Browsing by Subject "PHYSICAL STABILITY"

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  • Rautaniemi, Kaisa; Vuorimaa-Laukkanen, Elina; Strachan, Clare J.; Laaksonen, Timo (2018)
    Pharmaceutical scientists are increasingly interested in amorphous drug formulations especially because of their higher dissolution rates. Consequently, the thorough characterization and analysis of these formulations are becoming more and more important for the pharmaceutical industry. Here, fluorescence lifetime-imaging microscopy (FLIM) was used to monitor the crystallization of an amorphous pharmaceutical compound, indomethacin. Initially, we identified different solid indomethacin forms, amorphous and gamma- and alpha-crystalline, on the basis of their time-resolved fluorescence. All of the studied indomethacin forms showed biexponential decays with characteristic fluorescence lifetimes and amplitudes. Using this information, the crystallization of amorphous indomethacin upon storage in 60 degrees C was monitored for 10 days with FLIM. The progress of crystallization was detected as lifetime changes both in the FLIM images and in the fluorescence-decay curves extracted from the images. The fluorescence-lifetime amplitudes were used for quantitative analysis of the crystallization process. We also demonstrated that the fluorescence-lifetime distribution of the sample changed during crystallization, and when the sample was not moved between measuring times, the lifetime distribution could also be used for the analysis of the reaction kinetics. Our results clearly show that FLIM is a sensitive and nondestructive method for monitoring solid-state transformations on the surfaces of fluorescent samples.
  • Stukelj, Jernej; Svanback, Sami; Agopov, Mikael; Lobmann, Korbinian; Strachan, Clare J.; Rades, Thomas; Yliruusi, Jouko (2019)
    Amorphous materials exhibit distinct physicochemical properties compared to their respective crystalline counterparts. One of these properties, the increased solubility of amorphous materials, is exploited in the pharmaceutical industry as a way of increasing bioavailability of poorly water-soluble drugs. Despite the increasing interest in drug amorphization, the analytical physicochemical toolbox is lacking a reliable method for direct amorphous solubility assessment. Here, we show, for the first time, a direct approach to measure the amorphous solubility of diverse drugs by combining optics with fluidics, the single particle analysis (SPA) method. Moreover, a comparison was made to a theoretical estimation based on thermal analysis and to a standardized supersaturation and precipitation method. We have found a good level of agreement between the three methods. Importantly, the SPA method allowed for the first experimental measurement of the amorphous solubility for griseofulvin, a fast crystallizing drug, without the use of a crystallization inhibitor. In conclusion, the SPA approach enables rapid and straightforward determination of the supersaturation potential for amorphous materials of less than 0.1 mg, which could prove highly beneficial in the fields of materials science, analytical chemistry, physical chemistry, food science, pharmaceutical science, and others.
  • Palomäki, Emmi A. K.; Yliruusi, Jouko K.; Ehlers, Henrik (2019)
    In this paper, the effect of the gaseous environment on recrystallization of amorphous paracetamol was investigated. The experiments were conducted with a headspace gas consisting of dry air, dry carbon dioxide, dry nitrogen and humid air in four temperatures ranging from 5 degrees C below onset of T-g to 5 degrees C above onset of T-g. The recrystallization was monitored using Raman spectroscopy and subsequent multivariate analysis. In temperatures below onset of T-g, the presence of oxygen delayed the onset of recrystallization, with an increasing delay with lower temperature. When comparing samples exposed to dry headspace gases, the crystallization was fastest below onset of Tg when exposed to nitrogen. Being an inert gas, nitrogen did not seem to interfere with the molecules allowing them to freely find their inherent arrangement, whereas the presence of oxygen delayed the formation of stabile nuclei. Above onset of T-g, no differences in onset of crystallization was detected between dry gas atmospheres. Amorphous paracetamol crystallized to form II in all measurements and the samples did not reach full crystallinity within the duration of the experiments. The results show that the headspace gas has an effect on nucleation in the amorphous sample.
  • Semjonov, Kristian; Salm, Maia; Lipiäinen, Tiina; Kogermann, Karin; Lust, Andres; Laidmäe, Ivo; Antikainen, Osmo; Strachan, Clare J.; Ehlers, Henrik; Yliruusi, Jouko; Heinämäki, Jyrki (2018)
    Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus (R)) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus (R) significantly improved the dissolution rate of IND at pH 6.8 (79.9 +/- 0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus (R) in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau.
  • Kääriäinen, Tommi Olavi; Kemell, Marianna Leena; Vehkamäki, Marko Juhani; Kääriäinen, Marja-Leena; Correia, Alexandra; Almeida Santos, Helder; Marques dos Santos Bimbo, Luis Maria; Hirvonen, Jouni Tapio; Hoppu, Pekka; George, Steven M.; Cameron, David C.; Ritala, Mikko Kalervo; Leskelä, Markku Antero (2017)
    Organic solid pharmaceutical powders are used for the preparation of various drug dosage forms. Primary particles in powder form undergo several processing steps first in pharmaceutical formulations followed by pharmaceutical manufacturing to final dosage form of a drug. These unit operations involve both handling of powders in aqueous or solvent solutions and drying. There will be a probable rise for a demand for the different unit operations in the requirements of protecting the active pharmaceutical ingredient or challenges in powder handling. Besides pharmaceutical manufacturing, there are many biological interfaces where control of surface characteristics of pharmaceutical powders can improve the therapeutic response and bioavailability. In this work, we have modified acetaminophen particles with atomic layer deposition (ALD) by conformal nanometer scale coatings in a one-step coating process. According to the results, ALD comprising common chemistries for Al2O3, TiO2 and ZnO is shown to be a promising coating method for solid pharmaceutical powders. Acetaminophen does not undergo degradation during the ALD coating and maintains its stable polymorphic structure. The nanometer scale ALD coating can sustain the drug release. ALD oxide coated acetaminophen particles show different cytocompatibility assessed in in vitro intestinal Caco-2 cells.
  • Novakovic, Dunja; Peltonen, Leena; Isomäki, Antti Olavi; Fraser-Miller, Sara J.; Hagner Nielsen, Line; Laaksonen, Timo; Strachan, Clare (2020)
    The distinction between surface and bulk crystallization of amorphous pharmaceuticals, as well as the importance of surface crystallization for pharmaceutical performance, is becoming increasingly evident. An emerging strategy in stabilizing the amorphous drug form is to utilize thin coatings at the surface. While the physical stability of systems coated with pharmaceutical polymers has recently been studied, the effect on dissolution performance as a function of storage time, as a further necessary step toward the success of these formulations, has not been previously studied. Furthermore, the effect of coating thickness has not been elucidated. This study investigated the effect of these polymer-coating parameters on the interplay between amorphous surface crystallization and drug dissolution for the first time. The study utilized simple tablet-like coated dosage forms, comprising a continuous amorphous drug core and thin polymer coating (hundreds of nanometers to a micrometer thick). Monitoring included analysis of both the solid-state of the model drug (with SEM, XRD, and ATR FTIR spectroscopy) and dissolution performance (and associated morphology and solid-state changes) after different storage times. Stabilization of the amorphous form (dependent on the coating thickness) and maintenance of early-stage intrinsic dissolution rates characteristic for the unaged amorphous drug were achieved. However, dissolution in the latter stages was likely inhibited by the presence of a polymer at the surface. Overall, this study introduced a versatile coated system for studying the dissolution of thin-coated amorphous dosage forms suitable for different drugs and coating agents. It demonstrated the importance of multiple factors that need to be taken into consideration when aiming to achieve both physical stability and improved release during the shelf life of amorphous formulations.