supercritical fluid technology
Download as PPT, PDF3 likes875 views
This document discusses supercritical and subcritical fluid technology for drug delivery applications. It begins with definitions of critical temperature and pressure as well as supercritical fluids. It then describes various processes that use supercritical fluids like CO2 as solvents or antisolvents to precipitate drug particles, including RESS, PGSS, SAS, ASES, GAS, and SEDS. It provides details on the equipment and operating parameters for each process. The document discusses how these techniques can be used for particle engineering applications like size reduction and modifying solid state properties. Finally, it outlines other applications of supercritical fluids like extraction, sterilization and chromatography.
supercritical fluid technology
- 1. Supercritical and Subcritical Fluid Technology in Drug Delivery 1 By:Rajesh L. Dumpala (B.Pharm, M. Pharm.) PhD. ( Pursuing) Research Scientist, Alembic Research Centre. Vadodara E.Mail:-rdumpala64@gmail.com
- 2. List of Abbreviations Supercritical fluid(SF) Supercritical Carbon dioxide(SC-CO2) Rapid Expansion of Supercritical Solution (RESS) Rapid Expansion of a Supercritical Solution into a Liquid Solvent (RESOLV) The Gas Anti-solvent (GAS) Particles by Compressed Antisolvent (PCA) Supercritical Antisolvent (SAS) 2
- 3. List of Abbreviations Aerosol Solvent Extraction System (ASES) Solution Enhanced Dispersion by Supercritical Fluids (SEDS) Particles from Gas-Saturated Solutions/Suspensions (PGSS) Depressurization of an Expanded Liquid Organic Solution (DELOS) Continuous Powder Coating Spraying Process (CPCSP) Carbon dioxide Assisted Nebulization with a Bubble Dryer (CAN-BD) Supercritical Fluid-Assisted Atomization (SAA) 3
- 4. Introduction 4 CRITICAL TEMPERATURE If the temp. is elevated sufficiently, a value is reached above which it is impossible to liquefy a gas irrespective of the pressure applied. This temp. above which a liquid can no longer exist, is known as CRITICAL TEMPERATURE CRITICAL PRESSURE The pressure required to liquefy a gas at it’s critical temperature is the CRITICAL PRESSURE, which is also the highest vapour pressure that the liquid can have.
- 5. Introduction 5 SFs are GASES/LIQUIDS that are at temperatures and pressures above their critical point. Possess properties of both liquid and gas. Density as of liquid Flow properties as of gas Useful for thermolabile material SFs is dense but highly compressible, particularly near the SCF region
- 6. Commonly used SC material 6
- 7. 7 Phase diagram of CO2 Why CO2 is preferred over other materials? Inexpensiveness Non-flammability Non-toxicity Recyclability Environment benignity GRAS HYDROPHOBIC
- 8. Processing using supercritical fluids 8 Operations where the SCF acts as a solvent (RESS, RESOLV); Operations where the SCF acts as an antisolvent (GAS, SAS, PCA, ASES, SEDS); Particles from a gas-saturated solutions (PGSS, DELOS, CPCSP); CO2-assisted spray-drying (CAN-BD, SAA).
- 9. SCF TECHNIQUES FOR PARTICLE ENGINEERING Precipitation from supercritical solutions composed of supercritical fluid and solute Precipitation from solutions using SCFs or compressed gases as antisolvents Precipitation from Gas Saturated Solutions (PGSS) RESS PCA SAS ASES GAS SEDS
- 10. The Rapid Expansion of Supercritical Solution Process Mechanism Saturation of SCF with substrate(s) Depressurizing the solution through heated nozzle Rapid nucleation of the substrate(s) Product 10
- 11. RESS Equipment Process Variables Pre-expansion Temperature Capillary length Spraying Distance Pressure Solute Solubility Aggregation 11
- 12. Rapid Expansion of a Supercritical Solution into a Liquid Solvent Process 12 This technique is used in order to minimize the particles aggregation during the jet expansion. Step 2 Depressurization of SC solution in to water at room temp.(ctg. Polymers and Surfactants for stabilization of nanosupension) Step 1 Mixing of SC-CO2 and solute mixture to generate supersaturated solution.
