week 12 presentations - nanoparticlenanoparticles.org/emu/surfmod/wk12/wk12.pdf · 2007-04-07 ·...

Surface Modification (PC 591 CRN 27828) Winter, Wednesday, 5:00-6:40 pm; 115 Sill Hall

Instructor – Professor John Texter (201 Sill Hall, [email protected])

Week 12 Presentations Week 12 – April 4th Encapsulation and controlled release

20 min – Heidi - JCR-05-102-313 Microencapsulation 15 min – Askarali - jp011958z Polymersomes 15 min – Sen – - AngewChemie1998 LbL assembly of microcapsules 15 min – Chirag - ma062562u Nanocontainers via self-assembly 20 min – John Texter - Motifs Motifs for microencapsulation

Copies of the presentations follow in the above listed order. The file ends with a list of potential questions for Exam #4.

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Microencapsulationby solvent extraction/evaporation

by Heidi Perez

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20 min – Heidi - JCR-05-102-313

Microencapsulation processes

Solvent/extraction evaporation- does not require high temperatures or phase separation inducing agents- controlled sizes can be achieved through careful selection of conditions and materials- high encapsulation efficiency and low solvent content can be obtained

Phase separation ( coaservation)- difficult to eliminate residual solvents- coaservating agents remain in the microspheres- not suitable for production of small microcapsules- supercritical gases can be used as separation agents to reduce hazardous residues

Spray drying- simple and high throughput but not suitable for temperature sensitive compounds- control of particle size is difficult

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20 min – Heidi - JCR-05-102-313

Major substeps of microsphere preparationIncorporation of the active compound by dissolution or dispersion in a organic solvent containing the matrix forming materialFormation of the microdroplets (Emulsification) of the organic phase in a second continuous (often aqueous )phase immiscible with the first oneSolvent removal of the solvent from the dispersed phase by the continuous phase (optionally followed by solvent Evaporation) either one transforming the droplets into solid microspheresHarvestingDrying the microcapsules

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20 min – Heidi - JCR-05-102-313

Processing steps in the solventextraction/ evaporation process

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20 min – Heidi - JCR-05-102-313

Incorporation of active compoundCodissolution in a common solvent for the matrix and the active compoundDispersion of finely pulverized solid material , (the finer and the more spherical the particles the better),this step can by achieved by ultrazonification impeller of static stirring, high speed rotor-stator mixing or microfluidization.Emulsification of an aqueous solution of the compound of interest immiscible with the matrix material solution . For hydrophilic compounds a stable W/O emulsion with low droplet volume fraction of with low ratio of active compound increase encapsulation efficiency . Surfactants can lower encapsulation efficiency and affect pores size in the shells.

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20 min – Heidi - JCR-05-102-313

Emulsification: Determines size and size distribution

Stirring: simplest process, depend on the speed geometry, size and number of impeller(s), viscosity of dispersed and continuous phase, interfacial tension between phases , surfactant or stabilizer, volume ratio (concentration) of the dispersed/ continuous mediaStatic mixing: flow obstacles in a tube , recombining and splitting repeatedly the fluid passing through the tube size and distribution depends on: flow rate (size), interfacial tension, concentration geometry of the baffles, etc.Extrusion (Single pathway systems, Multichannel systems, Membranes):dispersed phase is directly fed into the continuous phase. The dispersed phase upon leaving the pathway at high speed forms droplets into the slow flow of continuous phase. In extrusion flow is laminar thus allowing narrow size distrubutionsDripping ( single drop formation, jet excitation) dispersed phase is dripped from a needle and form droplets by entering a electrostatic field or vibration of the liquid jet. Collection and solvent removal take place in a bath of methanol at -10C.

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20 min – Heidi - JCR-05-102-313

Emulsification: Static mixing

Two static mixers with turbulent flow in parallel for scale up microcapsule production

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20 min – Heidi - JCR-05-102-313

Emulsification: multichannel extrusion

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20 min – Heidi - JCR-05-102-313

Emulsification: dripping

Membrane Electrostatic dripping

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20 min – Heidi - JCR-05-102-313

Jet excitation

Emulsification:dripping

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20 min – Heidi - JCR-05-102-313

Solvent removalDispersed phase must be slightly soluble in the continuous

phase so partitioning into the continuous phase occurs leading to precipitation of the dispersed phase.

For solvent extraction amount of composition of the continuous phase is selected so all the solvent in the disperse phase is selected

Usually a non solvent for the active compound is chosen. Some hydrophobic solvents can be difficult to remove from the product, thus aqueous solution are used as continuous phase even for microencapsulation of hydrophilic compounds. pH, viscosity and osmotic pressure can be controlled to reduce active compound migration from the capsules to the continuous media.

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20 min – Heidi - JCR-05-102-313

Solvent removalEvaporation: controlled by process temperature, lowering system

pressure, gradient concentration between dispersed and continuous phase

Liquid extraction: two step process. First: dispersed phase is mixed with small amount with continuous phase to emulsify and get desired droplet sizeSecond: more continuous phase/extraction agent is added to leach all solvent from the hardening microspheres.

