HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES: GENERAL CONCEPTS
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Transcript of HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES: GENERAL CONCEPTS
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HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES:
GENERAL CONCEPTS
Mario Grassi([email protected])
Department of Chemical Engineering (DICAMP)UNIVERSITY OF TRIESTE
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NON-THERMALLY ACTIVATED CHEMISTRY [1]
ELECTROCHEMISTRY MECHANOCHEMISTRY
1 - INTRODUCTION
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Physico-chemical transformations(Crystalline network and surface
modifications)
MECHANOCHEMISTRY
Chemical reactions
MECHANICAL ENERGY SUPPLY
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1900The term
“mechanochemistry” is introduced
Construction materials, mineral fertilizers, functional ceramics.Germany, Japan, Israel USSR
1960
2 - MECHANOCHEMISTRY EVOLUTION
PREHISTORIC TIMES
explosion excitation under mechanical action.France, England, Russia
1970MATERIAL SCIENCE:nickel- and iron base superalloys
1950
MINERAL RAW PROCESSING
1988International
Mechanochemical Association
19931st International Conference on
Mechanochemistry
1980PHARMACEUTICAL
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3 - WHY MECHANOCHEMISTRY IN THE PHARMACEUTICAL FIELD?
1Getting pharmaceutical products avoiding the use of solvents(their elimination can be difficult, expensive and can alter drug activated status)
2 Possibility of increasing the bioavailability of poorly water soluble drugs (class 2 drugs [2])
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Drug Crystal
4 - MECHANISMS: ONE COMPONENT
Grinding medium
COLLIDING GRINDING MEDIA
HINT:Mechanical
energy supply
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Energy supply due to:
crystal
normal stresses
shear stresses
CRYSTAL DEFORMATION
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Microscopically:
Un-deformed crystal
Deformed crystal: unstable condition
1) Atoms distance variation2) Bond angles variation
Inte
rnal
En
erg
y
E
Energy relaxation(101 – 10-7s) [3]
HEAT PLASTIC DEFORMATION
BONDS RUPTURE(CHEMICAL REACTION)
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HEAT
MAIN PART
random AMORPHOUS
regular POLYMORPHS
PLASTIC DEFORMATION
COMMINUTION
DEFECTS
BONDS RUPTURE(CHEMICAL REACTION)
DRUG CHEMICAL MODIFICATION
MECHANOCHEMICAL ACTIVATED
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5 - SOLUBILITY AND CRYSTAL RADIUS r
Liquid
Solid
a
a + bLiquid a + b
a
r
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Liquid a + b
a
r
rTRv
nfis
snc
ssl
eC
C1
Kelvin equation[4]
sl = solid-liquid surface tension
vs = solid solute molar volume
R = universal gas constant
T = temperature
It holds for an ideal solution
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PARTICLE
CRYSTALS
AMORPHOUS
CRYSTALS
CRYSTALS
CRYSTAL
CRYSTALLITE
r
WHICH RADIUS ARE WE REFERRING TO?
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6 - STABILISATIONAmorphous and nanocrystal drugs are not stable (months, years)
STABILISING AGENT
POLYMER
amorphous drugnanocrystals
CYCLODEXTRIN
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7 - EXPERIMENTAL VERIFICATION OF ACTIVATION
2 - PXRD Diffraction peak broadening - disappearing[5, 7]
0
50
100
150
200
250
300
350
4 8 12 16 20 24 28 32
(deg)
Inte
ns
ity
(A
.U)
physical mixture
co-ground 2 h
NIMESULIDE - PVPcl
1 – DSC: melting enthalpy and temperature reduction
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3 – IN VITRO Test Increased release kinetics[5]
0
5
10
15
20
25
0 5 10 15 20 25
t(min)
C(m
g/c
m3)
0 h 0.5 h 1 h 2 h 4 h
NIMESULIDE - PVPcl
WATER 37°C, pH = 5.5
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4 – IN VIVO Test Increased Bioavailability
NIFEDIPINE – PEG600 HPMC [8]
0102030405060708090100
0 2 4 6 8
t(h)
C(ng/ml)
coground
physical mixture
Blood concentration (Beagle dogs)
AUC = 47 ng h/mlCmax = 9 ng/mlTmax = 1.4 h
AUC = 122 ng h/mlCmax = 89 ng/mlTmax = 0.5 h
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8 – MILLS TYPES [3]
1 BALLS MILLS(Tumbling mills, Planetary, vibrational, Spex mills and attritors)
2 SHEAR ACTION MILLS(Rollers)
3 SHOCK ACTION MILLS(Jet mills, high peripheral-speed pin mills )
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BALLS MILLS [9, 10]
Tumbling mill
Inco Alloys International
