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.