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Process-induced disorder of pharmaceutical materials: Mechanisms and quantification of disorder
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Galenisk farmaci)
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. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 228
Keywords [en]
Milling, Comminution, Powder flow, Amorphisation, Raman spectroscopy, Atomic force microscopy, Plastic stiffness, Elastic stiffness
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-317801ISBN: 978-91-554-9860-3 (print)OAI: oai:DiVA.org:uu-317801DiVA, id: diva2:1082886
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: 2018-01-13
List of papers
1. Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer
Open this publication in new window or tab >>Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer
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2013 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 11, p. 4036-4045Article 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.

Keywords
powder technology, powder flow, compaction, mixing, amorphisation, mechanical activation, vitrification, crystal defect, friction, sliding
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210559 (URN)10.1002/jps.23713 (DOI)000325550400019 ()
Available from: 2013-11-13 Created: 2013-11-11 Last updated: 2017-12-06Bibliographically approved
2. Comminution-amorphisation relationships during ball milling of lactose at different milling conditions
Open this publication in new window or tab >>Comminution-amorphisation relationships during ball milling of lactose at different milling conditions
2017 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 528, no 1-2, p. 215-227Article in journal (Refereed) Published
Abstract [en]

The purpose of the study was to investigate the relationship between comminution and amorphisation of alpha-lactose monohydrate particles during ball milling under different milling conditions, including ball-to-powder mass ratio, milling time and ball diameter. The results revealed that at a constant ball filling ratio, ball-to-powder mass ratio of 25:1 resulted in the lowest minimum particle diameter of similar to 5 mu m and the highest degree of apparent amorphous content of 82%. The rate of comminution was high during early stage of milling whereas the degree of apparent amorphous content increased gradually at a slow rate. An increased ball-to-powder mass ratio during milling increased both the rate of comminution and the rate of amorphisation. Using a given ball-to-powder mass ratio, the ball diameter affected the degree of apparent amorphous content of the particles while the particle diameter remained unchanged. The relationship between comminution and amorphisation could be described as consisting of two stages, i.e. comminution dominated and amorphisation dominated stage. It was proposed that the rate constant of comminution and amorphisation are controlled by stress energy distribution in the milling jar and the stress energy distribution is regulated by the ball motion pattern that can be affected by the process parameter used.

Keywords
Ball milling, process-induced disordering, amorphisation, comminution, comminution rate constant, α-lactose monohydrate, stress energy distribution
National Category
Chemical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-317797 (URN)10.1016/j.ijpharm.2017.05.043 (DOI)000408007600020 ()28546073 (PubMedID)
Note

Title in dissertation list of articles: "Comminution-amorphisation relationships during ball milling of lactose at different stress energies"

Available from: 2017-03-19 Created: 2017-03-19 Last updated: 2017-11-27Bibliographically approved
3. Influence of degree of disorder on the Heckel yield pressure: a comparison between milled and physical mixtures of lactose
Open this publication in new window or tab >>Influence of degree of disorder on the Heckel yield pressure: a comparison between milled and physical mixtures of lactose
(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.

Keywords
Milling-induced disorder, plasticity, elasticity, compression, amorphous lactose, Raman spectroscopy
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-317799 (URN)
Available from: 2017-03-19 Created: 2017-03-19 Last updated: 2018-01-13
4. Considerations on the quantitative analysis of apparent amorphicity of milled lactose by Raman spectroscopy
Open this publication in new window or tab >>Considerations on the quantitative analysis of apparent amorphicity of milled lactose by Raman spectroscopy
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2016 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 511, no 1, p. 488-504Article 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.

Keywords
Raman spectroscopy, Lactose, Amorphous content, Spectral data analysis, Principal component analysis (PCA), Milling induced disorder
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-304150 (URN)10.1016/j.ijpharm.2016.07.001 (DOI)000382263700051 ()27397869 (PubMedID)
Available from: 2016-10-03 Created: 2016-10-03 Last updated: 2018-01-14Bibliographically approved
5. Determination of Interfacial Amorphicity in Functional Powders
Open this publication in new window or tab >>Determination of Interfacial Amorphicity in Functional Powders
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2017 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 33, no 4, p. 920-926Article in journal (Refereed) Published
Abstract [en]

The nature of the surfaces of particles of pharmaceutical ingredients, food powders, and polymers is a determining factor for their performance in for example tableting, powder handling, or mixing. Changes on the surface structure of the material will impact the flow properties, dissolution rate, and tabletability of the 2 powder blend. For crystalline materials, surface amorphization is a phenomenon which is known to impact performance. Since it is important to measure and control the level of amorphicity, several characterization techniques are available to determine the bulk amorphous content of a processed material. The possibility of characterizing the degree of amorphicity at the surface, for example by studying the mechanical properties of the particles' surface at the nanoscale, is currently only offered by atomic force microscopy (AFM). The AFM PeakForce QNM technique has been used to measure the variation in energy dissipation (eV) at the surface of the particles which sheds light on the mechanical changes occurring as a result of amorphization or recrystallization events. Two novel approaches for the characterization of amorphicity are presented here. First, since particles are heterogeneous, we present a methodology to present the results of extensive QNM analysis of multiple particles in a coherent and easily interpreted manner, by studying cumulative distributions of dissipation data with respect to a threshold value which can be used to distinguish the crystalline and amorphous states. To exemplify the approach, which is generally applicable to any material, reference materials of purely crystalline alpha-lactose monohydrate and completely amorphous spray dried lactose particles were compared to a partially amorphized alpha-lactose monohydrate sample. Dissipation data are compared to evaluations of the lactose samples with conventional AFM and SEM showing significant topographical differences. Finally, the recrystallization of the surface amorphous regions in response to humidity was followed by studying the dissipation response of a well-defined surface region over time, which confirms both that dissipation measurement is a useful measure of surface amorphicity and that significant recrystallization occurs at the surface in response to humidity.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-317609 (URN)10.1021/acs.langmuir.6b03969 (DOI)000393269700010 ()
Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-11-29Bibliographically approved

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