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Pharmaceutical micro-particles give amorphous sucrose higher physical stability
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.
2011 (English)In: Internation Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 409, no 1-2, 96-103 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to explore how pharmaceutical micro-sized filler particles affect the amorphous stability of sucrose in sucrose/filler particle composites produced by freeze-drying. Focus was put on the filler particles' properties crystallinity, hygroscopicity, hydrophobicity, and surface area, and their influence on physical stability of the amorphous phase. The micro-sized filler particles were examined with Blaine permeametry, gas adsorption, pycnometry, gravimetric vapour sorption, X-ray diffraction, and light microscopy before composites of sucrose and micro-sized filler particles were prepared by freeze-drying. The stability of the composites was examined with X-ray diffraction, differential scanning calorimetry (DSC), and microcalorimetry. All composites were amorphous and showed higher stability compared to pure amorphous sucrose, which was evident from a delay in heat and moisture-induced crystallization. However, calcium carbonate and oxazepam micro-sized filler particles lost their ability to stabilize the amorphous sucrose when exposed to humidity. The dry glass transition temperature (T-g) was higher for the composites, indicating the stabilization was mediated by a reduced molecular mobility of the amorphous phase.

Place, publisher, year, edition, pages
2011. Vol. 409, no 1-2, 96-103 p.
Keyword [en]
Amorphous, Sucrose, Physical stability, Freeze-drying, Crystallization, Micro-particles
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-153962DOI: 10.1016/j.ijpharm.2011.02.031ISI: 000290135800012PubMedID: 21356288OAI: oai:DiVA.org:uu-153962DiVA: diva2:418518
Available from: 2011-05-23 Created: 2011-05-23 Last updated: 2016-09-01Bibliographically approved
In thesis
1. Pharmaceutical Nanocomposites: Structure–Mobility–Functionality Relationships in the Amorphous State
Open this publication in new window or tab >>Pharmaceutical Nanocomposites: Structure–Mobility–Functionality Relationships in the Amorphous State
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amorphous materials are found in pharmaceutical formulations both as excipients and active ingredients. Indeed, these formulations are becoming an essential strategy for incorporating drugs into well-performing solid dosage forms. However, there is an unmet need of better understanding of the microstructure and component interactions in amorphous formulations to be able to design materials with improved functionalities. The aim of this thesis is to give deepened knowledge about structure-mobility-functionality relationships in amorphous for-mulations by studying composites produced from sugars and filler particles. The structure, the mobility, and physical stability of the composite materials were studied using calorimetry, X-ray diffraction, microscopy, spectroscopy, and molecular dynamics simulations. Further, the moisture sorption of the composites was determined with dynamic vapor sorption. The compression mechanics of the composites was evaluated with compression analysis.

It was demonstrated that fillers change the overall properties of the amorphous material. Specifically, the physical stability of the composite was by far improved compared to the amorphous sugar alone. This effect was pronounced for formulations with 60 wt% filler content or more. Amorphous lactose that normally recrystallizes within a few minutes upon humidity exposure, could withstand recrystallization for several months at 60% RH in composites with 80 wt% cellulose nanocrystals (CNC) or sodium montmorillonite (Na-MMT). The increased physical stability of the amorphous sugars was related to intra-particle confinement in extra-particle voids formed by the fillers and to immobilization of the amorphous phase at the surface of the fillers. Also, the composite formation led to increased particle hardness for the lactose/CNC and the lactose/Na-MMT nanocomposites. The largest effect on particle hardness was seen with 40-60 wt% nanofiller and could be related to skeleton formation of the nanofillers within the composite particles. The hygroscopicity for the lactose/Na-MMT nanocomposites decreased as much as 47% compared to ideal simple mixtures of the neat components. The nanofillers did not influence the water sorption capacity in the amorphous domains; however, lactose (intercalated into Na-MMT) interacted with the sodium ions in the interlayer space which led to the lowered hygroscopicity of this phase.

The thesis advanced the knowledge of the microstructure of amorphous pharmaceutical com-posites and its relationship with pharmaceutical functionalities. It also presented new approaches for stabilizing the amorphous state by using fillers. The concept illustrated here might be used to understand similar phenomena of stabilization of amorphous formulations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 79 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 220
amorphous, pharmaceutical composites, solid state, structure, molecular mobility, spray-drying, freeze-drying, moisture sorption, physical stability, compression
National Category
Materials Chemistry
Research subject
Pharmaceutical Science
urn:nbn:se:uu:diva-300159 (URN)978-91-554-9642-5 (ISBN)
External cooperation:
Public defence
2016-09-23, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2016-08-31 Created: 2016-08-03 Last updated: 2016-09-05

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