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Many balls
Few balls
PlanetaryFritsch
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Vibrational
Sweco
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Spex mills
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Attritors
Union Process, Akron, OH
vertical
Horizontal
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SHEAR ACTION MILLS: Rollers
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Jet mills
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Pin mills
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MILLS ENERGY [3]
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9 – CENTRAL QUESTION
MILL OPERATION CONDITIONS
GROUND MATERIAL
PROPERTIES
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1 TRIALS AND ERROR(small variations of the operating conditions)
2MATHEMATICAL MODELLING APPROACH(attainment of general principles working for a wide range of operating conditions and different mills)
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MATHEMATICAL MODELLING APPROACH
a1) Grinding media dynamics
a) Mill dynamics
b) How energy is transferred to charge
c) Effect of the energy received on chargeA
C
C
Cp
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EXAMPLE: VIBRATORY MILL
Lost energy (thermal dissipation)
Kinetic and potential energy due to bodies motion
Available energy for mechanochemical activation
a) Mill dynamics
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a1) Grinding media dynamics
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b) Energy transfer to charge (uniformity conditions)[9]
Grinding mediumCharge
k = charge fraction involved in one hint
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CLASSES
1-k k 0 0
0(i)n012345
n
1(i) 2(i) 3(i)
0(1)-k 0(1) k0(1)-k 1(1) k1(1)-k 2(1) 0
0(2)-k 0(2) k0(2)-k 1(2) k1(2)-k 2(2) k2(2)-k 3(2)
0(3)-k 0(3) k0(3)-k 1(3) k1(3)-k 2(3) k2(3)-k 3(3)
0(4)-k 0(4) k0(4)-k 1(4) k1(4)-k 2(4) k2(4)-k 3(4)
0(n-1)-k 0(n-1) k0(n-1)-k 1(n-1) k1(n-1)-k 2(n-1) k2(n-1)-k 3(n-1)
1 0 0 0
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0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
0 250000 500000 750000 1000000 1250000n
0
1
2
3
4 5
6
kni
ei
knn
!χ i
0 = 5%
1 = 15%
2 = 22%
3 = 22%
4 = 17%
5 = 10%
6 = 5%
rem = 4%
k = 10-5 (n-1)
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Crystal Nano Crystal
Amorphous
k-1
k1
k-2k2
k3
k-3
c) Effect of the energy received on charge [10]
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0
20
40
60
80
100
120
0.00E+00 5.00E+08 1.00E+09 1.50E+09i(n)
X(-
)
Xc XncXa Xc sperimXnc sperim Xa sperim
COMPARISON BETWEEN THEORY AND EXPERIMENTS
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10 REFERENCES
1. Tkacova K. 1993. First international conference on mechanochemistry: an introduction. Proc. First Intl. Conf. on Mechanochemitsry. Cambridge Interscience Publishing. 1:9-17.
2. Amidon GL, Lennernäs H, Vinod PS, Crison JR. 1995. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 12: 413-420.
3. Tkacova K. 1989. Mechanical Activation of Minerals. Amsterdam, New York: Elsevier.
4. Adamson, Gast . Physical Chemistry of Surfaces; Wiley Interscience, New York, Toronto, 1997, chapters II, III and X.
5. Grassi M, Grassi G, Lapasin R, Colombo I. 2007. Understanding drug release and absorption mechanisms: a physical and mathematical approach. Boca Raton: CRC Press
6. Brun, Lallemand, Quinson, Eyraud. J. De Chimie Physique, 70(6) (1973) 979-989.
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7. Bergese P, Colombo I, Gervasoni D, Depero LE. 2003. Assessment of the x-ray diffraction-absorption method for quantitative analysis of largely amorphous pharmaceutical composites. J. Appl. Cryst. 36: 74-79.
8. Sugimoto M, Okagaki T, Narisawa S, Koida Y, Nakajima K. 1998. Improvement of dissolution characteristics and bioavailabilty of poorly water-soluble drugs by novel cogrinding method using water-soluble polymer. Int. J. Pharm. 160: 11-19.
9. Delogu F, Cocco G. 2000. Relating Single-Impact Events to Macrokinetic Features in Mechanical Alloying Processes. J. Mat. Synthesis and Processing 8: 271-277.
10.D. Manca, N. Coceani, L. Magarotto, I. Colombo, M. Grassi. High-Energy Mechanochemical Activation of Active Principles. Convegno GRICU 2004, Nuove Frontiere di Applicazione delle Metodologie dell’Ingegneria Chimica, Porto d’Ischia (Na), 12-15 Settembre 2004, Volume I, 123-126.