Otto von Guericke University Magdeburg

Faculty for Process and Systems Engineering Department of Process Engineering

Mechanical Process Engineering

Production of monodisperse latex particles

Heterogeneous polymerisation processes for latex particles

Emulsion polymerisation process for monodisperse polystyrene NP

Poly-(n-butyl-2-cyanoacrylate) NP for medicine and pharmacy

Miniemulsion process - theoretical and experimental approachp p pp

L i N i l T h lLecture series: Nanoparticle Technology

Heterogeneous polymerisation techniques of particle formationpolymerisation

auxiliaries (e.g. initiators, buffer, emulsifier, stabiliser)

monomers polymer polymerisation

buffer, emulsifier, stabiliser)

Homogeneous systems: bulk polymerisation, solution polymerisation bulk polymeric mass

Heterogeneous systems: emulsion polymerisation, suspension polymerisation, dispersionHeterogeneous systems: emulsion polymerisation, suspension polymerisation, dispersion polymerisation, precipitation polymerisation, miniemulsion polymerisation latex partices

polymer latex particles

nodi

sper

se

artic

les

emulsion polymerisation

nd gr

owth

mon pa

dispersion polymerisation

emulsifier free emulsion polymerisation

rse s cleat

ion

an

precipitation polymerisation suspension polymerisation

p p y

polyd

isper

parti

cles

nu

0.01 μm 0.1 μm 1.0 μm 10 μm 100 μm 1000 μm

Suspension polymerisation process (Perl polymerisation)

redispersion by agitationfy

ing

redispersion creaming

interfacial tension e

mul

sify

coalescence agglomerationcreaming

atio

n

polymerisation polymerisation deagglomeration

polym

erisa

I monomer droplets before reaching identity point i l

secondary perls

p

g y p monomer sparely soluble in water, monomer redispersion by agitation, stabilisation of droplets

(0.15-5 mm) by polyvinylalcohol or BaSO4 (emulsion)

primary perls

II monomer droplets after reaching identity point

initiator (e.g. AIBN) soluble in monomer, polymerisation inside monomer droplets (suspension)

g y p

Precipitation polymerisation process

monomer dissolves in continuous phase - homogeneous solution (e.g. water-based polymeri-sation of acetonitrile, polymerisation of styrene in hexane or ethanol)

initiator is soluble in continuous phase initiation and polymerisation in the homogeneous phase - homogenous nucleation (primary

particles) agglomeration of nuclei - coagulative nucleation (particles are polydisperse 0.1 - 1000 μm) polymerisation medium is a precipitant for the resulting polymer)

Dispersion polymerisation process

monomer dissolves in continuous phase - homogeneous solution (e.g. water-based polymerisa- monomer dissolves in continuous phase homogeneous solution (e.g. water based polymerisation of acetonitrile, polymerisation of styrene in hexane or ethanol)

initiator is soluble in continuous phase initiation and polymerisation in the homogeneous phase - homogenous nucleation (primary initiation and polymerisation in the homogeneous phase homogenous nucleation (primary

particles) presence of stabilizer !!! - sterical stabilisation - (spherical particles 0.1 - 1000 μm without sufficient stabilisation - agglomeration of primary particles - coagulative nucleation without sufficient stabilisation agglomeration of primary particles coagulative nucleation polymerisation medium is a precipitant for the resulting polymer)

Emulsion polymerisation process

Theory according Fikentscher and HarkinsTheory according Fikentscher and Harkins

I Period of particle formation (Nucleation) Inside the O/W emulsion, there are micelles (5-10 nm), surfac-tant stabilized monomer droplets (1 10 µm) and initiatortant stabilized monomer droplets (1-10 µm), and initiator. Monomer is solubilizised inside micelles. Initiator forms radi-cals, later with in water sparely soluble monomer (styrene 4 g/L at 70°C) oligo radicals These oligo radicals are stabilized byat 70 C) oligo-radicals. These oligo-radicals are stabilized by surfactant (swollen micelles), or solubilizised in monomer con-taining micelles. Polymerisation starts, formation of small latex particle Ratio of monomer/water is 0 1–0 5 temperature fromparticle. Ratio of monomer/water is 0.1–0.5, temperature from 40°C to 80°C. Disappearance of micelles. II Period of growthII Period of growth Latex particles grow until monomer droplets in emulsion aregone. Increasing surface area of the latex particle adsorpts more surfactant molecules, no micelles. Disappearance of droplets.surfactant molecules, no micelles. Disappearance of droplets. III Period of final polymerisation Rest of monomers in the latex particles (50-300 nm) are polymerRest of monomers in the latex particles (50 300 nm) are polymerized.

