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Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer
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.
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2013 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 11, 4036-4045 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of the research was to investigate the degree of solid-state amorphisation during powder flow and to propose a mechanism for this transformation. Micro-particles of griseofulvin (about 2m in diameter) were mixed in a shear mixer under different conditions to influence the inter-particulate collisions during flow, and the degree of amorphisation was determined by micro-calorimeter. The amorphisation of griseofulvin particles (GPs)during repeated compaction was also determined. The GPs generally became disordered during mixing in a range from about 6% to about 86%. The degree of amorphisation increased with increased mixing time and increased batch size of the mixer, whereas the addition of a lubricant to the blend reduced the degree of amorphisation. Repeated compaction using the press with ejection mode gave limited amorphisation, whereas repeated compaction without an ejection process gave minute amorphisation. It is concluded that during powder flow, the most important inter-particulate contact process that cause the transformation of a crystalline solid into an amorphous state is sliding. On the molecular scale, this amorphisation is proposed to be caused by vitrification, that is the melting of a solid because of the generation of heat during sliding followed by solidification into an amorphous phase.

Place, publisher, year, edition, pages
2013. Vol. 102, no 11, 4036-4045 p.
Keyword [en]
powder technology, powder flow, compaction, mixing, amorphisation, mechanical activation, vitrification, crystal defect, friction, sliding
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-210559DOI: 10.1002/jps.23713ISI: 000325550400019OAI: oai:DiVA.org:uu-210559DiVA: diva2:664020
Available from: 2013-11-13 Created: 2013-11-11 Last updated: 2017-12-06Bibliographically approved
In thesis
1. On the chemical and processing stability of pharmaceutical solids: Solid form dependent water presenting capacity and process induced solid form transformation
Open this publication in new window or tab >>On the chemical and processing stability of pharmaceutical solids: Solid form dependent water presenting capacity and process induced solid form transformation
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a need for improving our knowledge and understanding about formation mechanisms and nature of amorphous state in order to prevent the unintended presence of disorder in solid pharmaceutical products and reduce the related stability issues. The suggested theory that water binding capacity of amorphous cellulose affects the chemical stability of hydrolysis sensitive drugs in formulations with cellulose based excipients needs a clarification and water-cellulose interaction profiles need to be examined.  This thesis has addressed these questions.

Chemical, mechanical and thermal methods have been used to create partially or predominantly amorphous solids. Mechanisms and the pathways for transformation to amorphous phase and the characteristic qualities of this phase is studied in order to give some tools to predict, to control or prevent the creation of disorder in a crystalline structure. The water interaction with amorphous pharmaceutical materials has been studied to improve stability of hydrolysis sensitive drugs. 

 

The transition to amorphous state during handling of pharmaceutical material, referred to as mechanical activation in processes like blending, mixing and compression is substantially a consequence of vitrification. The process is described as creation of hot spots where friction caused by particle sliding raise the temperature above the melting point of the material. The fast cooling process promotes creation of a local disordered molecular arrangement. It is possible to decrease the degree of amorphisation and undesired stability problems by reducing the friction and inhibit the creation of crystal defects during processing.

 

The glass-forming propensity is an inherent material characteristic related to molecular size and structure and is not process dependent. Molecules with a couple of aromatic rings are often poor glass-formers. Less symmetrical, branched molecular structures with presence of electronegative atoms are more readily transformed to and exist in amorphous state when handled and stored at temperatures below their glass transition temperature.

 

The interaction profile of cellulose with water is strongly dependent on solid state structure of cellulose. Crystallinity is the key parameter in water presenting capacity of cellulose. Amorphous regions have a capacity to bind the water and decrease water mobility and in that way reduce cellulose water presenting capacity despite higher moisture content in partially amorphous cellulose compared to crystalline cellulose. The fact that higher amorphous content decreases cellulose water presenting capacity is a promising lead to improve stability of hydrolysis sensitive drugs in compositions with cellulose. This knowledge could be applicable to other pharmaceutical materials as the differences between crystalline and amorphous states of material are generally the same for different kind of materials.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 203
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-261785 (URN)978-91-554-9325-7 (ISBN)
Public defence
2015-10-23, B22 Biomedicum, Daghammarsköldsväg, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2015-11-26 Created: 2015-09-04 Last updated: 2016-01-13Bibliographically approved
2. Process-induced disorder of pharmaceutical materials: Mechanisms and quantification of disorder
Open this publication in new window or tab >>Process-induced disorder of pharmaceutical materials: Mechanisms and quantification of disorder
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One of the most important prerequisites in the drug development is to attain a reproducible and robust product in terms of its nature, and its chemical and physical properties. This can be challenging, since the crystalline form of drugs and excipients can be directly transformed into the amorphous one during normal pharmaceutical processing, referred to as process-induced amorphisation or process-induced disorder. The intention of this thesis was to address the mechanisms causing disorder during powder flow and milling and, in association with this, to evaluate, the ability of Raman spectroscopy and atomic force microscopy (AFM) to quantify and characterize process-induced disorder.

The amorphisation mechanisms were controlled by stress energy distribution during processing, which in turn was regulated by a series of process parameters. Compression and shearing stress caused by sliding were stress types that acted on the particles during powder flow and ball milling process. However, sliding was the most important inter-particulate contact process giving rise to amorphisation and the transformation was proposed to be caused by vitrification. The plastic stiffness and elastic stiffness of the milling-induced particles were similar to a two-state particle model, however the moisture sorption characteristics of these particles were different. Thus the milled particles could not be described solely by a two-state particle model with amorphous and crystalline domains. 

Raman spectroscopy proved to be an appropriate and effective technique in the quantification of the apparent amorphous content of milled lactose powder. The disordered content below 1% could be quantified with Raman spectroscopy. AFM was a useful approach to characterize disorder on the particle surfaces.

In summary, this thesis has provided insight into the mechanisms involved in process-induced amorphisation of pharmaceutical powders and presented new approaches for quantification and characterization of disordered content by Raman spectroscopy and atomic force microscopy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 228
Keyword
Milling, Comminution, Powder flow, Amorphisation, Raman spectroscopy, Atomic force microscopy, Plastic stiffness, Elastic stiffness
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-317801 (URN)978-91-554-9860-3 (ISBN)
Public defence
2017-05-12, B22, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2017-04-21 Created: 2017-03-19 Last updated: 2017-05-10

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Pazesh, SamanehHöckerfelt, Mina HeidarianAlderborn, Göran

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