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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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 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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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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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 3 – Reciprocating cylinder

Useful for• tablets• beads• controlled release formulations

Standard volume• 200-250 ml per station

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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 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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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 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 !

pharmaceutical analysis lect-3 -1

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