Emulsion polymerisation process

number of latex particles depends on rate of radical formation, rate of increase in volume of polymer particle, interfa-cial area occupied by surfactant molecules, total concentration of surfactant in the micelle p y f , f f

rate of polymerisation - r = k3 (f · k1 / k4)1/2 [I]1/2[M] degree of polymerisation - P = k3 [M] · t with t interval of successive entries of radicals in

monomer-polymer particle

Emulsifier free emulsion process

p y p

monomer dissolves sparely in continuous phase (styrene - 4 g/L in water at 70°C) initiator (e.g. potassium peroxodisulphate) is soluble in continuous phase Initiator forms radicals, later in water with the monomer oligo- and macro-radicals (e.g. po-f , g ( g p

tassium alkoxysulphate radicals), homogenous nucleation (primary particles) - stabilized by polymer (charged by sulphate

groups on surface) g p f ) without sufficient stabilisation - agglomeration of primary particles - coagulative nucleation particles) polymerisation medium is a precipitant for the resulting polymer)p y p p f g p y ) ratio monomer to water much smaller than in normal emulsion polymerisation)

Free radical polymerisation process of styrene

Initiation: generation of free radicals I 2 R· (1) reaction with monomer to form growing chains R· + M R1· (2) r1 = k1 · [I] with k1 = 68.9 ·10-6 s-1 for potassium peroxodisulphate in water at 80 °C

Propagation (growth): monomer is added to radicals Mi· + M Mi+1· (3) r3 = k3 · [M][M·] with k3 = 176 L/(mol·s) for styrene at 60 °C, k3 independent on chain length

Termination (stop): bimolecular combination of two radicals Mi· + Mj· Mi+j (4a) disproportionation of two radicals Mi· + Mj· Mi + Mj (4b)

k 2 i h k 2 10 7 /( l ) f 60 °C r4 = k4· [M·]2 with k4 = 7.2 · 10-7 L/(mol·s) for styrene at 60 °C

Polymerisation rate: r = k3 (f · k1 / k4)1/2 [I]1/2[M] with f is the radical efficiency y 3 (f 4) [ ] [ ] f ff y

Experimental set-up for the polystyrene emulsion polymerisation process

Process parameter

temperature: 55°C - 85 °C duration: 2.0 - 24 hours water

surfactantwater: 100 -150 mL surfactant (sodium dodecyl sulphate): 0.06 - 1.2 g initiator (potassium peroxodisulphate: 0.06 - 2.0 g

surfactant buffer styrene initiator

buffer (borax): 0.01 -0.2gstyrene: 9.0 g discontinuous

stirred tank reactor

initiator

250 mL

polystyrene latex particle co-monomer (sodium styrene sulphonate): 0.45 - 1.0 g addition after 15 - 120 min

characterisation: particle size distribution zeta-potential

number of stirrer revolutions: 500 rpm circumferential speed: 0.58 s-1

zeta-potential f p

Experimental process parameter for polystyrene latex particles

Tab. 1: Process parameter for the emulsion polymerisation process with SDS (for 150 mL water)

charges SDS in g KPS in g borax in g temperature in °C process in hours S1 0 18 0 06 0 01 85 6S1 0.18 0.06 0,01 85 6S2 0.06 0.06 0,01 55 24 S3 0.06 0.06 0,01 65 24 S4 0 06 0 06 0 01 85 6S4 0.06 0.06 0,01 85 6S5 0.06 0,24 0,03 85 6

