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Drugs and polymers in dissolving solid dispersions: NMR imaging and spectroscopy
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Physical Chemistry.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The number of poorly water-soluble drug substances in the pharmaceutical pipeline is increasing, and thereby also the need to design effective drug delivery systems providing high bioavailability. One favourable formulation approach is preparation of solid dispersions, where dispersing a poorly water-soluble drug in a water-soluble polymer matrix improves the dissolution behaviour and the bioavailability of the drug. However, in order to take full advantage of such formulations the impact of material properties on their performance needs to be investigated.

 

An experimental toolbox has been designed, and applied, for analysing the processes which govern the behaviour of solid pharmaceutical formulations in general, and that of solid dispersions in particular. For the purpose of monitoring multifaceted phenomena in situ during tablet dissolution, nuclear magnetic resonance (NMR) spectroscopy and NMR imaging are superior to many other techniques, both on macroscopic and molecular levels. The versatility of NMR with its isotope and chemical selectivity allows one to follow the influence of the original tablet properties on polymer mobilisation, drug migration and water penetration selectively. Mapping these processes on relevant time scales in dissolving tablets highlighted the gel layer inhomogeneity below the originally dry tablet surface as a key factor for drug release kinetics.

 

Furthermore, NMR relaxometry has been shown to provide novel information about the particle size of the drug and its recrystallisation behaviour within swelling solid dispersions. The NMR experiments have been complemented and supported by investigation of the crystalline state, the powder morphology and the surface composition of the dry solid dispersions. These experiments have been performed by X-ray photoelectron spectroscopy (XPS),  scanning electron microscopy (SEM), powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and dynamic contact angle (DAT) measurements.

 

The methods presented in this thesis provide a new avenue towards better understanding of the behaviour of solid dispersions, which in turn may result in more effective distribution of promising drug candidates despite their low water-solubility.

Abstract [sv]

En allt större andel av de läkemedelssubstanser som idag är av intresse för den farmaceutiska industrin är svårlösliga i vatten. För att trots detta erhålla hög biotillgänglighet måste man utveckla beredningsformer som medger effektiv frisättning av den aktiva substansen. En lovande sådan beredningsform utgörs av fasta dispersioner, där den svårlösliga substansen finfördelas i en vattenlöslig polymer. För att utnyttja dessa dispersioners potential fullt ut måste dock materialegenskapernas inverkan på deras beteende kartläggas i större utsträckning än vad som tidigare gjorts.

 

En uppsättning experimentella metoder har i detta arbete utvecklats och använts för att analysera de processer som styr beteendet hos fasta läkemedelsberedningar i allmänhet, och fasta dispersioner i synnerhet. För observation av sådana processer in situ, under pågående tablettupplösning, är NMR-spektroskopi (kärnmagnetisk resonans-spektroskopi) och NMR-avbildning överlägsna många andra tekniker, både på makroskopisk och på molekylär nivå. NMR är en mångsidig metod med både isotop- och kemisk selektivitet. Genom att utnyttja dessa möjligheter kan de enskilda sambanden mellan den ursprungliga tablettens materialegenskaper och polymermobilisering, vatteninträngning och den aktiva substansens migrering följas separat. Kartläggning av dessa processer, på relevanta tidsskalor i tabletter under upplösning, påvisar att gellagrets inhomogenitet inuti den ursprungliga tabletten har stor betydelse för frisättningskinetiken.

 

Vidare visar sig NMR-relaxometri ge värdefull information om den aktiva substansens partikelstorlek och dess omkristallisationsbeteende i fasta dispersioner under svällning och upplösning. NMR-experimenten kompletteras med oberoende karakterisering av det kristallina tillståndet, pulvermorfologin och ytsammansättningen hos de torra fasta dispersionerna. Dessa experiment utförs med hjälp av XPS (röntgen-fotoelektronspektroskopi), SEM (elektronmikroskopi), pXRD (pulver-röntgendiffraktion), DCS (differentiell kalorimetri), FTIR (infraröd Fourier transform spektroskopi) och DAT (dynamisk kontaktvinkel) mätningar.

