Physical Testing 1.Solutions 2.Disperse systems 3.Aerosols 4.Powders 5.Tablets 6.Sustained release products 7.Coated tablets 8.Hard & soft shell capsules 9.Microcapsules

Tablets 1.Appearance 2.Organoleptic properties, chewability, mouth feel 3.Hardness 4.Thickness 5.Disintegration 6.Dissolution 7.Porosity

Tablets Appearance Subjective by an inspector Quantitative Rating index 0: unchanged ↓ 5: vastly changed

Tablets Appearance Subjective by an inspector Quantitative Rating index Comparison with color chips or charts Reflection Dissolving & measuring the solution spectrophotometrically Photography

Tablets Appearance Subjective by an inspector Quantitative Rating index Comparison with color chips or charts Reflection Dissolving & measuring the solution spectrophotometrically Photography Gives coordinate numbers which could allow quantitative treatment of the color change

Tablets Appearance Subjective by an inspector Quantitative Rating index Comparison with color chips or charts Reflection Dissolving & measuring the solution spectrophotometrically Photography It measures the average spectral intensity Qualitative appearance description is necessary

Tablets Appearance Subjective by an inspector Quantitative Rating index Comparison with color chips or charts Reflection Dissolving & measuring the solution spectrophotometrically Photography Procedure should be well controlled

Tablets Appearance Subjective by an inspector Quantitative Rating index Comparison with color chips or charts Reflection Dissolving & measuring the solution spectrophotometrically Photography Reflection measurements are carried by tristimulus meter

Tablets Appearance Subjective by an inspector Quantitative Rating index Comparison with color chips or charts Reflection Dissolving & measuring the solution spectrophotometrically Photography Reflectance values at three spectral regions are recorded as x, y and z Days Log(x/x*)

Tablets Hardness Hardness is the capability of tablets to withstand stress Tablet How to test for hardness? Hardness is force at which tablets break Force Fixed

Tablets Hardness Factors affecting hardness: 1.Number of bonds between particles 2.Strength of bonds 3.Distribution of bonds Average and standard deviation of each item Density distribution in tablets using X-ray CT

Tablets Hardness How bonds between particles form? Tablet preparation Wet processingDry processing (direct compression & slugging) Binder forms soft bridges between particles drying Hard bridges Drug + excepeints with good flowability & low elasticity limit compression Bond formation Applied pressure (stress) should exceed elastic limit of the compressed material to avoid brittle fracture or plastic deformattion

Tablets Hardness Factors affecting hardness during compression:

Tablets Hardness Stages Occurring During Compression Factors affecting hardness during compression:

Tablets Hardness Factors affecting hardness during compression:

Tablets Hardness Force applied by the upper punch force transmitted to the lower punch force lost to the die ejection force Forces and pressures operating on a powder under compression in a punch and die assembly. Factors affecting hardness during compression:

Tablets Hardness Factors affecting hardness during compression: 1.Applied pressure 2.Stress exerted on the tablet when upper punch is released 3.Stress upon tablet ejection from the die

Tablets Hardness Factors affecting hardness during compression: 1.Applied pressure Pressure Hardness H (hardness) α N (number of bonds) H = β N N* Tablet lamination & capping Pressure Thickness

Tablets Hardness Factors affecting hardness during compression: 1.Applied pressure 2.Stress exerted on the tablet when upper punch is released S (stress) α P (applied pressure) If S > H → Tablet lamination

Tablets Hardness Factors affecting hardness during compression: 1.Applied pressure 2.Stress exerted on the tablet when upper punch is released 3.Stress upon tablet ejection from the die If E > H → Tablet lamination or capping Tablet expansion

Tablets Hardness Causes for change of hardness on storage 1.Improper compression pressure 2.Expansion reasons 3.Chemical interaction 4.Crystallization of soluble drug or excepient due to moisture sorption. 5.Moisture redistribution

Tablets Hardness Causes for change of hardness on storage 1. Moisture redistribution This could lead to softer or harder tablets within short periods of time after manufacture. Time (days) Hardness 10 Time (days) Hardness 10

Tablets Hardness Causes for change of hardness on storage 1.Moisture redistribution When produced, tablets are not in equilibrium. Moisture redistribution could make bonds of lower or higher moisture content with consequent change in hardness

Tablets Hardness Causes for change of hardness on storage 1.Moisture redistribution Moisture redistribution could occur between granules of different sizes. Larger granules will have higher moisture content at the beginning. Each granules is associated with one given drying time t*. Drying is a diffusion process

Tablets Hardness Causes for change of hardness on storage 1.Moisture redistribution Moisture redistribution could occur between granules of different sizes. m o : initial moisture content of a granule m: amount of moisture left in a granule D: Diffusion coefficient of water in the granule a: granule diameter

Tablets Hardness Causes for change of hardness on storage 1.Moisture redistribution Moisture redistribution could occur between different tablet components Tablet is made of 2 components I and II Each has its moisture isotherm The tablet has a moisture content of 40 mg water per g of dry tablet weight EXAMPLE

Tablets Hardness Causes for change of hardness on storage 1.Moisture redistribution Moisture redistribution could occur between different tablet components Percent relative humidity Moisture content (mg/g) EXAMPLE Component I Component II

Tablets Disintegration Complete disintegration is the state in which any residue of the unit remaining on the screen of the test apparatus is a soft mass having no firm core. (except fragments of insoluble tablet coat or capsule shell)

Tablets Disintegration Dissolution medium d L q Factors affecting disintegration time 1.Disintegrant conc. 2.N: number of particles (per pore) that must be wetted before the tablet can disintegrate. 3. Porosity 4. Interfacial tension & contact angle between tablet & disintegration medium. 5. Viscosity of the disintegration medium.

