Physical Testing

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

2. Solutions Parenteral Oral -Appearance -Precipitation -Swirly precipitates -Whiskers -Clouds -Sterility -Volume -Dielectric constant -pH -Appearance -Precipitation -Organoleptic properties -Loss of dye -Bacterial growth -Volume -Dielectric constant -pH

3. Appearance in solutions Discoloration could be due to Oxidation Photodegradation

4. Log A Slope = - Ea / 2.303 R Log k 1000 T Appearance in solutions Discoloration could be Analytically detectable Analytically NOT detectable • Loss of dye could be treated like a drug substance. • Arrhenius plotting can be used for prediction

5. Appearance in solutions Discoloration can be detected by Color standards (Roche color standard) Dubosque colorimetry Standard Test a b -Length of the light bath in tube b is changed. -This length indicates concentration -Numbers obey Beer’s Law & are logarithmically proportional to conc. 1 2 3 4 -Measure intensity of discoloration -Results are difficult to analyze

6. Swirly precipitates in solutions Due to interaction with container Most common in Can be detected by Visually by a parenteral inspector Determining number of positive vials/box Mechanical counting (Coulter Counter)

7. Swirly precipitates in solutions Due to interaction with container Most common in Can be solved by Lyophilization Re-formulation Change of container Establishing % probability of finding vials with swirls

8. Whiskers in solutions Due to pinholes Most common in

9. Whiskers in solutions Due to pinholes Most common in Ampoule was tight at time of manufacture and the strain caused crack during storage (improper anealling) Hole was present but non-detectable at time of manufacture (too small to detect) Sealing Verification (Leaker testing) Rapid heat sealing line Incorrect flame temperature

10. Clouds in solutions Precipitation can be induced by Chemical change (hydrolysis) Exceeding drug solubility or forming a product with limited solubility Change in drug form (polymorph)

11. Clouds in solutions Cloud time (t*) is the time at which the solubility is exceeded A + H2O → B S

12. Lnt* 25o t* 40o 50o 60o 70o 90o 3.355 2.7 2.8 2.9 3.0 3.1 Clouds in solutions Cloud time (t*) is the time at which the solubility is exceeded Cloud times Can be plotted by Arrhenius plotting 1000/T

13. Clouds in solutions Precipitation can be inhibited by Precipitation is tied into solubility Precipitation is a nucleation and crystal growth phenomenon Inhibitors (viscosity inducers) Micellar solubilization Co-solvents Complexation Viscosity testing

14. Organoleptic properties Taste Flavor Type Level Sensory panel test -Human tester -Scale from 1 to 5 for example -measures should be taken to minimize bias in evaluation -Not recommended to use elevated temperatures

15. Organoleptic properties Measures to minimize bias in evaluation -Determination of organoleptic capacity of the tester -Ability to describe the flavor well -Ability to duplicate results -Ability to remember results -Ability to detect new flavors (eg. due to interaction with container.)

16. Organoleptic properties Electronic tongueis an instrument that measures and compares tastes.

17. Disperse systems Suspensions Emulsions Liquid Semi-solid Liquid Semi-solid (ointment) -Appearance -Organoleptic Properties -Ease of re-dispersion -Sedimentation volume -Sedimentation rates -Particle size -Zeta potential - Rheological properties -Dissolution -polymorphism -Preservation stability -Accelerated testing Ointment Suppository

18. Suspensions Deflocculated Flocculated Rheology

19. Suspensions Deflocculated Zeta Potential Flocculated zeta potential  It is the difference in potential between surface of the tightly bound layer (shear plane) and electro neutral region of the solution.

20. Suspensions Deflocculated Flocculated 20 2ry minimum 1ry minimum 10 Potential energy 0 -10 -20 0 6 12 18 24 Distance Potential energy diagram for two particles

21. Liquid Suspensions Deflocculated Ease of re-dispersion (Shaking test) Flocculated Drug in supernatant Subjective Quantitative To rotate the bottle under reproducible conditions for x rotations 6 12 18 Number of rotations

22. Liquid Suspensions Deflocculated Sedimentation volume Flocculated Dosage level (g/cm3) Density (g/cm3) 1 2 3 4

23. Liquid Suspensions Deflocculated Sedimentation volume Flocculated There are suspensions that do not settle, When the YIELD VALUE of the suspension is so larger than the gravitational force. Yield value Viscosity Solid content Complete rheological profile should be carried at different time intervals during stability study to ensure that the yield value did not change

24. Liquid Suspensions Deflocculated Sedimentation rate Flocculated Re-flocculation Settling towards equilibrium volume Two phasic curve On shaking Equilibrium follicle

25. Liquid Suspensions Deflocculated Sedimentation rate Flocculated Log x-Height Settling time measurements Time

26. Liquid Suspensions Deflocculated Dissolution Flocculated Drug Dissolved Cubic root of Undissolved drug Time Hixon-Crowel Time

27. Liquid Suspensions Deflocculated Dissolution Flocculated Drug Dissolved Time In [% not dissolved-10] First order (Sigma minus) Time

28. Liquid Suspensions Deflocculated Preservation stability Flocculated Chemical assay of the used preservatives & their decomposition products Methyl, ethyl, propyl, and butyl esters of 4-hydroxybenzoic acid

29. Liquid Suspensions Deflocculated Accelerated testing Flocculated Freeze-thaw cycle Centrifugation Temperature testing Shaking at 37oC

30. Liquid Suspensions Deflocculated Accelerated testing Flocculated Freeze-thaw cycle Centrifugation Temperature testing Shaking at 37oC To judge qualitatively if caking will take place It accelerate settling by making particles move more rapidly and allowing fine particles to slip into the interstices of larger ones

