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

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

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

Saturated drug solution Coated beads and granules Dissolution medium Saturated drug solution

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

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

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

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

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

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

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.

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

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)

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

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

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

Created by dissolved drug (A/ρ) 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) A Drug dose, ρ drug density Some tablets are not porous but depend on the dissolution of the drug to create porous network

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

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.

Osmotic pump Impervious coat Laser drilled hole

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

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. time % remaining Mt = Mo - k t This dosage form is less prone to change in dissolution on storage than other types of dosage forms.

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

Gel forms Tablets made of gel forming substances Dissolution medium

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

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

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

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

Release mechanism krosmear peppas Log time Log % remaining krosmear peppas 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

Coated tablets sugar film enteric

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

(Improper drying between coats) 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)

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

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

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

(not noticeable initial defective procedures) 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)

Coated tablets film Required tests during stability program Appearance 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

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

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

Coated tablets enteric Required tests during stability program 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

Coated tablets enteric Required tests during stability program 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

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

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

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

Microcapsules Required tests during stability program 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) Mol. weight