Tablets Disintegration Factors affecting disintegration time t N : disintegration time N: number of particles (per pore) that must be wetted before the tablet can disintegrate. q: disintegrant particles per linear length of pore d: average pore diameter f: interfacial tension φ: contact angle : viscosity

Tablets Disintegration Factors affecting disintegration time Disintegration time is the: 1.Larger the more disintegrant particles must swell to make the tablet disintegrate 2.The longer the finer the pore (the smaller d is) 3.The smaller the larger the disintegrant conc 4.The smaller the larger the value of (the smaller the contact angle and interfacial tension.

Tablets Disintegration Factors affecting disintegration time during storage 1.Disintegrate conc. 2. number of particles (per pore) that must be wetted before the tablet can disintegrate. 3. Porosity 4. Interfacial tension & contact angle between tablet & disintegration medium. 5. Viscosity of the disintegration medium.

Tablets Disintegration Factors affecting disintegration time during storage 1.Disintegrate conc. 2. number of particles (per pore) that must be wetted before the tablet can disintegrate. 3. Porosity 4. Interfacial tension & contact angle between tablet & disintegration medium. 5. Viscosity of the disintegration medium.

Tablets Disintegration Factors affecting disintegration time during storage 1.Disintegrate conc. 2. number of particles (per pore) that must be wetted before the tablet can disintegrate. 3. Porosity Moisture absorption Time Disintegration time

Tablets Disintegration Factors affecting disintegration time during storage 1.Disintegrate conc. 2. number of particles (per pore) that must be wetted before the tablet can disintegrate. 3. Porosity

Tablets Dissolution

Tablets Dissolution Apparatus Basket Paddle Slight changes in compression pressure during formulation could solve this problem

Tablets Dissolution Conditions RPMPresence of air Dissolution medium 50, 100, 150 TypeVolume

Tablets Dissolution Test Complete dissolution curve One point determination Time % dissolved Dissolution constants (parameters)

Tablets Dissolution Test One point determination t 50%, t 90% Time % dissolved Complete dissolution curve

Tablets Dissolution Test One point determination Dissolution Efficiency Time % dissolved Complete dissolution curve

Tablets Dissolution Test One point determination Median dissolution time Time % dissolved Complete dissolution curve

Tablets Dissolution Test Complete dissolution curve One point determination Dissolution rate = amount dissolved after t time/t Time % dissolved

Tablets Dissolution Test One point determination Essential during stability testing Time % dissolved Complete dissolution curve

Time % dissolved Tablets Dissolution Test One point determination Q 30, Q 50 % drug dissolved after 30 or 50 min Enough for QC Complete dissolution curve

Tablets Storage stability of dissolution profiles Factors affecting dissolution on storage 1.Tablet expansion → lighter tablets → apparent slowing down

Tablets Storage stability of dissolution profiles 1.Tablet expansion → lighter tablets → apparent slowing down 2.Change of disintegration (under RT storage condition only) Factors affecting dissolution on storage

Tablets Storage stability of dissolution profiles 1.Tablet expansion → lighter tablets → apparent slowing down 2.Change of disintegration (under RT storage condition only) 3.Change of particle size Time (month) Particle size Factors affecting dissolution on storage

Tablets Storage stability of dissolution profiles M o : initial drug amount in the dosage form M: Drug amount left undissolved at time t K: Dissolution constant (time -1 ) T: dissolution time T i : dissolution lag time (Is a function of disintegration)

Tablets Storage stability of dissolution profiles Time % dissolved Initial dissolution profile

Tablets Storage stability of dissolution profiles Time % dissolved Initial dissolution profile Decreased K

Tablets Storage stability of dissolution profiles Time % dissolved Initial dissolution profile Decreased K

Tablets Storage stability of dissolution profiles Time % dissolved Initial dissolution profile Decreased K Both

Tablets porosity It is the fraction of voids between tablet particles

This is done by immersing the specimen in a mercury bath and then applying increasing pressure (up to 4000 bar), thus forcing mercury into smaller and smaller pores of the specimen. The measured quantities are the applied pressure and the corresponding volume of mercury forced into the specimen. Tablets porosity

Tablets Disintegration/Dissolution/Porosity Two tablet sets, with high and low porosities, were prepared using different compression forces. Time % drug dissolved Disintegration time More porous Less porous More porous Less porous

Tablets Tablet sets with high and low porosities have radically different particle release rates. Time Number of particles Less porous More porous Rationalize Disintegration/Dissolution/Porosity

Mg disintegrated Time Mg dissolved or disintegrated Mg disintegrated Mg dissolved Tablets Disintegration/Dissolution/Porosity

Tablets In-vivo to in-vitro correlation If two batches of the same product and formula are tested, then, a higher dissolution curve implies better in- vivo performance (lower T max, Higher C max, Higher AUC or combination of them) This could be correct for different products or not.

Tablets In-vivo to in-vitro correlation Methods of correlation Calculating and correlating an in-vitro parameter with an in-vivo eg: a. Point to point correlation % dissolved % absorbed

Tablets In-vivo to in-vitro correlation Methods of correlation Calculating and correlating an in-vitro parameter with an in-vivo eg: a. Point to point correlation b.MDT and MRT (MRT is a measure of the average length of time a drug molecule is in the body). b. C max and percentage dissolved after 15 min for an immediate release dosage form.

Q 15 C max Tablets In-vivo to in-vitro correlation Methods of correlation