- 13. The Gas Anti-solvent Mechanism Step 3 Solute precipitates in microparticles Step 2 Mixing, expansion and supersaturation of solution mixture Step 1 Antisolvent Solution of Active Substance 13
- 14. GAS Equipment 14 Process variables Rate of addition of antisolvent Temperature and pressure in precipitator Solvent
- 15. Particles by Compressed Antisolvent and Supercritical Antisolvent 15 In the Particles by Compressed Antisolvent (PCA) and Supercritical Antisolvent (SAS), the CO2 (supercritical for SAS, or subcritical for PCA) is first pumped inside the high-pressure vessel until the system reaches the fixed pressure and temperature, then, the organic solution is sprayed through a nozzle into the SCF bulk determining the formation of the particles that are collected on a filter at the bottom of the vessel
- 16. 16 Process variables Rate of addition of antisolvent Temperature and pressure in precipitator Solvent SAS/PCA Equipment
- 17. Aerosol Solvent Extraction System Process Mechanism Spraying of active substance & solvent mixture Compressed SCF (CO2) Dissolution into the liquid droplets due to large volume expansion Sharp rise in the supersaturation within the liquid mixture Formation of small & uniform particles Step 1 Step 2 Step 3 17
- 18. ASES Equipment Process Variables Temperature Liquid solution pressure Operating vessel pressure 18
- 19. Solution Enhanced Dispersion by Supercritical Fluids process Mechanism Active substance solution Spontaneous contact of liquid solution & SCF Simultaneous spraying of SCF Particle precipitation 19
- 20. SEDS Equipment Process Variables Type of nozzle Pressure Temperature 20
- 21. Advantages It can be used for the water-soluble compounds • Proteins • Peptides, by introducing organic solvent(Binary system) Suitable for scaling-up Highly controlled & reproducible technique Manufacturing according to GMP requirement 21 Solution Enhanced Dispersion by Supercritical Fluids process
- 22. 22 Schematic representation of the GAS, SAS, ASES, PCA, and SEDS processes and their basic operational principles.
- 23. Particles from Gas-Saturated Solutions/Suspensions Process Mechanism SCF (CO2) is dissolved in solution or melt of solid Expansion of gas saturated solution Generation of solid particles or liquid droplets 23
- 24. PGSS Equipment Process Variable Pressure Temperature 24
- 25. This process is designed for making particles of materials that absorb supercritical fluid at high concentrations The technique can be used for formation of microspheres with an embedded substance Highly suitable for polymer powder production, particularly for coating applications 25 Particles from Gas-Saturated Solutions/Suspensions Process
- 26. Depressurization of an Expanded Liquid Organic Solution Process 26 The CO2 expands in an autoclave where an organic solution of the solute to be micronized is dispersed Ternary mixture solute–solvent–compressed gas is depressurized by rapid reduction of the system pressure to atmospheric conditions The temperature drop is the driving force that causes the nucleation and precipitation of the drug The CO2 does not act as an antisolvent, but as a co- solvent to nebulize and cool the organic solution The process is not necessarily supercritical, in fact the operative pressure does not exceed the critical point of the CO2/solvent mixture
- 27. Continuous Powder Coating Spraying Process 27 CPCSP, the main components (binder and hardener) are melted in separated vessels to avoid a premature interaction with the polymer The molten polymer is fed into a static mixer, and homogenized with compressed carbon dioxide. The different components are intensively mixed and the formed solution expanded through a nozzle into a spray tower.
- 28. Carbon dioxide Assisted Nebulization with a Bubble Dryer 28 The near-critical or supercritical CO2 and the solution are pumped through a near zero volume to give rise to an emulsion which expands through a flow restrictor into a drying chamber at atmospheric pressure to generate aerosols of micro bubbles and micro droplets that are dried by a flux of warm nitrogen
- 29. Supercritical Fluid-Assisted Atomization 29 In the case of SAA (Supercritical Fluid-Assisted Atomization) the supercritical CO2 and the solution are mixed into a vessel loaded with stainless steel perforated saddle which assures a large contact surface between liquid solution and the SCF; then the mixture is sprayed in a precipitator at atmospheric pressure under a flow of hot N2. The main difference between CAN-BD and SAA processes is represented by the mixing part of the equipment and, therefore, by the extent of solubilization of the SC-CO2 in the liquid solution.
