Dissolution

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Dissolution studies Factor affecting dissolution and Invitro- Invivo Correlation

By Yogesh K. Chaudhari

M Pharm 1st Yr) Mumbai University

Dissolution

*What is dissolution?- Dissolution is a process in which a solid substance

solubilizes in a given solvent to yield a solution i.e. mass transfer from the solid surface to the liquid phase.

- It depends on the affinity between the solid substance and solvent.

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Dissolution

- It quantifies the speed of the dissolution process. - It depends on chemical natures of the solvent and solute, temperature (and possibly to a small degree, the

pressure), degree of undersaturation, presence of a means of mixing, interfacial surface area, and the presence of "inhibitors" (e.g., substances adsorbed

on the surface). It is defined as the amount of drug substance that goes

in solution per unit time under standardized conditions of temperature, pH and solvent composition and constant surface area.

*Rate of dissolution

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Dissolution

*Need of dissolution

Drug in the blood and the

body

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Dissolution

- Initial mechanical lag. - Wetting of dosage form.- Penetration of dissolution medium.- Disintegration.- De-aggregation. - Dissolution.- Occlusion of some particles.

*Mechanism of dissolution

The S-Shaped dissolution curve of solid dosage form5

Dissolution

- For optimization of formulation and quality control.- To identify the manufacturing variable, like the

binding agent effect, mixing effects, granulation procedure, coating parameters and comparative profile studies.

- To show that the release of drug from the tablet is close to 100%.

- To show that the rate of drug release is uniform batch to batch.

- And to show that release is equivalent to those batches proven to be bioavailable and clinically effective.

*Application of dissolution studies

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Dissolution

*Theories of dissolution

1. Diffusion layer model

2. Danckwert’s model

3. Interfacial barrier model

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Dissolution

- Also called ‘film theory’.

- 2 steps are involved:1. Interaction of solvent with drug

surface to form a saturated drug layer , called stagnant layer.

2. Diffusion of drug molecules from stagnant layer into bulk of the system.

*1. Diffusion layer model

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Dissolution

Noyes- Whitney’s equation:

where,dC/ dt = dissolution rate of the drug,k = dissolution rate constant,Cs = concentration of drug in

the stagnant layer, andCb = concentration of drug in

the bulk of the solution at time t.

Diffusion layer Model

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Dissolution

Modified Noyes-Whitney’s equation:

Where,D = diffusion coefficient (diffusivity) of the drugA = surface area of the dissolving solidKw/o = water/oil partition coefficient of the drug.V = volume of dissolution mediumh = thickness of the stagnant layer(Cs – Cb)= concentration gradient for diffusion of drug.

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Dissolution

- Noyes- Whitney’s equation represents first order kinetics, for which the driving force is concentration gradient.

- This is true for in- vitro dissolution which is characterized by non sink condition.

- The in- vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation I.e. Cb = 0 .

- Under sink condition, dissolution rate follows zero order kinetics.

Dissolution rate under sink and non- sink conditions

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Dissolution

*The Hixson-Crowell Cube Root Law

- Major assumptions in Noyes-Whitney relationship is that the surface area remains constant throughout dissolution process.

- However, size of drug particles will decrease as drug dissolves. and thus changes the effective surface area.

- Thus, Hixson & Crowell modified the equation to represent rate of appearance of solute by weight in solution.

where, M0 = initial mass of powder M = mass of powder dissolved in time, t k = cube root dissolution rate constant

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Dissolution

*2. Danckwert’s Model- Also called “Penetration or Surface Renewal Theory”.

- Danckwert’s takes into account the eddies or packets that are present in the agitated fluid which reach the solid- liquid interface, absorb the solute by diffusion and carry it into the bulk of solution.

- These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory.

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Dissolution

Where,m = mass of solid dissolved, andγ = rate of surface renewal (or the interfacial tension)

Danckwert’s Model

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Dissolution

*3. Interfacial Barrier Model

- Drug dissolution is a function of solubility rather than diffusion.

