alternative method of dissolution testing ,dissolution requirement.problem of variable contol i dissolution testing

1. BIOPHARMACEUTIC
CONSIDERATIONS IN DRUG
PRODUCT DESIGN AND IN VITRO
DRUG PRODUCT PERFORMANCE
Presented By
Sujitha Mary
M Pharm
St Joseph College Of Pharmacy
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2. TOPICS
 Alternative methods of Dissolution testing
 Meeting Dissolution Requirements
 Problems of variable Control in Dissolution Testing
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3. DISSOLUTION TESTING
 Dissolution and drug release tests are in-vitro tests that
measure the rate and extent of dissolution or release of the
drug substance from a drug product, usually aq.medium
under specified conditions.
 It is an important QC procedure for the drug product and
linked to product performance in-vivo.
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4. NEED FOR DISSOLUTION TESTING:
 Evaluation of bioavailability.
 Batch to batch drug release uniformity.
 Development of more efficacious and therapeutically optical
dosage forms.
 Ensures quality and stability of the product.
 Product development, quality control, research and
application.
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5. ALTERNATIVE METHODS OF
DISSOLUTION TESTING
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6. 6
USP
DISSOLUTIO
N TEST
METHODS
OFFICIAL
METHOD Or
COMPENDIA
L METHOD
NON-OFFICIAL
METHODS
Or NON-
COMPENDIA
L METHOD

7. NON-OFFICIAL APPARATUS
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 Intrinsic dissolution method
 Diffusion cell method
 Peristalsis method
 Rotating bottle method

8. 1) ROTATING BOTTLE METHOD
 It is used – controlled release beads.
 Dissolution medium may be easily changed. eg: artificial gastric juice
to artificial intestinal juice
 It consists of rotating rack to hold sample drug products in bottles and
they are capped tightly & rotated in 37°C temperature bath.
 Sample are decanted through a 40 mesh screen and residue are
assayed.
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9.  An equal volume of fresh medium is added to the remaining
drug residues within the bottles and the dissolution test is
continued.
 The main disadvantage is that this procedure is manual
and tedious
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10. 2) INTRINSIC DISSOLUTION METHOD
 A new drug may be tested for dissolution without the effect of
excipients or the fabrication effect of processing.
 The dissolution of a drug powder by maintaining a constant surface
area is called intrinsic dissolution. Expressed as mg/cm²/min.
 In one method, the basket method is adapted to test dissolution of
powder by placing the powder in a disk attached with a clipper to the
bottom of the basket.
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11. 3) PERISTALSIS METHOD
 To stimulate hydrodynamic condition of GIT tract in an invitro
dissolution device.
 It consists of rigid plastic cylindrical tubing fitted with septum and
rubber stopper at both ends.
 Dissolution chamber consists of a space between septum and lower
stopper.
 Dissolution medium is pumped with peristaltic action through the
dosage form.
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12. 4) DIFFUSION CELL
 Static or flow through diffusion cells are used to characterize invitro drug
release and drug permeation kinetics from a topical drug product eg:
Ointment, cream or transdermal drug product.
 The Franz diffusion cell is static diffusion system used to characterize drug
permeation through skin model.
 The skin is mounted on the Franz diffusion cell and the drug product is
placed on the skin surface.
 The drug permeates across the skin into a receptor fluid compartment that
may be sampled at various times.
 This system is used for selection of appropriate formulation that has
optimum drug delivery.
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13. 13