Extraction/ evaporation: Rapid extraction reduces loss of active compound, and a combination of solvent and extraction improve encapsulation efficiency.After emulsion formation, enough extraction solvent is added to start skin formation, then the rest of the solvent is removed by evaporation

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20 min – Heidi - JCR-05-102-313

Harvesting and dryingMicrospheres are separated by filtration or centrifugationSpheres are then rinsed to remove dispersion stabilizers and uncapsulated active compoundMicrospheres are dried at room temperature ot at reduced pressure moderate heat or by lyophilization to obtain a free flowing powder. Drying removes remaining solvent from inside and outside of the particlesPores in the shells, and recristallization of the active compond during drying affect release of the active compound

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20 min – Heidi - JCR-05-102-313

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20 min – Heidi - JCR-05-102-313

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20 min – Heidi - JCR-05-102-313

Physical methods of encapsulation

Spray drying Spray chilling Rotary disk atomization Fluid bed coating Stationary nozzle coextrusionCentrifugal head coextrusionSubmerged nozzle coextrusionPan coating

Microcapsules in a textile fabric

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20 min – Heidi - JCR-05-102-313

Chemical Methods of EncapsulationPhase separation Solvent evaporation Solvent extractionInterfacial polymerization Simple and complex coacervationIn-situ polymerization Liposome technology Nanoencapsulation

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20 min – Heidi - JCR-05-102-313

Shell materialsProteins Polysaccharides Starches Waxes Fats Natural and synthetic polymers Resins

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20 min – Heidi - JCR-05-102-313

Release MechanismsControlled, sustained, delayedTargeted release (surface modified capsules) Enteric, thermal, pressureOsmotic, pH-induced, pulsatile(electric or light) release Biodegradable or salt-induced release Oral, injectable,Pulmonary, intranasalImplantable drug delivery (patches)

Electronic ink microcapsules20

20 min – Heidi - JCR-05-102-313

What to encapsulate?Acids Activated carbons Active metals Adhesives Alcohols AldehydesAmines Amino acids Animal feed ingredients Antibiotics Antibodies Antioxidants Antiseptics Aqueous solutions Bacteria BiocellsBleaches Catalysts Chemiluminescent materials Corrosion inhibitors Deodorants Dyes Drugs and therapeutic compoundsEnzymesFlame retardants

Flavors

Food ingredientsFuels Fumigants Fungi Fungicides Hydrocarbons Indicators Inks Inorganic salts Ion-exchange resins Liquid hydrocarbons Lubricant additives Monomers Oils Organometallic compounds Oxidizers Paints Peptides Perfumes Peroxides Pesticides Pharmaceuticals Phase-change materials Phenols Photographic agents

PigmentsProteins RadioprotectorsReflective products Resin-curing agents (crosslinkers)RetinoidsSalts Sealants Solvents SterilantsSteroids Sweeteners Vaccine adjuvantsViruses Vitamins Water

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20 min – Heidi - JCR-05-102-313

ReferencesSergio Freitas, Hans P. Merkle, Bruno Gander,Microencapsulation by solvent extraction/evaporation: reviewing the state of the art odmicrosphere preparation process technology, Journal of controlled release, 102( 2005) 313-332www.syngenta.com/en/day_in_life/microcaps.aspxhttp://www.celessence.com/http://www.microteklabs.com/http://www.swri.org/4org/d01/microenc/microen/#microtech

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20 min – Heidi - JCR-05-102-313

QuestionsBriefly describe the steps followed for micro sphere preparationName two variables that can be controlled during microsphere preparation and that control active compound release from microcapsules

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20 min – Heidi - JCR-05-102-313

Cross-linked Polymersome Membranes: Vesicles with Broadly Adjustable

Properties

Askarali ThathaJohnapashaPc 591

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15 min – Askarali - jp011958z

IntroductionPolymersome:

- Bilayered membranes of amphiphilic synthetic polymers which are similar to liposomes, which use naturally occurring lipids.- While having most of the properties of natural liposomes, polymersomes exhibit increased stability and reduced permeability.- These membranes have been fabricated by the free radical polymerization of self- assembled, block copolymer vesicles.- limited reactivity and membrane fragility under local stress of nano-confined crosslinking.- A diblock copolymer of poly(ethylene oxide)-polybutadiene that has a hydrophilic weight fraction like that of lipids and forms robust fluid phase membranes in water.- They sustain free radical polymerization of the hydrophobic butadiene, thereby generating a semipermeable nano-shell.

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-Stable in chloroform and can also be dehydrated and re-hydrated without rendering the thick membrane core.- In purely aqueous solutions, several di- and tri-blocks have now been shown capable of self-assembly into “polymersomes” that range from nanoscale,to cell-sized giant vesicles with thick as well as extraordinarily tough membranes .- The results imply defect free membranes many microns-squared in area.- Surface elastic moduli as well as sustainable wall stresses greater than any natural lipid membrane, appear consistent with strong tethering between close-packed neighbors.- More massive block copolymers considerably broaden the general synthetic approach.- Application: blending in the hydrogenated analogue poly(ethylene oxide)-polyethylethylene modulates the effective elastic constants as well as the rupture strength by orders of magnitude.

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Experimental Methods

• Block copolymers- anionic polymerization.

• Vesicles form spontaneously upon hydration of either bulk copolymer or dried films of copolymer obtained after chloroform evaporation.

• Aqueous solutions range from pure water to sucrose solutions of 300 mOsmto phosphate-buffered saline.