Tab. 2: Process parameter for the emulsion polymerisation process with NaSS (for 150 mL water)

charges SDS in g Na SS in g addition after min

KPS in g borax in g temperature in °C

process in hours

SF1 1 2 1 0 15 2 0 0 2 85 2SF1 1.2 1.0 15 2.0 0.2 85 2 SF2 0.3 1.0 25 1.0 0.1 85 2 SF2a 0.3 0.45 40 0.4 0.04 85 3 SF2b 0 2 0 45 40 0 4 0 04 85 3SF2b 0.2 0.45 40 0.4 0.04 85 3 SF3 0.2 0.45 60 0.4 0.04 70 5

SF4 0.2 0.45 90 0.1 0.01 70 5

SF5 0.06 0.9 120 0.06 0.03 85/50 6

SF5 0.06 0.9 120 0.06 0.03 85/50 6

L. Vorweg, Elektrokinetische Untersuchungen an Modellkolloiden zur Beurteilung ihrer Stabilität, Dissertation 1997, Universität Potsdam

Characterisation of the polystyrene latex particles

dynamic light scattering particle size distribution Q0(d), Q3(d)

particle size frequency distribution q0(d), q3(d)

polydispersity index PDI

from autocorrelation function g(τ)

median particle diameter d50,0, d50,3

mean particle diameter dm,0, dm,3

l di it i d PDI d /df f g( )

log g(τ) = a + b τ + c τ2 + ...

PDI = 2 c / b2 = σ2

polydispersity index: PDI = d50,3 /d50,0

non-uniformity index: U = PDI - 1

σ2 = d d U σ = dm,0 dm,0 U

electrophoretic mobility zeta - potential ζ

streaming potential surface charge density σ

Principle of dynamic light scattering correlation functionco elatio fu ctio

g (τ)= e-2·D·K²·τ D diffusion constant

Laser Optics Sample

K scattering light vector

τ delay time Photo multiplier correlator Optical Unit

Optical unit of photon correlation spectroscopy

Stokes – Einstein – equation

Optical Unit

Optical unit of photon correlation spectroscopy d = D3

Tk B

d particle diameter

g( )

I(t) small particle

large particle p

kB Boltzmann constant

T absolute temperature small particle

Scattering light intensity time function auto correlation function

η dynamical viscosity

time

large particle

Scattering light intensity – time – function auto correlation function

Determination of the zeta – potential for nanoparticle characterisation

Ch di t ib ti d i ti l i l t i l fi ld

anode cathode

Charge distribution around a moving particle in an electrical field

laser beams interference pattern scattering light detector Helmholtz-Smoluchowski–equation

ζ = 0Ev

particle ζ zeta - potential

E electrical intensityDetection of particle velocity in an interference pattern system

of two lasers

E electrical intensity v particle velocity η viscosity ε·ε0 dielectric constant

Experimental results for polystyrene latex particles

mean particle diameter 75.7 nm (number), 98.8 nm (volume)PDI = 0.124, zeta-potential -60.4 mV

80

100

Polystyrene S1P l S20(d

) in

%

60

80 Polystyrene S2

ribu

tion

Q0

40

le si

ze d

istr

20mean particle diameter 194.4 nm (number) 242.1 nm (volume)PDI = 0.084, zeta-potential -46.8 mV

Part

icl

0 100 200 300 4000

Particle diameter d in nmV i ti f ti l i f l t l t ti l d d b l i l i tiParticle diameter d in nmVariation of particle sizes of polystyrene latex particles produced by emulsion polymerisation – from styrene, potassium peroxodisulphate, borax (stabilisation with sodium dodecyl sulphate)

Experimental results for polystyrene latex particles

100

Polystyrene latex nanoparticles stabilised with SDS and NaSS

%

80 Polystyrene SF1Polystyrene SF2aon

Q0(d

) in

60

Polystyrene SF2a Polystyrene SF3 Polystyrene SF2Polystyrene SF4e

dist

ribu

tio

20

40y y

Polystyrene SF5 Polystyrene SF2b

Part

icle

size

0 50 100 150 2000

20P

0 50 100 150 200

Particle diameter d in nmVariation of particle sizes of polystyrene latex particles produced by emulsion polymerisation –

from styrene, sodium styrene sulfonate, potassium peroxodisulphate, borax(stabilisation with sodium styrene sulfonate and dodecyl sulphate)

