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Dissolution - Theory and concepts

Theory of Dissolution

 Dissolution is the process by which a solid enters into solution.
 In 1897 Noyes and Whitney came up with: “The rate of solution of
solid substances in their own solution.”
 dc / dt = K (Cs-Ct)
 According to their research, rate of dissolution of solid substances is determined by rate of diffusion of a very thin layer of saturated solution that forms instantaneously around the solid particle. They developed the mathematical relationship that correlates the dissolution rate to the solubility gradient of the solid.

Diffusion layer model / film theory

 In 1904, Nerst and Brunner applied Fick’s law of diffusion to the
Noyes-Whitney equation. (Diffusion layer model / film theory)
 dc / dt = K D.S / v.h (Cs-Ct)

Cube root law of dissolution

 In 1931, Hixson and Crowell came up with Cube root law of
dissolution.
 W01/3-W1/3 = Kt

Scheme of dissolution

Later Wagner followed by Carstensen gave the scheme of dissolution.
 Initial mechanical lag
 Wetting of the dosage form
 Penetration of the dissolution medium into the dosage form
 Disintegration
 Deaggregation of the dosage form and dislodgement of the granules
 Dissolution
 Occlusion of some particles of the drug.

According to Carstensen wetting of the solid dosage form surface controls the liquid access to the solid surface which is the limiting factor.

Types of Dosage Forms:

 High solubility – High permeability drugs
 Low solubility – High permeability drugs
 High solubility – Low permeability drugs
 Low solubility – Low permeability drugs

Similarity Factor (Profiling)

f2 = 50 C log {[1+(1/n)3 ( Ri - Ti ) ] C 100}

 The above equation defines f2, where Ti and Ri show the average percents dissolved from test and reference products at the time point (i), and n is the number of time points.
 The similarity should be justified by dissolution profiles,
 covering at least three time points, attained at three different buffers (normally pH range 1-6.8; in cases where it is considered necessary pH range 1-8).
 In the case of a drug or excipients that are insensitive to pH, profiles from only two buffer systems are required.
 A minimum of three time points (zero excluded)
 The time points should be the same for the two formulations
 Twelve individual values for every time point for each formulation
 Not more than one mean value of > 85% dissolved for any of the formulations
 The relative standard deviation or coefficient of variation of any product should be less than 20% for the first point and less than 10% from second to last time point.

Dosage Forms

 Immediate release dosage forms
• powders, granules / beads, tablets, capsules
 Controlled release dosage forms
• powders, granules / beads, tablets, capsules
 Transdermal systems
 Implants

As per USP dissolution apparatus can be classified as:

1. Rotating Basket (Ph.Eur./BP/JP)
2. Paddle (Ph.Eur./BP/JP)
3. Reciprocating Cylinder (Ph.Eur.)
4. Flow Through Cell (Ph.Eur./BP/JP)

Selection of dissolution Apparatus depends on the intended application like:
Quality control
1. Check batch homogeneity
2. Check batch to batch conformity
3. Check stability
Research & Development
1. Checking drug release behavior of preformulations
2. In vitro simulation of the gastrointestinal passage
In Vitro In Vivo Correlation

Various Types of Dissolution Apparatus:
Apparatus 1

Useful for capsules,beads,delayed release / enteric coated dosage forms,floating dosage forms, surfactants in media
Standard volume:900/1000 ml, 1, 2, 4 liter vessels
Advantages
Full pH change during the test, automation
Disadvantages
Disintegration-dissolution interaction,hydrodynamic „dead zone“
under the basket degassing is particularly important, limited volume à
sink conditions for poorly soluble drugs.

Apparatus 2

Useful for tablets,capsules,beads,delayed release / enteric coated dosage forms.
Standard volume:900/1000 ml
Method of first choice.