• By free radical polymerization, Polybutadiene in the cores of the vesicle membranes were cross-linked in solution.

• radicals generated through a K2S2O8 initiator and a redox couple, Na2S2O5/FeSO4 .7H2O.

• Inorder to prevent the rupture the vesicles during addition of these reagents, the osmolarity was balanced.

• the extent of reaction was established by measuring changes in membrane rupture tension.

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Formation and osmotic deflation of OB2, i.e., (EO)26-(BD)46

A - Brightfield image of bulk copolymer hydratingand vesiculating into a 200 mOsm sucrose

solution.- Giant, spherical, unilamellar vesicles predominate.

B- Dilution into 300 mOsm phosphate-buffered saline (PBS) increases the internal osmotic pressureby deflating a spherical, non-crosslinked vesicle.- A smooth vesicle contour is generated.- the refractive index difference between sucroseand PBS makes vesicles appear dark in phase Contrast imaging, proving the integrity of the vesicle’s membrane.

C- When cross-linked and subsequently diluted into PBS, the vesicle deflates with dents and wrinkles, characteristic of a solid like membrane.

D- schematics of the diblock copolymer membranes,showing a close-packed arrangement of copolymers

with a hydrophobic core thickness d.

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• Giant unilamellar vesicles form spontaneously when slivers of bulk EO26-BD46 (designated OB2) are added to aqueous solutions.

• vesicles exhibit several characteristics indicative of a fluid-phase membrane.

• First, when sheared from their substrate and isolated, vesicles transform morphologically with smooth contours (Figure 1B).

• Second, like any lipid bilayer, these uncross-linked OB2 vesicles dissolve readily when a good solvent such as chloroform is added at only a fraction of a percent.

• on average, 46 double bonds that are readily available for cross-linking by common means of solution polymerization on each molecule in the self-assembled vesicle contains a hydrophobic block .

• When the giant polymersome vesicles are exposed to free radicals in an osmotically balanced medium, massive cross-linking is achieved.

• The membrane transformation from liquid to solid state is directly observable upon osmotic deflation of the originally spherical vesicle as creases, folds, wrinkles, and dents proliferate (Figure 1C).

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• The membrane transformation from liquid to solid state is directly observable upon osmotic deflation of the originally spherical vesicle as creases, folds, wrinkles, and dents proliferate (Figure 1C).

• Like the deflation of a micron-sized rubber ball, these features reflect the fact that molecules cannot significantly rearrange within the surface to relax accumulated strain.

• Membrane integrity through sustained retention of small moleculeencapsulants such as sucrose (Figure 1C)seen through phase contrast images.

• Vesicle shape as well as membrane thickness are minimally affected by the cross-linking reagents or the reaction process itself as long as solution osmolarity is held constant.

• Separate cryo-TEM images show the hydrophobic core thickness to be d =9 +/- 1 nm

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Stability of individual vesicles of cross-linked OB2 dutransfer into chloroform (A), air (B), or vacuum (C).

The top two images show a sucrose-containing vesicle held by a micropipet in PBS solution and viewed in phase contrast(dark) or brightfield.

The middle image shows a vesicle transferred into chloroform and held there for 30 min, followed by transfer back into aqueous solution.

(B) A vesicle in aqueous solution pulled into a micropipet and then removed from the chamber and imaged within seconds after exposure to air.

Rehydration occurs immediately

(C) Scanning electron micrograph of a vesicle prepared simply by vacuum-drying without staining or fixation.

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• Cross-linked polymersomes were first tested for stability in chloroform (CHCl3), an excellent solvent for OB2.

• No alteration of vesicle size, shape, volume, or area for as long as the vesicle was held in solvent when transferred in to CHCl3 (Figure 2A).

• Upon transferring the vesicle back to aqueous solution, the vesicle’s geometry is unaffected, indicative of full retention of the encapsulated solute, sucrose.

• Loss of even a few weight percent sucrose from the vesicle into the chloroform would again have lengthened the aspirated projection due to a decrease in vesicle volume during osmotic equilibration.

• The encapsulated sucrose is still retained inside the vesicle as again directly imaged by phase contrast microscopy.

• Stability and integrity of the cross-linked membrane down to the molecular scale are thus confirmed.

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• A simple cycle of dehydration-rehydration.• water-air interface.• As the picoliters of encapsulated water vaporate through

the increasingly wrinkled membrane, the vesicle collapses.

• The phase contrast again indicated retention of encapsulated solutes.

• Demonstrates the tremendous increase in elastic stiffness and mechanical stabilityachieved by full, covalent cross-linking of an OB2 vesicle.

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Deformability of cross-linked OB2 vesicles in compariswith non-crosslinked OB2.

A- Viewed in brightfield, this OB2 vesicle was cross-linked in a highly deflated (nonspherical) state.

B- Further aspiration of a similar vesicle generates a nominal membrane tension, τ , in the aspirated direction which is proportional to the applied pressure but nonlinear with the extension of themembrane, L, into the pipet.

C- Brightfield imaging of cross-linked vesicles in aspiration often shows membrane wrinkles as well.

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• Upon cross-linking in a flaccid state (Figure 3A), OB2 membranes clearly respond with a more solidlike character in deformation.

• Brightfield imaging often shows corrugations of buckled membrane radiating away from the micropipet entrance (Figure 3C).

