Eerikäinen, Hannele

VTT Processes, Biologinkuja 7, P.O.Box 1602, FI–02044 VTT, Finland

VTT Publications 563, May 2005, 112 p. + app. 55 p. [in English]
ISBN 951–38–6443–X (soft back ed.)
ISBN 951–38–6444–8 (PDF edition)

Keywords: methacrylic polymer nanoparticles, preparation of drug nanoparticles, aerosol flow reactor method, drug release, solubility properties, particle size, morphology, crystallinity, thermal properties, drug content

Abstract

Drug-containing polymer nanoparticles are submicron-sized particles consisting of drug and stabilising or functional polymer. In this experimental study, methacrylic polymer nanoparticles with and without incorporated model drug were prepared using a novel method, namely, aerosol flow reactor method. This method involves first preparing a solution containing the drug and the polymer, followed by spraying the solution as nanosized droplets into a carrier gas stream, then drying the nanoparticles in a tubular laminar flow reactor tube, and finally collecting the nanoparticles. Model polymers used in this study were Eudragit L, Eudragit E, and Eudragit RS, which are commonly used methacrylic polymers in the pharmaceutical industry. Model drugs studied were beclomethasone dipropionate, ketoprofen, and naproxen.

Various properties of the prepared nanoparticles were studied, such as particle size and size distribution, morphology, crystallinity, thermal properties, drug content, and drug release. It was found that this method could be used to produce amorphous, spherical, homogeneous matrix-type drug-polymer nanoparticles. The size of the particles was adjusted between 90 and 200 nm by the concentration of the solution. The morphology of the particles varied as a function of the properties and composition of the starting solution.

The nanoparticles were collected as dry powders, but the stability of the powders in an amorphous form was found to be dependent on the interactions between the drug and the polymer. When the amount of the drug in the nanoparticles was below the solubility limit of the drug in the polymer, the amorphous nanoparticles were found to be stable and no crystallisation of the drug took place. When the amount of the drug was larger than the solubility limit, large crystalline structures were formed due to crystallisation of the drug. The crystallisation was also dependent on the thermal properties of the drug, as amorphous nanoparticles consisting of a drug having a high glass transition temperature could be collected at room temperature. A low glass transition temperature of the drug led to crystallisation of the drug at ambient conditions, when the drug amount in the nanoparticles was larger than the solubility limit. Drug release from the nanoparticles could be modified by using polymers having specific solubility properties.

Contents

Abstract
Preface
List of original publications
List of symbols and abbreviations
1. Introduction
2. Review
2.1 Structures of drug nanoparticles
2.2 Applications of drug nanoparticles
2.2.1 Biodegradable and non-biodegradable materials
2.2.2 Oral administration
2.3 Theory of dissolution
2.4 Amorphous drug materials and amorphous solid solutions consisting of drug and polymer
2.5 Polymer materials of the study
2.6 Methods of preparation of drug nanoparticles
3. Objective of the study
4. Experimental
4.1 Aerosol flow reactor method for the preparation of nanoparticles
4.1.1 Starting solution and atomisation
4.1.2 Solvent evaporation
4.1.3 Particle sampling and collection
4.2 Materials
4.2.1 Drug materials
4.2.2 Polymer materials
4.3 Instrumentation and characterisation
5. Results
5.1 Particle size, particle size distribution, and particle morphology (I, II, III, IV)
5.1.1 Particle size and particle size distribution as a function of solution concentration (IV)
5.1.2 Particle size and particle morphology (I, II, III)
5.2 Collection and properties of bulk nanoparticle powder (III, IV, V)
5.2.1 Collection of the nanoparticles (III, IV, V)
5.2.2 Drug release from nanoparticles containing ketoprofen (IV, V)
5.2.3 Drug release from nanoparticles containing beclomethasone dipropionate
5.2.4 Stability of the nanoparticles
6. Summary and conclusions
References
Appendices
Publications I–V

Figures and Tables

Figure 1. Schematics of exemplary types of drug nanoparticles. A. A matrix-type nanoparticle, where the drug molecules are evenly dispersed in the polymer matrix. B. A core-shell nanoparticle, where a core containing the drug is covered with a polymer shell. C. A matrix-type nanoparticle, where drug crystals are imbedded in a polymer matrix. Adapted from [20].