14. DISSOLUTION TESTING OF
ENTERIC-COATED PRODUCTS
 The product is first tested with 0.1 N HCl for 2 hrs.
 The buffer medium – pH 6.8
 The buffer stage generally runs for 45 mins.
 The time specified in the monograph.
 The objective is that no significant dissolution occurs in the acid
phase.
 A specified percentage of drug must be released in the buffer phase
 Specifications are set in the individual drug monographs
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15. DISSOLUTION APPROACHES FOR
NOVEL/ SPECIAL DOSAGE FORMS
 New dosage forms are developed for improving patient
compliance increase the therapeutic response
 Eg: these products are: oral suspensions, orally
disintegrating tablets, medicated chewing gums, soft
gelatin capsules , nanoparticles and liposomal drugs
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16.  Drug release test for some of these products can use conventional
dissolution apparatus
 Drug release tests for medicated chewing gum and extended-release
parenteral products
specialized dissolution apparatus or a modified dissolution apparatus
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17. CALIBRATION
Why ?
 to confirm suitability of the equipment and proper operation
of the apparatus
When ?
 before using new test equipment at regular intervals
(„every 6 months“)
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18. • Apparatus
suitability test[usp-
pvt]
Chemical
caliberation
• Verification of
physical
parameters
Mechanical
caliberation
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19. USP PERFORMANCE VERIFICATION
TEST
 For detecting problems associated with dissolution apparatus that are
found.
 The result- pass the acceptance criteria.
 The Prednisone tablets were renamed as “Reference Standard Tablets”
 dissolution is a complex system that is mainly consist of 3 components:
1) Analyst
2) dissolution apparatus
3) analytical procedure/ instrument
 These 3 components must interact with together optimally or the result
can be misleading.
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20.  The USP performance verification test (PVT) qualifies the intrument and
analyst to perform dissolution testing.
 PVT requires chemical calibration with calibrator tablets that may be
obtained from USP-NF.
 PVT is also useful to compare performance of different dissolution
apparatus used in different laboratories.
 The calibration tablets, either prednisone tablets for dissolution tests are
used to qualify USP dissloution apparatus 1 & 2.
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21. MECHANICAL CALIBRATION
 It is a critical component of the qualification of the apparatus.
 The FDA has introduced a mechanical calibration approach that
considers mechanical specifications of the instrument design and its
manufacture (FDA Guidance, January 2010).
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22. Verification of physical parameters specified in the
pharmacopoeia: USP apparatus 1 and 2
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23. MEETING
DISSOLUTION
REQUIREMENTS
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24.  Dissolution test times and specifications are usually establised on the
basis of an evalution of dissolution profile data.
 USP-NF sets dissolution requirements for many products.
 The requirements apply to both the basket and the paddle methods.
 The amount of drug dissolved within a given time period (Q) is
expressed as a percentage of label content.
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25.  Q is specified in the monograph for drug product to pass
the dissolution test.
 This value is generally specified in USP monograph of a
given drug product.
 Three stages (S1, S2, S3) of testing are allowed by USP-
NF.
 The dissolution test consists of testing 6 dosage units.
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26.  If the dissolution test fails to meet the criteria for S1, then 6
more dosage units are tested.
 Dissolution testing continues until the dissolution criteria
are met or until the 3 stages are exhausted.
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27. 27

28. PROBLEMS OF VARIABLE
CONTROL IN DISSOLUTION
TESTING
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29.  Depending on the particular dosage form involved, the variables may
or may not exert a pronounced effect on the rate of dissolution of the
drug or a drug product.
 Variations of 25% or more may occur with the same type of
equipment and procedure.
 The centering and alignment of the paddle is critical.
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30.  Turbulence can create increased agitation
higher dissolution rate
 Wobbling and tilting due to worn equipment should be avoided.
 The basket method is less sensitive to the tilting effect.
 The basket method is more sensitive to clogging due to gummy
materials.
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31.  Dissolved gas in the medium may form air bubbles on the surface
of the dosage form unit and can affect dissolution in both the basket
and paddle methods.
 In the absence of in vivo data, it is generally impossible to make
valid conclusions about bioavailability from the data.
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32.  The use of various testing methods makes it even more difficult to
interpret dissolution results because there is no simple correlation
among results obtained.
 For many drug products, the dissolution rates are higher with the
paddle method.
 Dissolution results at 50 rpm of paddle method = dissolution results
at 100 rpm of basket method.
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33.  For eg: In a study of sustained release theophylline tablets
compressed at various degrees of hardness, at 50rpm,
dissolution with paddle method for tablets of 4Kg hardness.
Tablets of 6.8Kg hardness with similar
dissolution profile were obtained at 125 rpm for both the
apparatus over a period of 6hrs.
With both methods, the dissolution rates were
obtained.
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34.  The composition of the formulation as well as the process variables
in manufacturing may both be important.
 No simple correlation can be made for dissolution results obtained
with different methods.
 The selection of dissolution method is based on the type of drug
product to be tested.
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35.  For eg:
a low density preparation may be poorly wetted in the
basket method .
a gummy preparation may clog up the basket screen;
the paddle method is preferred.
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36. REFERENCE
 Leon Shargel, Applied Biopharmaceutics & Pharmacokinetics; 4th
edition, page no. 132-136.
 Brahmankar D.M.; Jaiswal S.B., Biopharmaceutics and
Pharmacokinetics- A Treatise, Vallabh Prakashan, New delhi, India.
(2009) pp 325-329.
 Dissolution Technologies: http://www.dissolutiontech.com
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