- 30. Process Role of supercritical fluid Role of organic solvent Mode of phase separation 1. RESS Solvent Co-solvent Pressure/temper ature-induced 2. GAS/ SAS Antisolvent Solvent Solvent-induced 3. ASES Antisolvent Solvent Solvent-induced 4. SEDS Antisolvent/disp ersing agent Solvent/non- solvent Solvent-induced 5. PGSS Solute _ Pressure/temper ature/solvent- induced Table 1 : Summary of available Supercritical fluid technology 30 Particle Formation Processes With Supercritical Fluid
- 31. Application of Supercritical Fluid 31 DRUG DELIVERY Particle and Crystal Engineering (Size Reduction and Solid State Chemistry) Particle Coating Particulate Dosage Form Cyclodextrin Inclusion Complexes Extrusion Liposomes Preparation Microspheres
- 32. Other Application of Supercritical Fluid 32 Sterilization Solvent Removal Extraction Supercritical and Subcritical Chromatography
- 33. Particle and Crystal Engineering (Size Reduction and Solid State Chemistry) 33 DRUG DELIVERY
- 34. Particle design of APIs is important for Making solid dosage forms with suitable physicochemical properties Control biopharmaceutical properties Maximize the efficiency and minimize the required dosage 34 Particle Design & Its Importance
- 35. Standard Micronization Processes Supercritical Fluid Based Techniques Multiple-step processes Difficult to control Mechanical stress leads to damage Increased surface energy leads to adhesion and agglomeration Single step process Easy to control No mechanical stress Little or no adhesion & agglomeration Standard Micronization Processes Vs Supercritical Fluid Based Techniques 35
- 37. Particle Formation Processes With Supercritical Fluid Requirements of an ideal particle formation process Operates with relatively small quantities of organic solvent(s) Molecular control of process Single step, scalable process for solvent-free final product 37
- 38. 38 Ability to control desired particle properties Suitable for wide range of chemical types of therapeutic agents and formulation excipients Capability for preparing multi-component system GMP compliant process Particle Formation Processes With Supercritical Fluid
- 39. Advantages Supercritical fluid based techniques mild operating temperatures single step process recovery and recycle of fluid green technology solvent free products 39
- 40. SEM images of nabumetone (a) Before RESS process (b) After RESS process 40 Advantages
- 41. Comparison of particle size and dissolution rate Mean particle size= 32.6 µm (original) KW= 0.0217 min-1 (original) Mean particle size= 3.3 µm (processed) KW= 0.0749 min-1 (Processed) 41 Advantages
- 43. Crystallization 43 Salmeterol xinafoate Habit modification to obtain low bulk density particles was possible by changing the operating conditions Attractive features Improving performance of dry powder inhaler Powder flow Reduce the surface free energy Smooth surface of particle
- 44. Polymorphism 44 Pseudopolymorph Two types of polymorph Enantiotropic Monotropic Metastable to stable. New polymorph of Fluticasone propionate is prepared by the SEDS technique. Particle size & shape is controlled by SEDS. New polymorph exhibit improved drug delivery characteristics in a metered dose inhaler.