Table 1. Examples of applications and preparation methods of nanoparticles.
a) Range of mean particle sizes reported in the publication, expressed as mean±standard deviation of the distribution, where available. Geometric standard deviation used for lognormal distributions is described in [42].

Figure 2. Schematic representation of a model depicting the dissolution process [113].

Figure 3. Diagrammatic representation of a solid carboxylic acid, HA, dissolving into a reactive medium containing hydroxide ion and buffer components B and BH+ with a Nernst diffusion layer existing between the solid and the bulk solution. Sink conditions exist in the bulk solution, and the products, BH+, A-, and H+, diffuse out of the diffusion layer at a rate determined by their chemical reactivity and diffusivity [116].

Figure 4. Schematic depiction of the variation of enthalpy (or volume) as a function of temperature for crystalline and amorphous (glassy) solid material [129].

Figure 5. Schematics of particle formation in the aerosol flow reactor method.

Figure 6. Experimental set-up used in the preparation of nanoparticles (N2 = clean, dry pressurized nitrogen, Vac. = vacuum, l/min = standard litres per minute, Kr-85 aerosol neutraliser using 85Kr b-source, DMA = differential mobility analyser, CPC = condensation particle counter) (II, IV, V).

Figure 7. Temperature (t (K), upper part) and velocity contours (u (m/s), lower part) in the aerosol flow reactor, 80 °C temperature, 1.5 l/min carrier gas flow rate. Courtesy of David P. Brown (published with permission) [213, 214].

Table 2. Physicochemical properties of the drug materials studied.

Table 3. Physicochemical properties of the polymer materials studied.

Figure 8. Determination of glass transition temperatures for exemplary curves. A) Nanoparticles containing 25% (w/w) ketoprofen / 75% (w/w) Eudragit E, B) Nanoparticles containing 0% (w/w) ketoprofen / 100% (w/w) Eudragit L.

Figure 9. Particle size distributions for the various starting solution concentrations (IV).

Figure 10. Geometric number mean diameter and calculated particle volume as a function of starting solution concentration. The dashed line represents linear least squares fit of particle volume data points (r2 =0.99070) (IV).

Figure 11. Geometric number mean diameter of the nanoparticles containing various amounts of drug and polymer as a function of temperature. Total concentration of solids was 1 g/l (III).

Figure 12. TEM image of a hollow BDP nanoparticle produced (I).

Figure 13. A summary of the effects of various parameters on particle morphology (II).

Figure 14. SEM images of polymer nanoparticles containing 50% (w/w) Eudragit L and 50% (w/w) BDP. The nanoparticles were prepared from A) a good solvent (ethanol) or B) a mixture of a good solvent (ethanol) and a poor solvent (water). Nominal magnification 50000x.

Figure 15. X-ray diffraction patterns of the nanoparticles. A) Untreated ketoprofen. B) 50% (w/w) ketoprofen / 50% (w/w) Eudragit L nanoparticles. C) 25% (w/w) ketoprofen / 75% (w/w) Eudragit L nanoparticles. Curve A was reduced by a factor of 4 to fit in the same image. The curves are shifted along y-axis for clarification (IV).

Figure 16. Differential scanning calorimetry thermograms of the nanoparticles. A) Untreated ketoprofen. B) 50% (w/w) ketoprofen / 50% (w/w) Eudragit L nanoparticles. C) 33% (w/w) ketoprofen / 67% (w/w) Eudragit L nanoparticles. D) 25% (w/w) ketoprofen / 75% (w/w) Eudragit L nanoparticles. E) 10% (w/w) ketoprofen / 90% (w/w) Eudragit L nanoparticles. F) 100 % (w/w) Eudragit L nanoparticles. Curve A was reduced by a factor of 20 to fit in the same image. The curves are shifted along y-axis for clarification (IV).

Figure 17. TEM image showing amorphous, spherical nanoparticles prepared. Nanoparticles containing 25% (w/w) ketoprofen and 75% (w/w) Eudragit L. Electron optical magnification 5600x (IV).

Figure 18. Exemplary SEM images of the collected nanoparticle powders. A) Nanoparticles containing 33% (w/w) ketoprofen and 67% (w/w) Eudragit L. Nominal magnification 50000x. B) Nanoparticles containing 10% (w/w) naproxen and 90% (w/w) Eudragit L. Nominal magnification 50000x. C) Nanoparticles containing 67% (w/w) ketoprofen and 33% (w/w) Eudragit L. Nominal magnification 10000x. D) Nanoparticles containing 67% (w/w) naproxen and 33% (w/w) Eudragit L. Nominal magnification 10000x (IV).

