Browsing by Subject "solubility"

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  • Pajunoja, Aki; Lambe, Andrew T.; Hakala, Jani; Rastak, Narges; Cummings, Molly J.; Brogan, James F.; Hao, Liqing; Paramonov, Mikhail; Hong, Juan; Prisle, Nonne L.; Malila, Jussi; Romakkaniemi, Sami; Lehtinen, Kari E. J.; Laaksonen, Ari; Kulmala, Markku; Massoli, Paola; Onasch, Timothy B.; Donahue, Neil M.; Riipinen, Ilona; Davidovits, Paul; Worsnop, Douglas R.; Petaja, Tuukka; Virtanen, Annele (2015)
    Aerosol climate effects are intimately tied to interactions with water. Here we combine hygroscopicity measurements with direct observations about the phase of secondary organic aerosol (SOA) particles to show that water uptake by slightly oxygenated SOA is an adsorption-dominated process under subsaturated conditions, where low solubility inhibits water uptake until the humidity is high enough for dissolution to occur. This reconciles reported discrepancies in previous hygroscopicity closure studies. We demonstrate that the difference in SOA hygroscopic behavior in subsaturated and supersaturated conditions can lead to an effect up to about 30% in the direct aerosol forcinghighlighting the need to implement correct descriptions of these processes in atmospheric models. Obtaining closure across the water saturation point is therefore a critical issue for accurate climate modeling.
  • Yli-Halla, Markku; Lumme, Ilari (Suomen metsätieteellinen seura, 1987)
  • Jaatinen, Hannakaisa (Helsingfors universitet, 2016)
    This thesis work was carried out in Biology Section of Experimental Therapeutics Programme in Spanish National Cancer Research Center in Madrid. The aim of this work was to carry out characterization of ADME profile of novel protein kinase inhibitors synthesized by the Medicinal Chemistry Section of Experimental Therapeutics Programme. ADME refers to absorption, distribution, metabolism and excretion. ADME screening provides crucial information when choosing new chemical entities (NCEs) and lead compounds with desirable properties for further development and for clinical studies. ADME screening is carried out in the early discovery phase in order to avoid costly failures in the later stages. The protein kinase inhibitors used in this work were designed against three different targets. However, the targets cannot be disclosed in this work due to confidentiality reasons and thus they will be referred to as X, Y, and Z. The ADME characterization was performed in a high-throughput format to screen fast compounds with desired properties. To carry out ADME characterization for the novel compounds, several in vitro assays and in vivo pharmacokinetic studies were carried out. The work was started by setting up an LC-MS/MS detection method for each compound. All in all, LC-MS/MS detection method was set up for 63 new compounds. The detection method was used to analyze the results of different in vitro and in vivo studies. In vitro assays included kinetic solubility assay, parallel artificial membrane permeability assay (PAMPA), microsomal metabolic stability assay, plasma protein binding assay, and solubility in biological fluids. The solubility in biological fluids assay was performed only for the two compounds that were selected for the pharmacokinetic (PK) study. Pharmacokinetic properties of the compounds selected for the pharmacokinetic study using the Balb/C mice were further analyzed by their pharmacokinetic parameters. These parameters were calculated by applying non-compartmental model in the WinNonlin software. One compound, ETP-871, showed promising results in the pharmacokinetic study. Another compound ETP-827 was cleared too fast from the body. Too fast excretion is undesirable since low plasma concentration of the drug is insufficient to reach the therapeutic effect. For the compound ETP-827 a new PK study with higher dose was carried out. Due to the confidentiality reasons, these further studies are not presented in this work.
