1. Pore Structure Analysis of Advanced Pharmaceutical Products Dr. Akshaya Jena and Dr. Krishna Porous Materials, Inc. 83 Brown Road, Ithaca, NY 14850 Dr. Akshaya Jena and Dr. Krishna Porous Materials, Inc. 83 Brown Road, Ithaca, NY 14850

2. Porous Materials, Inc. Topics FImportance of Porosity in Advanced Pharmaceutical Products FInadequacy of Mercury Intrusion Porosimetry FTwo novel techniques FResults and Discussion FSummary and Conclusion FImportance of Porosity in Advanced Pharmaceutical Products FInadequacy of Mercury Intrusion Porosimetry FTwo novel techniques FResults and Discussion FSummary and Conclusion

3. Porous Materials, Inc. Importance of Porosity in Advanced Pharmaceutical Products FAdvanced pharmaceutical products FExamples: –Artificial skin –Blood clotting material –Dialysis membrane –Blood delivery system –Hydrogels –Tissue culture substrates –And many more FAdvanced pharmaceutical products FExamples: –Artificial skin –Blood clotting material –Dialysis membrane –Blood delivery system –Hydrogels –Tissue culture substrates –And many more

4. Porous Materials, Inc. FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow FPerformance and efficiency of such products  Pore characteristics FPerformance and efficiency of such products  Pore characteristics

5. Porous Materials, Inc. Pore distribution  Barrier & flow FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow

6. Porous Materials, Inc. Pore volume  Holding capacity FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow Pore distribution  Barrier & flow FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow Pore distribution  Barrier & flow

7. Porous Materials, Inc. Permeability  Rate of the process FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow Pore distribution  Barrier & flow Pore volume  Holding capacity FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow Pore distribution  Barrier & flow Pore volume  Holding capacity

8. Porous Materials, Inc. FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow Pore distribution  Barrier & flow Pore volume  Holding capacity Permeability  Rate of the process FPerformance and efficiency of such products  Pore characteristics FImportant characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow Pore distribution  Barrier & flow Pore volume  Holding capacity Permeability  Rate of the process FNeed for reliable, accurate and safe techniques

9. Porous Materials, Inc. Inadequacy of Mercury Intrusion Porosimetry FMercury intrusion porosimetry often used for pore structure analysis Principle of mercury intrusion porosimetry

10. Porous Materials, Inc. FIntrusion volume gives pore volume FPressure yields pore size, D D = - 4  cos  /p  = surface tension of Hg  = contact angle of Hg P = differential pressure FIntrusion volume gives pore volume FPressure yields pore size, D D = - 4  cos  /p  = surface tension of Hg  = contact angle of Hg P = differential pressure FMercury is forced in to pores

11. Porous Materials, Inc. –Constricted pore diameter –The largest pore diameter –Permeability FHigh pressure used in this technique can damage pore structure of the delicate products FUses toxic mercury, creates health hazards, pollutes environment, and makes samples unusable –Constricted pore diameter –The largest pore diameter –Permeability FHigh pressure used in this technique can damage pore structure of the delicate products FUses toxic mercury, creates health hazards, pollutes environment, and makes samples unusable FIt cannot measure:

12. Porous Materials, Inc. Novel Techniques Capillary Flow Porometery FPores of sample spontaneously filled with wetting liquid FPressurized gas is used to remove liquid from pores to allow gas flow Capillary Flow Porometery FPores of sample spontaneously filled with wetting liquid FPressurized gas is used to remove liquid from pores to allow gas flow

13. Porous Materials, Inc. D = 4  cos  /p  = surface tension of wetting liquid  = contact angle of wetting liquid P = differential pressure FPressure and flow rates through wet and dry samples are used to compute properties FThe PMI Capillary Flow Porometer used in this investigation D = 4  cos  /p  = surface tension of wetting liquid  = contact angle of wetting liquid P = differential pressure FPressure and flow rates through wet and dry samples are used to compute properties FThe PMI Capillary Flow Porometer used in this investigation FPressure yields pore diameter, D

14. Porous Materials, Inc. The PMI Capillary Flow Porometer

15. Porous Materials, Inc. FSample is placed on a membrane whose largest pore size is smaller than the smallest in the sample Liquid Extrusion Porosimetry

16. Porous Materials, Inc. FPores of sample and membrane are filled with a wetting liquid Liquid Extrusion Porosimetry

17. Porous Materials, Inc. FPressurized gas is used to displace liquid from pores without the membrane and with membrane under the sample Liquid Extrusion Porosimetry

