Pore Structure Analysis of Advanced Pharmaceutical Products

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

2. Topics • Importance of Porosity in Advanced Pharmaceutical Products • Inadequacy of Mercury Intrusion Porosimetry • Two novel techniques • Results and Discussion • Summary and Conclusion

3. Importance of Porosity in Advanced Pharmaceutical Products • Advanced pharmaceutical products • Examples: • Artificial skin • Blood clotting material • Dialysis membrane • Blood delivery system • Hydrogels • Tissue culture substrates • And many more

4. Performance and efficiency of such products  Pore characteristics • Important characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow

5. Performance and efficiency of such products  Pore characteristics • Important characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier properties Mean pore diameter  Barrier & flow Pore distribution  Barrier & flow

6. Performance and efficiency of such products  Pore characteristics • Important 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

7. Performance and efficiency of such products  Pore characteristics • Important 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

8. Performance and efficiency of such products  Pore characteristics • Important characteristics: Constricted pore diameter  Barrier properties The largest pore diameter  Barrier propertiesMean pore diameter  Barrier & flow Pore distribution  Barrier & flow Pore volume  Holding capacity Permeability  Rate of the process • Need for reliable, accurate and safe techniques

9. Inadequacy of Mercury Intrusion Porosimetry • Mercury intrusion porosimetry often used for pore structure analysis Principle of mercury intrusion porosimetry

10. Mercury is forced in to pores • Intrusion volume gives pore volume • Pressure yields pore size, D D = - 4g cos q /p g = surface tension of Hgq = contact angle of HgP = differential pressure

11. It cannot measure: • Constricted pore diameter • The largest pore diameter • Permeability • High pressure used in this technique can damage pore structure of the delicate products • Uses toxic mercury, creates health hazards, pollutes environment, and makes samples unusable

12. Novel Techniques Capillary Flow Porometery • Pores of sample spontaneously filled with wetting liquid • Pressurized gas is used to remove liquid from pores to allow gas flow

13. Pressure yields pore diameter, D D = 4 g cos q/p g = surface tension of wetting liquidq = contact angle of wetting liquid P = differential pressure • Pressure and flow rates through wet and dry samples are used to compute properties • The PMI Capillary Flow Porometer used in this investigation

14. The PMI Capillary Flow Porometer

15. Sample is placed on a membrane whose largest pore size is smaller than the smallest in the sample Liquid Extrusion Porosimetry

16. Pores of sample and membrane are filled with a wetting liquid Liquid Extrusion Porosimetry

17. Pressurized gas is used to displace liquid from pores without the membrane and with membrane under the sample Liquid Extrusion Porosimetry

18. Pressure yields pore diameter D = 4 g cos q/p D = pore diameterg = surface tension of wetting liquid q = contact angle of wetting liquidP = differential pressure • Volume of displaced liquid gives pore volume & permeability

19. The PMI Liquid Extrusion Porosimeter used in this investigation

20. Advantages • All required properties measurable • Use of low pressure-Samples not damaged • No toxic materials use -no health hazard -no environmental pollution -no sample contamination

21. Results and Discussion Dialysis membranes Requirements • Primary function-Filtration • Important characteristics: • The largest pore diameter • Mean pore diameter • Pore distribution • Flow rate

22. Capillary Flow Porometery Flow rate vs Differential pressure for dry and wet samples

23. Pore diameter  from measured pressures • The largest pore diameter  from pressure for flow initiation  1.023 mm • Mean flow pore diameter  from mean flow pressure  0.458 mm

24. Pore distribution Normalized pore distribution function vs. pore diameter

25. Pore distribution • In any pore size range  area = % flow through pores in the range

26. Pore distribution • Almost 80% flow  through 0.2 – 0.7 mm pores

27. Permeability • Dry curve yields gas permeability • Liquid permeability measurable using attachments • Mercury Intrusion Porosimetry Cannot measure any of the these properties

28. Conclusion • All required properties including very small pore diameters were measured by capillary flow porometry, although mercury intrusion technique could not measure any of the properties. • Pressures required was only about 50 psi • No toxic material was used • Capillary flow porometry was the appropriate technique

29. Artificial skin Requirements • Primary function-allow growth of blood vessels and be breathable • Pores are much larger than the pore providing barrier properties • Pore size & distribution are in the range for blood vessels to grow • Adequate gas and vapor permeability to be breathable.

30. Capillary Flow Porometry Flow rate vs Differential pressure for dry and wet samples

31. Pore diameter  from measured pressures • The largest pore diameter  from pressure for flow initiation  74.932 mm • Mean flow pore diameter  from mean flow pressure  31.489 mm

32. Pore distribution • A broad pore range • Uniform distribution Normalized pore distribution function vs pore diameter

33. Permeability • Appreciable gas permeation shown by dry curve Flow through dry curve as a function of differential pressure

34. Mercury Intrusion Porosimetery Cannot measure any of the these properties

35. Conclusion • Large constricted pore diameters, broad distribution and permeability were measured by capillary flow poromerty, although mercury intrusion technique could not measure any of these properties. • Pressures required was only about 3 psi • No toxic material was used • Capillary flow porometry was the appropriate technique

36. Hydrogels Requirements • Primary applications: • Dressings • Wound gels • Burn dressings • Electrodes • Skin disorders treatments • Carriers for hormones and drugs • Drug delivery implants

37. Hydrogels Requirements • Properties • Pore volumes  liquid holding capacity • Pore size & distribution  flow rates & barrier property • Liquid permeability  rate of the process

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

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

40. Pore volume • Total pore volume  0.421 cm 3/g • Porosity  67.12% • Pressure only about 5 psi Pore volume of hydrogel

41. Pore volume distribution • Pore distribution of hydrogel • For a given range Area = pore volume • Pores have a narrow range  5-20 mm

42. Liquid permeability • The flow rate yields liquid permeability Typical plot of flow rate of water vs pressure

43. 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.

44. 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.

45. 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.

46. 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. 5. Products like hydrogels, which retain their integrity in only certain liquid environments, could be tested.

47. 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. 6. Mercury intrusion could not used for such measurements.

48. Thank You