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Interfacial and material aspects of powders with relevance to pharmaceutical tableting performance
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science. RISE.ORCID iD: 0000-0001-5894-7123
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tablets are the most common forms of drug administration. They are convenient to administer and easy to manufacture. However, problems associated with the adhesion of the powders to the tableting tools are common. This phenomenon is known as sticking and even though it has been well documented and studied, it remains poorly understood. The many factors that contribute to good performance of the powders make the sticking problem difficult to solve.

The goal of this study is to establish a relationship between the properties measured at the nanoscale to the overall tablet mechanical properties, tablet performance and powder pre-processing induced modifications. By using atomic force microscopy (AFM) we aim to develop an analytical method to characterize the mechanical and adhesive properties of the pharmaceutical powders at the nanoscale. Other methodologies such as scanning electron microscopy (SEM), thermal analyses (DSC, TGA) and tablet strength test were also used. The materials used in this study are commonly used excipients, a sticky drug and magnesium stearate (MgSt). Two different approaches offered by AFM were employed: sharp tip imaging and colloidal probe force measurements. Nano-mechanical properties of the materials were evaluated with a sharp tip cantilever showing that higher adhesion correlates with higher tablet cohesion and that both are significantly affected by the presence of MgSt. AFM characterization of the particle surface mechanical properties at the nanoscale was also used to detect the crystallinity and amorphicity levels of the materials. New approaches to presenting such data considering the particle heterogeneity and to track the dynamics of surface recrystallization are revealed. Adhesive interactions between a steel sphere and sticky and non-sticky powders were performed with the colloidal probe technique. Sticky materials presented a higher adhesion against the steel surface, and reveal the mechanism of stickiness.

This work thus contributes to the provision of predictability of the performance of formulations at an early stage of the development process.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2017. , p. 92
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2017:14
Keywords [en]
atomic force microscopy, excipients, surface characterization, tableting, milling, amorphisation
National Category
Materials Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-203125ISBN: 978-91-7729-293-7 (print)OAI: oai:DiVA.org:kth-203125DiVA, id: diva2:1081036
Public defence
2017-03-24, F3, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20170315

Available from: 2017-03-15 Created: 2017-03-13 Last updated: 2017-12-18Bibliographically approved
List of papers
1. 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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-203167 (URN)10.1021/acs.langmuir.6b03969 (DOI)000393269700010 ()2-s2.0-85011117083 (Scopus ID)
Note

QC 20170313

Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2017-12-19Bibliographically approved
2. Milling induced amorphisation andrecrystallization of α-lactose monohydrate
Open this publication in new window or tab >>Milling induced amorphisation andrecrystallization of α-lactose monohydrate
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 537, no 1-2, p. 140-147Article in journal (Refereed) Published
Abstract [en]

Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the alpha-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed alpha-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between un-processed a-lactose, 1 h and 20 h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1 h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1 h milled lactose and a fully amorphous thermal profile for the 20 h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spraydried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low-water glass transition.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
tableting, milling, lactose, amorphisation, recrystallization, mechanical properties, atomic force microscopy, differential scanning calorimetry, TGA
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:kth:diva-220332 (URN)10.1016/j.ijpharm.2017.12.021 (DOI)000424263700016 ()29262302 (PubMedID)2-s2.0-85038844261 (Scopus ID)
Note

QC 20171219

Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2018-02-22Bibliographically approved
3. Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure
Open this publication in new window or tab >>Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure
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2015 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, no 1-2, p. 315-323Article in journal (Refereed) Published
Abstract [en]

Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle-particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Adhesion, Atomic force microscopy, Excipients, Profilometry, Surface roughness, Tableting, lactose, magnesium stearate, mannitol, microcrystalline cellulose, Article, chemical binding, chemical structure, controlled study, drug formulation, elasticity, hydrophilicity, lubrication, mechanics, priority journal, scanning electron microscopy, strength, tablet, tablet hardness, tablet property, tablet surface
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:kth:diva-167709 (URN)10.1016/j.ijpharm.2015.03.049 (DOI)000353999100034 ()2-s2.0-84928336238 (Scopus ID)
Note

QC 20150602

Available from: 2015-06-02 Created: 2015-05-22 Last updated: 2018-01-11Bibliographically approved
4. AFM colloidal probe measurements implicate capillary condensation in punch-particle surface interactions during tableting
Open this publication in new window or tab >>AFM colloidal probe measurements implicate capillary condensation in punch-particle surface interactions during tableting
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(English)Article in journal (Refereed) Submitted
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-203318 (URN)
Note

QCR 20170322

Available from: 2017-03-15 Created: 2017-03-15 Last updated: 2017-12-18Bibliographically approved

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