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Influence of degree of disorder on the Heckel yield pressure: a comparison between milled and physical mixtures of lactose
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Galenisk farmaci)
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. (Galensik farmaci)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The purpose of this study was to investigate the effect of degree of amorphisation of a series of lactose powders, prepared by milling α-lactose monohydrate powders for different time periods, on the plastic stiffness of the particles. As references, a series of physical mixtures consisting of original crystalline particles and amorphous particles obtained by spray-drying was used. In addition, the effect of powder pre-storage humidity on the mechanical properties was investigated. The particle plastic stiffness was assessed by the Heckel yield pressure derived from the relationship between porosity of the powder column and the applied compression pressure during confined powder compression.

 

For milled particles of a low degree of disorder, a decreased particle size increased the particle plastic stiffness. For milled particles of constant particle size, the plastic stiffness decreased with an increased degree of disorder while the elastic stiffness seemed independent of the degree of disorder. The presence of moisture caused a recrystallization of milled particles with low degree of disorder which increased their plastic stiffness.

 

For the physical mixtures of crystalline and amorphous particles, similar relationships between plastic stiffness and amorphous content as for the milled powders were obtained. A reasonable explanation is that the nature of the milled particles is represented by a two-state system with crystalline and amorphous domains.

Keyword [en]
Milling-induced disorder, plasticity, elasticity, compression, amorphous lactose, Raman spectroscopy
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-317799OAI: oai:DiVA.org:uu-317799DiVA: diva2:1082882
Available from: 2017-03-19 Created: 2017-03-19 Last updated: 2017-03-19
In thesis
1. 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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