- Intermediate concentration exist at the interface as a result of solvation.-Dissolution rate per unit area, G is given by,

where, Ki = effective interfacial transport

constant.15

Dissolution

*Factors affecting dissolution rate

1. Factors related to Physicochemical Properties of Drug

2. Factors related to Drug Product Formulation

3. Processing Factor4. Factors Relating Dissolution Apparatus

5. Factors Relating Dissolution Test

Parameters16

*Factor related to physicochemical

properties of drug 1. Particle size of drug- There is a direct relationship between surface area of drug and

its dissolution rate. Since, surface area increases with decrease in particle size, higher dissolution rates may be achieved through reduction of particle size.

- E.g. Micronisation of non-hydrophobic drug like griseofulvin leads to increase in dissolution rate.

- Micronisation of hydrophobic powders can lead to aggregation and floatation, when powder is dispersed into dissolution medium.

- E.g. hydrophobic drugs like aspirin, phenacetin and phenobarbital shows decrease in dissolution rate, as they tend to adsorb air at the surface and inhibit their wettability.

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Dissolution

2. DRUG SOLUBILITY

- Solubility of drug plays a prime role in controlling its dissolution from dosage form. Aqueous solubility of drug is a major factor that determines its dissolution rate.

- E.g. Poorly soluble drug :griseofulvin, spironolactone Hydrophilic drug :neomycin

Solubility

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Dissolution

3. Solid state characteristics- Solid phase characteristics of drug, such as amorphicity, crystallinity, state of hydration and polymorphic structures have significant influence on dissolution rate.

- Anhydrous forms dissolve faster than hydrated form because they are thermodynamically more active than hydrates. E.g. Ampicillin anhydrate faster dissolution rate than trihydrate.

- Amorphous forms of drug tend to dissolve faster than crystalline materials. E.g. Novobiocin suspension, Griseofulvin.

- Metastable(high activation energy)polymorphic form have better dissolution than stable form. 19

4. Salt formation - It is one of the common approaches used to increase drug solubility and dissolution rate. E.g. sodium and potassium salts of Penicillin G, phenytoin, barbiturates etc.

- While in case of Phenobarbital, dissolution of sodium salt was slower than that of weak acid.

Dissolution and absorption of an acidic drug administered in salt form

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Dissolution

*Factors related to drug product formulation 1. Binders and granulating agents:- In general, the hydrophilic ( aqueous) binders

show better dissolution profile with poorly wettable drugs like phenacetin by imparting hydrophilic properties to the granule surface.

- Large amounts of such binders increase hardness and decrease disintegration / dissolution rates of tablets.

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Dissolution

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Rate of dissolution of phenacetin from ▲powder, ● granules, and ○ tablet in diluted gastric juice.

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2. Disintegrants- Disintegrating agent added before & after the granulation affects the dissolution rate.

- E.g. Phenobarbital tablet showed that when copagel (low viscosity grade of Na CMC) added before granulation decreased dissolution rate but if added after did not had any effect on dissolution rate.

- Microcrystalline cellulose is a very good disintegrating agent but at high compression force, it may retard drug dissolution.

- Starch is not only an excellent diluent but also superior disintegrant due to its hydrophilicity and swelling property.

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Effect of starch content on dissolution rate of salicylic acid tablet, ○ 5 %, ● 10 % and × 20 %

starch in granules.

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3. Effect of lubricants / anti-frictional agents - The nature, quantity, and quality of lubricants added can affect the dissolution rate.

- Lubricants are hydrophobic in nature (several metallic stearate & waxes) which inhibit wettability, penetration of water into tablet so decrease in disintegration and dissolution.

- The use of soluble lubricants like SLS and Carbowaxes promote drug dissolution.

- E.g. Magnesium stearate, a hydrophobic lubricant, tend to retard the dissolution rate of salicylic acid tablet, whereas sodium lauryl sulfate enhances its dissolution, due to its hydrophobic but surface activity, which increases wetting and better solvent penetration into tablet.