31. Liquid Suspensions Deflocculated Accelerated testing Flocculated Freeze-thaw cycle Centrifugation Temperature testing Shaking at 37oC It accelerates only the initial settling rate Can’t predict well further settling nor caking

32. Liquid Suspensions Deflocculated Accelerated testing Flocculated Freeze-thaw cycle Centrifugation Temperature testing Shaking at 37oC To alternate storage temperature every 24h (eg. 25oC to -5oC) To predict crystal growth that could happen under normal conditions of shipping and use

33. Liquid Suspensions Deflocculated Accelerated testing Flocculated Freeze-thaw cycle Centrifugation Temperature testing Shaking at 37oC Temperatures shouldn’t exceed the temperature at which suspended drug is soluble

34. Disperse systems Suspensions Emulsions Liquid Semi-solid Liquid Semi-solid (ointment) -Appearance -Organoleptic Properties -Ease of re-dispersion -Sedimentation volume -Sedimentation rates -Particle size -Zeta potential - Rheological properties -Dissolution -Polymorphism -Preservation stability -Accelerated testing Ointment Suppository -Consistency, shape -Polymorphism -Rheological properties -Release rate -Migration of drug -Stability with container

35. Semi-solid Suspensions Deflocculated Migration of drug Flocculated Migration of the dispersed drug within a semi-solid product is quite possible when another phase is present. Aluminum wrap with polyethylene lining Rate of drug disappearance will follow first order reaction Rate is proportional to Sp - Ss

36. Disperse systems Suspensions Emulsions Liquid Semi-solid Liquid Semi-solid (ointment) • -Appearance • -Organoleptic Properties • -Globule size & viscosity • -Electrical conductivity • -Dissolution • Rheological properties • Emulsion type • -Stability of emulsifier • -Accelerated testing -Appearance -Organoleptic Properties -Ease of re-dispersion -Sedimentation volume -Sedimentation rates -Particle size -Zeta potential - Rheological properties -Dissolution -Preservation stability -Accelerated testing Ointment Suppository -Consistency -Polymorphism - Rheological properties -Release rate -Migration of drug -Stability with container

37. Liquid Emulsions Emulsions are meta stable systems Thermodynamically, emulsions are more energetic than the ground state system which is simply the totality of the two phases separated. There is always potential for oil droplet re-merging

38. Liquid Emulsions Creaming: Droplets move upwards ( droplets density< Droplets of continuous phase)Sedimentation: Droplets move downwards ( droplets density> droplets of continuous phase)Flocculation: >2 droplets stick together and form aggregateCoalescence: >2 droplets merge together and form single large dropletsPhase inversion: o/w emulsion changes to w/o emulsion or vice versa.

39. Liquid Emulsions Creaming and coalescence • Breaking can be manifested in: • Separation of oil particles on the surface (oiling) • Different colors on dipping finger in the emulsion (creaming) • Change in draining off the skin (creaming) • Separation into two phases (coalescence)

40. Liquid Emulsions Breaking and coalescence • Reasons for emulsion breaking: • Chemical instability between the emulsifier and any other ingredient • Improper choice of the emulsifier (HLB) • High electrolyte concentration • Instability of an emulsifier • Too low viscosity • Temperature

41. Liquid Emulsions Stability of the emulsifier/protective colloid system Chemical instability Change of particle size Change of emulsion characteristics Hydrolysis Interaction with other emulsion components

42. Liquid Emulsions Emulsion type Phase inversion affects emulsion use, appearance and stability It is associated with creaming (a distinct difference in appearances in various regions of the emulsion ), separation and graininess of feel.

43. Liquid Emulsions Electrical conductivity This indicate the state of dispersion of an emulsion system If significant changes were recorded over short periods of time, then the emulsion system is not satisfactory

44. Liquid Emulsions Appearance Correlation between globule size and appearance of emulsions

45. Liquid Emulsions Globule size and viscosity Globules collide and hence coalesce leading to increased viscosity. Thus checking emulsion viscosity is a prime indicator of potential for progressing creaming and breaking. Viscosity is a function of droplet size and phase ratio viscosity large droplet size Small droplet size Volume fraction of oil

46. Liquid Emulsions Globule size and viscosity Complete rheograms using multiple point viscometers (cone and plate viscometer) • Microscopy (for large size) • Electronic counters (Coulter counter) • Photon correlation spectroscopy (for very small size) • Diffuse reflectance spectroscopy The proper method should be chosen for each system It is recommended to use more than one method for confirmation especially in parenteral emulsions

47. Liquid Emulsions Globule size and viscosity 1=Coulter counter before (intermediate particle size) 2= Photon correlation spectroscopy before (small P.S.) 3=Coulter counter (after) 4= Photon correlation spectroscopy after 1, 3= Microscopy before (large P.S.) 2, 4= Microscopy after

48. Liquid Emulsions Rheological properties • Factors affecting rheological properties: • Globule size • The viscosity of the internal phase • The viscosity of the external phase • Phase volume ratio • Type and amount of emulsifier • Particle size distribution

49. Liquid Emulsions Accelerated testing Freeze-thaw cycle Centrifugation Temperature testing Shaking If the preparation fails the accelerated tests it may be all right, but if it passes the test it should be all right. If done on storage, results could differ due to other factors such as chemical decomposition of the emulsifier

50. Liquid Emulsions Accelerated testing Freeze-thaw cycle Centrifugation Temperature testing Shaking It is done at 2-3 hertz It increases the intensity and frequency of collisions between globules which could happen during transport in real use