• Radial folds in this region would tend to stiffen against bending and should thus flatten the membrane.

• Prior to buckling, the deformation is largely reversible and effectively elastic;• Plots of the effective tension , τ against the extensional strain measure x =

L/Rp generally leads to three quasi-linear regimes labeled in Figure 3B.• The slope for each of the three quasilinear regimes nonetheless provides

phenomenological measures of membrane bending, shear, and dilational resistance.

• The remarkable stability of a cross-linked versus a noncrosslinked membrane (Figure 3B) motivates a chemically controllable approach to property modulation.

• The fully hydrogenated Homologue of OB2 is the copolymer poly(ethylene oxide)-polyethylethylene (EO40-EE37 designated OE7).

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Elasticity and mechanical stability of cross-link-diluted OB2vesicles made by blending in varying molar ratios of the noncrosslinkableanalogue OE7.

Three effective elastic constants were deduced from the three regimes of aspirationThe three elastic constants appear to scale linearly with cross-link dilution above a critical fraction of OB2The effective rupture tension, τR, is a more nonlinear function of cross-link dilution.

Above XOB2 ~15% ( =XC), τR increases monotonically with weak power-law scaling (lower inset). Below XC, τR exhibits a minimum: the entire gray region highlights cross-link-induced destabilization.

Polymerizations are complete within 10 min of initiation.

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Discussion

• In comparison to a critical strain of 5% or less that is universal to lipid membranes, polymersome membranes can withstand dilational strains of almost 20% before rupture.

• Assuming an isotropicaly cross-linked shell, the strain energy is expected to be stored locally as both in-plane stretching and bending.

• Effective Elastic Moduli: slightly deflated cross-linked vesicles, bending and stretching are again expected to be prominent.

• In aspiration of this cell, the lipid bilayer initially resists bending before the underlying spectrin network contributes a shear resistance at more modest pressures.

• At higher pressures, a buckling instability leads to membrane folds which, because of bilayer fluidity, are smoothed out at the highest pressures where the cohesiveness of the lipid resists rupture.

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• Cross-Linking Efficiency: relates to the shear elasticity to rubber elasticity theory.

• A finite interlamellar cross-linking such as this is more than enough to prevent chloroform inclusions from forming within the copolymer bilayer.

• An overallefficiency for intermolecular cross-linking is broadly estimated by normalizing against the number of butadiene units.

• Rigidity Percolation through a Nano-Stack: The tightly interconnected nature of the cross-linked OB2 membrane as well as its obvious integrity as a permeability barrier reinforce the idea of a close-packed arrangement of copolymers.

• Although the linearity of the rupture energy with respect to the mole fraction of the polymerizable component is consistent with rubber elasticity theory, the extrapolated offset by a critical fraction XC=16 +/- 2% appears nontrivial.

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Summary:• Stability tests reported here for a polymer membrane provide very

direct evidence of thorough and durable cross-linking over length-scales of microns.

• Because defects as small as a sucrose molecule would be rapidly revealed through permeation and stress-sensitive rupture, the proof here appears robust.

• Efficient cross-linking is possible and tunable through blending at the nanoscale, with dramatic effects on strength and durability and a definitive transition from interface-dominated properties to cross-link-dominated.

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Thank You

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Novel Hollow Polymer Shells By Colloid-Templated

Assembly of PolyelectrolytesPC591

Surface Modification

Sen Song

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15 min – Sen – - AngewChemie1998

Current work

• Problems: polydispersity, uneven shell coverage and core solidification;

• Liquid Liposomes: limited Stability and low permeability for polar molecules;

• The new method: consecutive deposition of oppositely charged polyelectrolytes

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Hollow polyelectrolyte shells

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Steps

• poly(sodiumstyrenesulfonate) (PSS) ------negatively charged

• Poly (allylaminehydrochloride) (PAH) ------positively charged

• Monodisperse weakly cross-linked melamineformaldehyde(MF) colloidal particles ------- positively charged

MF-PSS-PAH-PSS-PAH---------Desired thickness

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SEM of Shell

• The numerous folds and creases are attributed to drying of the shells

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TEM of Shell

• Homogeneous curvature of the shells proves that the fabricated shells preserve both the diameter and the spherical shape of the template particles

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AFM of ShellA: Three-layer B: Nine-layer

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Features of fabricated polyelectrolyte shells

• The composition and thickness can be controlled;

• Fabricated with controlled physical and chemical properties;

• Novel structures for micro- and nano-compartmentalization of materials

• Readily permeable by small polar molecules• Extremely stable against chemical and physical

influences.

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Nanocontainers Formed by Self-Assembly of Poly(ethylene oxide)-b -poly(glycerol monomethacrylate)-Drug ConjugatesCristiano Giacomelli, Vanessa Schmidt, and Redouane Borsali

PC 591SURFACE MODIFICATION

Chirag PatelE00631574

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15 min – Chirag - ma062562u

(PEO-b-PG2MA-) drug conjugates The synthesis, self-assembly behavior, and delivery properties of poly(ethylene oxide)-b-poly- (glycerol monomethacrylate)- (PEO-b-PG2MA) drug conjugates is described.The use of these assemblies as delivery vehicles is motivated by their ability to incorporate and release poorly water-soluble, hydrophobic and/or highly toxic compounds, also minimizing drug degradation and wastage, and hence increasing bioavailability.Double hydrophilic PEO b- PG2MA copolymers, synthesized by ATRP using a PEO-based macroinitiator, are used for post-polymerization conjugation to the hydrophobic nonsteroidal anti-inflammatory agent indomethacin (IND).

