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  • 1.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Pharmaceutical cocrystals: formation mechanisms, solubility behaviour and solid-state properties2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The primary aim of pharmaceutical materials engineering is the successful formulation and process development of pharmaceutical products. The diversity of solid forms available offers attractive opportunities for tailoring material properties. In this context, pharmaceutical cocrystals, multicomponent crystalline materials with definite stoichiometries often stabilised by hydrogen bonding, have recently emerged as interesting alternative solid forms with potential for improving the physical and biopharmaceutical properties of a drug substance. There are, however, gaps in our understanding of the screening, scale-up and formulation operations required for effective use of cocrystals in drug product development. The objective of this thesis was to improve fundamental understanding of the formation mechanisms, solution behaviour and solid-state properties of pharmaceutical cocrystals. The solution chemistry and solubility behaviour of a diverse set of cocrystals were studied. It was found that the thermodynamic stability regions of the cocrystals and their components were defined by the phase solubility diagrams. Spray drying was introduced as a new method of preparing cocrystals; the formation mechanisms are illustrated. The cocrystals were more soluble than the respective drugs alone and the solubility-pH profiles were able to be predicted by mathematical models using a eutectic point determination approach. The cocrystal solubility was pH-dependent and could be engineered by the choice of coformers; this is valuable information for designing robust formulations. The solubility advantage of cocrystals was retained by the use of excipients that imparted kinetic and thermodynamic stability. The retention of drug-coformer association in processed cocrystals has been revealed, introducing a novel concept with potential implications for solid dosage form development. The final study demonstrated that the structure of the crystals and the particle engineering processes affected the solidstate and bulk particle properties of the cocrystals.This thesis contributes to the field of pharmaceutical science by advancing our understanding of crystallization processes and formulation development, thus enabling pharmaceutical cocrystals into drug products.

  • 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.
    Alzghoul, Ahmad
    Luleå University of Technology, Department of Engineering Sciences and Mathematics, Product and Production Development.
    Kaialy, Waseem
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Data mining of solubility parameters for computational prediction of drug–excipient miscibility2014In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 40, no 7, p. 904-909Article in journal (Refereed)
    Abstract [en]

    Computational data mining is of interest in the pharmaceutical arena for the analysis of massive amounts of data and to assist in the management and utilization of the data. In this study, a data mining approach was used to predict the miscibility of a drug and several excipients, using Hansen solubility parameters (HSPs) as the data set. The K-means clustering algorithm was applied to predict the miscibility of indomethacin with a set of more than 30 compounds based on their partial solubility parameters [dispersion forces , polar forces and hydrogen bonding ]. The miscibility of the compounds was determined experimentally, using differential scanning calorimetry (DSC), in a separate study. The results of the K-means algorithm and DSC were compared to evaluate the K-means clustering prediction performance using the HSPs three-dimensional parameters, the two-dimensional parameters such as volume-dependent solubility and hydrogen bonding , and selected single (one-dimensional) parameters. Using HSPs, the prediction of miscibility by the K-means algorithm correlated well with the DSC results, with an overall accuracy of 94%. The prediction accuracy was the same (94%) when the two-dimensional parameters or the hydrogen-bonding (one-dimensional) parameter were used. The hydrogen-bonding parameter was thus a determining factor in predicting miscibility in such set of compounds, whereas the dispersive and polar parameters had only a weak correlation. The results show that data mining approach is a valuable tool for predicting drug–excipient miscibility because it is easy to use, is time and cost-effective, and is material sparing.

  • 4.
    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.

  • 5.
    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.

  • 6.
    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

  • 7.
    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.

  • 8.
    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.

  • 9.
    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

  • 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 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.

  • 11.
    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.

  • 12.
    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.

  • 13.
    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.

  • 14.
    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.

  • 15.
    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.

  • 16.
    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.

  • 17.
    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.

  • 18.
    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.

  • 19.
    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.

  • 20.
    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.

  • 21.
    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.

  • 22.
    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.

  • 23.
    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.

  • 24.
    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.

  • 25.
    Velaga, Sitaram
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Basavoju, Srinivas
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Khan, Wasim
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    New salts of Ciprofloxacin and Norfloxacin with Acesulfame2007In: 2007 AAPS annual meeting and exposition: November 11-15, 2007 San Diego Convention Center, San Diego, CA, American Association of Pharmaceutical Scientists , 2007Conference paper (Other academic)
  • 26.
    Velaga, Sitaram
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Basavoju, Srinivas
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Khan, Wasim
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Structural and pharmaceutical properties of new salts of antibacterial drugs2007In: 5th International Symposium on Solid Oral Dosage Forms, May 7-9th in Stockholm, Sweden, 2007Conference paper (Refereed)
  • 27.
    Velaga, Sitaram
    et al.
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Basavoju, Srinivas
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Alhalaweh, Amjad
    Luleå University of Technology, Department of Health Sciences, Medical Science.
    Khan, Wasom
    Boström, Dan
    Umeå university.
    Indomethacin-saccharin cocrystal: a new solid phase with improved physical properties2007In: 2007 AAPS annual meeting and exposition: November 11-15, 2007, San Diego Convention Center, San Diego, CA, American Association of Pharmaceutical Scientists , 2007Conference paper (Other academic)
1 - 27 of 27
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