- 45. Polymorphism 45 An equimolar mixture of carbamazepine polymorphs I and III was processed with supercritical CO2 to obtain a crystallographically pure phase. It has been proved that the suspension in supercritical CO2 leads to an almost quantitative conversion of form I into form III. SF Treatment %Form III 0 47.9 6 88.3 9 90.6 23 91.2 48 94.7
- 47. Particle coating 47 Conventional coating process uses organic solvents Use of aqueous solutions; but it increases drying time due to latent heat of vaporization of the water Low temperature & pressure allows to coat sensitive material like PROTIEN Paraffin irregularly shaped particles of bovine serum albumin (BSA) and insulin Protein particles were coated with trimyristin (Dynasan® 114) and Gelucire® 50-02, two glyceride mixtures with a melting point of 45 and 50 ◦C
- 48. Particulate Dosage Form 1. Cyclodextrin Inclusion Complexes 48 DRUG DELIVERY
- 49. Cyclodextrin(CD) Inclusion Complexes 49 CDs are cyclic Oligosaccharide can able to include a guest molecule in to their hydrophobic internal cavity either fully or partially. Improved physico-chemical & organoleptic properties Example: A successful complexation (94% inclusion yield) between piroxicam and β-cyclodextrin (β-CD) was obtained by. The inclusion experiments were performed by keeping a physical mixture of β-CD and piroxicam for 6 h in contact with CO2 at 150 ◦C and 15MPa without the use of organic solvents.
- 50. Particulate Dosage Form 2. Extrusion 50 DRUG DELIVERY
- 51. Extrusion 51 Capability of SC-CO2 to plasticize polymers at low temperature can be exploited in the extrusion process SC-CO2 can both change the rheological properties of the material, and behave as an expansion agent. The dissolution of a large amount of SC-CO2 determines a polymer expansion and viscosity reduction. The viscosity reduction results in lower mechanical constraints and decreases the required operating temperature, thus allowing processing of thermolabile compounds.
- 52. Extrusion 52 Examples Extrusion of PVP-VA (polyvinylpyrrolidone-co-vinyl acetate), Eudragit and ethylcellulose, in which pressurized CO2 was injected at a constant pressure rate. The specific surface area and the porosity of the polymers increased after treatment with carbon dioxide, eventually resulting in enhanced polymer dissolution in water.
- 53. Particulate Dosage Form 3. Liposomes 53 DRUG DELIVERY
- 54. Liposomes 54 The preparation of liposomes formulation on industrial scale is still a major issue mainly due to the need of the large amount of organic solvents and the high energy consume. The 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and cholesterol were dissolved in supercritical carbon dioxide modified with ethanol. Rapid expansion of the supercritical solution into an aqueous phase containing a marker results in the formation of liposomes encapsulating the marker.
- 55. 55
- 56. Particulate Dosage Form 4. Microspheres and Microprticles 56 DRUG DELIVERY
- 57. Microspheres and Microprticles 57 Particles with irregular geometry, composed of an active substance in form of aggregates or molecularly dispersed solid embedded into a matrix. They are called ‘microspheres’. Particles with spherical geometry, composed of a core of active substance surrounded by a solid polymeric or proteic shell. They are called ‘microcapsules’.
- 58. Microspheres and Microprticles 58 Microparticles by the RESS co-precipitation of a drug (lovastatin) and a biodegradable polymer (poly(D, l-lactic acid) (DL-PLA)).The co-precipitation of the polymer and the drug led to a heterogeneous population of microparticles consisting of microspheres containing a single lovastatin needle, larger spheres containing several needles, microspheres without protruding needles and needles without any polymer coating. Formation of microspheres of flavones and a polymer (Eudragit- 100 or PEG 6000) by spraying at atmospheric pressure, a suspension of flavonoids in a supercritical solution of the polymer and a co-solvent.
- 59. Microspheres and Microprticles 59 A process called polymer liquefaction using supercritical solvation (PLUSS). The carrier is a polymer that is saturated with carbon dioxide under supercritical conditions, causing polymer swelling and liquefaction at a temperature much below its glass transition or fusion temperature. The active-carrier mixture is atomized through a nozzle into a low pressure vessel, leading to microcapsules, as claimed on the example of IBDV vaccine inside polycaprolactone (MW 4000).
- 60. Limitations Poor solubility of pharmaceutical ingredients in supercritical fluids Difficult to scale-up Particle aggregation Nozzle blockage When co-solvents are used advantage of green technology is lost N2O and light hydrocarbons are hazardous and less environment friendly 60
- 61. 61
- 62. 62