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(PEO-b-PG2MA) drug conjugates PEO-b-(PG2MA-IND) copolymer chains self-assemble into spherical nanoparticles in water, whose hydrodynamic size and morphology (micelles or vesicles)depend on both the amount of IND and the PG2MA block length. This system is proven to be able to stabilize, transport and deliver physically encapsulated (free) IND (F-IND). The maximum F-IND loadings ranged from 13 to 20% w/wp, thus reaching remarkable IND payloads (i.e., covalently bound B-IND + physically entrapped F-IND) as high as 58% w/wpThe release of IND is a pH-dependent process, which is governed by intrinsic molecular characteristics of F-IND (aqueous dissociation behavior) and pH-sensitivity of ester linkages in the conjugates.

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Synthesis of PEO-b-(PG2MA-IND)

Double hydrophilic diblock copolymer-drug conjugates showing selfassembly properties is prepared as follows.Double hydrophilic poly(ethylene oxide)-b-poly(glycerol monomethacrylate) (PEO-b-PG2MA) block copolymer, which exhibits pendent hydroxyl groups in the PG2MA block is obtained by ATRP of G2MA in methanol using PEO macroinitiators and Cu/bpy catalyst.In the following step, the pendent hydroxyl groups of PG2MA blocks are used for post-polymerization conjugation with carboxylic acid moiety of the hydrophobic drug IND by esterification.

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(i) α-bromoisobutyryl bromide, Et3N, toluene, overnight, room temperature; (ii) G2MA, CuBr/bpy, MeOH, 20°C; (iii) indomethacin, DCC/DMAP, DMF, 72 h, room temperature.

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Behavior of amphiphilic PEO-b-(PG2MA-IND) polymer-drug conjugates

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(PEO-b-PG2MA) drug conjugates

The resulting amphiphilic macromolecule-drug conjugates (PEO-b-(PG2MA-IND)) are found to self-assemble into spherical micellar nanoparticles or vesicles in selective solvent (water).This originates a particular core-shell system in which the core-forming block (PG2MA-IND) resembled the drug to be physically encapsulated (IND). Hence, such micellar nano-containers are able to transport two or more hydrophobic molecules - IND chemically linked to the polymer via acid sensitive ester bonds and another physically entrapped - which can be released either simultaneously in a pH-triggered process or selectively by initial passive diffusion of unbound species.

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(PEO-b-PG2MA) drug conjugates

The size and morphology of nano-objects originated from the self-assembly of PEO-b-(PG2MA-IND) block copolymer drug solutions depended on both the amount of IND and the PG2MA block length.The length and the hydrophobic character of the core-forming block determine the micelle dimensions, and consequently the loading efficiency, drug release profile, partition coefficient, bioavailability, and biodistribution of the carrier system.The final drug content depends, on the targeted IND/OH molar ratio.

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Release of INDTotal IND payload (i.e., covalently bound IND + physically entrapped IND) ranges from 28 up to 58% w/wp.The release of drugs from block copolymer nanocarriers

depends upon several physical-chemical parameters such as drug diffusion rate, partition coefficient between drug and hydrophobic segment, micelle/vesicle stability, and the copolymer biodegradation rate, etc.In the case of stimuli-responsive systems, these parameters can

change dramatically as a function of the environmental surroundings, leading to triggered release processes.From a drug delivery standpoint, esters, carbonates, amides, andurethanes are linkers susceptible toward hydrolysis in acidic media, yielding to the so-called passive hydrolysis, and the rate of hydrolysis decreases in the order ester > carbonate > amides > uretanes.

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Release of INDThe release of IND from nanocarries (originated from self-assembly of PEO-b-(PG2MA-IND) block copolymer-drug conjugates) as a function of the solution pH in absence and in presence of F-IND.

Percentage of IND released as a function of time as determined by variations in the UV absorbance at λmax= 320 nm for 1.0 mg/mL PEO113-b-(PG2MA40-IND21) conjugates at pH = 7.4 (a) and pH = 2.1 (b) in absence and in presence of 0.18 mg/mL F-IND, as indicated.

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Release of IND

At pH = 7.4 and in the absence of F-IND(Figure a, open symbols), the amount of IND released from the nanoparticles increased slightly as a function of time. After a rapid release of 10% of the initial IND payload (0.40 mg/mL) during the initial 2-3 h period, a quite stable plateau is systematically observed, suggesting that ester bound cleavage hardly occurred. This can be interpreted as corresponding to the passive diffusion of a given amount (typically 10-20%) of unbound IND that could not be completely separated during purification by selective precipitation of block copolymer drug conjugates.Upon exposure to pH = 2.1 solutions, PEO-b-(PG2MA-IND) micellar solutions without added F-IND (Figures b, open symbols) exhibited sustained release with slow kinetics. It seems clear that acid medium favored acid hydrolysis of ester bounds, only 25% of total IND payload (0.40 mg/mL) diffused out of the nanoparticles during 21 h. Indeed, from this amount 15% consisted in hydrolyzed B-IND while 10% is F-IND (Figure a). Likewise, much slower release rate was observed in presence of F-IND (Figure b, filled symbols).

