crs young scientist 2010 final 2

8/2/2019 CRS Young Scientist 2010 Final 2

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Solubility Improvement by Solid StateProperties Modification

2002-2010 Eurand. All rights reserved.

Young Scientist Workshop Development of Poorly Soluble DrugsPortland (OR)July, 10, 2010

Paolo Gatti, PhDSenior Scientist,

Formulation Team Leader


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1. Influence of drug solid state properties

on solubility


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Increases by: Increasing surface area (A)

Increasing equilibrium solubility (Cs)

Increases by: Reducing melting enthalpy

Reducing melting tempertature (Tm)

Solubility and Solid State Properties

Cs: Equilibrium solubility of the drug R: gases constant

D: Diffusion coefficient of the drug in solution V: Volume of the solution

h:stagnant layer thickness A:Surface area of the solid drug (bulk property)

S:Activity coefficient of the drug in solution : Melting molar enthalpy of the drug

T: Solution temperature Tm:Melting temperature of the drug

Hm

Solubilization rate Equilibrium solubility

(Hm)

CChV

DA

dT

dCS

)]([ 111

m

m

s

STTR

H

eC


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Micronized crystalline solid

Dissolution rate increase (Kinetic effect)

Crystalline structure

Long range order Hm>0 Micrometric size range(Indicative: 1-100 micron)

Higher surface area

than original solid



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Nanocrystalline solid

than originalsolid

Dissolution rate increase (Kinetic effect)Solubility increase (Thermodynamic effect)

Nanometric size range

0


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Crystals and crystallites

Most solid crystalline materials are polycrystalline, that is they are made of

a large number of crystallites possibly randomly oriented.

Crystallites can have contact interfaces (boundaries), can be separated by

distortions or strains in the solid structure and/or can be embedded in

region of amorphous material.

Crystallite is a domain of solid having the same properties of a single

crystal


Structure stress


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Amorphous solid

No long range order

(Less than 2 nm extension)

Negligible melting enthalpy compared to original solid

Dissolution rate increase (Kinetic effect)

Solubility increase (Thermodynamic effect)



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Griseofulvin case study

Griseofulvin

solid state

Crystalline domains

average diameter

Equilibrium solubility

(g/ml)

Amorphous -- 235.0 2.0

Nanocrystals 89.8 nm 60.2 4.3

Micronized crystals 6 m 11.9 0.5

Grassi, Grassi, Lapasin, Colombo, UnderstandingDrugRelease and Absorption Mechanisms, Chap. VI, CRCPress,2007

From IDR data



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DSC and XRPD traces color codeBlue line: native drug nanocrystals Red line: recrystallized drug microcrystals

DSC Pattern

Temperature (C)

200 205 210 215 220 225 230

HeatFlow(

mW

g-1)

2

4

6

8

10

12

14

16

18

20

native drug

re-crystallized drug

XRD Pattern

2 (deg)

10 15 20 25 30

Intensity

(a.u.)

0

2000

4000

6000

8000

10000

re-crystallized drug

native drug

Grassi, Grassi, Lapasin, Colombo, UnderstandingDrugRelease and Absorption Mechanisms, Chap. VI, CRC

Press,2007

Griseofulvine solid state analysis

DSC trace XRPD trace


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2.Solid state properties modifications:

applications to pharmaceutical product

development


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Solid state properties modifications

Property change Final drug status Bulk product type

Crystal size

reduction

MicrocrystalsMicronized API powder

Solid dispersion (micro)

Nanocrystals

Nanosuspension

Solid nanocrystalsSolid dispersion (nano)

Nanocomposite

Solid phasetransition

AmorphousSolid dispersion (Solid solution)

Amorphous powder

Metastable(pseudo)Polymorph

API PowderSolid (nano)dispersion

Molecular dispersion Solid solution (true)


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Modified solid

Bottom-Uptechnologies

Top-Downtechnologies

DemolitionOriginal solid phase is disintegrated

Solid state properties modifications

Build-upFrom free molecules

to the new solid phase

Two possible strategies


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2.1 Size reduction


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Size reduction - Nanocrystals

Top-Down

Dry Milling

Wet Milling

High Pressure Homogenization

Bottom-Up

Precipitation

Process type

Applicable technologies

Biorise HEMA (Eurand)

Dissocubes and IDD-P (Skyepharma)

