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Preparation of Pharmaceutical Powders using Supercritical Fluid Technology: Pharmaceutical Applications and Physicochemical Characterisation of Powders
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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. , p. 50
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 308
Keywords [en]
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)
Keywords [sv]
Galenisk farmaci
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-4006ISBN: 91-554-5880-7 (print)OAI: oai:DiVA.org:uu-4006DiVA, id: diva2:164106
Public defence
2004-03-12, B41, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2004-02-18 Created: 2004-02-18 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Preparation and characterisation of Hydrocortisone particles using a Supercritical Fluids extraction process
Open this publication in new window or tab >>Preparation and characterisation of Hydrocortisone particles using a Supercritical Fluids extraction process
2002 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 231, no 2, p. 155-166Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91388 (URN)10.1016/S0378-5173(01)00870-5 (DOI)11755268 (PubMedID)
Available from: 2004-02-18 Created: 2004-02-18 Last updated: 2017-12-14Bibliographically approved
2. Supercritical fluids crystallisation of budesonide and flunisolide
Open this publication in new window or tab >>Supercritical fluids crystallisation of budesonide and flunisolide
2002 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 19, no 10, p. 1564-1571Article 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.

Keywords
Budesonide, chemistry, Crystallization, Fluocinolone Acetonide, analogs & derivatives, chemistry, Solvents/chemistry
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:uu:diva-91389 (URN)10.1023/A:1020477204512 (DOI)12425477 (PubMedID)
Available from: 2004-02-18 Created: 2004-02-18 Last updated: 2017-12-14Bibliographically approved
3. Stability and aerodynamic behaviour of glucocorticoid particles prepared by a supercritical fluids process
Open this publication in new window or tab >>Stability and aerodynamic behaviour of glucocorticoid particles prepared by a supercritical fluids process
2004 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 21, no 4, p. 501-509Article 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.

Keywords
Chromatography; Supercritical Fluid/*methods, Drug Stability, Glucocorticoids/*chemical synthesis, Particle Size, Powders
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91390 (URN)10.1016/j.ejps.2003.11.006 (DOI)14998581 (PubMedID)
Available from: 2004-02-18 Created: 2004-02-18 Last updated: 2017-12-14Bibliographically approved
4. Supercritical fluids processing of recombinant human Growth Hormone
Open this publication in new window or tab >>Supercritical fluids processing of recombinant human Growth Hormone
2005 (English)In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 31, no 2, p. 135-149Article in journal (Refereed) Published
Abstract [en]

The aim of the study was to investigate the feasibility of precipitating recombinant human growth hormone (hGH) from aqueous solutions using conventional and modified techniques of solution-enhanced dispersion (SEDS) by supercritical fluids. The study investigated the effect on hGH stability of adding isopropanol either as a cosolvent with the original aqueous protein solution (conventional process) or to the supercritical carbon dioxide before mixing with the aqueous protein solution (modified process). The influence of the addition of sucrose (with or without isopropanol) on the precipitation behavior and stability of the protein was also studied. Experiments were performed under various processing conditions (pressure 100-200 bars and temperature 40-50 degrees C), and with various flow rates and solution compositions (CO2/isopropanol and protein solution). Bioanalytical characterization of the resulting powders involved spectrophotometry, sodium dodecyl sulfate-polycrylamide gel electrophoresis, reverse-phase high performance liquid chromatography (RP-HPLC), and size exclusion chromatography. Solid-state characterization was performed using differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and Karl Fischer techniques. Results showed that with both conventional and modified methods, under optimum processing conditions, the presence of sucrose in the solution decreased the destabilizing effects of the solvent and/or process on the structure of hGH. More hGH was dissolved from the precipitated powders containing sucrose than from those containing only isopropanol. Reverse-phase HPLC indicated that about 94% of the hGH was recovered in its native form. The proportion of dimers and oligomers was reduced in the presence of sucrose; about 92% of the soluble protein was present in monomer form under optimal conditions. The remaining undissolved protein was in monomeric form. The precipitated powders were amorphous, containing particulate aggregates in the size range 1-6 microm with 5-10% residual moisture content. In conclusion, hGH was successfully precipitated from aqueous solution using SEDS technology. The presence of sucrose in the protein solution promoted the precipitation of hGH and reduced aggregation and improved dissolution.

Keywords
Chemistry; Pharmaceutical, Chromatography; Gel, Chromatography; High Pressure Liquid, Chromatography; Supercritical Fluid, Drug Stability, Human Growth Hormone/*chemistry, Precipitation, Recombinant Proteins, Solvents
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91391 (URN)10.1081/DDC-200047368 (DOI)15773281 (PubMedID)
Available from: 2004-02-18 Created: 2004-02-18 Last updated: 2017-12-14Bibliographically approved

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