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HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES: GENERAL CONCEPTS

HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES: GENERAL CONCEPTS. Mario Grassi ( mariog@dicamp.univ.trieste.it) Department of Chemical Engineering (DICAMP) UNIVERSITY OF TRIESTE. 1 - INTRODUCTION. NON-THERMALLY ACTIVATED CHEMISTRY [1]. ELECTROCHEMISTRY. MECHANOCHEMISTRY.

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HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES: GENERAL CONCEPTS

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  1. HIGH-ENERGY MECHANOCHEMICAL ACTIVATION OF ACTIVE PRINCIPLES: GENERAL CONCEPTS Mario Grassi (mariog@dicamp.univ.trieste.it) Department of Chemical Engineering (DICAMP) UNIVERSITY OF TRIESTE

  2. 1 - INTRODUCTION NON-THERMALLY ACTIVATED CHEMISTRY [1] ELECTROCHEMISTRY MECHANOCHEMISTRY

  3. MECHANOCHEMISTRY Physico-chemical transformations (Crystalline network and surface modifications) Chemical reactions MECHANICAL ENERGY SUPPLY

  4. 2 - MECHANOCHEMISTRY EVOLUTION 1st International Conference on Mechanochemistry 1993 International Mechanochemical Association 1988 MATERIAL SCIENCE: nickel- and iron base superalloys 1970 Construction materials, mineral fertilizers, functional ceramics. Germany, Japan, Israel USSR 1960 explosion excitation under mechanical action. France, England, Russia 1950 MINERAL RAW PROCESSING The term “mechanochemistry” is introduced 1900 PREHISTORIC TIMES 1980 PHARMACEUTICAL

  5. Getting pharmaceutical products avoiding the use of solvents (their elimination can be difficult, expensive and can alter drug activated status) 1 2 Possibility of increasing the bioavailability of poorly water soluble drugs (class 2 drugs [2]) 3 - WHY MECHANOCHEMISTRY IN THE PHARMACEUTICAL FIELD?

  6. 4 - MECHANISMS: ONE COMPONENT HINT: Mechanical energy supply Grinding medium Drug Crystal COLLIDING GRINDING MEDIA

  7. normal stresses crystal shear stresses CRYSTAL DEFORMATION Energy supply due to:

  8. Atoms distance variation • Bond angles variation DE Internal Energy Deformed crystal: unstable condition Energy relaxation (101 – 10-7s) [3] Un-deformed crystal PLASTIC DEFORMATION BONDS RUPTURE (CHEMICAL REACTION) HEAT Microscopically:

  9. PLASTIC DEFORMATION BONDS RUPTURE (CHEMICAL REACTION) HEAT MAIN PART DRUG CHEMICAL MODIFICATION COMMINUTION random AMORPHOUS DEFECTS POLYMORPHS regular MECHANOCHEMICAL ACTIVATED

  10. 5 - SOLUBILITY AND CRYSTAL RADIUS r Liquid a + b Liquid a + b r a a Solid

  11. a + b Liquid r a Kelvin equation[4] It holds for an ideal solution gsl = solid-liquid surface tension vs = solid solute molar volume R = universal gas constant T = temperature

  12. PARTICLE CRYSTAL CRYSTALS r CRYSTALS CRYSTALS AMORPHOUS CRYSTALLITE WHICH RADIUS ARE WE REFERRING TO?

  13. 6 - STABILISATION STABILISING AGENT CYCLODEXTRIN POLYMER nanocrystals amorphous drug Amorphous and nanocrystal drugs are not stable (months, years)

  14. 7 - EXPERIMENTAL VERIFICATION OF ACTIVATION 1 – DSC: melting enthalpy and temperature reduction 2 - PXRD Diffraction peak broadening - disappearing[5,7] NIMESULIDE - PVPcl

  15. 3 – IN VITRO Test Increased release kinetics[5] NIMESULIDE - PVPcl WATER 37°C, pH = 5.5

