did not improve stabilization of sCT, in which around 7 % degraded impurities were found at a condition of 180 ºC inlet temperature. Yet no obvious degraded impurities were found in plain sCT spray-dried powder under the conditions studied. The LC-MS analysis showed that oxidation was the main degradation pathway at high inlet temperature. Other minor impurities originated from deamidation of Asn26, N-O acyl migration on Ser29 and dimerization by cross-linkage of the disulfide bonds. Two fragments, i.e. H-(Cys1-Gly28)-OH and H-(Ser29-Pro32)-NH2, could also be found when the degraded ester bond between Gly28 and Ser29 was further hydrolysed in phosphate buffer.Salmon calcitonin can be spray-dried into dry powders with good physical integrity under certain conditions. Chemical stability of sCT in spray-dried powder could be improved by the optimization of formulation and process variables.

  • 22.
    Antzutkin, Oleg
    et al.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Wong, Alan
    Physics Department, University of Warwick, Coventry, UK CV4 7AL.
    Dupree, Ray
    Physics Department, University of Warwick, Coventry, UK CV4 7AL.
    Solid-state 17O, 13C and 15N NMR: from tackling structure of Alzheimer's Aβ fibrils to studies on anti-inflammatory drugs, Indomethacin-saccharin cocrystal2007Conference paper (Other academic)
  • 23.
    Ariane, Mostapha
    et al.
    School of Chemical Engineering, University of Birmingham.
    Kassinos, Stavros
    Department of Mechanical and Manufacturing Engineering, University of Cyprus.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alexiadis, Alessio
    School of Chemical Engineering, University of Birmingham.
    Discrete multi-physics simulations of diffusive and convective mass transfer in boundary layers containing motile cilia in lungs2018In: Computers in Biology and Medicine, ISSN 0010-4825, E-ISSN 1879-0534, Vol. 95, p. 34-42Article in journal (Refereed)
    Abstract [en]

    In this paper, the mass transfer coefficient (permeability) of boundary layers containing motile cilia is investigated by means of discrete multi-physics. The idea is to understand the main mechanisms of mass transport occurring in a ciliated-layer; one specific application being inhaled drugs in the respiratory epithelium. The effect of drug diffusivity, cilia beat frequency and cilia flexibility is studied. Our results show the existence of three mass transfer regimes. A low frequency regime, which we called shielding regime, where the presence of the cilia hinders mass transport; an intermediate frequency regime, which we have called diffusive regime, where diffusion is the controlling mechanism; and a high frequency regime, which we have called convective regime, where the degree of bending of the cilia seems to be the most important factor controlling mass transfer in the ciliated-layer. Since the flexibility of the cilia and the frequency of the beat changes with age and health conditions, the knowledge of these three regimes allows prediction of how mass transfer varies with these factors.

  • 24.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Umeå universitet.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Crystal Structures of Hydrates of Norfloxacin2006In: 2006 AAPS Annual Meeting and Exposition, American Association of Pharmaceutical Scientists , 2006Conference paper (Refereed)
    Abstract [en]

    Description: Purpose: The aim was to identify new phases of norfloxacin and to analyse their crystal structures. Methods: Norfloxacin was crystallized in methanol under various conditions using solvent-drop grinding method. The single crystal X-ray diffraction data sets were collected on a Bruker Nonius Kappa CCD, using Mo Kα radiation (λ = 0.71073 Å). Results: Norfloxacin mono-and trihydrates were identified. Mono and trihydrates crystallize in Pbca, P21/c space groups respectively. One of the water molecules in trihydrate is in disorder. In these structures, inversion related norfloxacin molecules form stacked layers with quinolone moieties and stabilized by ππ (3.449 to 4.016 Å) interactions. The norfloxacin molecules in stacked layers generate hydrophilic channels to include water molecules through O-HO, O-HO¯ and N-HO¯ interactions. A significant difference in the torsional angles of the piperazinyl ring of norfloxacin in mono-, di- (reported), and trihydrate was evident for conformational flexibility. Conclusion: We report crystal structures of mono and trihydrates of norfloxacin that are channel hydrates. Norfloxacin may exhibit conformational polymorphism

  • 25.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization2008In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 25, no 3, p. 530-41Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate. MATERIALS AND METHODS: Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin-saccharin cocrystal (hereafter IND-SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND-SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin. RESULTS: The IND-SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND-SAC cocrystal is unique vis-a-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND-SAC cocrystal system was considerably faster than that of the stable indomethacin gamma-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND-SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods. CONCLUSIONS: The IND-SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N-Hcdots, three dots, centeredO hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (gamma-form).

  • 26.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical cocrystal and salts of norfloxacin2006In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 6, no 12, p. 2699-2708Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the structural and pharmaceutical properties of norfloxacin (a poorly soluble antibacterial drug), its cocrystal, and salts. Norfloxacin in the anhydrous form (form A, 1) was crystallized. It was cocrystallized with isonicotinamide (2), and organic salts were prepared with succinic acid, malonic acid, and maleic acid (3-5, respectively). These phases were characterized by differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy, and powder X-ray diffraction (PXRD). Single-crystal X-ray diffraction data were obtained, and crystal structures were solved. The apparent solubility of these phases was determined. Robust O-H⋯O, O-H⋯O-, O-H⋯N, N-H⋯O, N+-H-O -, and N-H⋯N interactions were present in all these structures. Quinolone moieties in these structures stack with π⋯π interactions and form channels to include CHCl3 or H2O. Herein we report a new cocrystal and salts of norfloxacin with improved aqueous solubility

