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Preparation and characterisation of Hydrocortisone particles using a Supercritical Fluids extraction process
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2002 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 231, no 2, 155-166 p.Article in journal (Refereed) Published
Abstract [en]

Crystallisation and subsequent milling of pharmaceutical powders by traditional methods often cause variations in physicochemical properties thereby influencing bioavailability of the formulation. Crystallisation of drug substances using supercritical fluids (SFs) offers some advantages over existing traditional methods in controlling particle characteristics. The novel particle formation method, solution enhanced dispersion by supercritical (SEDS) fluids was used for the preparation of hydrocortisone (HC) particles. The influence of processing conditions on the solid-state properties of the particles was studied. HC, an anti-inflammatory corticosteroid, particles were prepared from acetone and methanol solutions using the SEDS process. The solutions were dispersed with supercritical CO(2), acting as an anti-solvent, through a specially designed co-axial nozzle into a pressured vessel maintained at a specific constant temperature and pressure. The temperatures and pressures studied were 40-90 degrees C and 90-180 bar, respectively. The relative flow rates of drug solution to CO(2) were varied between 0.002 and 0.03. Solid-state characterisation of particles included differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), solubility studies and scanning electron microscopy (SEM) examination. The aerodynamic properties of SEDS prepared particles were determined by a multistage liquid impinger (MLI). Particles produced from acetone solutions were crystalline needles, melting at 221+/-2 degrees C. Their morphology was independent of processing conditions. With methanol solutions, particles were flakes or needles depending on the processing temperature and pressure. This material melted at 216+/-1 degrees C, indicating a different crystal structure from the original material, in agreement with observed differences in the position and intensity of the XRPD peaks. The simulated lung deposition, using the MLI, for HC powder was improved after SEDS processing. It was possible to produce and control the crystallinity, morphology, and aerodynamic properties of HC particles with the SEDS technique. This method may be useful for the processing of inhalation powders.

Place, publisher, year, edition, pages
2002. Vol. 231, no 2, 155-166 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-91388DOI: 10.1016/S0378-5173(01)00870-5PubMedID: 11755268OAI: oai:DiVA.org:uu-91388DiVA: diva2:164102
Available from: 2004-02-18 Created: 2004-02-18 Last updated: 2017-12-14Bibliographically 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.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 308
Keyword
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
Identifiers
urn:nbn:se:uu:diva-4006 (URN)91-554-5880-7 (ISBN)
Public defence
2004-03-12, B41, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2004-02-18 Created: 2004-02-18Bibliographically approved

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