Browsing by Subject "dissolution"

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  • Toropainen, Elisa; Fraser-Miller, Sara J.; Novakovic, Dunja; Del Amo, Eva M.; Vellonen, Kati-Sisko; Ruponen, Marika; Viitala, Tapani; Korhonen, Ossi; Auriola, Seppo; Hellinen, Laura; Reinisalo, Mika; Tengvall, Unni; Choi, Stephanie; Absar, Mohammad; Strachan, Clare; Urtti, Arto (2021)
    Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d(50)) categories of the experimental suspensions were 0.37-1.33 and 3.12-3.50 mu m and their viscosity levels were 1.3, 7.0, and 15 mPa center dot s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4-4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions.
  • Åkerlund, Helena (Svenska handelshögskolan, 2004)
    Economics and Society
    This dissertation is based on the assumption that fading customer relationships are important phenomena to understand in order for companies to prevent a future relationship termination, manage a desired relationship termination, or manage the situation where the relationship strength temporarily or permanently has weakened but where the customer still stays with the same service provider. It is assumed that fading could take different forms and develop through a range of different processes. The purpose of the thesis is therefore to define and describe fading, reveal different types of fading relationship processes, and discuss the dynamics of these processes. In services literature there is a lack of research focusing on the weakening of customer relationships. Fading therefore represents a new approach to understanding issues related to the ending of customer relationships. A fading relationship process could precede a relationship ending, but could also represent a temporal weakening of the relationship without leading to termination. It thus distinguishes the concept from other concepts within ending research which focus solely on relationships that have been terminated, taking a larger aspect of the relationship into account (as a relationship could build on constant changes). A pilot study created an understanding of difficulties related to understanding and detecting fading customer relationship, which led to a follow-up study incorporating qualitative interviews in relationship dyads characterised as fading with both private banking customers and their respective financial advisor. The focus remained on the understanding of the fading process resulting in a model for analysing different types of fading processes. Four types of fading processes were also revealed; the crash landing process, the altitude drop process, the fizzle out process and the try out process. The dissertation contributes to a broadened understanding of different types of fading processes within the research area of ending relationships emphasising the dynamic aspects of the phenomenon. Managerial implications include the management of different types of fading processes and also the understanding of the financial advisor’s role in influencing the development of these processes. Helena Åkerlund is associated with CERS, the Centre for Relationship Marketing and Service Management at Hanken, Swedish School of Economics and Business Administration, Helsinki
  • 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.
  • 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).
  • Piipponen, Anu (Helsingfors universitet, 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.
  • 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.
  • Novakovic, Dunja; Isomäki, Antti; Pleunis, Bibi; Fraser-Miller, Sara J.; Peltonen, Leena Johanna; Laaksonen, Timo; Strachan, Clare Joanna (2018)
    The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.