  • 27.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical salts of fluoroquinolone antibacterial drugs with acesulfame sweetener2012In: Molecular Crystals and Liquid Crystals, ISSN 1542-1406, E-ISSN 1563-5287, Vol. 562, no 1, p. 254-264Article in journal (Refereed)
    Abstract [en]

    Novel organic salts of norfloxacin and ciprofloxacin with artificial sweeteners such as saccharin and acesulfame were prepared. The two salts 1 and 2 were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Finally, the crystal structures were solved by single crystal X-ray diffraction data and the structures were analyzed in terms of supramolecular synthons. In norfloxacin acesulfamate 1, two norfloxacin cations and two acesulfame anions form an eight membered cyclic tetramer supramolecular synthon. The salt, ciprofloxacin acesulfamate 2, has a similar structure as salt 1. This study contributes the importance of crystal engineering and supramolecular chemistry to the pharmaceutical applications in terms of interactions and structural correlations in the design of new solid phases. Supplemental materials are available for this article. Go to the publisher's online edition of Molecular Crystals and Liquid Crystals to view the free supplemental file

  • 28.
    Basavoju, Srinivas
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Khan, Wasim
    Biovitrum AB, Stockholm.
    Boström, Dan
    Umeå universitet.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical Co-crystallization of Norfloxacin2006In: 2006 AAPS Annual Meeting and Exposition, American Association of Pharmaceutical Scientists , 2006Conference paper (Refereed)
    Abstract [en]

    Description: Aim: The objective of the study was to prepare co-crystal and salts of norfloxacin and to investigate their structural and pharmaceutical properties. Methods: Norfloxacin was crystallized in a series of solvents in an effort to investigate the polymorphism. Norfloxacin was also co-crystallized with isonicotinamide and succinic acid in different solvents. We have characterised these materials using DSC, IR, Raman and PXRD. The single crystal X-ray diffraction data was obtained and crystal structures were solved. The solubility and moisture sorption behaviour (0-90%RH) of these materials were determined. Results: Norfloxacin Anhydrate, 1 crystallizes in the triclinic P-1 space group with one neutral molecule in the asymmetric unit. The carboxylic acid group participates in the intramolecular O­­-HO (D=2.525 Å) hydrogen bonding with carbonyl group of the quinolone moiety. NorfloxacinIsonicotinamideCHCl3, 2 crystallizes in the centrosymmetric C2/c space group with one molecule of norfloxacin, one molecule of isonicotinamide and one molecule of CHCl3.in the asymmetric unit. Four molecules of norfloxacin generate a rectangular host type network with N-HO (D=2.668 Å) and N-HO (D=2.657 Å) interactions. Two isonicotinamide molecules form robust amideamide (N-HO, D=2.889 Å) homodimer synthon and fits into the rectangular grid (N-HO, D=2.929 Å). The CHCl3 molecules lie in the channels of the host frame work. Norfloxacin (Succinate)0.5 Hydrate, 3 crystallizes in the triclinic P-1 space group with one norfloxacin cation, half molecule of succinate dianion and one H2O molecule in the asymmetric unit. The two succinate anions and two norfloxacin cations form a cyclic tetramer synthon (N-HO, D=2.726 Å) and extends with H2O molecules through the hydrophilic channel generated by quinolone stacked layers (ππ, 4.041 Å) along the a-axis via O-HO (D=2.928 Å) interactions. The rank order of the solubility of these materials was 1<2

  • 29.
    Bradley, Jonathan P.
    et al.
    Department of Physics, Warwick University, Coventry.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Antzutkin, Oleg
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Brown, Steven P.
    Department of Physics, Warwick University, Coventry.
    Probing intermolecular crystal packing in gamma-indomethacin by high-resolution 1H solid-state NMR spectroscopy2011In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 11, no 8, p. 3463-3471Article in journal (Refereed)
    Abstract [en]

    An NMR crystallography approach that combines experimental solid-state magic-angle-spinning (MAS) NMR with calculation is applied to the gamma polymorph of the pharmaceutical molecule, indomethacin. First-principles calculations (GIPAW) for the full crystal structure and an isolated molecule show changes in the (1)H chemical shift for specific aliphatic and aromatic protons of over -1 ppm that are due to intermolecular CH-pi interactions. For the OH proton, (1)H double-quantum (DQ) CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra reveal intermolecular H-H proximities to the OH proton of the carboxylic acid dimer as well as to specific aromatic CH protons. The enhanced resolution in (1)H DQ-(13)C spectra, recorded at 850 MHz, enables separate (1)H DQ build-up curves (as a function of the DQ recoupling time) to be extracted for the aromatic CH protons. Supported by eight-spin density-matrix simulations, it is shown how the relative maximum intensities and rates of build-up provide quantitative insight into intramolecular and intermolecular H-H proximities that characterize the crystal packing

  • 30.
    Chattoraj, Sayantan
    et al.
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Shi, Limin
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Chen, Miles
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Alhalaweh, Amjad
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Sun, Changquan Calvin
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Origin of Deteriorated Crystal Plasticity and Compaction Properties of a 1:1 Cocrystal between Piroxicam and Saccharin2014In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 14, no 8, p. 3864-3874Article in journal (Refereed)
    Abstract [en]

    The 1:1 cocrystal between piroxicam and saccharin exhibits significantly deteriorated powder compaction properties compared to both coformers. The molecular origin of this effect is revealed by a systematic investigation of crystal mechanical properties, probed with nanoindentation, and crystal structure analysis. The order of bulk powder tabletability of the three materials is identical to that of single crystal plasticity (saccharin > piroxicam > cocrystal). The lowest plasticity of the cocrystal is confirmed by its highest crystal hardness and the highest yield strength. The low plasticity of the cocrystal is attributed to structural packing features that discourage plastic deformation. This work demonstrates that cocrystallization, even though it may be useful to improve pharmaceutically relevant properties, must be carefully evaluated to avoid unexpected problems in formulation and drug product manufacturing due to compromised mechanical properties.

