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Physical Testing

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  1. Physical Testing • Solutions • Disperse systems • Aerosols • Powders • Tablets • Sustained release products • Coated tablets • Hard & soft shell capsules • Microcapsules

  2. Physical Testing a. coated beads and granules b. erosion tablets c. insoluble matrices d. osmotic pump e. gel forms Sustained release products

  3. Coated beads and granules Sugar crystal Drug in sugar matrix film Semi-permeable Impermeable + soluble filler

  4. Coated beads and granules Dissolution medium Saturated drug solution

  5. Coated beads and granules There are three stages in the dissolution 0 < t < ti : penetration of medium into the pellet, ti is the time it takes for this to complete (lag time) ti < t < tf : dissolution takes place under constant conc. gradient (drug solubility in the medium) tf is the time where all drug inside is dissolved but not yet diffused t > tf : slow dissolution It is difficult to get the last 5-10% of drug to release

  6. Coated beads and granules Factors affecting dissolution: • Film thickness Thin coat % released Thick coat time

  7. Coated beads and granules Factors affecting dissolution: • Film thickness • Amount of soluble filler in the film ↑ filler % released ↓ filler time

  8. Coated beads and granules Kinetics of dissolution: ? ? ln %remaining Thick coat Thin coat time M mass not dissolved, Mo total dose, K dissolution constant, ti lag time

  9. Coated beads and granules Kinetics of dissolution: ln %remaining time M mass not dissolved, Mo total dose, K dissolution constant, ti lag time

  10. Coated beads and granules Stability of dissolution profile on storage (during stability program) Tracing of k and ti at different time intervals Calculating Similarity Factor It is a logarithmic reciprocal square root transformation of the sum squared error

  11. Coated beads and granules Stability of dissolution profile on storage (during stability program) Tracing of k and ti at different time intervals Calculating Similarity Factor Where Rt and Tt are the cumulative percent of drug released for reference and test assay at time t, respectively, n is the number of time points. Generally, a value of f2 close to 100 (range: 50–100) ensure sameness between the profiles.

  12. Coated beads and granules Stability of dissolution profile on storage (during stability program) Tracing of k and ti at different time intervals Calculating Similarity Factor Accelerated testing is not of much use

  13. Erosion tablets Tablets made of substances which does not dissolve or disintegrate but erode away (eg. Waxy substances). Non-eroded (undissolved drug) Eroded portion (dissolved drug)

  14. Erosion tablets Factors affecting dissolution: • Substance type • Drug to substance ratio • Tablet dimensions

  15. Erosion tablets Dissolution Kinetics Hixon-crowel 3√ remaining time M mass not dissolved, Mo total dose, Ke erosion constant, ti time required for tablet wetting

  16. Erosion tablets Stability of dissolution profile on storage (during stability program) Tracing of ke and ti at different time intervals Calculating Similarity Factor Accelerated testing is not of much use

  17. Insoluble matrices Tablets made of porous insoluble matrix Factors affecting dissolution: • Surface area through which diffusion takes place • Drug loading • Porosity Inherent Created by dissolved drug (A/ρ) ADrug dose, ρdrug density Some tablets are not porous but depend on the dissolution of the drug to create porous network

  18. Insoluble matrices Dissolution Kinetics Dissolution occurs by diffusion from the insoluble matrix and the release rate is given by Higuchi square root law % remaining √ time

  19. Insoluble matrices Stability of dissolution profile on storage (during stability program) Tracing of ki and ti at different time intervals Calculating Similarity Factor Accelerated testing could be used if the physical properties of both drug and polymer do not change at elevated temperatures.

  20. Osmotic pump Impervious coat Laser drilled hole

  21. Osmotic pump Saturated solution of osmotic pressure > outer pressure Dissolution medium

  22. Osmotic pump Difference in osmotic pressure is the driving force that forces the liquid out through the hole. It is independent of remaining drug conc. Release follows zero order kinetics. % remaining Mt = Mo - k t time This dosage form is less prone to change in dissolution on storage than other types of dosage forms.

  23. Osmotic pump Stability of dissolution profile on storage (during stability program) Tracing of k0 and t0 at different time intervals Calculating Similarity Factor Accelerated testing is not of much use

  24. Gel forms Tablets made of gel forming substances Dissolution medium

  25. Gel forms Tablets made of gel forming substances Drug dissolve and diffuse out through gel Dissolution medium

  26. Gel forms Tablets made of gel forming substances Gel layer becomes thicker & diffusion path becomes longer Dissolution medium

  27. Gel forms Tablets made of gel forming substances Gel erosion could occur Dissolution medium

  28. Gel forms = Tablets made of gel forming substances Release is a hybrid of diffusion and erosion

  29. Release mechanism krosmear peppas Log % remaining Log time n an exponent that characterized the release mechanism. n ≤ 0.5 Fickian diffusion 0.5 < n > 1 non-Fickian model (anomalous transport) n ≥ 1 zero order

  30. Coated tablets sugar film enteric

  31. Coated tablets sugar film enteric Barrier coat (polymer) Sub-coat (talc+gelatin) Dye coat (sucrose syrup+dye lake) Finishing coat Polish coat (Beeswax)

  32. Coated tablets sugar film enteric Stability problems on storage (during stability program) • Chipped tablets • Split tablets in the periphery Improper barrier coat trapped moisture (Improper drying between coats)

  33. Coated tablets sugar film enteric Required tests during stability program • Appearance • Gloss (subjectively, glossmeter) • SEM • Friability (for chipped tablets) • Disintegration • Dissolution

  34. Coated tablets film sugar enteric Aqueous film coat (HMC, HPMC)

  35. Coated tablets film sugar enteric Advantages of film coat over sugar coat • Less labor intensive • Allow engraving to show through • Allow appearance of deep color with little dye

  36. Coated tablets film sugar enteric Stability problems on storage (during stability program) • Dislodging or rupture of film • Change of appearance Formula (film and tablet core) Method of preparation (not noticeable initial defective procedures)

  37. Coated tablets film sugar enteric Required tests during stability program • Appearance • Gloss (subjectively, glossmeter) • SEM • Measure force necessary to strip film from tablet (Tensile tester machine eg. Instron tester) • Disintegration • Dissolution

  38. Coated tablets enteric sugar film Acid resistance coat (CAP, Shellac) Sugar coat for immediate dose

  39. Coated tablets enteric sugar film Stability problems on storage (during stability program) Polymerization of coating polymer

  40. Coated tablets enteric sugar film Required tests during stability program • Appearance • Gloss (subjectively, glossmeter) • SEM • Measure force necessary to strip film from tablet (Instron tester) • Disintegration • Dissolution of drug in sugar coat • Dissolution of drug in tablet

  41. Coated tablets enteric sugar film Required tests during stability program Dissolution of drug in tablet 1 h in SGF at 37oC 2 h in SIF at 37oC No disintegration, softening or cracking Disintegration at the end point

  42. Capsules Stability problems on storage (during stability program) • Cross-linking of gelatin and pellicle formation Check in simulated gastric fluid

  43. Capsules Stability problems on storage (during stability program) • Cross-linking of gelatin and pellicle formation • Moisture shift Capsule shell Moisture content (mg/g) Capsule content Soft shell Brittle shell Percent relative humidity

  44. Microcapsules Stability problems on storage (during stability program) Loss of intact polymer (microcapsule decomposition)

  45. Microcapsules Required tests during stability program Mol. weight • Loss in polymer weight by gel permeation chromatography • Detection of polymer degradation products (eg. Lactic acid in case of poly(L-lactide) polymer) • Decrease in weight averaged molecular weight • SEM Time (days)