Tab 1: Results of the emulsion polymerisation process with SDS

Experimental results for polystyrene latex particles Tab. 1: Results of the emulsion polymerisation process with SDS

charges d10,0 in nm d50,0 in nm d90,0 in nm dm,0 in nm dm,3 in nm PDI zeta-poten-tial in mV

9 6S1 53.2 71.3 104 75.7 98.8 0.124 - 60.4 S2 132 184 275 194.4 242.1 0.084 - 46.8 S3 84.3 110 151 113.7 128.1 0.006 - 42.2 S4 82 5 109 153 113 2 130 7 0 007 42 4

Tab. 2: Results of the emulsion polymerisation process with SDS/NaSS

S4 82.5 109 153 113.2 130.7 0.007 - 42.4 S5 123 172 263 183.6 237.6 0.076 (- 1.4)

f p y p

charges d10,0 in nm d50,0 in nm d90,0 in nm dm,0 in nm dm,3 in nm PDI zeta-poten-tial in mV

SF1 13 2 17 7 25 7 18 68 26 97 0 329 54 9SF1 13.2 17.7 25.7 18.68 26.97 0.329 - 54.9 SF2 40.4 52.4 72.1 54.41 61.72 0.021 - 86.4 SF2a 20.6 27.3 38.6 28.60 34.60 0.129 - 80.8 SF2b 73 7 97 4 138 102 2 121 6 0 044 (0 0)SF2b 73.7 97.4 138 102.2 121.6 0.044 (0.0) SF3 37.0 48.3 66.2 49.90 56.60 0.007 - 72.8

SF4 39.4 51.9 72.9 54.13 63.38 0.055 - 58.1

SF5 67 8 89 3 127 93 64 111 2 0 035 - 71 3

SF5 67.8 89.3 127 93.64 111.2 0.035 - 71.3

Results and discussion

Monodisperse polystyrene latex nanoparticles with mean diameters dm,0 from 75 nm to 185 nm can be produced with an emulsion polymerisation process using styrene, potassium peroxodisulphate, borax, and sodium dodecylsulphate.peroxodisulphate, borax, and sodium dodecylsulphate.

The nanoparticles are stabilised by sodium dodecylsulphate (sterically/electrostatically), the zeta-potential ranges from - 42.6 to - 60.4 mV.

The polydispersity index goes from 0 007 to 0 124 (nearly monodisperse nanoparticle systeme) The polydispersity index goes from 0.007 to 0.124 (nearly monodisperse nanoparticle systeme).

Monodisperse polystyrene latex nanoparticles with mean diameters dm,0 from 18 nm to 185 nm can be produced with an emulsion polymerisation process using styrene potassiumcan be produced with an emulsion polymerisation process using styrene, potassium peroxodisulphate, sodium styrene sulphonate, borax, and sodium dodecylsulphate.

The nanoparticles are stabilised by sodium polystyrene sulphonate and sodium dodecylsulphate(sterically/electrostatically) the zeta potential ranges from 54 9 to 80 8 mV (higher by NaSS)(sterically/electrostatically), the zeta-potential ranges from - 54.9 to - 80.8 mV (higher by NaSS).

The polydispersity index goes from 0.007 to 0.329 (nearly monodisperse nanoparticle systeme). With i i t t th l t ti l t ll (S2 S4) d With increasing process temperature, the polystyrene nanoparticles get smaller (S2 - S4), and the surface charge density get higher (?) - potassium peroxodisulphate disintegration ratehigher. Th i l i i fl d b h f i i i d l The nanoparticle sizes are influenced e.g. by the surfactant, initiator and co-polymerconcentration.

Nanoparticles as carriers for medicine and pharmacy

Natural polymer nanoparticles proteins albumine

gelatinepolysaccharide dextrane

alginateg chitosane

Synthetic (bio)-polymer nanoparticlesSynthetic (bio)-polymer nanoparticles aliphatic polyester poly-(glycolic acid)

poly-(lactid acid)poly (lactid acid) poly-(lactid acid-co-glycolic acid) poly-(ε-caprolactone) poly-(methacrylate)

poly (methylmethacrylate)Wh t t d f f t i ? poly-(methylmethacrylate) poly-(butylmethacrylate)

poly-(alkylcyanoacrylate) poly-(n-butyl-2-cyanoacrylate) l ( h l ) l l

What to need for a perfect nano carrier?