  • 31.
    Cho, Wonkyung
    et al.
    College of Pharmacy, Yonsei University.
    Kim, Min-Soo
    College of Pharmacy, Pusan National University.
    Jung, Min-Sook
    College of Pharmacy, Chungnam National University.
    Park, Junsung
    College of Pharmacy, Yonsei University.
    Cha, Kwang-Ho
    College of Pharmacy, Yonsei University.
    Kim, Jeong-Soo
    College of Pharmacy, Chungnam National University.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Park, Hee Jun
    College of Pharmacy, Chungnam National University.
    Hwang, Sung-Joo
    College of Pharmacy, Chungnam National University.
    Design of salmon calcitonin particles for nasal delivery using spray-drying and novel supercritical fluid-assisted spray-drying processes2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 478, no 1, p. 288-296Article in journal (Refereed)
    Abstract [en]

    The overall aim of this study was to prepare a nasal powder formulation of salmon calcitonin (sCT) using an absorption enhancer to improve its bioavailability. In this work, powder formulations for nasal delivery of sCT were studied using various absorption enhancers and stabilizers. Powders were prepared by two different methods: conventional spray-drying (SD) and novel supercritical fluid-assisted spray-drying (SASD) to investigate the role of CO2 in the particle formation process. The prepared sCT powder formulations were characterized by several analyses; powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), and the Fourier transform infrared (FT-IR) spectroscopy method. The particle size distribution was also evaluated. In vivo absorption tests were carried out in Sprague-Dawley rat using the prepared powder formulations, and the results were compared to those of raw sCT. Quantitative analysis by high-performance liquid chromatography (HPLC) indicated that sCT was chemically stable after both the SD and SASD processes. Results of PXRD, SEM, and FT-IR did not indicate a strong interaction or defragmentation of sCT. The in vivo absorption test showed that SD- and SASD-processed sCT powders increased the bioavailability of the drug when compared to the nasal administration of raw sCT. In addition, SASD-processed sCT exhibited higher nasal absorption when compared with SD-processed sCT in all formulations due to a reduction of particle size. The results from this study illustrate that the preparation of nasal powders using the SASD process could be a promising approach to improve nasal absorption of sCT.

  • 32.
    Dalpiaz, Alessandro
    et al.
    University of Ferrara.
    Marchetti, Nicola
    University of Ferrara.
    Cavazzini, Alberto
    University of Ferrara.
    Pasti, Luisa
    University of Ferrara.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Gavini, Elisabetta
    University of Sassari.
    Beggiato, Ssrah
    University of Ferrara.
    Ferraro, Luca
    University of Ferrara, Department of Clinical and Experimental Medicine, Pharmacol Sect.
    Quantitative determination of zolmitriptan in rat blood and cerebrospinal fluid by reversed phase HPLC-ESI-MS/MS analysis: application to in vivo preclinical pharmacokinetic study2012In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 901, p. 72-78Article in journal (Refereed)
    Abstract [en]

    A fast HPLC-ESI-MS/MS method has been developed and validated for the quantification of the potent and selective antimigraine zolmitriptan in rat blood and cerebrospinal fluid (CSF). The assay has been then applied for in vivo preclinical studies. The analytical determination has been used to obtain pharmacokinetics of zolmitriptan in the two biological matrices after its intravenous or nasal administration. Liquid-liquid extraction of zolmitriptan was performed from 100μL rat blood samples in the presence of N 6-cyclopentyladenosine (internal standard) with the employment of ethyl acetate. Calibration standards were prepared by using blood matrix and following the same liquid-liquid extraction procedure. CSF samples were analyzed without any pre-treatment steps and by using an external calibration method in pure water matrix. Chromatographic separation was performed under reversed phase and a gradient elution condition on a C18 packed column (100×2.0mm, 2.5μm particles diameter). The mobile phase was a mixture between acetonitrile, water and formic acid (0.1% v/v). The applied HPLC-MS/MS method allowed low limits of detection, as calculated from calibration curves, of 6.6 and 24.4ng/mL for water matrix and rat blood extracts, respectively. Linearity of the calibration curves was established up to 5μM (1.44μg/mL), as well as good assay accuracy. The intravenous infusion of 20μg zolmitriptan to male Sprague-Dawley rats produced blood concentrations ranging from 9.4±0.7 to 1.24±0.07μg/mL within 10h, with a terminal half-life of 3.4±0.2h. The nasal administration of a water suspension of 20μg zolmitriptan produced blood concentrations ranging from 2.92±0.21 to 0.85±0.07μg/mL within 6h. One hour after zolmitriptan intravenous infusion or nasal administration, its CSF concentrations were 0.0539±0.0016 and 0.0453±0.0012μg/mL, respectively. This study determined the suitability of the herein proposed method to investigate the pharmacokinetics of zolmitriptan after its administration by means of novel formulations and, hence, to evaluate the efficacy of innovative nose-to-brain drug delivery in preclinical studies.