18. Porous Materials, Inc. D = 4  cos  /p D = pore diameter  = surface tension of wetting liquid  = contact angle of wetting liquid P = differential pressure FVolume of displaced liquid gives pore volume & permeability D = 4  cos  /p D = pore diameter  = surface tension of wetting liquid  = contact angle of wetting liquid P = differential pressure FVolume of displaced liquid gives pore volume & permeability FPressure yields pore diameter

19. Porous Materials, Inc. The PMI Liquid Extrusion Porosimeter used in this investigation

20. Porous Materials, Inc. FAll required properties measurable FUse of low pressure-Samples not damaged FNo toxic materials use -no health hazard -no environmental pollution -no sample contamination FAll required properties measurable FUse of low pressure-Samples not damaged FNo toxic materials use -no health hazard -no environmental pollution -no sample contamination Advantages

21. Porous Materials, Inc. Results and Discussion Dialysis membranes Requirements FPrimary function-Filtration FImportant characteristics:  The largest pore diameter  Mean pore diameter  Pore distribution  Flow rate Dialysis membranes Requirements FPrimary function-Filtration FImportant characteristics:  The largest pore diameter  Mean pore diameter  Pore distribution  Flow rate

22. Porous Materials, Inc. Capillary Flow Porometery Flow rate vs Differential pressure for dry and wet samples

23. Porous Materials, Inc. –The largest pore diameter  from pressure for flow initiation  1.023 mm –Mean flow pore diameter  from mean flow pressure  0.458 mm –The largest pore diameter  from pressure for flow initiation  1.023 mm –Mean flow pore diameter  from mean flow pressure  0.458 mm FPore diameter  from measured pressures

24. Porous Materials, Inc. Normalized pore distribution function vs. pore diameter FPore distribution

25. Porous Materials, Inc. –In any pore size range  area = % flow through pores in the range FPore distribution

26. Porous Materials, Inc. –Almost 80% flow  through 0.2 – 0.7  m pores FPore distribution

27. Porous Materials, Inc. FPermeability –Dry curve yields gas permeability –Liquid permeability measurable using attachments –Dry curve yields gas permeability –Liquid permeability measurable using attachments FMercury Intrusion Porosimetry Cannot measure any of the these properties

28. Porous Materials, Inc. FAll required properties including very small pore diameters were measured by capillary flow porometry, although mercury intrusion technique could not measure any of the properties. FPressures required was only about 50 psi FNo toxic material was used FCapillary flow porometry was the appropriate technique FAll required properties including very small pore diameters were measured by capillary flow porometry, although mercury intrusion technique could not measure any of the properties. FPressures required was only about 50 psi FNo toxic material was used FCapillary flow porometry was the appropriate technique Conclusion

29. Porous Materials, Inc. Requirements FPrimary function-allow growth of blood vessels and be breathable FPores are much larger than the pore providing barrier properties FPore size & distribution are in the range for blood vessels to grow FAdequate gas and vapor permeability to be breathable. Requirements FPrimary function-allow growth of blood vessels and be breathable FPores are much larger than the pore providing barrier properties FPore size & distribution are in the range for blood vessels to grow FAdequate gas and vapor permeability to be breathable. Artificial skin

30. Porous Materials, Inc. Flow rate vs Differential pressure for dry and wet samples Capillary Flow Porometry

31. Porous Materials, Inc. –The largest pore diameter  from pressure for flow initiation  74.932  m –Mean flow pore diameter  from mean flow pressure  31.489  m –The largest pore diameter  from pressure for flow initiation  74.932  m –Mean flow pore diameter  from mean flow pressure  31.489  m FPore diameter  from measured pressures

32. Porous Materials, Inc. FA broad pore range FUniform distribution FA broad pore range FUniform distribution FPore distribution Normalized pore distribution function vs pore diameter

33. Porous Materials, Inc. Flow through dry curve as a function of differential pressure FPermeability –Appreciable gas permeation shown by dry curve

34. Porous Materials, Inc. FMercury Intrusion Porosimetery Cannot measure any of the these properties

35. Porous Materials, Inc. FLarge constricted pore diameters, broad distribution and permeability were measured by capillary flow poromerty, although mercury intrusion technique could not measure any of these properties. FPressures required was only about 3 psi FNo toxic material was used FCapillary flow porometry was the appropriate technique FLarge constricted pore diameters, broad distribution and permeability were measured by capillary flow poromerty, although mercury intrusion technique could not measure any of these properties. FPressures required was only about 3 psi FNo toxic material was used FCapillary flow porometry was the appropriate technique Conclusion