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ConclusionPoly(ethylene oxide)-b-poly(glycerol monomethacrylate)-Drug Conjugates(PEO-b-(PG2MA-IND) are synthesized by ATRP of PG2MA with PEO followed by esterification with Carboxylic moiety of IND.The release of IND is a pH-dependent process, which is governed by intrinsic molecular characteristics of F-IND (aqueous dissociation behavior) and pH-sensitivity of ester linkages in the conjugates.At approximately neutral pH, the ester bound linkages are stable and the diffusion of F-IND out of the carrier is favored, whereas sustained release with slow kinetics takes place under acidic pH conditions.

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Thank You

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Questions:

Describe the synthesis of Poly(ethylene oxide)-b-poly(glycerol monomethacrylate)-Drug Conjugates.Name the properties influenced by the length and the hydrophobic character of the core-forming block.Advantages of using (PEO-b-PG2MA-) drug conjugated systems.

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©2001-2006 Strider Research Corporation MENCP - 1

Microencapsulation

• Motivation to Microencapsulate• Applications• Morphologies• Double Emulsions• Polymeric Coating of Particles• Coacervation/Phase

Separation• Polymerization Around

Emulsions• Liquid Coatings• Polymerization Around

Pigments• Miscellaneous

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20 min – John Texter - Motifs


Motivation to Microencapsulate

Microencapsulation of a substance can change the apparent physical properties (color, shape, weight, volume, solubility, reactivity, durability, pressure sensitivity, heat sensitivity, photosensitivity).

Microencapsulation of liquids can yield an apparently solid, dry powder. Solid handling characteristics are obtained, but the internal liquid phase retains its reactivity (important for leuco-dyes used in pressure sensitive copy paper and for photochromic chemicals used for cross-linking polymers). Papers coated with such capsules, after drying, feel dry.

Handling characteristics are improved and chemical reactions are controlled (to take place at a particular time, such as when the capsule is ruptured).

Changes in weight or volume can be made. A dense compound may be converted to a form that floats by microencapsulating with entrained air.

Variations in thickness and composition of microcapsule walls yield variations in controlled release profiles. Sudden and total release may be obtained by mechanical means (crushing, deformation, melting, chemical reactions). Gradual release in pharmaceuticals and agriculture is controlled by diffusion rate and dissolution rate control.

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Motivation to MicroencapsulateMost microcapsule walls are only a few microns thick, and these capsule walls are in reality semipermeable membranes. Controlled release is often diffusion controlled (through such semipermeable membranes).

Protection of a substance from the effects of moisture, oxygen, ultraviolet light, chemical reaction, etc. can be achieved by microencapsulation. A desired chemical reaction can be staged by incorporating one reactant, in a microencapsulated form, in another reactant. Disruption of the capsule wall leads to the desired chemical reaction. Examples include dispersing oxidants in microcapsules within a fuel to yield an apparently one-component propellant, a mixture of rubber with microencapsulated solvent to produce a pressure sensitive adhesive tape, and an apparently “one-part” epoxy resin wherein the catalyst is dispersed in a microencapsulated state within the monomeric resin.

Rheological advantages can be obtained by dispersing liquids in microcapsules rather than in emulsions, because microcapsules typically interact less with each other than softer emulsion droplets, and this yields lower viscosities.

Unwanted leakage can lead to many different kinds of problems.

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Applications

Industry Prodcuts

Agriculture SeedsFertilizersPesticides

Foods FlavorsVitaminsMinerals

Cosmetics Anti-perspirantsPerfumesAdvertising materials

Pharmaceuticals DetoxicantsDrugsMineralsCold Remedies

Adhesives Bolt and Nut Adhesives

Imaging Carbonless CopyPaperAgX Heat DevelopableSilverless Color

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Morphologies

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Polymeric Coating of Particles

Polymeric shells can be produced by two basic methods:

(1) Adsorption of polymers onto particle surfaces

(see coacervation and phase separation)

(2) Adsorption of monomers onto particle surfaces, followed by polymerization.

Monomer binding to particle surfaces can be enhanced by:

binding a suitable preformed polymer

binding a reactive coupling agent

coating with an inorganic particle that has a greater affinity for the monomer

Radical (addition) polymerization, condensation, and oxidative polymerization have successfully been used to coat polymeric films on particles.

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Coacervation/Phase Separation

The capsule wall is formed from a water-soluble polymer. A condensed phase (coacervate) is formed when the polymer separates from the aqueous solution.

Such coacervation/phase separation can be driven four ways:

1. Oppositely charged polymers interact and form a “polymer salt”.

2. A nonelectrolyte additive, such as alcohol, decreases the polymer solubility so that it condenses at the interface in a polymer-rich phase.

3. The polymer is “salted out” by addition of salt. It condenses in a polymer-rich phase at the interface.

4. The solubility of the polymer is decreased by modifying the pH. The polymer condenses in a polymer-rich phase at the interface.

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Gelatin - desolvated with ethanol or sodium sulfate

Human serum albumin - desolvated with ammonium sulfate

Alkaline casein - desolvated with HCl or sodium sulfate

Ethylcellulose - 1% solution in carbon tetrachloride can be desolvated with cyclohexane.