  • 33.
    Dudenko, D.V.
    et al.
    Cardiff University.
    Williams, P.A.
    Cardiff University.
    Hughes, C.E.
    Cardiff University.
    Antzutkin, Oleg
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Brown, S.P.
    University of Warwick.
    Harris, K.D.M.
    Cardiff University.
    Exploiting the synergy of powder x-ray diffraction and solid-state NMR spectroscopy in structure determination of organic molecular solids2013In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 117, no 23, p. 12258-12265Article in journal (Refereed)
    Abstract [en]

    We report a strategy for structure determination of organic materials in which complete solid-state nuclear magnetic resonance (NMR) spectral data is utilized within the context of structure determination from powder X-ray diffraction (XRD) data. Following determination of the crystal structure from powder XRD data, first-principles density functional theory-based techniques within the GIPAW approach are exploited to calculate the solid-state NMR data for the structure, followed by careful scrutiny of the agreement with experimental solid-state NMR data. The successful application of this approach is demonstrated by structure determination of the 1:1 cocrystal of indomethacin and nicotinamide. The 1H and 13C chemical shifts calculated for the crystal structure determined from the powder XRD data are in excellent agreement with those measured experimentally, notably including the two-dimensional correlation of 1H and 13C chemical shifts for directly bonded 13C-1H moieties. The key feature of this combined approach is that the quality of the structure determined is assessed both against experimental powder XRD data and against experimental solid-state NMR data, thus providing a very robust validation of the veracity of the structure

  • 34.
    Fritz, Hans F.
    et al.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile.
    Ortiz, Andrea C.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Morales, Javier O.
    Luleå University of Technology, Department of Health Sciences, Medical Science. Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile.
    Preparation of a novel lipid-core micelle using a low-energy emulsification method2018In: Drug Delivery and Translational Research, ISSN 2190-393X, Vol. 8, no 6, p. 1807-1814Article in journal (Refereed)
    Abstract [en]

    High-energy methods for the manufacturing of nanomedicines are widely used; however, interest in low-energy methods is increasing due to their simplicity, better control over the process, and energy-saving characteristics during upscaling. Here, we developed a novel lipid-core micelle (LCM) as a nanocarrier to encapsulate a poorly water-soluble drug, nifedipine (NFD), by hot-melt emulsification, a low-energy method. LCMs are self-assembling colloidal particles composed of a hydrophobic core and a hydrophilic shell. Hybrid materials, such as Gelucire 44/14, are thus excellent candidates for their preparation. We characterized the obtained nanocarriers for their colloidal properties, drug loading and encapsulation efficiency, liquid state, stability, and drug release. The low-energy method hot-melt emulsification was successfully adapted for the manufacturing of small and narrowly dispersed LCMs. The obtained LCMs had a small average size of ~ 11 nm and a narrow polydispersity index (PDI) of 0.228. These nanocarriers were able to increase the amount of NFD dispersible in water more than 700-fold. Due to their sustained drug release profile and the PEGylation of Gelucire 44/14, these nanocarriers represent an excellent starting point for the development of drug delivery systems designed for long circulation times and passive targeting.

  • 35.
    Gavini, Elisabetta
    et al.
    Department of Chemistry and Pharmacy, University of Sassari.
    Rassu, Giovanna
    Department of Chemistry and Pharmacy, University of Sassari.
    Ferraro, Luca
    Department of Experimental and Clinical Medicine, Pharmacology Section, University of Ferrara.
    Beggiato, Sarah
    Department of Experimental and Clinical Medicine, Pharmacology Section, University of Ferrara.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Marchetti, Nichola
    Department of Chemistry, University of Ferrara.
    Bandiera, Pasquale
    Department of Biomedical Sciences, University of Sassari.
    Giunchedi, Paolo
    Department of Chemistry and Pharmacy, University of Sassari.
    Dalpiaz, Alessandro
    Department of Pharmaceutical Sciences, University of Ferrara.
    Influence of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting2013In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 83, no 2, p. 174-183Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to investigate the effect of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting. Mucoadhesive powder formulations consisted of antimigraine drug, zolmitriptan, and chitosans (various molecular weights and types) or hydroxypropyl methylcellulose (HPMC). Their suitability for nasal administration was evaluated by in-vitro and ex-vivo mucoadhesion and permeation tests. The formulations based on chitosan glutamate (CG) or HPMC were tested in-vivo because they showed good mucoadhesive properties and altered the permeation rate of the drug. The in-vivo results from intravenous infusion and nasal aqueous suspension of the drug or nasal particulate powders were compared. The plasmatic AUC values obtained within 8 h following intravenous administration appeared about three times higher than those obtained by nasal administration, independent of the formulations. Zolmitriptan concentrations in the cerebrospinal fluid obtained from nasal and intravenous administrations were respectively 30 and 90 times lower than the concentrations of the drug in the blood. Thus, nasal administration potentiated the central zolmitriptan activity allowing a reduction of the drug peripheral levels, with respect to the intravenous administration. Among nasally administered formulations, CG microparticles showed the highest efficacy in promoting the central uptake of zolmitriptan within 1 h.