Ref.: A. Musyanovych, K. Landfester, Formation of smart nanocapsules for defined slow or sudden release Max Planck Institut für Polymerforschung lecture poly-(oxyethylene)-glycole slow or sudden release, Max-Planck-Institut für Polymerforschung, lecture

Transportation of nanoparticles trough the blood-brain barrier (BBB)

Blood-brain barrier: separation of circulating blood and cerebrospinal fluid (CSF) in the central nervous system (CNS). Problem: Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria) and large or hydrophilic molecules into the CSF, cells of the barrier actively transport metabolic products such as glucose across the barrier.f y p p g

dextrane (polysaccharide)

chitosane (polysaccharide)

derivates of polyoxyethylenes

Surface modification (coating) of nanoparticles is necessary!

(p y ) α-1.6-glucopyranose polymer with α-1.2, α-1.3, and α-1.4 side chains

c itosa e (polysacc a ide)

β-1,4 - 2-Acetamido-2-desoxy-β-D-glucopyranose polymer,

de ivates of polyoxyet yle es

poloxamer polymers (from POE and POP chains)

molar mass MW = 70,000 g/mol

2,000 monomer units, linear linked

poloxamine polymers (from POE, POP, ethylenediamine chains)

polyoxyethyleneglycole (from POE)polyoxyethyleneglycole (from POE) polysorbate (POE sorbitan mono stearate) e.g. Tween 80

Emulsion polymerisation process

I Period of particle formation (Nucleation)

I Period of particle formation (Nucleation)Inside the O/W emulsion, there are micelles (5-10 nm), surfac-tant stabilized monomer droplets (1-10 µm), and initiator (e.g.hydrochloric acid, OH-). Monomer is (a) solubilizised insidey , ) ( )micelles, and sparely dissolved in water. Initiator forms mono-mer ions, with the in water sparely soluble monomer (N-butyl-2-cyanoacrylate) oligo-ions. These oligo-ions are stabilized bysurfactant (swollen micelles), or solubilizised in monomer con-taining micelles. Polymerisation starts, formation of small latexparticle.

II Period of growth Latex particles grow until monomer droplets in emulsion are

I i f f h l i l dgone. Increasing surface area of the latex particle adsorpts moresurfactant molecules, no micelles. Disappearance of droplets. III P i d f fi l l i tiIII Period of final polymerisation Rest of monomers in the latex particles (50-300 nm) are polymerized.

Couvreur,P.; Kante,B.; Grislain,L; Roland,M.; Speiser,P.: Toxicology of polyalkylcyanoacrylate nanoparticles II. Doxorubicin-loaded nano-particles, J. Pharm. 71 (1982) 790-792Kreuter, J.: Evaluation of nanoparticles as a drug-delivery system I: Preparation methods, Pharm. Acta Helv. 58 (1983) 196-209Sommerfeld, P.; Sabel, B.A.; Schroeder, U.: Long-term stability of PBCA nanoparticle suspensions, J. Microencapsulation 17 (2000) 69-79

   

Polymerisation process in miniemulsions

     

phase II polymerisation process high shear

ultra sonic waves

phase I

phase I: water surfactant

i iti t

nanodroplets: kinetically stable

small (100 - 500 nm)

nano-reactors: 100 - 500 nm polymer particle is 1:1 copy

of nanodroplets

Laplace pressure:

initiator phase II: oil monomer

small (100 - 500 nm) homogeneous in size

of nanodroplets

Physical characteristics of emulsion droplets

di l h2

aplace p essu e:

Shear rate to rupture:

radius Laplace pressure shear rate to rupturein nm in MPa in s-1

10 2.0 109

100 0.2 108

1 000 0 02 107

rL

Cr

micro-emulsion: thermodynamically stable emulsion (oil, water, surfactant, co-surfactant)

1,000 0.02 1010,000 0.002 106

only kinetically stable emulsion: nano-emulsion (1 - 100 nm) mini-emulsion (100 - 1,000 nm) macro-emulsion > 1.0 μm

 

Growth of miniemulsion droplets

Ostwald ripening

coalescence

diffusion of oil through the

collision andfusion of

water phase

oil droplets

i f lsuppression of coalescence

effective surfactants

suppression of Ostwald ripening

h d h bi l t ith effective surfactants Sodium dodecyl sulphate

Lutrol F68

hydrophobic solvents with a very low solubility in the continuous phase have to be used