Nanocrystals (Elan-Nanosystems)

Biorise SIA (Eurand)NanoEdge (Baxter)


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Elan-Nanosystems nanocrystal formulationsWet process conducted in beador pearl millloaded with:

Crystalline drug suspended in aqueous or organic vehicle

Suspension stabilizers and wetting agents

Size reduction Top-DownMarketed technologies examples

Milling media (up to 75% of the mill volume)Low energy process

Minor risk of degradation / phase transition

than in dry or high pressure homogenization

processes

Suspension of nanocrystals into theprocess vehicle

Application for parenteral administration

(nanocrystals smaller than 200 nm) Schematic representation of media milling process(From E.Merisko- Liversidge et al., Eur.J.Ph.Sci ,18(2003), 113)


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Elan-Nanosystems nanocrystal formulationsPros

Low energy milling

Suitable for drugs insoluble both in water and organic solvents

Wide suspension concentration range 1-400 mg/ml

Cons

Possible milling material erosion

Nanosuspension stabilization against aggregation is needed

Time consuming (from hours up to days)Solvent removal step in downstream process to solid dosage forms

Spray-drying, freeze drying, wet granulation,

Possible nanocrystals aggregation



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Elan-Nanosystems nanocrystal formulations

Four products on the market (oral administration)

Rapamune (2000, Wyeth) Syrolimus Immunosuppressant

Emend (2001, Merck) Aprepitant Antiemetic

TriCor (2004, Abbott) Fenofibrate treatment of hypercholesterolemia

MegAce ES (2005, Par Pharmaceuticals) Megestrol acetate Anticachetic

http://www.pharmalot.com/wp-content/uploads/2008/03/tricor.jpg


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Dissocube e IDD-P by Skyepharma


Working pressure up to 4000 bar

Cavitation shockwaves energy breaks solid particlesin the region across the gap

Gap diameter between 5 and 30 microns Drug suspension pass through the homogenizer one

or more times depending on the desired final size anddrug milling behaviour

Wet process in high pressure or jet stream homogenizers

Crystalline drug suspended in aqueous or hydrophilic organic solvent

Stabilizer / wetting agent might be added

High pressur piston-gaphomogenizer (Dissocube)


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Jet stream homogenizer (IDD-P)


Particle collisions, shearforce, cavitation

Microfluidizer processor (Microfluidics)

Z or Y shaped fluidizer

Working pressure up to 2000 bar

Particles collision and shear force at the flows conjunctionresults in size reduction

Drug suspension pass through the homogenizer usaully 10-30 time.

Up to 50-100 cycles could be required depending on drug properties

One product on the market (oral administration)Triglide (Sciele Pharma Inc, 2005) Fenofibrate treatment of hypercholesterolemia
http://www.triglide.com/


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Pros

No milling media contamination

Suitable for drugs insoluble both in water and organic solvents

Cons

Drug has to be micronized before processing

Equipment high cost

Time consuming (IDD-P)

Several cycles into homogenizers (10-15 to 50-100)

Nanosuspension stabilization against aggregation is needed

Solvent removal step in downstream process to solid dosage forms

Spray-drying, freeze drying, wet granulation,

Possible nanocrystals aggregation



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Dry milling into vibrating or oscillating mill

Crystalline active ingredient and carrier are coprocessed

Composite product is obtained

Nanocrystals dispersed into the carrier

Possible formation of amorphous phase

Biorise HEMA by Eurand


Milling energy, drug/carrier interactions and

drug/carrier ratio mainly influence finished

product characteristics Nanocrystalline domains average size

Amorphous content


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Pros

Carrier stabilized nanocrystals

Possibility to obtain stabilized amorphous phase triggering process

conditionsSuitable for drugs insoluble both in aqueous and organic vehicles

Cons

High energy process product heating

Mill cooling during processLow melting point or thermally unstable drugs: case by case verification

Possible milling media contamination

Product adhesion to mill wall and milling media

Biorise HEMA by Eurand



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Biorise HEMA by EurandOne product on the market (oral administration)

Nimedex (Italfarmaco, ) Nimesulide Antiinflammatory


FAST ONSET


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Size reduction Bottom-UpMarketed technologies examples

Biorise SIA by EurandPrecipitation on solid

Drug dissolved in suitable organic solvent

Organic solution mixed with insoluble crosslinked carrier swelling

Solvent removed

Solid drug entrapment into/onto crosslinked carrier Nanocrystalline and/or amorphous phases solid dispersions