  • 36.
    Hyun, Sang-Min
    et al.
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Joon Lee, Benjamin
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Abuzar, Sharif Md
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Lee, Soohun
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Joo, Yechan
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Hong, Seung-Hyeon
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Kang, Han
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Kwon, Kyung-Ae
    Dae Hwa pharmaceutical Co., Ltd., 2145 Nambusunhwan-ro, Seocho-gu, Seoul, Republic of Korea.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Hwang, Sung-Joo
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Preparation, characterization, and evaluation of celecoxib eutectic mixtures with adipic acid/saccharin for improvement of wettability and dissolution rate2019In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 554, p. 61-71Article in journal (Refereed)
    Abstract [en]

    Celecoxib (CEL) is a selective cyclooxygenase-2 (COX-2) inhibitor therapeutically indicated for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, and inflammation. However, its poor solubility and dissolution rate significantly hinders its broader application. In this study, eutectic mixtures, as binary pharmaceutical compositions of CEL with adipic acid (ADI) and saccharin (SAC), were identified through a phase diagram and Tammann’s triangle intended to improve the wettability and dissolution rate of poorly water-soluble CEL. The contact angles at 0s in the liquid-solid interface were approximately θs (theta) 79.7° ± 0.50° and 86.65° ± 0.45° for CEL-ADI and CEL-SAC, respectively, which were much lower than the value obtained for CEL (92.05° ± 0.75° θ). Moreover, a comparison of the disk intrinsic dissolution rate and powder dissolution properties demonstrated that eutectic mixtures significantly increased the dissolution rate compared with CEL and physical mixtures. A general relationship was elucidated and indicated that the dissolution rate was increased as the contact angle decreased (correlation coefficient, r = 0.9966 ± 0.0031). Therefore, CEL-ADI and CEL-SAC eutectics may offer a novel formulation strategy to enhance the solubility and oral bioavailability of CEL.

  • 37. Högberg, Sofie
    et al.
    Lundström, Staffan
    Luleå University of Technology, Department of Engineering Sciences and Mathematics, Fluid and Experimental Mechanics.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Ljung, Anna-Lena
    Fluid mechanics of particle deposition in human lungs2005In: Contributed paper abstracts / American Association of Pharmaceutical Scientists: annual meeting and exposition, 2005Conference paper (Other academic)
    Abstract [en]

    Aim: To develop an ideal Computational Fluid Dynamic (CFD) model, which provides knowledge of fundamental characteristics of particles and their eventual deposition patterns in the respiratory system, to design an effective formulation for a specific therapeutic application (local or systemic) Methods: The whole flow field was measured in a single measurement using Particle Image Velocimetry (PIV). The concept was to add small sized particles to the flow. These particles were then illuminated by a thin laser-layer in the region of interest and the motion of the formed speckle pattern was captured by a CCD-camera. Results: In a preliminary study, the flow in the uppermost three generations of airways, with a focus on branches of rectangular cross-sections, has been investigated. This geometry was easily built from blocks of PMMA. The model captured the main flow features. A qualitative agreement between experiments and simulations was obtained as shown in Figure 1, a snap-shot taken during inhalation. The experiments further enable a more detailed study of the quality and trust of the simulations. The result of this is then applied on a more realistic model of the uppermost airways and the particle deposition simulated (Figure 2). Fig 1 Fig 2 Figure 1: PIV-measurements showing the velocity field, the upper CFD-graph is obtained for a k-? turbulent flow and the lower graph shows the field for a laminar; Figure 2: Virtual model of the upper part of the air-ways. Please notice that the grid was refined for the initial simulations Conclusions: Preliminary studies were initiated with an ultimate aim of developing a complete lung model. Our efforts so far yielded a good understanding of experimental and numerical visualisation of the flow in the uppermost airways and we are currently engaged in quantifying the results.

  • 38.
    Jung, Min-Sook
    et al.
    Chungnam National University.
    Kim, Jeong-Soo
    Chungnam National University.
    Kim, Min-Soo
    Chungnam National University.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Cho, Wonkyung
    Chungnam National University.
    Hwang, Sung-Joo
    Chungnam National University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Bioavailability of indomethacin-saccharin cocrystals2010In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 62, no 11, p. 1560-1568Article in journal (Refereed)
    Abstract [en]

    Pharmaceutical cocrystals are new solid forms with physicochemical properties that appear promising for drug product development. However, the in-vivo bioavailability of cocrystals has rarely been addressed. The cocrystal of indomethacin (IND), a Biopharmaceutical Classification System class II drug, with saccharin (SAC) has been shown to have higher solubility than IND at all pH. In this study, we aimed to evaluate the in-vitro dissolution and in-vivo bioavailability of IND-SAC cocrystals in comparison with IND in a physical mixture and the marketed product Indomee (R).MethodsScale-up of the cocrystals was undertaken using cooling batch crystallisation without seeding. The chemical and physical purity of the up-scaled material was verified using high-performance liquid chromatography, differential scanning calorimetry and powder X-ray diffraction. The IND-SAC cocrystals and IND plus SAC were mixed with lactose and the formulations were placed into gelatin capsules. In-vitro dissolution studies were then performed using the rotating basket dissolution method. The intrinsic dissolution rate of IND and IND-SAC cocrystals was also determined. Finally, a bioavailability study for the formulations was conducted in beagle dogs. The plasma samples were analysed using high-performance liquid chromatography and the pharmacokinetic data were analysed using standard methodologies.Key findingsThe bulk cocrystals (i.e. scaled-up material) were chemically and physically pure. The in-vitro dissolution rate of the cocrystals was higher than that of IND and similar to that of Indomee (R) at pH 7.4 and pH 1.2. The in-vivo bioavailability of the IND-SAC cocrystals in dogs was significantly higher (ANOVA, P < 0.05) than that of IND but not significantly different from Indomee (R) (ANOVA, P > 0.05).ConclusionsThe study indicates that the improved aqueous solubility of the cocrystals leads to improved bioavailability of IND. Thus, the cocrystals are a viable alternative solid form that can improve the dissolution rate and bioavailability of poorly soluble drugs.