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(A) Effect of magnesium stearate on dissolution rate of salicylic acid from rotating disc made from fine salicylic acid powder, ○ 3 % Mg. Stearate, ● no lubricant added.

(B) Effect of lubricant on dissolution rate of salicylic acid contained in compressed tablet, × 3 % Mg. Stearate , ● no lubricant, and ○ 3 % Sodium lauryl sulphate.

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4. Coatings - In general, the deleterious effect of various coatings on drug dissolution from a tablet dosage form is in the following order: Enteric coat > Sugar coat > Non- enteric film coat.

5. Buffers- Buffers are sometimes useful in creating the right atmosphere for drug dissolution, e.g. buffered aspirin tablets. 6. Complexing agents - A complexed drug may have altered stability, solubility, molecular size, partition coefficient and diffusion coefficient.

- E.g. Enhanced dissolution through formation of a soluble complex of ergotamine tartarate-caffeine complex and hydroquinone-digoxin complex.

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*Processing factors1.Method of granulation

- Wet granulation has been shown to improve the dissolution rate of poorly soluble drugs by imparting hydrophilic properties to the surface of granules.

- A newer technology called as APOC “Agglomerative Phase of Comminution” was found to produce mechanically stronger tablets with higher dissolution rates than those made by wet granulation. A possible mechanism is increased internal surface area of granules produced by APOC method.

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2. Compression force

- The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet. - The curve obtained by plotting compression force versus rate of dissolution can take one of the 4 possible shapes

1. tighter bonding increases hardness

2 . higher compression force cause deformation crushing or fracture of drug particle or convert a spherical granules into disc Shaped particle

3.& 4. both conditionDissolution

1 2

3 4

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*Factors related to dissolution apparatus

1. AGITATION

- Rate of dissolution depends on type of agitation used, the degree of laminar and turbulent flow in system, the shape and design of stirrer.

- Speed of agitation should be such that it prevent turbulence and sustain a reproducible laminar flow, which is essential for obtaining reliable results.

- So, agitation should be maintained at a relatively low

rate.

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2. SAMPLING PROBE POSITION & FILTER- Sampling probe can affect the hydrodynamic of the system.

- USP states that sample should be removed at approximately half the distance from the upper surface of basket or paddle and surface of dissolution medium and not closer than 1 cm to the side of the flask.

3. STIRRING ELEMENT ALIGNMENT- The USP / NF states that the axis of the stirring element must not deviate more than 0.2 mm from the axis of the dissolution vessel.

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*Factors related to dissolution test

parameters 1. Vibration- The excessive vibration of dissolution apparatus increases dissolution rates.2. Vessel design and construction- Plastic vessels provide more perfect

hemisphere than glass vessels.3. Temperature control- Should be maintained at 37 ± 0.5 º C4. Dissolution medium parameters- Surface tension, pH, Viscosity, De-aeration

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*Dissolution apparatus

Based on the absence or presence of sink conditions, there are two principal types of apparatus: 1 . Closed- compartment apparatus: It is basically a limited volume apparatus operating under non-sink conditions. e.g. beaker type apparatuses such as the rotating basket and the rotating paddle apparatus.

2 . Open- compartment ( continuous flow- through ) apparatus: It is the one in which the dosage form is contained in a column which is brought in continuous contact with fresh, flowing dissolution medium ( perfect sink condition ). 3 . A third type called as dialysis systems are used for very poorly aqueous soluble drugs for which maintenance of sink conditions would otherwise require large volume of dissolution fluid.

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*USP compendial apparatus

1. Basket type (USP apparatus 1)2. Paddle type (USP apparatus 2)3. Reciprocating cylinder type (USP

apparatus 3)4. Flow - through cell type (USP

apparatus 4)5. Paddle over disc type (USP apparatus

5)6. Cylinder type (USP apparatus 6)7. Reciprocating holder type (USP

apparatus 7)

*Basket type (USP apparatus 1)

Design:Vessel:- Made up of transparent, inert material(borosilicate glass) Semi hemispherical bottom Capacity: 1000ml

Shaft:- Stainless steel 316 Rotates smoothly without significance wobble

Basket:- Stainless steel 316 Gold coatings up to 0.0001 inch (2.5 µm)

Water bath:- Maintained at 37± 0.5˚cDissolution 35

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- Dosage form contained within basket- Dissolution should occur within Basket- pH change by media exchange

Uses:- Capsules, tablets, delayed release dosage form, suppositories, floating dosage forms.