Drug solubility into carrier solid solutions

Crosslinked carrier network is a constrain to crystals growth Average size below 100 nm

Stabilizing effect Maximum polymer network openingi.e. 40-50 nm for crospovidone


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Size reduction Bottom-UpMarketed technologies examples

NanoEdge by Baxter

Precipitation in liquid + homogenization Drug and surfactant dissolved in suitable water miscible solvent

Aqueous buffer containing surfactant added into drug solution Drug precipitation

Homogenization of the suspension contributes to reduce drug

crystal size

Solid powder can be obtainedSpray drying, freeze drying, etc.


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2.2 Amorphous phase


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Amorphous Phase

Bulk Drug

Solid dispersion

Homogeneous mixture of solid drug into solid carrier(s) Amorphous

Crystalline (micro-, nano-)

Solid SolutionMolecular dispersion of drug into solid carrier(s)Some authors consider in this category also amorphous

drug dispersions


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Amorphous PhaseSolid Dispersions (Solid Solutions)

Top-Down

Dry Co-Milling

Bottom-Up

Solvent evaporation

Hot melt processing

Process type

Applicable technologies

Biorise HEMA (Eurand)Biorise SIA (Eurand)

Meltrex (Soliqs)

Nanomorph (Soliqs)


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Thermal

Solvent

Mechanical Co-milling Biorise HEMA

Solvent evaporation

Precipitation

Hot Melt Extrusion Meltrex

Hot Melt Granulation

Spray congealing

Ultra-raffreddamento

Top-Down

Bottom-Up

Amorphous PhaseSolid Dispersions

Biorise SIA

Nanomorph


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Solid APISolid

Excipient

Mixing

Liquid mixture Hard capsules filling

Melting

MoltenExcipient

Cooling

Spraycongealing

Multiparticolate(mcrospheres, pellets)

Cool down tosolid

Milling, sizing

Multiparticolate(granules, powder)

Solid dosage formdownstream

Melting Molten API



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Drug

Solid

excipient(s)

Mixing

Physical blend Hot melt extrusion

Monolithicmatrix

Hot melt granulation

Multiparticulate(granules, pellets)

Solid formsdownstream

Highshear

Lowshear

Fluidbed

Pelletization

Multiparticulate(granules, pellets)



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From http://www.soliqs.com/Technology.17.0.html

Melt Extrusion line for production of tablet shaped dosage form byMeltrex Technology
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Drug

Solid

excipient(s)

Mixing

Solvent evaporation

Filtration / solventremoval

Solid(micro/nanoparticles)

Solvent

Superctitical fluid Spray drying Vacuum dryingFreeze drying

Solid product Solid forms downstream

Solid(powder)


Antisolventprecipitation

Liquid

Suspension

Solution
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Promising approach with several applications and advantagesSolubility enhancement, controlled release, stability enhancement, etc.

Much research work both in academia and industry but.

.limited practical application..Few marketed products based on solid dispersion/solution technologies

Gris-PEG (Pedinol Pharm.) Griseofulvine dispersed in Poliethylene glycol

Cesamet(Valeant Pharm.) Nabilone dispersed in Polyvinylpyrrolidone

Prograf (Fujisawa) Tacrolimus dispersed in HPMC

Certicabe (Novartis) Everolimus dispersed in HPMC

Kaletra(Abbott) Lopinavir and Ritonavir in solid matrix by Meltrex technology

.because of some formulation and development issues

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Example of success: Kaletra

Meltrex tablets Lopinavir+Ritonavir Anti-HIV product (Abbott)

FDA Approved in 2005

Designed as an improvement of origina Kaletra Soft-gel capsules


Meltrex technology

PK profile comparable to that of capsules, but no food effect

Dosing regimen and patient compliance improvement

From three-six capsules/day to two-four tablets/day of comparable size

Solid formulation more stable than liquid

Room temperature instead refrigerated storage
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Major issuesChemical and/or physical stability

Crystallization of amorphous phases impacts product performance, i.e.

drug solubility / solubility rate

Carrier and/or drug

Molecular mobility - Promoted by Exceeding glass transition temperature of the system

Plasticizing effect of water (or other solvents)