Lutrol F68

Forces: same chemical potential in each droplet - osmotic pressure vs. Laplace pressure K. Landfester: Recent developments in miniemulsions - Formation and stability mechanisms, Macromol. Symp. 150 (2000) 171-178

Schematic representation of poly(alkylcyanoacrylate) formation

initiation

propagation

termination

Poly(alkylcyanoacrylate) formation via a stepwise anionic polymerisation by anionic initiation, reversible propagation, and reversible terminationp p g ,

Nicolas, J.; Couvreur, P.: Synthesis of poly-(alkylcyanoacrolate)-based colloidal nanomedicines, WIREs Nanomedicine and Nanobiotechnology 1(2009) 111-127

Initiation and propagation of an alkylcyanoacrylate polymerisation process

base

nulceophile

radical

Initiation and propagation steps involved during a polymerisation process to PACA initiated by a base *(B-), a nucleophile (Nu), and a radical (P*).

Nicolas, J.; Couvreur, P.: Synthesis of poly-(alkylcyanoacrolate)-based colloidal nanomedicines, WIREs Nanomedicine and Nanobiotechnology 1(2009) 111-127

Experimental set-up for the PBCA mini-emulsion polymerisation process

il h ( 4 °C)HO [CH CH O]

oil phase (temperature 4 °C)n-butyl-2-cyanoacrylate (monomer) 1.200 g soybean oil 0.072 g

HO-[CH2-CH2-O]80- -[CH2-CH(CH3)-O]27- -[CH2-CH2-O]80-H

L l F68 Pl i F68

water phase (pH 1.0) 0.1 M phosphoric acid H3PO4 4.8 mL

Na C12 H25 SO4 sodium dodecylsulfate

Lutrol F68, Pluronic F68

p p 3 4sodium dodecylsulfate (surfactant) 0.024 g Lutrol F68 (Poloxamer 188) 0.060 g (surface modification, surfactant)

sodium dodecylsulfate

rhodamine 123 (fluorescence marker) 0.018 g

process parameter (polymerization process) rhodamine 123 sonofication

temperature 0°C, 4 min, Sonoplus HD70, power 70 %

l i tiO/W mini-emulsion

Poly-(n-butyl-2-cyanoacrylate)-NP

characterisation: ti l i di t ib ti

polymerization 30 seconds after sonofication 0.1 M ammonia NH3 4.8 mL duration of polymerization process 5 minparticle size distribution

zeta-potential duration of polymerization process 5 min pH 7.0 adjusted

Experimental results for poly-(butylcyanoacrylate) - nanoparticles

100in

%

80Q0(d)

Q3(d)

utio

n Q

r(d)

40

60

mean particle diameter 51.3 nm (number)167 6 nm (volume)si

ze d

istr

ibu

20

40 167.6 nm (volume)PDI = 0.210 (light scattering), PDI = 3.27 (PSD)

zeta-potential - not measurable

Part

icle

s

0 100 200 300 400 500 600 7000

zeta-potential - not measurable

Particle diameter d in nm

P ti l i di t ib ti Q (d) d Q (d) f l (b t l l t ) ti l ti lParticle size distributions Q0(d) and Q3(d) of poly-(butylcyanoacrylate) nanoparticles, particles without addition of the fluorescence marker rhodamine 123

Experimental results for poly-(butylcyanoacrylate) - nanoparticles

sample 2: mean particle diameter 69.2 nm (number), PDI = 0.214 (light scattering) 184.3 nm (volume), PDI = 2.66 (PSD)

80

100

r(d) i

n %

60

80Reproducibility of the mini-emulsion processsample 1 Q0(d) Q3(d)

l 2 Q (d) Q (d)ribu

tion

Qr

40

sample 2 Q0(d) Q3(d)

sample 1cle

size

dis

tr

20

pmean particle diameter 51.3 nm (number) 167.6 nm (volume)PDI = 0.210 (light scattering), PDI = 3.27 (PSD)

Part

ic

0 100 200 300 400 500 600 700 8000

PDI 0.210 (light scattering), PDI 3.27 (PSD)