 

De metoder som presenteras i den här avhandlingen pekar mot nya vägar att nå djupare förståelse för beteendet hos fasta dispersioner, vilket i sin tur kan leda till att fler lovande läkemedelssubstanser kan distribueras effektivt trots begränsad vattenlöslighet.

Place, publisher, year, edition, pages
Stockholm: KTH , 2010. , 76 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2010:1
National Category
Physical Chemistry Physical Chemistry Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-11783ISBN: 978-91-7415-510-5 (print)OAI: oai:DiVA.org:kth-11783DiVA: diva2:281756
Public defence
2010-01-21, hörsal F3, Lindstedtsvägen 26, KTH, Stockholm, 09:30 (English)
Opponent
Supervisors
Note
QC 20100915Available from: 2009-12-18 Created: 2009-12-17 Last updated: 2010-09-15Bibliographically approved
List of papers
1. Polymer mobilization and drug release during tablet swelling: A 1H NMR and NMR microimaging study
Open this publication in new window or tab >>Polymer mobilization and drug release during tablet swelling: A 1H NMR and NMR microimaging study
2007 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 122, 199-205 p.Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to investigate the swelling characteristics of a hydroxypropyl methylcellulose (HPMC) matrix incorporating the hydrophilic drug antipyrine. We have used this matrix to introduce a novel analytical method, which allows us to obtain within one experimental setup information about the molecular processes of the polymer carrier and its impact on drug release. Nuclear magnetic resonance (NMR) imaging revealed in situ the swelling behavior of tablets when exposed to water. By using deuterated water, the spatial distribution and molecular dynamics of HPMC and their kinetics during swelling could be observed selectively. In parallel, NMR spectroscopy provided the concentration of the drug released into the aqueous phase. We find that both swelling and release are diffusion controlled. The ability of monitoring those two processes using the same experimental setup enables mapping their interconnection, which points on the importance and potential of this analytical technique for further application in other drug delivery forms.

Keyword
Magnetic resonance imaging, Nuclear magnetic resonance spectroscopy, Hydroxypropyl methylcellulose, Swelling, Gel formation, Diffusion
Identifiers
urn:nbn:se:kth:diva-11785 (URN)10.1016/j.jconrel.2007.07.007 (DOI)000250068700010 ()
Note
QC 20100915Available from: 2009-12-18 Created: 2009-12-18 Last updated: 2017-12-12Bibliographically approved
2. Relationships between solid dispersion preparation process, particle size and drug release: an NMR and NMR microimaging study
Open this publication in new window or tab >>Relationships between solid dispersion preparation process, particle size and drug release: an NMR and NMR microimaging study
2010 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 76, no 2, 311-319 p.Article in journal (Refereed) Published
Abstract [en]

Solid dispersion tablets prepared by either spray drying or rotoevaporation and exhibiting different grain and pore sizes were investigated under the process of hydration-swelling-gelation. H-2 and H-1 NMR microimaging experiments were used to selectively follow water penetration and polymer mobilization kinetics, respectively, while the drug release kinetics was followed by H-1 NMR spectroscopy. The obtained data, in combination with morphological information by scanning electron microscopy (SEM), reveal a complex process that ultimately leads to release of the drug into the aqueous phase. We find that the rate of water ingress has no direct influence on release kinetics, which also renders air in the tablets a secondary factor. On the other hand, drug release is directly correlated with the polymer mobilization kinetics. Water diffusion into the originally dry polymer grains determines the rate of grain swelling and the hydration within the grains varies strongly with grain size. We propose that this sets the stage for creating homogeneous gels for small grain sizes and heterogeneous gels for large grain sizes. Fast diffusion through water-rich sections of the inhomogeneous gels that exhibit a large mesh size is the factor which yields a faster drug release from tablets prepared by rotoevaporation.

