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Supercritical fluids crystallisation of budesonide and flunisolide
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Inorganic Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2002 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 19, no 10, 1564-1571 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Budesonide and flunisolide anhydrate were crystallized using the solution enhanced dispersion by supercritical fluids (SEDS) technique. The aim was to investigate the possibility of preparing different pure polymorphs.

Methods: 0.25% w/v solutions of each drug were prepared from acetone and methanol. Operating conditions were 40-80°C and 80-200 bars. The flow rate of drug solution was 0.3 mL/min and that of CO2 was 9-25 mL/min. Sample characterizations included differential scanning calorimetry, X-ray powder diffraction, variable temperature X-ray diffraction, scanning electron microscopy, and solubility studies.

Results: The particle morphology of budesonide was dependent on the nature of the solvent. SEDS processing of flunisolide with acetone at 100 bars resulted in the formation of polymorphic mixtures at 80°C and a new polymorph III at 60 C and 40°C. With methanol at 100 bars another new polymorph IV was formed with different particle morphology at 80°C and a polymorphic mixture at 60°C.

Conclusion: Using the SEDS, microparticles of crystalline budesonide were prepared and new polymorphs of flunisolide were produced. Particle characteristics were controlled by the temperature, pressure and relative flow rates of drug solution and CO2.

Place, publisher, year, edition, pages
2002. Vol. 19, no 10, 1564-1571 p.
Keyword [en]
Budesonide, chemistry, Crystallization, Fluocinolone Acetonide, analogs & derivatives, chemistry, Solvents/chemistry
National Category
Inorganic Chemistry
URN: urn:nbn:se:uu:diva-91389DOI: 10.1023/A:1020477204512PubMedID: 12425477OAI: oai:DiVA.org:uu-91389DiVA: diva2:164103
Available from: 2004-02-18 Created: 2004-02-18 Last updated: 2013-05-16Bibliographically approved
In thesis
1. Preparation of Pharmaceutical Powders using Supercritical Fluid Technology: Pharmaceutical Applications and Physicochemical Characterisation of Powders
Open this publication in new window or tab >>Preparation of Pharmaceutical Powders using Supercritical Fluid Technology: Pharmaceutical Applications and Physicochemical Characterisation of Powders
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main aim of the thesis was to explore the potential of supercritical fluid (SF) techniques in the field of drug delivery. In particular, the relatively recently developed solution-enhanced dispersion by supercritical fluids (SEDS) technology has been employed in the preparation of particles/powders.

The manufacturing, stability and bioavailability of a dosage form strongly depend on the physicochemical properties of the formulation particles. For example, dry powder inhalation (DPI) for administering drugs to the respiratory tract require particles in a narrow size range (1-5 μm) to be effective. The identification of polymorphs and control of purity are also important issues since the physicochemical properties and therapeutic effects of the alternative forms of a drug may differ substantially. Solvent-based traditional crystallisation processes provide the product that may require further down-stream processing to obtain particles for advanced drug delivery applications. This can result in unwanted changes in the physicochemical properties of the particles and thus affect the performance of the dosage form. SF processing has addressed many of the challenges in particle formation research. Among several SF technologies developed for particle processing over the last decade, the SEDS process with its specially designed co-axial nozzle with mixing chamber has resulted in improved control over the particle formation process. Carbon dioxide (CO2) was used as the SF, because it has low critical points and is non-toxic, non-flammable and relatively inexpensive.

The initial part of the thesis concerns the formation of particles of model drugs such as hydrocortisone, budesonide and flunisolide using SEDS technology and the determination of the influence of processing conditions and solvents on particle characteristics such as size, shape and crystal structure. Particles of model drugs of differing shapes in a size range suitable for inhalation delivery were prepared. In the process, two new polymorphic forms of flunisolide were identified. This was the first report of SEDS technology being shown as a polymorph-screening tool. The remainder of the thesis deals with the development of SEDS technology for precipitating therapeutic proteins such as recombinant human growth hormone (hGH) from aqueous solutions. Powders of hGH were precipitated using SEDS without significant changes in the chemical or physical stability of the protein. The addition of sucrose to hGH in the feed solution promoted precipitation and minimised the detrimental effects of the solvent and/or the process on the physical aggregation of the protein.

In conclusion, this thesis highlights the applicability of the SEDS process in drug delivery research and advances general understanding of the particle formation phenomenon. The SEDS process may also prove to be a potential alternative technology for the precipitation of stable powders of therapeutic proteins.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 50 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 308
Pharmaceutics, Supercritical fluid, Gas Anti-Solvent, SEDS, Crystallisation, Particle design, Polymorphs, Dry powder inhalation, Solid-state behaviour, Therapeutic proteins, Precipitation, Stability, Recombinant human growth hormone (hGH), Galenisk farmaci
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-4006 (URN)91-554-5880-7 (ISBN)
Public defence
2004-03-12, B41, BMC, Husargatan 3, Uppsala, 10:15
Available from: 2004-02-18 Created: 2004-02-18Bibliographically approved

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