  • Kinnari, Päivi (Helsingfors universitet, 2010)
    Most new drug molecules discovered today suffer from poor bioavailability. Poor oral bioavailability results mainly from poor dissolution properties of hydrophobic drug molecules, because the drug dissolution is often the rate-limiting event of the drug's absorption through the intestinal wall into the systemic circulation. During the last few years, the use of mesoporous silica and silicon particles as oral drug delivery vehicles has been widely studied, and there have been promising results of their suitability to enhance the physicochemical properties of poorly soluble drug molecules. Mesoporous silica and silicon particles can be used to enhance the solubility and dissolution rate of a drug by incorporating the drug inside the pores, which are only a few times larger than the drug molecules, and thus, breaking the crystalline structure into a disordered, amorphous form with better dissolution properties. Also, the high surface area of the mesoporous particles improves the dissolution rate of the incorporated drug. In addition, the mesoporous materials can also enhance the permeability of large, hydrophilic drug substances across biological barriers. T he loading process of drugs into silica and silicon mesopores is mainly based on the adsorption of drug molecules from a loading solution into the silica or silicon pore walls. There are several factors that affect the loading process: the surface area, the pore size, the total pore volume, the pore geometry and surface chemistry of the mesoporous material, as well as the chemical nature of the drugs and the solvents. Furthermore, both the pore and the surface structure of the particles also affect the drug release kinetics. In this study, the loading of itraconazole into mesoporous silica (Syloid AL-1 and Syloid 244) and silicon (TOPSi and TCPSi) microparticles was studied, as well as the release of itraconazole from the microparticles and its stability after loading. Itraconazole was selected for this study because of its highly hydrophobic and poorly soluble nature. Different mesoporous materials with different surface structures, pore volumes and surface areas were selected in order to evaluate the structural effect of the particles on the loading degree and dissolution behaviour of the drug using different loading parameters. The loaded particles were characterized with various analytical methods, and the drug release from the particles was assessed by in vitro dissolution tests. The results showed that the loaded drug was apparently in amorphous form after loading, and that the loading process did not alter the chemical structure of the silica or silicon surface. Both the mesoporous silica and silicon microparticles enhanced the solubility and dissolution rate of itraconazole. Moreover, the physicochemical properties of the particles and the loading procedure were shown to have an effect on the drug loading efficiency and drug release kinetics. Finally, the mesoporous silicon particles loaded with itraconazole were found to be unstable under stressed conditions (at 38 qC and 70 % relative humidity).
  • Saarikko, Elina (Helsingfors universitet, 2010)
    Biopharmaceutical Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption. For a BCS biowaiver, the in vitro dissolution study may be used as a surrogate for in vivo bioequivalence studies. Currently, BCS I drugs are accepted as biowaiver candidates by EMEA, FDA and WHO. EMEA and WHO also accept class III drugs in some conditions. The main difficulty in classifying drugs according to BCS is the determination of permeability. Biopharmaceutics Drug Distribution Classification System (BDDCS) was introduced to provide a surrogate for permeability. If the major route of elimination is metabolism, then the drug exhibites high permeability. There are two parts in this master thesis. BCS and BDDCS are discussed and evaluated in the literature part. The focus is in the BCS III drugs. The purpose of the experimental part is to evaluate BCS III drug, hydrochlorothiazide as a biowaiver candidate. Solubility of the drug substance and dissolution of the drug product was determined. Aim of the permeability studies with Caco-2 cells were to study if hydrochlorothiazide permeates by passive diffusion across the monolayer. Importance of paracellular diffusion was evaluated by opening tight junctions with EDTA. Influence of dissolution rate was evaluated by theoretical simulation. According to the results of this study, hydrochlorothiazide has good solubility in aqueous buffer. It has been reported to diffuse passively across the epithelial cells but in this study permeability increased when concentration decreased. This may be due to active transport. Hydrochlorothiazide diffuses partially through the tight junctions. Dissolution of the hydrochlrothiazide tablet was very rapid. Drug eliminates almost entirely by metabolism, it is also BDDCS class III drug. EMEA and WHO accept BCS III drugs as biowaiver candidate if dissolution rate is very rapid. According to this, hydrochlorothiazide could be suggested as a biowaiver candidate. There are also other issues to be considered, for example excipients used in tablets. Since hydrochlorothiazide has been discovered to be absorbed in the upper part of the small intestine, the influence of excipients is especially important. This possible influence should be evaluated before the final decision of biowaiver.
  • Krasnov, Andrei (Helsingfors universitet, 2011)
    Use of natural xanthine derivates in medicine is complicated with their physical properties. Theobromine is poorly soluble while theophylline is highly sensitive to hydration. The aim of this study was to improve bioavailability of xanthines by co-crystallization, theophylline was also cocrystallized with carboxylic acids (capric, citric, glutaric, malenic, malonic, oxalic, stearic, succinic) and HPMC. Co-crystallization was performed by slow evaporation and ball milling. Physical stability was checked by wet granulation and water sorption methods, solubility was measured by intrinsic tablet dissolution. Theobromine formed co-crystal with other xanthines and theophylline interacted with all acids except stearic and HPMC, the latter showed alternative interactions based on hydrogen bonding. Hydration resistance was good in theophylline:succinic acid co-crystal and excellent in complexes containing capric, stearic acids and HPMC. Theophylline:HPMC showed improved solubility. The reported approach can promote use of xanthines and can be recommended for other compounds with similar problems.