Keyword
Gel layer formation, Rotoevaporation, Spray drying, Hydroxypropyl methylcellulose, HPMC, Diffusion
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:kth:diva-24544 (URN)10.1016/j.ejpb.2010.06.006 (DOI)000283756700021 ()2-s2.0-77957281261 (Scopus ID)
Note
QC 20100915. Uppdaterad från submitted till published (20101207).Available from: 2010-09-15 Created: 2010-09-15 Last updated: 2017-12-12Bibliographically approved
3. Surface composition and contact angle relationships for differently prepared solid dispersions
Open this publication in new window or tab >>Surface composition and contact angle relationships for differently prepared solid dispersions
2008 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 70, 478-485 p.Article in journal (Refereed) Published
Abstract [en]

Solid dispersions are promising drug delivery forms which offer the possibility to disperse a hydrophobic drug in a hydrophilic matrix and thereby improve the dissolution behavior and the bioavailability of the drug. One important aspect and a prerequisite in understanding the drug dissolution mechanism from solid dispersions is a better analytical monitoring of the solid dispersion surface properties, such as powder surface composition and water adsorption properties. In this paper, we have considered chemical and structural surface analysis data for solid dispersions processed by spray drying or roto-evaporation and compared these data with information obtained by contact angle measurements. Firstly, we establish the usefulness and suitability of X-ray photoelectron spectroscopy (XPS) for determination of surface chemical composition and scanning electron microscopy (SEM) for determining the structure of solid dispersions composed of different types of carriers, drugs and drug concentrations. Secondly, we measure contact angles of solid dispersions to describe wettability, to finally establish a link between the surface chemical composition, the powder structure and the wetting behavior. These experimental methods offer a rapid screening tool for the selection of carrier, drug concentration and/or process in early development. In addition, they provide a useful tool for investigating structural aspects of solid dispersions which have intrinsic relevance for drug dissolution and stability.

Keyword
Solid dispersions, Roto-evaporation, Wettability, Spray drying, Contact angle, Surface composition, XPS, Powder morphology
Identifiers
urn:nbn:se:kth:diva-11786 (URN)10.1016/j.ejpb.2008.05.026 (DOI)000260697400008 ()2-s2.0-52949135898 (Scopus ID)
Note
QC 20100915Available from: 2009-12-18 Created: 2009-12-18 Last updated: 2017-12-12Bibliographically approved
4. Polymer–drug interactions and wetting of solid dispersions
Open this publication in new window or tab >>Polymer–drug interactions and wetting of solid dispersions
2009 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 39, no 1-3, 125-133 p.Article in journal (Refereed) Published
Abstract [en]

We demonstrate the ability of drugs to influence the wetting of solid dispersion tablets in unexpected ways. Five model drugs of different water solubility and ability to interact with the involved polymers were incorporated in hydrophilic polymer matrices, made of either hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP). The physical mixtures of all combinations of drug and polymer presented surface hydrophobicities, as measured by the equilibrium advancing contact angle of water, which are expected for materials that do not influence the interactions of each other with water. However, the solid dispersions containing HPMC deviated from this regular behaviour and displayed contact angles below those of the pure compounds involved, either drug or polymer. This behaviour is explained by changed surface exposure of HPMC side groups, as a result of changes in intermolecular hydrogen bonds. In addition to water contact angle measurements, we employed NMR imaging to monitor the time course of water ingress and swelling.

Keyword
Contact angle, Hydrophilic matrices, Nuclear magnetic resonance imaging, Hydroxypropyl methylcellulose (HPMC), Polyvinyl pyrrolidone (PVP)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-11787 (URN)10.1016/j.ejps.2009.11.005 (DOI)000274672300018 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note
QC 20100915Available from: 2009-12-18 Created: 2009-12-18 Last updated: 2017-12-12Bibliographically approved
5. Estimating the size range of drug nanoparticles in solid dispersions by NMR spectroscopy
Open this publication in new window or tab >>Estimating the size range of drug nanoparticles in solid dispersions by NMR spectroscopy
(English)Manuscript (preprint) (Other academic)
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-24545 (URN)
Note
QC 20100915Available from: 2010-09-15 Created: 2010-09-15 Last updated: 2012-01-11Bibliographically approved
6. Recrystallization of drug nanoparticles in solid dispersion tablets by multinuclear NMR spectroscopy and NMR microimaging
Open this publication in new window or tab >>Recrystallization of drug nanoparticles in solid dispersion tablets by multinuclear NMR spectroscopy and NMR microimaging
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences
Identifiers
urn:nbn:se:kth:diva-24547 (URN)
Note
QC 20100915Available from: 2010-09-15 Created: 2010-09-15 Last updated: 2012-01-11Bibliographically approved

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