  • 39.
    Kaialy, Waseem
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Nokhodchi, Ali
    University of Kent.
    Effect of carrier particle shape on dry powder inhaler performance2011In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 421, no 1, p. 12-23Article in journal (Refereed)
    Abstract [en]

    he aim of this study was to characterise the aerosolisation properties of salbutamol sulphate (SS) from dry powder inhaler (DPI) formulations containing different carrier products. The difference in the elongation ratio (ER) of the different carriers was highlighted. Different set of carriers, namely commercial mannitol (CM), commercial lactose (CL), cooling crystallised mannitol (CCM), acetone crystallised mannitol (ACM) and ethanol crystallised mannitol (ECM) were used and inspected in terms of size, shape, density, crystal form, flowability, and in vitro aerosolisation performance using Multi Stage Liquid Impinger (MSLI) and Aerolizer® inhaler device. Solid-state and morphological characterization showed that CM product was in pure β-form having particles with smaller ER (CM: ER = 1.62 ± 0.04) whereas ACM and ECM mannitol particles were in pure α form with higher ER (ACM: ER = 4.83 ± 0.18, ECM: ER = 5.89 ± 0.19). CCM product crystallised as mixtures of β-form and δ-form and showed the largest variability in terms of particle shape, size, and DPI performance. Linear relationships were established showing that carrier products with higher ER have smaller bulk density (Db), smaller tap density (Dt), higher porosity (P), and poorer flow properties. In vitro aerosolisation assessments showed that the higher the ER of the carrier particles the greater the amounts of SS delivered to lower airway regions indicating enhanced DPI performance. Yet, DPI performance enhancement by increasing carrier ER reached a “limit” as increasing carrier ER from 4.83 ± 0.18 (ACM) to 5.89 ± 0.19 (ECM) did not significantly alter fine particle fraction (FPF) of SS. Also, carrier particles with higher ER were disadvantageous in terms of higher amounts of SS remained in inhaler device (drug loss) and deposited on throat. Linear relationship was established (r2 = 0.87) showing that the higher the carrier ER the lower the drug emission (EM) upon inhalation. Moreover, poorer flowability for carrier products with higher ER is disadvantageous in terms of DPI formulation dose metering and processing on handling scale. In conclusion, despite that using carrier particles with higher ER can considerably increase the amounts of drug delivered to lower airway regions; this enhancement is restricted to certain point. Also, other limitations should be taken into account including higher drug loss and poorer flowability.

  • 40.
    Kaialy, Waseem
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Nokhodchi, Ali
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Influence of lactose carrier particle size on the aerosol performance of budesonide from a dry powder inhaler2012In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 227, p. 74-85Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to evaluate the effect of carrier particle size on properties of dry powder and its effect on dry powder inhaler (DPI) performance. Commercial α-lactose-monohydrate, a commonly used carrier in DPI formulations, was carefully sieved to obtain different lactose size fractions, namely Lac A (90–125 μm), Lac B (63–90 μm), Lac C (45–63 μm), Lac D (20–45 μm), and Lac E (< 20 μm). The lactose samples were analysed in terms of size, shape, solid state, density, and flowability. Lactose particles were blended with budesonide (< 5 μm) powder to generate five different formulations. These formulations were then evaluated in terms of budesonide-lactose adhesion properties, drug content homogeneity, and in vitro aerosolisation performance. The results demonstrated that lactose samples with smaller particle volume mean diameter have higher amorphous lactose content, higher true density (linear, r2 = 0.9932), higher surface smoothness (linear, r2 = 0.8752), smaller angularity (linear, r2 = 0.921), smaller bulk density, higher porosity (linear, r2 = 0.914), poorer flowability, and higher specific surface area. In general, the smaller the lactose particles the smaller are the budesonide-lactose adhesion properties. Budesonide formulated with smaller lactose particles exhibited smaller aerodynamic diameter and higher amounts of budesonide were delivered to lower stages of the impactor indicating improved DPI aerosolisation performance. However, the use of lactose particles with smaller volume mean diameter had a detrimental effect on budesonide content homogeneity and caused an increase in the amounts of budesonide deposited on oropharyngeal region. Therefore, particle size of the lactose within dry powder inhaler formulations should be selected carefully. Accordingly, higher drug aerosolisation efficiency of lactose particles with smaller size may have to be balanced due to considerations of other disadvantages including poorer flowability, reduced formulation stability, higher potential side effects, and higher dose variability.

