Download - Pharmaceutical Analysis Lect-3 -1
PHARMACEUTICAL ANALYSIS
COURSE NO: PHM-CHEM-7201 - part V
Lecture 3
Ajmal Nasir Ph.D
Executive Director Highnoon laboratories Ltd
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SOLID DOSAGE ANALYSIS
IPC SAMPLING Pool Q.C sample
Composite sample
10 or 20 tablets
Grinding
Alloquit equall to 1 unit weight
Sample preparation
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% Of claim = -------- X ------- X ------X -------- x ------- x---------X P
WhereWs = weight of standardWt = Weight of sample takenP = Potency of materialAs = Absorption of standardAt = Absortption of Sample takenLc = label claim in mgsMW = Average weight of units
AT Ws 5 100 100 Mw
As 100 100 WT 5 Lc
SOLID DOSAGE ANALYSIS
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DISSOLUTION Drugs Transfer to blood Through Membrane of GI
Tract as Solution. Most of the drugs are Solid Dosage Form Drug Must Go into Solution in Stomach. If absorption is slow concern is absorption. If Drug is slow to go in Solution than Solubility is
the issue. Drugs with less than 1g/100ml is with this issue
and high dosage are required. Drug Dissolution is the step to be controleed for
better Bio availability.
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DissolutionDiffusion Through the Stagnant Layer
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Dissolution Consider that each particle of drug
formulation is surrounded by a stagnant layer of solution.
After an initial period we will have a steady state set-up where drug is steadily dissolved at the solid-liquid interface and diffuses through the stagnant layer
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Dissolution If diffusion is the rate determining step we
can use Fick's first law of diffusion to describe the overall process.
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Fick's first law
•D is the diffusion coefficient• A the surface area, •Cs the solubility of the drug,• Cb the concentration of drug in the bulk solution• h the thickness of the stagnant layer.
If Cb is much smaller than Cs then we have so-called "Sink Conditions" and the equation reduces to
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Dissolution
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DISSOLUTION Surface area, A The surface area per gram (or per dose) of a solid drug can
be changed by altering the particle size. A cube 1 cm on each side has a surface area of 6 cm2. If this cube is broken into cubes with sides of 0.1 cm, the
total surface area is 60 cm2. Grinding have irregular shapes and even larger
surface areas. As A increases the dissolution rate will also increase.
Improved bioavailability has been observed with griseofulvin, digoxin, etc.
Methods of particle size reduction include mortar and pestle, mechanical grinders, fluid energy mills, solid dispersions in readily soluble materials (PEG's).
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Dissolution Diffusion layer thickness, h This thickness is determined by the
agitation in the bulk solution. In vivo no control over this Agitation. It is important though when we perform in
vitro dissolution studies. Agitation rate must be controlled to co
relate in vitro and in vivo Results.
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Dissolution The apparent thickness of the
stagnant layer can be reduced when the drug dissolves into a reactive medium.
A weakly basic drug in an acidic medium, the drug will react (ionize) with the diffusing proton (H+) and this will result in an effective decrease in the thickness of the stagnant layer.
The effective thickness is now h' not h.
Also the bulk concentration of the drug is effectively zero. For this reason weak bases will dissolve more quickly in the stomach.
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Dissolution Diffusion coefficient, D The value of D depends on the size of the
molecule and the viscosity of the dissolution medium.
Increasing the viscosity will decrease the diffusion coefficient and thus the dissolution rate.
This could be used to produce a sustained release effect by including a larger proportion of something like sucrose or acacia in a tablet formulation.
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Dissolution Drug solubility, Cs Solubility is another determinant of
dissolution rate. As Cs increases so does the dissolution
rate. We can now look at ways of changing the
solubility of a drug.
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Salt formIf we look at the dissolution
profile of various salts. Salts of weak acids and
weak bases generally have much higher aqueous solubility than the free acid or base, therefore if the drug can be given as a salt the solubility can be increased and we should have improved dissolution.
One example is Penicillin V.
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DissolutionCrystal form Some drugs exist in a number of crystal
forms or polymorphs. These different forms may well have
different solubility properties and thus different dissolution characteristics.