P ti l di t d iParticle diameter d in nm Particle size distributions Q0(d) and Q3(d) of poly-(butylcyanoacrylate) nanoparticles, without the fluorescence marker rhodamine 123, reproducibility of the mini-emulsion process

Experimental results for poly-(butylcyanoacrylate) - nanoparticles

100in

%

80Q0(d)

Q3(d)

utio

n Q

r(d)

40

60

mean particle diameter 68.9 nm (number)149 8 nm (volume)si

ze d

istr

ibu

20

40 149.8 nm (volume)PDI = 0.190 (light scattering), PDI = 2.17 (PSD)

zeta-potential: - 47.5 mV

Part

icle

s

0 100 200 300 400 500 600 7000

zeta potential: 47.5 mV

Particle diameter d in nm

P ti l i di t ib ti Q (d) d Q (d) f l (b t l l t ) ti lParticle size distributions Q0(d) and Q3(d) of poly-(butylcyanoacrylate) nanoparticles, particle surface is coated with the fluorescence marker rhodamine 123

Experimental results for poly-(butylcyanoacrylate) - nanoparticles

sample 4: mean particle diameter 42.3 nm (number), PDI = 0.178 (light scattering) 148.5 nm (volume), PDI = 3.51 (PSD) zeta-potential: - 42.5 mV

80

100p

Qr(d

) in

%

60

Reproducibility of the mini-emulsion processsample 3 Q0(d) Q3(d)

sample 4 Q0(d) Q3(d)stri

butio

n Q

40

sample 4 Q0(d) Q3(d)

sample 3mean particle diameter 68.9 nm (number)

ticle

size

dis

20 149.8 nm (volume)PDI = 0.190 (light scattering), PDI = 2.17 (PSD)zeta-potential: - 47.5 mV

Part

0 100 200 300 400 500 600 700 8000

Particle diameter d in nm

Particle size distributions Q0(d) and Q3(d) of poly-(butylcyanoacrylate) nanoparticles, coated with the fluorescence marker rhodamine 123, reproducibility of the mini-emulsion process

Experimental results for poly-(butylcyanoacrylate) - nanoparticles

100

sample 3: mean particle diameter 68.9 nm (number), PDI = 0.190 (light scattering) 149.8 nm (volume), PDI = 2.17 (PSD)

80

100

Qr(d

) in

%

60

Influence of rhodamine 123sample 1 Q0(d) Q3(d) without rhodamine 123

l 3 Q (d) Q (d) ith h d i 123istr

ibut

ion

Q

40

sample 3 Q0(d) Q3(d) with rhodamine 123

sample 1mean particle diameter 51 3 nm (number)rt

icle

size

di

0

20mean particle diameter 51.3 nm (number) 167.6 nm (volume)PDI = 0.210 (light scattering), PDI = 3.27 (PSD)

Par

0 100 200 300 400 500 600 700 8000

Particle diameter d in nm

Influence of the fluorescence marker rhodamine 123 on the particle size distributions Q0(d) and Q3(d) of poly-(butylcyanoacrylate) nanoparticles

Aim: to control size and zeta-potential of PBCA nanoparticle small, narrow distributed NPs with negative zeta potential

Influence of process parameter on PBCA nanoparticles during production: short ultrasonic duration gives small particles (2 minutes) pH value has no influence on particle size, zeta potential is pH dependent

amount of surfactant has no definite influence on particle size, but a ratio surfactant/monomer of 0.2 seems to be reasonable a monomer mass fraction of 12 wt-%seems to offer the smallest size Rhodamine 123 Lutrol F68 SDS PBCA NPs seems to be the most promising (smallest particle size, most negative zeta-potential)

In vivo Confocal Neuroimaging testing of PBCA nanoparticles: Rhodamine 123 Lutrol F68 SDS PBCA particles have no good transition over BBB, but Rhodamine 123 DEAE-Dextran Lutrol F68 PBCA NPs: biggest size and positive ZP, but still go well over BBB Rhodamine 123 Tween 80 PBCA nanoparticles cross the BBB at the best Surface properties of the particles have more influence than zeta-potential and size for overcoming the blood-brain barrier!

Summery