Browsing by Subject "liukenemisnopeus"
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(2016)Pharmaceutical nanocrystals are under one micrometer sized crystals composed of pure active pharmaceutical ingredient (API) and stabilizer. Their apparent dissolution rate is improved compared to conventionally sized crystals. Rapid dissolution is mainly due to increased intrinsic surface area of API powder. Solubility increase is significant only with very small, under 100 nm crystals. Nanocrystal formulations with improved dissolution rates can be utilized to increase bioavailability of fairly insoluble BCS class II APIs. Few nanocrystal based products are already on market. Common methods for dissolution study of nanocrystals arecompendial dissolution apparatus 1 or 2, which usually rely on sampling and separation of undissolved fraction. The reliability of these methods is dependent of the separation efficiency. Unfortunately separation becomes more tedious with diminishing crystal size. Thus it would be desirable to replace the methods that require sampling and separation with methods that do not require separation of undissolved fraction (in situ methods), preferably with continuous detection. With the dialysis method the separation is easily achieved. However, the rate limiting step is not dissolution but diffusion through the dialysis membrane. Electrochemical in situ detection methods can only be applied to electroactive APIs. Utilization of in situ UV probes for monitoring nanocrystal dissolution is limited by the UV absorbance of the nanocrystals themselves. To date, light scattering methods have mainly been applied to solubility studies, with few attempts on dissolution studies. In this study the light scattering, dialysis and compendial paddle methods were compared for their ability to monitor the dissolution of indometacin nanosuspensions (NS). Light scattering experiments were performed with Zetasizer equipment. Three poloxamer 188 stabilized NSs, with average diameters (Dz) of 300 nm, 600 nm, and 900 nm, were evaluated. Dissolution studies were executed in sink conditions (under 30% of saturated concentration) and in slightly higher concentration (intermediate conc., 30-50% of saturated concentration) at pH 5.5. The compendial paddle method was performed on the same suspensions with the same medium at intermediate concentration. In the dialysis method the studied NS had a Dz value of 350 nm. The pH of the dissolution medium was 7.4, and the membrane was made of regenerated cellulose. Experimental results were fitted to exponential equation and the dissolution time DT, i.e. time to reach 99% dissolution, was determined based on the equation. In sink conditions the dissolution of all of the NSs was so rapid that reliable estimations of dissolution times could not be made with the light scattering method. In intermediate concentration the dissolution time (51±12 s) of the 300 nm NS was significantly lower than those of 600 nm (340±80 s) and 900 nm (230±50 s) NSs with a confidence level of 5%. The slowest dissolution of the 600 nm NS could be attributed to its broad crystal size distribution. With the compendial paddle method no significant differences in dissolution times could be detected. Compendial dissolution times, about 600-700 s, were markedly longer than those from light scattering experiments. The dialysis method was unable to discriminate between 350 nm NS and indometacin solution, which can be explained by rapid dissolution of the nanocrystals, followed by slow diffusion across the dialysis membrane. Of the studied methods, light scattering was the only one to discriminate between dissolution times of various NSs. It was most applicable to narrow crystal size distributions. It is a fairly small scale method requiring only 1 mL of dissolution medium and about 10 µg of nanocrystals. The method was not dependent on chemical analysis. Theost important limitation was the fact that due to the operational method of the Zetasizer, the first data point was not acquired until about 20 s after the measurement started.
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(2013)The dissolution rate is one of the most important physicochemical properties of drug substances. Above all, it demonstrates the energetic interaction between solvent and solute molecules, and is therefore a valuable tool for understanding drug substance properties. Dissolution studies are a widely used method in many areas of the pharmaceutical development process, however, only lately has the value of dissolution testing in drug discovery and early development been assessed. The advantages of dissolution testing over other early screening methods, such as kinetic solubility and in silico screening, lies in the possibility of obtaining solid state dependent quantitative data, from small amounts of drug substances. While the general way of studying drug dissolution has been by the multiparticulate bulk approach, studying the constituent single particles of these systems, could give a deeper understanding of the core factors affecting the dissolution rate of drug substances. The aim of the present study was to develop a static and dynamic method, in which it would be possible to analyze the dissolution process of a single pure drug substance particle, by optical microscopy. Both methods produced practically identical dissolution profiles, for image analysis and UV-spectrophotometric data, from the same systems of a single dissolving particle. The dynamic method developed in the present study is the first flow-through technique, in which it is possible to assess the dissolution of a single freely moving drug particle, by continuous physical analysis. The possibility of using physical analysis instead of chemical analysis poses many advantages. These include reduced materials consumption, reduced experiment times, as well as a reduction in the possible sources of error. Most importantly, the advantage of physical analysis lies in the fact that no prior chemical knowledge about the studied substance is needed. This makes physical analysis an optimal technique for studying new chemical entities. The novel flow-through method succeeded in obtaining the dissolution characteristics and 3D particle morphological data, of a single pure drug substance particle, of sub-milligram initial weight. The theoretical detection limit of 1 pg, poses an intriguing opportunity for further development.
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(2022)Lääkeaineiden niukkaliukoisuus on yhä enemmän esiintyvä ongelma lääketeollisuudessa. Erityisesti BCS ryhmän II lääkeaineet ovat potentiaalisia liukoisuusominaisuuksia parantaville menetelmille. Tässä työssä näistä menetelmistä keskitytään nanokiteen, ko-kiteen ja ko-amorfisen systeemin muodostukseen ja lääkeaineena käytetään inodmetasiinia (BCS ryhmä II). Kyseisillä menetelmillä on onnistuttu parantamaan indometasiinin liukoisuusominaisuuksia, mutta vertailevia tutkimuksia ei ole aiemmin tehty. Nanokide valmistettiin märkäjauhamalla käyttäen poloksameeri 188 -stabilisaattoria. Ko-kiteen valmistuksessa käytettiin liuottimen haihdutus -menetelmää ja ko-muodostajana sakariinia. Ko-amorfisten systeemien ko-muodostajina käytettiin l-tryptofaania ja sitruunahappoa ja valmistus toteutettiin kuulamyllyllä jauhamalla. Karakterisointimenetelmillä (DLS, DSC ja XRPD) oli mahdollista todentaa nanokiteillä ja ko-kiteillä halutut ominaisuudet (partikkelikoko ja kiderakenne). Ko-amorfinen systeemi ei työssä käytetyllä menetelmällä saavuttanut amorfista rakennetta kummallakaan ko-muodostajalla. Vaikka jauhe osittain muuttui kellertäväksi (viitaten amorfiseen indometasiiniin) olivat XRPD:n ja DSC:n tulokset kiteiselle aineelle tyypillisiä. Nanokiteellä ja ko-kiteellä saavutettiin puhdasta indometasiinia parempi ominaisliukenemisnopeus sekä liukenemisnopeus jauheesta lapamenetelmällä. Systeemien välisessä vertailussa huomattiin, että nanokiteellä oli parempi liukenemisnopeus molemmissa kokeissa. Ero on selkeämmin nähtävissä lapamenetelmässä: pieni partikkelikoko mahdollistaa suuren suhteellisen pinta-alan liukenemista varten. Systeemien fysikaalista stabiilisuutta tutkittiin yhdeksän kuukauden ajan suljetussa muoviastiassa laboratorio-olosuhteissa (huoneenlämpö ja normaali ilmankosteus). Kummassakaan systeemissä ei ollut nähtävissä kiderakenteen muutoksia. Nanokiteillä oli havaittavissa lievää partikkelikoon kasvua, mikä on selitettävissä ennen koetta tehdyn sekoituksen tehottomuudella
Now showing items 1-3 of 3