Agitation:- Rotating stirrer Usual speed: 50 to 100 rpm

Disadvantage:- Formulation may clog to 40 mesh screen1- Automated Dissolution Basket Test.mp4 Fig. Basket stirring element

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*Paddle type (USP apparatus 2)Design:

Vessel:- Made up of transparent, inert material(borosilicate glass) Semi hemispherical bottom Capacity: 1000ml

Shaft:- The blade passes through shaft so that bottom of blade fuses with bottom of shaft.

Stirring elements:- Made of Teflon for laboratory purpose Stainless steel 316

Water bath:- Maintain at 37± 0.5˚c.

Sinkers:- Small loose wire helix used to prevent capsule/tablet from floating.

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- Dosage form should remain at the bottom center of the vessel.

- pH change by media change.

Useful for:- Tablets Capsules Agitation:- Rotating stirrer Usual speed: 25 to 100 rpm

Advantages:- Easy to use and robust pH change possible Can be easily adapted to apparatus 5

Disadvantages:- Floating dosage forms require sinker Positioning of tablet.

Fig. Paddle stirring element

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1- ERWEKA DT800 Dissolution Tester Offline System (1).mp4

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*Reciprocating cylinder type (USP apparatus 3)

Design:Vessel:- Cylindrical flat bottom glass vessel.

Agitation:- Reciprocating Generally 6-35 cycles/min

Volume of dissolution fluids:- 200-250 ml

Water bath:- Maintain at 37 ± 0.5˚C

Use:- Extended release

Dissolution

- The apparatus consist of a set of cylindrical flat– bottomed glass vessel equipped with reciprocating cylinders.

- The vessels are partially immersed in a suitable waterbath of any convenient size that permits holding the temperature at 37 º C ± 0.5 º C during the test.

- The dosage unit is placed in reciprocating cylinder & the cylinder is allowed to move in upward and downward direction constantly. Total distance it travels during stroke is 9.9- 10.1 cm.

Useful for:- Tablets, Beads, controlled release Formulations.

Advantages:- Easy to change the pH-profilesHydrodynamics can be directly influenced byvarying the dip rate.Disadvantages:- Small volume (max. 250 ml)

3 - ELECTROLAB Reciprocating cylinder USP Apparatus 3.mp441

Fig. Reciprocating cylinder

*Flow-through cell type (USP apparatus

4)The apparatus consist of a reservoir for the dissolution medium and a pump that forces medium through the cell holding the test sample.

Dissolution fluid is collected in separate reservoir.Temperature is maintained at 37 º C ± 0.5 º C. Useful for:- Low solubility drugs, powders and granules, micro particles, implants.

Advantages:- Easy to maintain sink condition.Easy to change media pH

Disadvantages:-De-aeration necessary High volumes of media Labor intensiveDissolution 42 Fig. Flow through cell

Dissolution

Tablets 12mm Tablets 22.6mm Powder/ Implants Suppository/ Granule soft gelatin capsule

Cell types

4 - ERWEKA USP4 flow through cell.mp4

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Dissolution

*Paddle over disc type (USP apparatus 5)

This uses the paddle apparatus 2 with a stainless steel disk designed for holding transdermal system at the bottom of the vessel.

The disk holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade.

Media volume used is 900 ml which is maintained at 37 º C ± 0.5 º C.

Useful for transdermal patches.Disadvantages:- Disk assembly restrict the size of patch.

Transdermal patch retainer ( Hanson style)

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Fig. Paddle over disc

*Cylinder type (USP apparatus 6)

This is a modification of Basketapparatus 1, in which the basket is replaced with a stainless steel cylinder as a stirring element.

