high-energy mechanochemical activation of active principles: general concepts
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HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES:
GENERAL CONCEPTS
Mario Grassi(mariog@dicamp.univ.trieste.it)
Department of Chemical Engineering (DICAMP)UNIVERSITY OF TRIESTE
NON-THERMALLY ACTIVATED CHEMISTRY [1]
ELECTROCHEMISTRY MECHANOCHEMISTRY
1 - INTRODUCTION
Physico-chemical transformations(Crystalline network and surface
modifications)
MECHANOCHEMISTRY
Chemical reactions
MECHANICAL ENERGY SUPPLY
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
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])
Drug Crystal
4 - MECHANISMS: ONE COMPONENT
Grinding medium
COLLIDING GRINDING MEDIA
HINT:Mechanical
energy supply
Energy supply due to:
crystal
normal stresses
shear stresses
CRYSTAL DEFORMATION
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)
HEAT
MAIN PART
random AMORPHOUS
regular POLYMORPHS
PLASTIC DEFORMATION
COMMINUTION
DEFECTS
BONDS RUPTURE(CHEMICAL REACTION)
DRUG CHEMICAL MODIFICATION
MECHANOCHEMICAL ACTIVATED
5 - SOLUBILITY AND CRYSTAL RADIUS r
Liquid
Solid
a
a + bLiquid a + b
a
r
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
PARTICLE
CRYSTALS
AMORPHOUS
CRYSTALS
CRYSTALS
CRYSTAL
CRYSTALLITE
r
WHICH RADIUS ARE WE REFERRING TO?
6 - STABILISATIONAmorphous and nanocrystal drugs are not stable (months, years)
STABILISING AGENT
POLYMER
amorphous drugnanocrystals
CYCLODEXTRIN
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
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
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
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 )
BALLS MILLS [9, 10]
Tumbling mill
Inco Alloys International
Many balls
Few balls
PlanetaryFritsch
Vibrational
Sweco
Spex mills
Attritors
Union Process, Akron, OH
vertical
Horizontal
SHEAR ACTION MILLS: Rollers
Jet mills
Pin mills
MILLS ENERGY [3]
9 – CENTRAL QUESTION
MILL OPERATION CONDITIONS
GROUND MATERIAL
PROPERTIES
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)
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
EXAMPLE: VIBRATORY MILL
Lost energy (thermal dissipation)
Kinetic and potential energy due to bodies motion
Available energy for mechanochemical activation
a) Mill dynamics
a1) Grinding media dynamics
b) Energy transfer to charge (uniformity conditions)[9]
Grinding mediumCharge
k = charge fraction involved in one hint
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
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)
Crystal Nano Crystal
Amorphous
k-1
k1
k-2k2
k3
k-3
c) Effect of the energy received on charge [10]
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
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.
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.
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