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Inhibition of Recrystallization of Amorphous Lactose in Nanocomposites Formed by Spray-Drying
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.
2015 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 104, no 11, 3760-3769 p.Article in journal (Refereed) Published
Abstract [en]

This study aims at investigating the recrystallization of amorphous lactose in nanocomposites. In particular, the focus is on the influence of the nano- to micrometer length scale nanofiller arrangement on the amorphous to crystalline transition. Further, the relative significance of formulation composition and manufacturing process parameters for the properties of the nanocomposite was investigated. Nanocomposites of amorphous lactose and fumed silica were produced by co-spray-drying. Solid-state transformation of the lactose was studied at 43%, 84%, and 94% relative humidity using X-ray powder diffraction and microcalorimetry. Design of experiments was used to analyze spray-drying process parameters and nanocomposite composition as factors influencing the time to 50% recrystallization. The spray-drying process parameters showed no significant influence. However, the recrystallization of the lactose in the nanocomposites was affected by the composition (fraction silica). The recrystallization rate constant decreased as a function of silica content. The lowered recrystallization rate of the lactose in the nanocomposites could be explained by three mechanisms: (1) separation of the amorphous lactose into discrete compartments on a micrometer length scale (compartmentalization), (2) lowered molecular mobility caused by molecular interactions between the lactose molecules and the surface of the silica (rigidification), and/or (3) intraparticle confinement of the amorphous lactose.

Place, publisher, year, edition, pages
2015. Vol. 104, no 11, 3760-3769 p.
Keyword [en]
amorphous, crystallization, glass transition, mobility, physical stability, solid state, stabilization, spray drying, factorial design
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-266687DOI: 10.1002/jps.24583ISI: 000362984100013PubMedID: 26182904OAI: oai:DiVA.org:uu-266687DiVA: diva2:868932
Available from: 2015-11-12 Created: 2015-11-10 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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