Chloramphenicol palmitate exists in at least two polymorphs.
The B form is apparently more bio available.
The recommendation might be that manufacturers should use polymorph B for maximum solubility and absorption.
A method of controlling and determining crystal form would be necessary in the quality control process.
Shelf-life could be aproblem as the more soluble (less stable( form may transform into the less soluble form.
In time the suspension may be much less soluble with variable absorption.
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DESIGN & CALIBRATION OF DISSOLUTION
APPRATUS
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Dosage forms to be tested
immediate release dosage forms• powders, granules / beads, tablets, capsules
controlled release dosage forms• powders, granules / beads, tablets, capsules
transdermal systems
implants
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Official Dissolution Monographs
United States Pharmacopeia
European Pharmacopoeia
British Pharmacopoeia
Japanese Pharmacopoeia
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Official dissolution apparatus
USP 30 classification
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)
5. Paddle Over Disk (Ph.Eur.)
6. Rotating Cylinder (Ph.Eur.)
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Which type of dissolution apparatus ?
Depends on intention
1. Quality controlexamining batch homogeneityexamining batch to batch conformityexamining stability
2. Research & Development examining drug release behavior of preformulations in vitro simulation of the gastrointestinal passage
3. IVIVC
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Apparatus 1 - Basket 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
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Apparatus 1 - Basket
Advantages• breadth of experience
(more than 200 monographs)
• full pH change during the test
• can be easily automated which is important for routine investigations
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Apparatus 1 - Basket
Disadvantages• disintegration-dissolution
interaction
• hydrodynamic „dead zone“ under the basket
degassing is particularly important
• limited volume sink conditions for poorly soluble drugs ?
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Apparatus 1 - Basket
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Apparatus 2 - Paddle
Useful for• tablets• capsules• beads• delayed release / enteric
coated dosage forms
Standard volume• 900/1000 ml
Method of first choice !!!
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Apparatus 2 - Paddle
Advantages• easy to use
• robust
• can be easily adapted
to apparatus 5
• long experience
• pH change possible
• can be easily automated
which is important for
routine investigations
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Apparatus 2 - Paddle
Disadvantages
• pH/media change is often difficult
• limited volume 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“
• sinkers for floating dosage forms
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Sinker types
JP/ USP / Ph. Eur. 5.3 Sinker
„a small loose piece of nonreactive material such as not more than a few turns of wire helix may be attached to dosage units that would otherwise float …“ „…. other validated sinker devices may be used“
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Coning
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Apparatus 2 - Paddle
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Apparatus 3 – Reciprocating cylinder
Useful for• tablets• beads• controlled release formulations
Standard volume• 200-250 ml per station
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Apparatus 3 – Reciprocating cylinder
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
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Apparatus 3 – Reciprocating cylinder
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Apparatus 4 – Flow-Through Cell
Useful for• low solubility drugs• microparticulates• implants• suppositories• controlled release formulations
Variations• open system• closed system
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Cell types
Tablets 12 mm Tablets 22,6 mm Powders / Granules Implants Suppositories /
Soft gelatine capsules
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Apparatus 4 – Flow-Through Cell
Advantages• easy to change media pH• pH-profile possible• sink conditions• different modes
a) open systemb) closed system
Disadvantages Deaeration necessary high volumes of media labor intensive
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Apparatus 4 – Flow-Through Cell
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Apparatus 5 – Paddle over disk
Useful for transdermal patches
Standard volume• 900 ml
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Apparatus 5 – Paddle over disk
Advantages standard equipment
(paddle) can be used, only add a stainless steel disk assembly
Disadvantages disk assembly restricts
patch size
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Apparatus 6 – Rotating cylinder
USP apparatus 7 – Reciprocating holder
most probably will be removed from the USP !!!
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Summary
Immediate release dosage forms: apparatus 1 or 2 (preferably 2)
Controlled release dosage forms: apparatus 1 or 2 using different media for QC apparatus 3 or 4 for R&D purposes
Beside the selection of an adequate dissolution apparatus, adequate test conditions are crucial for all purposes !