J. J. Marty et al, Pharm. Acta Helv., 53, 17 (1978)

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Two-Sheet Carbonless Copy Paper

U.S. Patents 2,711,375, 2,730,456, & 2,800,457 (1954-1957)

Gelatin-gum arabic microencapsulated leuco dye solution coated on back face of paper. Acid (attapulgite) clay coated in starch or copolymer latex binder on front face of second sheet. Writing or impact pressure causes leakage of leuco dye solution into contacting acid clay layer, wherein leuco dye oxidizes to form image dye.

Reproduced by permission from A. Kondo and J. W. Van Valkenburg, Microcapsule Processing and Technology, Marcel Dekker, New York, 1979.

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H. Fessi et al., European Patent Application 0274961 (1988)

N. Ammoury et al., Proc. 5th Int. Conf. Pharm. Technol., Vol. 4, Paris (1989), p. 46

Polylactic Acid Encapsulation

The preformed polymer is dissolved together with the substance (active agent) to be encapsulated in a solvent mixture such as benzyl benzoate, phospholipids, and acetone. This solution is injected through a capillary into an aqueous phase containing additional stabilizers. Particles in the 200-400 nm size range are obtained. Polymer diffuses to and adsorbs to the oil-water interface.

Encapsulation by Polymer Adsorption

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K. Widder et al., J. Pharm. Sci., 68, 79 (1979)

J. M. Gallo et al., Int. J. Pharm. Sci., 22, 63 (1984).

Encapsulation by Heat Denaturation of Albumin

Albumin (200 - 500 mg/ml) and the active agent (drug, nanoparticle) are suspended or dissolved in water and emulsified in an oil (40-80 parts oil per part aqueous phase). This emulsion is then added rapidly, dropwise, into preheated (100-180 °C) oil and held at temperature for 10 min. This heat treatment denatures the albumin, and the albumin segregates to the oil-water interface, forming a shell. After cooling the particles are removed by centrifugation and washed with either to remove adsorbed oil. Particle sizes in the range of 400-800 nm are obtained.

Encapsulation by Polymer Adsorption

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Interfacial PolymerizationAround Emulsions

P. W. Morgan, SPE J, 15, 485 (1959)

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Polyfunctional amine (Y) added to aqueous phase, diffuses to interface, reacts with (X) isocyanates or acid chlorides dissolved in oil phase.

Acid chlorides must hydrolyze slowly at solvent-water interface to allow for emulsification (sebacoyl chloride, terephthaloyl chloride, trimesoyl chloride - crosslinking).

Diisocyanates, polymeric isothiocyanates, etc.., must be soluble in solvent.

Amines such as ethylenediamine, hexamethylenediamine, triethylenetetramine added to aqueous phase; base is added to scavenge acid if acid chlorides used.

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Interfacial Polymerization(a)

Both the continuous phase and the disperse phase serve as a source of reactive species.Polyamines (e.g., ethylenediamine. ethylene tetramine, diethylenetriamine, hexamethylenediamine, 2,4,6-triaminotoluene) in the aqueous phase combine with polybasic acid chlorides (e.g., terephthaloyl chloride, adipic acid chloride) in the oil phase to yield polyamides.

Glycol polyols (e.g., ethylene glycol) in the aqueous phase combine with polybasic acid chlorides in the oil phase to yield polyesters.

Polyamines in the aqueous phase combine with bis-haloformates (e.g., hexamethylene bis-chloroformate) in the oil phase to yield polyurethanes.

Polyamines in the aqueous phase combine with polyisocyanates (toluenediisocyanate) in the oil phase to yield polyureas.

Glycol polyols in the aqueous phase combine with polyisocyanates in the oil phase to yield polyurethanes.

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Example: (Oil-in-water)

100 mg benzoyl leucomethylene blue and 200 mg terephthaloyl chloride (monomer X) are dissolved in 25 g chlorinated diphenyl. This solution in emulsified with 200 ml of 0.5% (w/w) aqueous sodium bicarbonate and 1 ml of Carbowax 600 (dispersing aid). The bicarbonate is used to neutralize acid produced in the interfacial polymerization.

50 ml of 10% aqueous ethylene glycol are added with stirring. A glycol polyphenol (e.g., bisphenol A) is then added to the aqueous phase, and polymerization commences to produce a polyester shell. The reaction time is only a few minutes, and the particle sizes are in the range of several μm.

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Microencapsulation after Electrocapillary Emulsification

Example: (Water-in-oil)

Poly(Nα,Nε-L-lysinediylterephthaloyl) encapsulated particles (400 nm diameter) by electrocapillary emulsification of aqueous hemolysate, L-lysine, and sodium carbonate into (at 0.042 ml/min) terephthaloyl dichloride solution in cyclohexane, chloroform, and tetraethylammonium chloride mixture. The emulsification was done using a motor driven syringe with a potential of 850 V applied between the needle (anode) and a platinum wire cathode located about 5 mm from the needle in the oil phase.

Arakawa & Kondo, Can. J. Physiol. Pharmacol., 58, 183 (1980).79



Isocyanate Polymerization

Some isocyanate groups react with water to give amines and carbon dioxide; these amines react with other isocyanates to produce polyurea; direct addition of amines not required.

