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Considerations on the quantitative analysis of apparent amorphicity of milled lactose by Raman spectroscopy
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.
Recipharm Pharmaceut Dev AB, Solna, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2016 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 511, no 1, 488-504 p.Article in journal (Refereed) Published
Abstract [en]

The main purpose of the study was to evaluate various pre-processing and quantification approaches of Raman spectrum to quantify low level of amorphous content in milled lactose powder. To improve the quantification analysis, several spectral pre-processing methods were used to adjust background effects. The effects of spectral noise on the variation of determined amorphous content were also investigated theoretically by propagation of error analysis and were compared to the experimentally obtained values. Additionally, the applicability of calibration method with crystalline or amorphous domains in the estimation of amorphous content in milled lactose powder was discussed. Two straight baseline pre-processing methods gave the best and almost equal performance. By the succeeding quantification methods, PCA performed best, although the classical least square analysis (CLS) gave comparable results, while peak parameter analysis displayed to be inferior. The standard deviations of experimental determined percentage amorphous content were 0.94% and 0.25% for pure crystalline and pure amorphous samples respectively, which was very close to the standard deviation values from propagated spectral noise. The reasonable conformity between the milled samples spectra and synthesized spectra indicated representativeness of physical mixtures with crystalline or amorphous domains in the estimation of apparent amorphous content in milled lactose.

Place, publisher, year, edition, pages
2016. Vol. 511, no 1, 488-504 p.
Keyword [en]
Raman spectroscopy, Lactose, Amorphous content, Spectral data analysis, Principal component analysis (PCA), Milling induced disorder
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-304150DOI: 10.1016/j.ijpharm.2016.07.001ISI: 000382263700051PubMedID: 27397869OAI: oai:DiVA.org:uu-304150DiVA: diva2:1014948
Available from: 2016-10-03 Created: 2016-10-03 Last updated: 2017-11-30Bibliographically approved
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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