Figure 19. Schematics of the drug-polymer structures formed in particle collection.

Table 4. Glass transition temperatures of the nanoparticles prepared from ketoprofen and various polymers. a) Also an endothermic transition corresponding to the melting of ketoprofen crystals was observed at 94 °C (V).

Figure 20. Differential scanning calorimetry thermograms of the ketoprofen nanoparticles. A) Untreated ketoprofen, B) Nanoparticles containing 50% (w/w) ketoprofen, C) Nanoparticles containing 33% (w/w) ketoprofen, D) Nanoparticles containing 25% (w/w) ketoprofen, E) Nanoparticles containing 10% (w/w) ketoprofen, F) Nanoparticles containing 5% (w/w) ketoprofen, G) Nanoparticles containing 0% (w/w) ketoprofen. Curve A was reduced by a factor of 20 to fit in the same image. The curves are shifted along y-axis for clarification (V).

Figure 21. Exemplary scanning electron microscopy images of the ketoprofen nanoparticles. A) Nanoparticles containing 25% (w/w) ketoprofen and 75% (w/w) Eudragit L. Nominal magnification 50000x. B) Nanoparticles containing 10% (w/w) ketoprofen and 90% (w/w) Eudragit RS. Nominal magnification 50000x. C) Nanoparticles containing 25% (w/w) ketoprofen and 75% (w/w) Eudragit E. Nominal magnification 5000x. D) Nanoparticles containing 25% (w/w) ketoprofen and 75% (w/w) Eudragit RS. Nominal magnification 10000x ().

Figure 22. Glass transition temperatures of the nanoparticles containing ketoprofen and polymer. For the calculated values, the glass transition temperature of the nanoparticles consisting of only polymer was used as the polymer glass transition temperature.

Figure 23. Exemplary infrared spectra at a wavenumber range of 2000–1500 cm-1. A) Pure ketoprofen. B) Nanoparticles containing 33% (w/w) ketoprofen. C) Pure polymer. The curves are shifted along y-axis for clarification (V).

Figure 24. Exemplary infrared spectra at a wavenumber range of 3500–2500 cm-1. A) Pure ketoprofen. B) Nanoparticles containing 33% (w/w) ketoprofen. C) Pure polymer. The curves are shifted along y-axis for clarification (V).

Figure 25. DSC scans of nanoparticles containing various amounts of BDP and Eudragit L. A) 100% (w/w) BDP, B) 80% (w/w) BDP / 20% (w/w) Eudragit L, C) 60% (w/w) BDP / 40% (w/w) Eudragit L, D) 50% (w/w) BDP / 50% (w/w) Eudragit L, E) 100% (w/w) Eudragit L. Observed crystallisation and melting of the crystals are marked with cr and m, respectively . The curves are shifted along y-axis for clarification (III).

Figure 26. Ketoprofen release for nanoparticles containing various amounts of drug as a function of time (IV). Pure ketoprofen denotes untreated, commercial, crystalline ketoprofen powder (particle size 90% less than 19 µm).

Figure 27. Ketoprofen release for nanoparticles containing various polymers as a function of time. All the nanoparticles studied for drug release contained 10% (w/w) ketoprofen (V). Pure ketoprofen denotes untreated, commercial, crystalline ketoprofen powder (particle size 90% less than 19 µm).

Figure 28. Schematic representation of dissolution of a polyelectrolyte containing carboxylic acid groups (Eudragit L).

Figure 29. Compartmental absorption and transit model [264].

Figure 30. CAT modeling (CAT predicted) of literature reference data (Observed) and CAT modeling (Nanoparticles predicted) of nanoparticles containing ketoprofen and Eudragit RS.

Figure 31. BDP release for pure BDP (particle size 90% less than 6 µm) and BDP nanoparticles.

Figure 32. X-ray diffraction patterns of nanoparticle dry powder containing 33% (w/w) ketoprofen and 67% (w/w) Eudragit L after 3 months storage time. A) Nanoparticle dry powder stored in a refrigerator. B) Nanoparticle dry powder stored at 25 °C at 0% relative humidity. C) Nanoparticle dry powder stored at 25 °C at 75% relative humidity. The curves are shifted along y-axis for clarification.

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