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Stability and aerodynamic behaviour of glucocorticoid particles prepared by a supercritical fluids 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.
2004 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 21, no 4, 501-509 p.Article in journal (Refereed) Published
Abstract [en]

Particle processing techniques using supercritical fluids (SF) are potential alternative technologies to design particles for inhalation. Powders of budesonide and flunisolide were prepared using solution enhanced dispersion by supercritical fluids (SEDS) process. The aim was to determine thermodynamic stability of different polymorphs of flunisolide including new forms from SEDS technology and to characterise micronised and SEDS produced powders of budesonide and flunisolide for their suitability as inhalation powders. Acetone and methanol solutions of budesonide and flunisolide, with a concentration of 2.5 mg/ml, were used for the particle preparation. The pressure was 100 bar and temperatures were 60 °C or 80 °C. The flow rates of CO2 and drug solution were 9 ml/min and 0.3 ml/min, respectively. Chemical purity of different polymorphs of flunisolide was estimated using high performance liquid chromatography (HPLC) and thermal behaviour was determined using differential scanning calorimetry (DSC). Particle morphology and surface examination were performed using scanning electron microscopy (SEM) and atomic force microscopy (AFM), respectively. The particle size distribution and density of the powders were determined with the help of Coulter Counter and helium pycnometer respectively. The in vitro deposition of the powders was studied using multistage liquid impinger (MLI). From the stability study, it was found that the two forms of flunisolide, polymorphs II and hemihydrate, were the most stable. Flunisolide form III was transformed to hemihydrate during the stability study. The chemical purity of the material was increased after SEDS processing. SEDS produced powders of budesonide and flunisolide form III from acetone showed narrow volumetric particle size distributions with 90% of the particles below 4 μm and geometric mean size around 3 μm. However, in the MLI study, budesonide powder obtained from SEDS with acetone showed favorable deposition in the lower stages with a mass median aerodynamic diameter (MMAD) of around 3 μm whilst the flunisolide form III was preferentially deposited in the higher stages of the MLI with MMAD of over 5 μm, due to aggregation of the particles. Particles of budesonide and flunisolide, in the size range, suitable for inhalation, were reproducibly produced using SEDS.

Place, publisher, year, edition, pages
2004. Vol. 21, no 4, 501-509 p.
Keyword [en]
Chromatography; Supercritical Fluid/*methods, Drug Stability, Glucocorticoids/*chemical synthesis, Particle Size, Powders
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-91390DOI: 10.1016/j.ejps.2003.11.006PubMedID: 14998581OAI: oai:DiVA.org:uu-91390DiVA: diva2:164104
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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