Limited drug load for molecular and amorphous dispersions

Drug solubility / miscibility in the carrier at solid state

oversaturation drug crystallizationProduct characterization

Special technique required for solid phases characterization

Validation for submission purposes could be complex

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2.3 Physical-chemical characterization of compositesystems containing nanocrystalline and

amorphous domains
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Bulk analysis

Particle SizeLaser light diffraction (LLD)Mercury porosimetry (MP)

Solid Phases (Qualitative and Quantitative)X-Ray powder diffraction analysis (XRPD)Differential scanning calorimetry (DSC)

Solubilization KineticSurface analysis

Specific Surface AreaMercury PorosimetryGas Adsorption

Surface Mapping

Liquid-Solid contact angleAtomic force microscopy + micro thermal analysis (AFM-TA)Scanning electron microscopy + energy dispersive spectroscopy (SEM-EDS)X-Ray Photo-electron spectroscopy (XPS)Micro Raman Spectroscopy

Techniques useful for Solid Phases Characterization

Solid state characterization
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Qualitative evaluation of solid phases

Crystalline vs amorphous

Quantitative evaluation of solid phases

Calibration curve : i.e. crystalline drug and carrier at different ratios

Crystallite size estimation

Scherrer equation relates increase of full-width of the peak at half of its maximal intensity(FWHM, ) with size of crystallites (), through a costant (K), x-Ray wavelength () and theBragg angle ()

Other microstructures features could affect FWHM enlargement beside crystallite size,therefore peaks fitting refinement (i.e. Rietveld method) and deconvolution analysis (i.e.Warren-Averbach) have to be applied

X Ray Powder Diffraction


cos

K
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2 (deg)

8 12 16 20 24 28 32 36 40

Intensity

(a.u.)

composite systemraw material
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DSCQualitative evaluation

Temperature (C)

60 80 100 120 140 160 180 200 220

HeatFlow(W/g)(composite)

0.76

0.80

0.84

0.88

HeatFlow(W/g)(rawmaterial)

5

10

15

20

Weight(%)

(composite)

99.3

99.4

99.5

99.6

99.7

99.8

99.9

100.0DSC signal of composite system

DSC signal of raw material

TGA signal of composite system

Raw griseofulvin (red trace): Solid-Liquid Phase transition happens at about 220C Heat flowscale 5-20 W/g

Composite system (blue trace): Endotherm at about 180C corresponds to Solid-Liquid phaseTransition of nanocrystalline griseofulvin (nanocomposite griseofulvin/crospovidone) Heat flow

scale 0.76-0.88 W/g

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For a composite sample containing drug in crystalline and amorphous phases the enthalpy offusion is the sum of enthalpy of fusion of each of the j solid phases:

Specific enthalpy of fusion usually is estimated using DSC data from pure crystalline drug / matrixphysical mixtures of known drug content.

Nanocrystalline phase specific melting enthalpy, being temperature dependant, can be calculatedapplying Kirchoff law starting from parameters experimentally measured for standard drug

DSCQuantitative evaluation

jj

mjs

m hmH


m :mass of the jthphasehm:specific enthalpy of fusion of the j

thphase

Drug X/Crospovidone 1:2 w/w

Biorise HEMA compositesDrug X melting points

About 148C: nanocrystals

About 160C: standard product
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Surface Mapping Techniques Phases

Liquid Solid Contact Angle MeasurementSolid phase type impact on contact angle value

Technique useful only for non swellable carriers

Atomic Force Microscopy+micro Thermal Analysis

Images obtained based on bothTopography

Thermal conductivity/diffusivity

40-50 nm resolution

Micro-Raman

Raman Microscope is a conventional Raman spectrometer confocally coupled

with an optical microscope

Laser beam can be focused at the sample surface with resolution down to 1 mScanning Electron Microscopy+Energy Dispersive X-Ray Spectroscopy (SEM-EDS)

Scanning electron microscope is coupled with a probe detecting X-Ray produced

by the interaction of electrons with the sample

X-Ray emission is different for each atom chemical mapping

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Composite microstructure andmorphology investigation

Nimesulide-Crospovidone Case Study

Nimesulide-Crospovidone composite case study
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2(deg)

5 10 15 20 25 30

Intensity

(a.u.) NN

PN

NC

NN : native (raw) nimesulide - PN : polymorphic nimesulide: mixture of forms I and II

