| 11. |
- Alhalaweh, Amjad, et al.
(författare)
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Preparation of Zolmitriptan-Chitosan microparticles by spray drying for nasal delivery
- 2009
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 38:3, s. 206-214
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 12. |
- Alhalaweh, Amjad, et al.
(författare)
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Solubility behavior and solution chemistry of indomethacin cocrystals in organic solvents
- 2011
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 11:9, s. 3923-3929
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Tidskriftsartikel (refereegranskat)abstract
- 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
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| 13. |
- Alhalaweh, Amjad, et al.
(författare)
-
Surface thermodynamics of mucoadhesive dry powder formulation of zolmitriptan
- 2011
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Ingår i: AAPS PharmSciTech. - : Springer Science and Business Media LLC. - 1530-9932. ; 12:4, s. 1186-1192
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 14. |
- Alhalaweh, Amjad, et al.
(författare)
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Theophylline cocrystals prepared by spray drying : physicochemical properties and aerosolization performance
- 2013
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Ingår i: AAPS PharmSciTech. - : Springer Science and Business Media LLC. - 1530-9932. ; 14:1, s. 265-276
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 15. |
- AlHayali, Amani
(författare)
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In vitro-solubility and supersaturation behavior of supersaturating drug delivery systems
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The development of new pharmaceutical products has been challenged by the growing number of poorly water-soluble drugs, which often lead to suboptimal bioavailability. Various approaches, such as the use of amor-phous solid dispersions and cocrystals, have been used to improve the solu-bility, and subsequent bioavailability, of these drug molecules. Supersaturat-ing drug delivery systems (SDDSs) have potential for achieving adequate oral drug bioavailability by increasing the drug solubility and creating a su-persaturated state in the gastrointestinal tract. However, there is a need for better understanding of the supersaturation behavior in SDDSs and of the factors affecting supersaturation. The main objective of this thesis was to improve understanding of the supersaturation solubility behavior in SDDSs with a particular focus on rapidly dissolving solid forms (amorphous forms/cocrystals).In the course of the work, a new formulation for ezetimibe using an amorphous solid dispersion was prepared, cocrystals of tadalafil were pre-pared, and oral films of silodosin were formulated for the first time. These new formulations were thoroughly characterized using a number of solid-state and pharmaceutical characterization techniques.The dissolution and supersaturation behavior of the prepared SDDSs were studied. The effects of various factors on the supersaturation and precipita-tion characteristics were investigated. These factors included the preparation method, the temperature of the dissolution medium, the type of dissolution biorelevant medium (gastric/intestinal) used, the permeability of the relevant gastrointestinal membranes, the addition of polymers, and the addition of surfactants. The amorphous solid dispersions, cocrystals and oral films that were prepared represent new drug formulations that provide significantly higher dissolution rates and supersaturated solubility than crystalline drug forms. Solid dispersions prepared by the melting method had better super-saturation properties than those prepared by spray drying. The precipitation kinetics of the solid dispersion were faster at 37 ̊C than at 25 ̊C in bio-relevant media. Implementation of an absorption tool during in vitro evalua-tion of supersaturation levels could improve the prediction accuracy of su-persaturation and precipitation. A better understanding of the effects of ex-cipients on the supersaturation and precipitation behavior of these types of formulation was obtained in this thesis. The improvement in supersaturation solubility obtained by adding polymers and surfactants was not proportional to the amounts of excipient used.This thesis has made notable contributions to the field of pharmaceutical science by advancing our understanding of the supersaturation solubility behavior of the newly prepared SDDSs.
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| 16. |
- AlHayali, Amani, et al.
(författare)
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Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe
- 2018
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 117, s. 147-153
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 17. |
- AlHayali, Amani, et al.
(författare)
-
Silodosin oral films : Development, physico-mechanical properties and in vitro dissolution studies in simulated saliva
- 2019
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Ingår i: Journal of Drug Delivery Science and Technology. - : Elsevier. - 1773-2247. ; 53
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 18. |
- Ali, Hassan, et al.
(författare)
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Solid-state vibrational spectroscopic investigation of cocrystals and salt of indomethacin
- 2012
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Ingår i: CrystEngComm. - 1466-8033 .- 1466-8033. ; 14:20, s. 6665-6674
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 19. |
- Ali, Hassan, et al.
(författare)
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Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin
- 2013
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 39:5, s. 625-634
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 20. |
- Alleso, Morten, et al.
(författare)
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Near-infrared spectroscopy for cocrystal screening : a comparative study with Raman spectroscopy
- 2008
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 80:20, s. 7755-7764
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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