  16. 4 – IN VIVO Test Increased Bioavailability NIFEDIPINE – PEG600 HPMC [8] Blood concentration (Beagle dogs) AUC = 122 ng h/ml Cmax = 89 ng/ml Tmax = 0.5 h AUC = 47 ng h/ml Cmax = 9 ng/ml Tmax = 1.4 h

  17. 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 )

  18. BALLS MILLS [9, 10] Tumbling mill Inco Alloys International

  19. Planetary Fritsch Many balls Few balls

  20. Vibrational Sweco

  21. Spex mills

  22. Attritors vertical Horizontal Union Process, Akron, OH

  23. SHEAR ACTION MILLS: Rollers

  24. Jet mills

  25. Pin mills

  26. MILLS ENERGY [3]

  27. 9 – CENTRAL QUESTION GROUND MATERIAL PROPERTIES MILL OPERATION CONDITIONS

  28. 1 TRIALS AND ERROR (small variations of the operating conditions) MATHEMATICAL MODELLING APPROACH (attainment of general principles working for a wide range of operating conditions and different mills) 2

  29. MATHEMATICAL MODELLING APPROACH a) Mill dynamics a1) Grinding media dynamics b) How energy is transferred to charge C C c) Effect of the energy received on charge Cp A

  30. EXAMPLE: VIBRATORY MILL a) Mill dynamics Available energy for mechanochemical activation Kinetic and potential energy due to bodies motion Lost energy (thermal dissipation)

  31. a1) Grinding media dynamics

  32. Grinding medium Charge b) Energy transfer to charge (uniformity conditions)[9] k = charge fraction involved in one hint

  33. n 0 1 2 3 4 5 n c0(i) c1(i) c2(i) c3(i) 0 0 1 0 k 0 1-k 0 c0(1)-k c0(1) kc0(1)-k c1(1) kc1(1)-k c2(1) 0 c0(2)-k c0(2) kc0(2)-k c1(2) kc2(2)-k c3(2) kc1(2)-k c2(2) kc0(3)-k c1(3) kc1(3)-k c2(3) c0(3)-k c0(3) kc2(3)-k c3(3) c0(4)-k c0(4) kc0(4)-k c1(4) kc1(4)-k c2(4) kc2(4)-k c3(4) c0(n-1)-k c0(n-1) kc0(n-1)-k c1(n-1) kc1(n-1)-k c2(n-1) kc2(n-1)-k c3(n-1) CLASSES - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

  34. c0 = 5% c1 = 15% c2 = 22% c3 = 22% c4 = 17% c0 c5 = 10% c1 c6 = 5% crem = 4% c2 c3 c4 c5 c6 k = 10-5 (n-1)

  35. c) Effect of the energy received on charge [10] k-1 Crystal Nano Crystal k1 k3 k-2 k-3 k2 Amorphous

  36. COMPARISON BETWEENTHEORY AND EXPERIMENTS

  37. 10 REFERENCES • Tkacova K. 1993. First international conference on mechanochemistry: an introduction. Proc. First Intl. Conf. on Mechanochemitsry. Cambridge Interscience Publishing. 1:9-17. • 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. • Tkacova K. 1989. Mechanical Activation of Minerals. Amsterdam, New York: Elsevier. • Adamson, Gast . Physical Chemistry of Surfaces; Wiley Interscience, New York, Toronto, 1997, chapters II, III and X. • Grassi M, Grassi G, Lapasin R, Colombo I. 2007. Understanding drug release and absorption mechanisms: a physical and mathematical approach. Boca Raton: CRC Press • Brun, Lallemand, Quinson, Eyraud. J. De Chimie Physique, 70(6) (1973) 979-989.

  38. 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. • 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. • Delogu F, Cocco G. 2000. Relating Single-Impact Events to Macrokinetic Features in Mechanical Alloying Processes. J. Mat. Synthesis and Processing 8: 271-277. • 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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