NC : nimesulide/crospovidone nanocomposite

Coherent domain (crystallite) size by XRPDprofile analysis using double-Voight and FPA#

= 17 3 nm

Strain: 3%-17%

# D. Balzar in R.L. Snyder, H.J. Bunge, J. Fiala (Eds),Defect and Microstructure analysis by diffraction;;International Union of Crystallography, OxfordUniversity Press, New York, 1999

Nimesulide/Crospovidone nanocomposites (1/2.5 w/w ) prepared by solvent

induced activation (F. Carli et al. Int. J. Pharm. 33, 115 (1986)) Nimesulide exists in two polymorphic modifications (P. Bergese et al. Comp. Sci. Technol.,

63, 1197 (2003))

Form I (Native material)

Form II that is metastable

Solid state characterization - microstructure
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Morphology Scanning electron microscopy

Epossidic

resinNC particles

Ultramicrotome


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Molecular Dispersion Scanning electron microscopy + energy dispersive X-rayspectroscopy (SEM-EDS)

Nimesulide: nonsteroidal antiinflammatory,

C13H12N2O5 S

Crospovidone:

cross-linked polyvinylpirrolidone, [C6H9NO]n

Sulphur main X-ray emission(Ka, 2.307 keV) overlaps with principal gold X-ray emissions:

the sample was sputtered with titanium

Sulphur can be used to track nimesulide molecules eventually dispersed into the

crospovidone network


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Molecular Dispersion Scanning electron microscopy + energy dispersive X-rayspectroscopy (SEM-EDS)

1.1740.542

0.304

Energy (KeV)

1 2 3 4

cps

0

5

10

15 peak area=0.542peak area=0.304

peak area=1.174

S

C

J. Phys. Chem. B, 2004, 108, 15488-15493Composites Part. A, 2005, 36, 443-448

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Raman shift (cm-1)

300 400 500 600 700 800 900

Intensity

(a.u.)

4000

6000

8000

10000

12000

14000

Intensity

(a.u.)

4000

4400

4800

52002

1

402

20

25

30

35

40

Leng

thY(m)

25 30 35 40

Length X (m)

200

150

100

50

Phases distribution Raman microscopy (Raman)

Amorphous

Crystalline


Surface scanning by collecting a Raman

spectrum with steps of 1 m2

Intensity projection of the crystalline

nimesulide peak at 402 cm-1

MAP

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Conclusions

Nimesulide Crospovidone composite case study

XRD: crystalline nimesulide is packed in 17 nm crystallites

SEM: nimesulide micro- and nanoparticles segregated onto the

crospovidone surface as well as wrapped up by the crospovidone matrix

EDS: there is a presence of nimesulide also in zones where the polymer

surface is free from nimesulide particles

Raman: domains of crystalline nimesulide surrounded by amorphousnimesulide


Nimesulide-Crospovidone composite case studyCaratterizzazione
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Conclusions


Nimesulide is constrained by the crospovidone into three main

arrangements:

an amorphous phase dispersed into the molecular crosslinked

network of the polymer

nanocrystals wrapped up by the polymer

drug layers, made of micro- and nanocrystals, segregated onto the

popcorn-like surface of the polymer

According to XRD data, the micro- and nanocrystals are highlydisordered and made of crystallites with an average diameter of 17 nm

Caratterizzazionechimico-fisica

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Paolo Gatti, PhD

Eurand RD Senior [email protected]

Or come at

Both 722

Technical questions

Thanks for Your Attention !!!
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SOLVATION AND DIFFUSION DEPEND ONSOLUTE AND SOLVENT CHEMICAL

NATURE AND ON SYSTEM CONDITIONS WETTING AND FUSION DEPEND ALSO

ON MICROSTRUCTURE OF THE SOLUTEIN THE SOLID STATE


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Time (s)

0 100 200 300 400

Concentration(mg/ml)

0

200

400

600

0 20 40 60

0

1

2

3

4

experimental data for 100% amorphous TEM

simulations

experimental data for 100% nanocrystalline MPA

Solubilization Kinetic

Amorphous and Nanocrystalline Composite Materials

Comparison of solubilization kinetics in non-sink conditions

(Dispersed Amount Method)

M. Grassi, I. Colombo, R. Lapasin,

J. Controlled Release 68 (2000), 97-113


crs young scientist 2010 final 2

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