36. Porous Materials, Inc. Requirements FPrimary applications: –Dressings –Wound gels –Burn dressings –Electrodes –Skin disorders treatments –Carriers for hormones and drugs –Drug delivery implants Requirements FPrimary applications: –Dressings –Wound gels –Burn dressings –Electrodes –Skin disorders treatments –Carriers for hormones and drugs –Drug delivery implants Hydrogels

37. Porous Materials, Inc. Requirements FProperties –Pore volumes  liquid holding capacity –Pore size & distribution  flow rates & barrier property –Liquid permeability  rate of the process Requirements FProperties –Pore volumes  liquid holding capacity –Pore size & distribution  flow rates & barrier property –Liquid permeability  rate of the process Hydrogels

38. Porous Materials, Inc. Requirements FProperties –Pore volumes  liquid holding capacity –Pore size & distribution  flow rates & barrier property –Liquid permeability  rate of the process Requirements FProperties –Pore volumes  liquid holding capacity –Pore size & distribution  flow rates & barrier property –Liquid permeability  rate of the process Hydrogels FMercury Intrusion Porosimetry In Appropriate –Hydrogels retain their integrity only in water –Therefore, mercury intrusion extrusion porosimetry can be used FMercury Intrusion Porosimetry In Appropriate –Hydrogels retain their integrity only in water –Therefore, mercury intrusion extrusion porosimetry can be used

39. Porous Materials, Inc. Requirements FProperties –Pore volumes  liquid holding capacity –Pore size & distribution  flow rates & barrier property –Liquid permeability  rate of the process FMercury Intrusion Porosimetry in Appropriate –Hydrogels retain their integrity only in water –Therefore, mercury intrusion extrusion porosimetry can be used Requirements FProperties –Pore volumes  liquid holding capacity –Pore size & distribution  flow rates & barrier property –Liquid permeability  rate of the process FMercury Intrusion Porosimetry in Appropriate –Hydrogels retain their integrity only in water –Therefore, mercury intrusion extrusion porosimetry can be used Hydrogels FLiquid extrusion Porosimetry –Water extrusion porosimetry appropriate FLiquid extrusion Porosimetry –Water extrusion porosimetry appropriate

40. Porous Materials, Inc. FPore volume –Total pore volume  0.421 cm 3 /g –Porosity  67.12% –Pressure only about 5 psi FPore volume –Total pore volume  0.421 cm 3 /g –Porosity  67.12% –Pressure only about 5 psi Pore volume of hydrogel

41. Porous Materials, Inc. FPore distribution of hydrogel –For a given range Area = pore volume –Pores have a narrow range  5-20  m FPore distribution of hydrogel –For a given range Area = pore volume –Pores have a narrow range  5-20  m FPore volume distribution

42. Porous Materials, Inc. Typical plot of flow rate of water vs pressure FLiquid permeability –The flow rate yields liquid permeability

43. Porous Materials, Inc. Summary and Conclusion 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability.

44. Porous Materials, Inc. Summary and Conclusion 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 3. These techniques used low pressures so that sample damage was minimized.

45. Porous Materials, Inc. Summary and Conclusion 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 3. These techniques used low pressures so that sample damage was minimized. 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 3. These techniques used low pressures so that sample damage was minimized. 4. No toxic and harmful material was used.

46. Porous Materials, Inc. Summary and Conclusion 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 3. These techniques used low pressures so that sample damage was minimized. 4. No toxic and harmful material was used. 1. Two novel techniques discussed. Capillary flow porometry Liquid extrusion porosimetry 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 3. These techniques used low pressures so that sample damage was minimized. 4. No toxic and harmful material was used. 5. Products like hydrogels, which retain their integrity in only certain liquid environments, could be tested.

47. Porous Materials, Inc. Summary and Conclusion 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 3. These techniques used low pressures so that sample damage was minimized. 4. No toxic and harmful material was used. 5. Products like hydrogels, which retain their integrity in only certain liquid environments, could be tested. 2. These techniques measured constricted pore diameter, the largest pore diameter, mean flow pore diameter, flow distribution, pore volume, pore volume distribution, liquid permeability and gas permeability. 3. These techniques used low pressures so that sample damage was minimized. 4. No toxic and harmful material was used. 5. Products like hydrogels, which retain their integrity in only certain liquid environments, could be tested. 6. Mercury intrusion could not used for such measurements.

48. Thank You