Sample is mounted to cuprophan (inner porous

cellulosic material) and entire system is adhere to cylinder.

The dosage unit is placed on the cylinder with release side out.

Useful for testing of transdermal patches.

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Fig. Cylinder type

Cylinder stirring element

*Reciprocating holder type (USP apparatus 7)

The assembly consist of a set of calibrated solution containers, a motor and drive assembly to reciprocate the system vertically.

The sample holder may take the form of disc, cylinder or a spring or acrylic rod, or it may simply be the rod alone.

Capacity is 50– 200 ml.

Reciprocating frequency is 30 cycles/ min.

Useful for transdermal patches and solid dosage forms.

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Dissolution

Holder types

7 - ERWEKA-RRT10-USP7-Reciprocating Disk 5.0 cm2 (1).mp4

7- ERWEKA-RRT10-USP7-Angled Disk.mp4

7- ERWEKA-RRT10-USP7-Teflon Cylinder(2).mp4

7- ERWEKA-RRT10-USP7-Spring Holder 1.45 inch (1).mp4

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Dissolution

*IVIVC (In vitro- in vivo

correlation)

IVIVC is an approach to describe the relationship between an in-vitro property of dosage form ( rate and extent of drug release) and a relevant in- vivo response ( plasma drug conc. or amount of drug

absorbed )48

Dissolution

*Purpose of IVIVC

- Serves as a surrogate for in- vivo bioavailability and to support biowaiver.

- Used in optimization of formulation.

- To reduce the number of human studies during formulation development.

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Dissolution

*Levels of correlation

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Dissolution

*Level A correlation- The % of drug dissolved at a given time is correlated to %

absorbed.

- Highest category of correlation.

- Represents point to point correlation between in vitro dissolution time course and in vivo response time course.

- Utilizes all the dissolution and plasma level data available to develop correlation.

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Dissolution

*Level B correlation

- The mean in vitro dissolution time (MDT) is compared either to the mean residence time (MRT) or to the mean in vivo dissolution time.

- Is not a point-to-point correlation.

- Does not reflects the actual shape of in- vivo plasma level curve.

- Level B correlations are rarely seen in NDAs.

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Dissolution

*Level C correlation

- One dissolution time point (t50% t90% etc.) is compared to one mean pharmacokinetic parameter such as AUC, Tmax , Cmax .

- A single point estimation and does not reflect the entire shape of plasma drug concentration curve.

- Weakest level of correlation.

- Can be useful in early stages of formulation development when pilot formulations are being selected.

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*References* D.M. Brahmankar, Sunil B. Jaiswal. pg. no. 29- 59 and 328- 335.* The science and practice of of pharmacy by Remington 21st edition Pg. no. 673- 688.* United states of pharmacopoeia, 2009. pg. no. 263- 276* Principles and Application of Biopharmaceutics and Pharmacokinetics by H.P. Tipnis and

Amrita Bajaj. Pg. no. 332- 350.* The theory and the practice of Industrial pharmacy by Lachman L, Liberman HA, Indian

edition 2009. Pg. no. 302- 303.* Article on Dissolution testing of various dosage forms by TK Indira.

(http://www.pharmainfo.net/Dissolution/dissolution-testing-various-dosage-forms)* http://apps.who.int/phint/en/p/docf/* www.wikipedia.com* www.ei-instrument.com for images* https://www.google.co.in/search?

q=theory+of+dissolution&espv=2&biw=1600&bih=799&site=webhp&source=lnms&tbm=isch&sa=X&sqi=2&ved=0CAgQ_AUoA2oVChMIjf-ckKuXyAIVUEiOCh2mUQ5i#imgrc=_

* http://www.pharmainfo.net/dissolution-test* https://www.youtube.com/watch?v=CTxc9CCXurk* https://www.youtube.com/watch?v=cG2IHw7S3nw* https://www.youtube.com/watch?v=vmohYJn89NA* https://www.youtube.com/watch?v=b40PbkbLP_M* https://www.youtube.com/watch?v=nFShFBlzT5k

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