  • 41.
    Llinas, Antonio
    et al.
    R&D AstraZeneca, Respiratory, Inflammation and Autoimmune iMed.
    Barbas, Rafael
    Unitat de Polimorfisme i Calorimetria and Unitat de Difracció de Raigs X, Centres Científics i Tecnològics, Universitat de Barcelona.
    Font-Bardia, Merce
    Unitat de Polimorfisme i Calorimetria and Unitat de Difracció de Raigs X, Centres Científics i Tecnològics, Universitat de Barcelona.
    Quayle, Michael J.
    R&D AstraZeneca, Global Medicines Development, Pharmaceutical Development.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Prohens, Rafel
    Unitat de Polimorfisme i Calorimetria and Unitat de Difracció de Raigs X, Centres Científics i Tecnològics, Universitat de Barcelona.
    Two New Polymorphic Cocrystals of Zafirlukast: Preparation, Crystal Structure, and Stability Relations2015In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 15, no 8, p. 4162-4169Article in journal (Refereed)
    Abstract [en]

    Two new cocrystals of zafirlukast with piperazine, existing in five different solid forms, have been discovered during a cocrystal screening. The crystal structure of one of these form has been determined by single crystal X-ray diffraction, and the stability landscape of the crystalline forms of the new cocrystal has been studied. In the present article, we extend the knowledge about the solid state of this important pharmaceutical drug for the treatment of asthma by reporting the crystal structures of two new solvates (acetonitrile and butanol) and the elusive anhydrous Form X, which have been solved by single crystal X-ray diffraction

  • 42.
    Lou, Benyong
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-formyl-1-piperazinyl)-3- quinolinecarboxylic acid2007In: Acta Crystallographica Section E: Structure Reports Online, ISSN 1600-5368, E-ISSN 1600-5368, Vol. 63, no 11, p. 4281-Article in journal (Refereed)
    Abstract [en]

    The formylation reaction of norfloxacin with N,N-dimethylformamide (DMF) gives the title compound, C17H18FN3O4. In the structure, molecules are connected via weak C-H...O, C-H...π and π-π interactions [perpendicular distance 3.423 Å and centroid-centroid distance 3.8141 Å].

  • 43.
    Lou, Benyong
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Hydrogen-bonding interactions in the 4-aminobenzoic acid salt of atenolol monohydrate2007In: Acta Crystallographica Section C: Crystal Structure Communications, ISSN 0108-2701, E-ISSN 1600-5759, Vol. 63, no 12, p. 714-716Article in journal (Refereed)
    Abstract [en]

    Atenolol {or 4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl-acetamide} crystallizes with 4-aminobenzoic acid to give the salt {3-[4-(aminocarbonylmethyl)phenoxy]-2-hydroxypropy1}- isopropylammonium 4-aminobenzoate monohydrate, C14H23- N2O3*C7H6NO2-*H2O. In the crystal structure, the water molecule, the carboxylate group of 4-aminobenzoate, and the hydroxy and ether O atoms of atenolol form a supramolecular R33(11) heterosynthon. Three other types of supramolecular synthons link the asymmetric unit into a two-dimensional structure.

  • 44.
    Lou, Benyong
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Monohydrous dihydrogen phosphate salts of norfloxacin and ciprofloxacin2007In: Acta Crystallographica Section C: Crystal Structure Communications, ISSN 0108-2701, E-ISSN 1600-5759, Vol. 63, no 12, p. 731-733Article in journal (Refereed)
    Abstract [en]

    Norfloxacin and ciprofloxacin crystallize with phosphoric acid in aqueous solution to give the salts 4-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-quinolyl)piperazinium dihydrogenphosphate monohydrate, C16H19FN3O3(+) x H2PO4(-) x H2O, and 4-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-7-quinolyl)piperazinium dihydrogenphosphate monohydrate, C17H19FN3O3(+) x H2PO4(-) x H2O, respectively. In the crystal structures, the phosphate anions and the piperazine rings of norfloxacin or ciprofloxacin form a 12-membered supramolecular synthon, viz. R4(4)(12). The synthons R4(4)(12) and R2(2)(8) formed between adjacent phosphate anions result in the three-dimensional structures.

  • 45.
    Lou, Benyong
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Boström, Dan
    Umeå university.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Polymorph control of Felodipine form II in an attempted cocrystallization2009In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 9, no 3, p. 1254-1257Article in journal (Refereed)
    Abstract [en]

    The metastable form II of racemic felodipine was obtained in an attempted cocrystallization with isonicotinamide. Its low temperature crystal structure was characterized by a 1D hydrogen-bonded chain consisting of four independent felodipine molecules.

  • 46.
    Malamatari, Maria
    et al.
    Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent .
    Ross, Steven A.
    Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent .
    Douroumis, Dennis
    Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent .
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Experimental cocrystal screening and solution based scale-up cocrystallization methods2017In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 117, p. 162-177Article in journal (Refereed)
    Abstract [en]

    Cocrystals are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. If one of the components is an active pharmaceutical ingredient (API), the term pharmaceutical cocrystal is often used. There is a growing interest among drug development scientists in exploring cocrystals, as means to address physicochemical, biopharmaceutical and mechanical properties and expand solid form diversity of the API. Conventionally, coformers are selected based on crystal engineering principles, and the equimolar mixtures of API and coformers are subjected to solution-based crystallization that are commonly employed in polymorph and salt screening. However, the availability of new knowledge on cocrystal phase behaviour in solid state and solutions has spurred the development and implementation of more rational experimental cocrystal screening as well as scale-up methods. This review aims to provide overview of commonly employed solid form screening techniques in drug development with an emphasis on cocrystal screening methodologies. The latest developments in understanding and the use of cocrystal phase diagrams in both screening and solution based scale-up methods are also presented. Final section is devoted to reviewing the state of the art research covering solution based scale-up cocrystallization process for different cocrystals besides more recent continuous crystallization methods.

