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Pharmaceutical Nanocomposites: Structure–Mobility–Functionality Relationships in the Amorphous State
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 220
Keyword [en]
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
Identifiers
URN: urn:nbn:se:uu:diva-300159ISBN: 978-91-554-9642-5OAI: oai:DiVA.org:uu-300159DiVA: diva2:951082
Public defence
2016-09-23, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-08-31 Created: 2016-08-03 Last updated: 2016-09-05
List of papers
1. Pharmaceutical micro-particles give amorphous sucrose higher physical stability
Open this publication in new window or tab >>Pharmaceutical micro-particles give amorphous sucrose higher physical stability
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.

Keyword
Amorphous, Sucrose, Physical stability, Freeze-drying, Crystallization, Micro-particles
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-153962 (URN)10.1016/j.ijpharm.2011.02.031 (DOI)000290135800012 ()21356288 (PubMedID)
Available from: 2011-05-23 Created: 2011-05-23 Last updated: 2016-09-01Bibliographically approved
2. Inhibition of Recrystallization of Amorphous Lactose in Nanocomposites Formed by Spray-Drying
Open this publication in new window or tab >>Inhibition of Recrystallization of Amorphous Lactose in Nanocomposites Formed by Spray-Drying
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.

Keyword
amorphous, crystallization, glass transition, mobility, physical stability, solid state, stabilization, spray drying, factorial design
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-266687 (URN)10.1002/jps.24583 (DOI)000362984100013 ()26182904 (PubMedID)
Available from: 2015-11-12 Created: 2015-11-10 Last updated: 2016-09-01Bibliographically approved
3. Structure and mobility of lactose in lactose/sodium montmorillonite nanocomposites
Open this publication in new window or tab >>Structure and mobility of lactose in lactose/sodium montmorillonite nanocomposites
Show others...
(English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827Article in journal (Refereed) Submitted
Abstract [en]

This study aims at investigating the molecular level organization and molecular mobility in montmorillonite nanocomposites with the uncharged organic low molecular weight compound lactose commonly used in pharmaceutical drug delivery, food technology, and flavoring. Nanocomposites were prepared under slow and fast drying conditions, attained by drying at ambient conditions and by spray-drying, respectively. A detailed structural investigation was performed with modulated differential scanning calorimetry, powder X-ray diffraction, solid-state nuclear magnetic resonance, scanning electron microscopy, microcalorimetry, and molecular dynamic simulations. The lactose was intercalated in the sodium montmorillonite interlayer space regardless of the clay content, drying rate, or humidity exposure. Although, the spray-drying resulted in higher proportion of intercalated lactose compared with the drying under ambient conditions, non-intercalated lactose was present at 20 wt% lactose content. This indicates limitations in maximum load capacity of nonionic organic substances into the montmorillonite interlayer space. Furthermore, a fraction of the intercalated lactose in the co-spray-dried nanocomposites diffused out from the clay interlayer space upon humidity exposure. Also, the lactose in the nanocomposites demonstrated higher molecular mobility than that of neat amorphous lactose. This study provides a foundation for understanding functional properties of nanocomposites, such as loading capacity and physical stability.

National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-300158 (URN)
External cooperation:
Available from: 2016-08-05 Created: 2016-08-03 Last updated: 2016-09-02Bibliographically approved
4. Confinement of Amorphous Lactose in Pores formed upon Co-Spray-Drying with Nanoparticles
Open this publication in new window or tab >>Confinement of Amorphous Lactose in Pores formed upon Co-Spray-Drying with Nanoparticles
(English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017Article in journal (Other academic) Submitted
Abstract [en]

This study aims at investigating factors influencing humidity induced recrystallization of amorphous lactose, produced by co-spray-drying with particles of cellulose nanocrystals (CNC) or sodium montmorillonite (Na-MMT). In particular, the focus is on how the nanoparticle shape and surface properties influence the nano- to micrometer length scale nanofiller arrangement in the nanocomposites and how the arrangements influence the mechanisms involved in the inhibition of the amorphous to crystalline transition. The nanocomposites were produced by co-spray-drying. Solid-state transformations were analyzed at 60-94% relative humidity using X-ray powder diffraction, microcalorimetry, and light microscopy. The recrystallization rate constant for the lactose/CNC and lactose/Na-MMT nanocomposites was lowered at nanofiller contents higher than 60% and were stable for months at 80% nanofiller. The most likely explanation to these results is spontaneous formations of mesoporous particle networks that the lactose is confined within upon co-spray-drying at high filler content. Compartmentalization and rigidification of the amorphous lactose proved to be less important mechanisms involved in the stabilization of lactose in the nanocomposites.

National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-300153 (URN)
External cooperation:
Available from: 2016-08-03 Created: 2016-08-03 Last updated: 2016-09-02Bibliographically approved
5. Humidity sorption of lactose/sodium montmorillonite nanocomposites
Open this publication in new window or tab >>Humidity sorption of lactose/sodium montmorillonite nanocomposites
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Understanding of water sorption is of high importance in materials science as water may change materials properties promoting degradation, relaxations, or recrystallization. In this study, we investigated the humidity sorption in co-spray-dried lactose/sodium montmorillonite nanocomposites with varying lactose loading with the aim to increase the knowledge of the water sorption in this type of materials. It was demonstrated that the intercalation of lactose in the Na‑MMT clay decreased hygroscopicity of the composite despite high water affinity of both materials. As the cations in interlayer space of montmorillonite play an essential role in water sorption in the clay, we gained the molecular level understanding of Na+ interactions with lactose molecules and clay surface in the nanocomposites with molecular dynamic simulations and 23Na solid-state NMR. In conclusion, we demonstrated that the decreased hygroscopicity of the materials can be explained by interactions of lactose with the Na+ and the clay surfaces in the MMT interlayer space of lactose/Na-MMT nanocomposites.

National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-300154 (URN)
Available from: 2016-08-03 Created: 2016-08-03 Last updated: 2016-09-01
6. Powder compression mechanics of spray-dried lactose nanocomposites
Open this publication in new window or tab >>Powder compression mechanics of spray-dried lactose nanocomposites
(English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476Article in journal (Other academic) Submitted
Abstract [en]

The aim of this study was to investigate the structural impact of the nanofiller incorporation on the powder compression mechanics of spray-dried lactose. The lactose was co-spray-dried with three different nanofillers, that is, cellulose nanocrystals, sodium montmorillonite, and fumed silica, which led to lower micron sized nanocomposite particles with varying structure and morphology. The powder compression mechanics of the nanocomposites and physical mixtures of the neat spray-dried components were evaluated by a rational evaluation method with compression analysis as a tool using the Kawakita equation and the Shapiro-Konopicky-Heckel equation. Particle rearrangement dominated the initial compression profiles due to the small particle sizes of the materials. The strong contribution of particle rearrangement in the materials with fumed silica continued throughout the whole compression profile, which prohibited an in-depth material characterization. However, the lactose/cellulose nanocrystals and the lactose/sodium montmorillonite nanocomposites demonstrated increased yield pressure compared with the physical mixtures indicating increased particle hardness. This increase has likely to do with a reinforcement of the nanocomposite particles by skeleton formation of the nanoparticles. In summary, the rational evaluation applying compression analysis proved to be a valuable tool for mechanical evaluation for this type of materials unless they demonstrate particle rearrangement throughout the whole compression profile.

National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-300156 (URN)
External cooperation:
Available from: 2016-08-05 Created: 2016-08-03 Last updated: 2016-09-02Bibliographically approved

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