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Spontaneous Polymerization

N-Alkyl cyanoacrylate emulsified in organic phase; it diffuses to emulsified interface and polymerizes spontaneously to form poly(n-alkyl cyanoacrylate).

HO- + CH2 CCN

CO2RHO CH2 C-

CN

CO2RCH2 C-

CN

CO2RCO2R

CNCCH2HO

Polymer growth is terminated with a proton.

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Cynaoacrylate monomer (1 ml) and the substance to be encapsulated are dissolved in an oil (8 ml) and ethanol (100 ml). This solution is added slowly through a capillary into a well stirred aqueous solution containing 0.5% (w/w) of a nonionic dispersing aid such as a Pluronic or stabilizing phospholipids at pH 6-7. Encapsulated particles having a polycyanoacrylate wall in the 200 - 400 nm size range are formed by anionic polymerization induced by hydroxide ions in the water.

N. Al Khouri Fallouh et al., Pharm. Acta helv., 61, 274 (1986).

N. Al Khouri Fallouh et al., Int. J. Pharm., 28, 125 (1986).

Interfacial Polymerization(c)

Polycyanoacrylate Encapsulation

Freeze fracture TEM of polyisobutylcyanoacrylate encapsulated particles.

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Urea/Formaldehyde Resins

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Free Radical polymerization

Ethenic monomers and initiator dissolved in oil phase prior to emulsification; polymerization initiated by heating.

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Wall Properties

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Capsules for Carbonless Copy Paper

D. R. Shackle et al., U.S. Patent 4,532,183 (1985)

Crystal violet lactone (7.2 g) was dissolved in 262 g monoiospropylbiphenyl at 80°C and mixed with 77.3 g of a 2.9% solution of Michler’s ketone and benzophenone (1:1 ratio) in trimethylolpropane-triacrylate.

After reaching room temperature, 0.5 g of a polyisocyanate prepolymer prepared from toluene diisocyanate and trimethylolpropane (Niax SF-50, Union Carbide) was added, and this mixture was emulsified in a Waring blender with an aqueous mixture containing 93.7 g of a 21% solution of isobutylene maleic anhydride copolymer (Isobam), 187.5 g of a 10% gum arabic solution, 37.5 g of hydroxyethyl-methacrylate, and 200 g of water.

This emulsion was diluted with 550 g water and placed in a3-liter roundbottomed flask and irradiated for 2 h with a 150 watt UV lamp.

The mononuclear capsules obtained had an average size of 12.5 μm.

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Polyaniline Coating of Copper Oxide Particles

Huang, Partch, & Matijević, J. Colloid Interface Sci. 170, 275-283 (1995)

Copper basic carbonate particles were obtained by aging 0.01 M cupric nitrate solution also 0.4 M in urea for 1 h at 85°C. Spherical 1.6 μm diameter CuO particles were prepared by calcining copper basic carbonate particles at 400°C for 1 h.

About 10 mg of dry CuO dispersed in 2 ml ethanol and 4 ml water, to which 0.4 ml aniline is added. This dispersion is agitated in an ultrasonic bath and then stabilized by adding 2 ml of aqueous (0.8%) PVA solution. This dispersion is then diluted to 10 ml with water, sealed, and heated at 100°C for 48 h with agitation.

The form of polyaniline obtained corresponds to that of polyleucoemeraldine.

Polymer shells corresponding to about 10% by weight are obtained.

The polymerization is driven, initially, by the CuO mediated oxidation of aniline.

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PC 591 Exam Questions from Wk 12 Presentation (Heidi) Briefly describe the solvent extraction method for microcapsule preparation. Name two variables that can be controlled during microcapsule preparation and that control active compound release from microcapsules. Describe 3 physical methods and 3 chemical methods of encapsulation. (Askarali) Describe and explain advantages of polymersomes over lipsosomes. Why were PEO block copolymers used in the polymersomes discussed? Describe in words an drawings the structure of vesicles made from a diblock copolymer. (Sen) Describe the layer-by-layer encapsulation technique for encapsulating template particles. In the layer-by-layer encapsulation method name three types of core particles that are suitable templates and explain why. (Chirag) Describe the synthesis of poly(ethylene oxide)-b-poly(glycerol monomethacrylate)-drug conjugates. Start with a methylether-PEG, alpha-bromoisobutyryl bromide, trimethyl amine, toluene, Cu(II)bipyridine, methanol, G2MA, indomethacin, DMF, and DCC/DMAP. Name the properties influenced by the length and the hydrophobic character of the core-forming block. What are the advantages of using (PEO-b-PG2MA-) drug conjugated systems? (John T) Describe three motivations for doing encapsulation. Describe three morphologies of microencapsulation. Describe how to encapsulate an oil-in-water emulsion by using a faormaldhyde/urea resin. Starting with urea and formaldehyde, show how to make methylourea, dimethylol urea, and a cross-linked resin of all of these components. Show how to make polyurethane capsule wall resin from diamines and diacylchlorides and from diisocyanates and diols. Describe encapsulation by coacervation of oil-in-water emulsions using gelatin and gum Arabic polymers, and any other needed reagents.

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week 12 presentations - nanoparticlenanoparticles.org/emu/surfmod/wk12/wk12.pdf · 2007-04-07 ·...

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