  • 47.
    Maruyoshi, K.
    et al.
    University of Warwick.
    Iuga, D.
    University of Warwick.
    Antzutkin, Oleg
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Sustainable Process Engineering.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Brown, S.P.
    University of Warwick.
    Identifying the intermolecular hydrogen-bonding supramolecular synthons in an indomethacin-nicotinamide cocrystal by solid-state NMR2012In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, no 88, p. 10844-10846Article in journal (Refereed)
    Abstract [en]

    Two-dimensional 1H double-quantum and 14N- 1H & 1H- 13C heteronuclear magic-angle spinning (MAS) NMR spectra recorded at natural isotopic abundance identify specific intermolecular COOH⋯N arom and CH arom⋯OC hydrogen-bonding interactions in the solid-state structure of an indomethacin-nicotinamide cocrystal, thus additionally proving cocrystal formation.

  • 48.
    Mohammad, Mohammad Amin
    et al.
    Damascus University, Department of Pharmaceutics and Pharmaceutical Technology, Facuöty of Pharmacology.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Bashimam, Mais
    Damascus University, Department of Pharmaceutics and Pharmaceutical Technology, Facuöty of Pharmacology.
    Al-Mardini, Mhd Amer
    Damascus University, Department of Pharmaceutics and Pharmaceutical Technology, Facuöty of Pharmacology.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Utility of Hansen solubility parameters in the cocrystal screening2010In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 62, no 10 - Spec issue, p. 1360-1362Article in journal (Other academic)
    Abstract [en]

    The objective of this study was to test if the miscibility between drug and coformer, as predicted by solubility parameters, can be used as a tool in the cocrystal research. Hansen Solubility Parameters (HSPs) of a model drug, indomethacin and thirty coformers were calculated according to the group contribution method. The distances in HSPs between indomethacin and each cocrystal former were then calculated using three validated miscibility tools. Twenty coformers were predicted and confirmed to be miscible with the drug. Interestingly, all cocrystals forming systems were miscible. Two new cocrystal systems were discovered through this approach. Therefore, the utility of the solubility parameters approach can enhance the effi ciency of cocrystal screening.

  • 49.
    Mohammad, Mohammad Amin
    et al.
    Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Hansen solubility parameter as a tool to predict cocrystal formation2011In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 407, no 1-2, p. 63-71Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to investigate whether the miscibility of a drug and coformer, as predicted by Hansen Solubility Parameters (HSPs), can indicate cocrystal formation and guide cocrystal screening. It was also our aim to evaluate various HSPs-based approaches in miscibility prediction. HSPs for indomethacin (the model drug) and over thirty coformers were calculated according to the group contribution method. Differences in the HSPs between indomethacin and each coformer were then calculated using three established approaches, and the miscibility was predicted. Subsequently, differential scanning calorimetry was used to investigate the experimental miscibility and cocrystal formation. The formation of cocrystals was also verified using liquid-assisted grinding. All except one of the drug-coformers that were predicted to be miscible were confirmed experimentally as miscible. All tested theoretical approaches were in agreement in predicting miscibility. All systems that formed cocrystals were miscible. Remarkably, two new cocrystals of indomethacin were discovered in this study. Though it may be necessary to test this approach in a wide range of different coformer and drug compound types for accurate generalizations, the trends with tested systems were clear and suggest that the drug and coformer should miscible for cocrystal formation. Thus, predicting the miscibility of cocrystal components using solubility parameters can guide the selection of potential coformers prior to exhaustive cocrystal screening work.

  • 50.
    Montenegro-Nicolin, Miguel
    et al.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago.
    Reyes, Patricio E.
    Instituto de Salud Pública de Chile, Santiago.
    Jara, Miguel O.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago.
    Vuddanda, Parameswara Rao
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Neira-Carrillo, Andrónico
    Advanced Center for Chronic Diseases (ACCDiS), Santiago.
    Butto, Nicole
    Advanced Center for Chronic Diseases (ACCDiS, )Santiago.
    Velaga, Sitaram
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Morales, Javier O.
    Luleå University of Technology, Department of Health Sciences, Medical Science. Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago.
    The Effect of Inkjet Printing over Polymeric Films as Potential Buccal Biologics Delivery Systems2018In: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 19, no 8, p. 3376-3387Article in journal (Refereed)
    Abstract [en]

    The buccal mucosa appears as a promissory route for biologic drug administration, and pharmaceutical films are flexible dosage forms that can be used in the buccal mucosa as drug delivery systems for either a local or systemic effect. Recently, thin films have been used as printing substrates to manufacture these dosage forms by inkjet printing. As such, it is necessary to investigate the effects of printing biologics on films as substrates in terms of their physical and mucoadhesive properties. Here, we explored solvent casting as a conventional method with two biocompatible polymers, hydroxypropyl methylcellulose, and chitosan, and we used electrospinning process as an electrospun film fabrication of polycaprolactone fibers due to its potential to elicit mucoadhesion. Lysozyme was used as biologic drug model and was formulated as a solution for printing by thermal inkjet printing. Films were characterized before and after printing by mechanical and mucoadhesive properties, surface, and ultrastructure morphology through scanning electron microscopy and solid state properties by thermal analysis. Although minor differences were detected in micrographs and thermograms in all polymeric films tested, neither mechanical nor mucoadhesive properties were affected by these differences. Thus, biologic drug printing on films was successful without affecting their mechanical or mucoadhesive properties. These results open way to explore biologics loading on buccal films by inkjet printing, and future efforts will include further in vitro and in vivo evaluations.

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