Advantages
Easy to use,robust,pH change possible,automation
Disadvantages
 pH/media change is often difficult

 limited volume à sink conditions for poorly soluble drugs ?

 hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,floating) and therefore may significantly affect drug dissolution „coning“

Apparatus 3

Useful for tablets,beads,controlled release formulations.

 Standard Volume
• 200-250 ml per Station
Advantages
• easy to change the pH
• pH-profiles
• hydrodynamics can be directly influenced by varying the dip rate
Disadvantages
• small volume (max. 250 ml)
• little experience
• limited data

Apparatus 4

 Useful For
• Low solubility drugs
• Microparticulates
• Implants
• Suppositories
• Controlled release formulations

 Variations
• Open System
• Closed System

Advantages
• easy to change media pH
• pH-profile possible
• sink conditions
• different modes

a) open system
b) closed system

Disadvantages
• Deaeration necessary
• high volumes of media
• labor intensive
 Useful for Transdermal patches.

 Standard volume
• 900 ml

Calibration

Verification of physical parameters: Height, wobbling, centring, rpm, temperature, vibration.

Apparatus suitability:The apparatus suitability is to check for parameters that can not be conveniently measured (vibration, vessel cleanliness, medium degassing ...) and also to provide an overall check of the system.

Trouble shooting

Vibration produces unwanted variation in dissolution data and mostly results in an increased dissolution rate

Internal vibration may be caused e.g. from frayed drive belts

External vibration may be caused by e.g. magnetic stirrers, centrifuges, vacuum pumps, old fridges, nearby construction, ...

Inability to properly measure vibration levels at various points within an apparatus is the main reason why calibrator tablets were originally developed .
Typical Vibration causes are:dissolution equipment placed planar,drive chain or belt free of tension and /or dirt,torn parts replaced,correctly functioning gear plates,individual spindles are not surging,bench/table stable,no sources of vibration nearby,no sources of vibration nearby.

Dissolution media should be:

• Correctly degassed,correct amount used (900/500 ml),Correct amount dosed (weight/volume),Dosing procedure gentle resaturation/spillage),Buffer correct (pH + 0.05 units, buffer salts, molarity),Correct temperature during test (32°C / 37°C + 0.5°C,Evaporation during test negligible.

Degassing:

• Insufficient degassing may result in decreased dissolution rates of several drugs.

• e.g. Prednisone Tablets but also a range of poorly soluble drugs are very sensitive to the amount of dissolved gases in the dissolution medium.

• The degassing procedure should therefore be efficient and reproducible for every test.

Deaeration

• Heat the dissolution medium to about 41°C.

• Vacuum filter through a 0.45-µm-porosity membrane into a flask, stirring with a magnetic stirrer.

• Continue to draw a vacuum and stir for an additional 5 min.

• Gently transfer the medium directly into the vessel.

• Rotating the apparatus 2 shafts to speed equilibration to 37°C is discouraged!!!

• Use medium promptly after equilibration.

Alternative deaeration methods
• As USP other validated deaeration techniques for removal of dissolved gases which may be used are:
 Heating
 Sonication
 Vacuum
 Helium Sparging (expensive)
Sampling
• Take each sample at the correct time point Sampling time points (+ 2%)
• Use a single glass syringe for each vessel
• Sample from the right location within the vessel between media surface and top of the paddle blade N.L.T. 10 mm from vessel wall
• Always use a suitable filter à check filter adsorption.

• check the clearity of the filtered sample.

• Filter the sample immediately after sampling.

For automated sampling check the tubings for cleanliness and integrity.

Physical conditions of vessels

• Vessels should be clean

• Vessel surface smooth and dimensions within specification Number

Tested Acceptance Criteria for immediate release dosage form.

S1 6 Each unit is not less than Q + 5%.

S2 6 Average of 12 units (S1 + S2) is equal to orgreater than Q,
and no unit is less thanQ 15%.

S3 12 Average of 24 units (S1 + S2 + S3) is equal to or greater
than Q, not more than 2 unitsare less than Q 15%, and no
unit is less than Q 25%

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