Dissolution method and ivivc by ranjeet singh

 Dissolution is a process of mass transfer of solid into the
solvent. It is a multiple process involving heterogeneous
swinging reaction/interaction between the phases of solute-
solute, solute-solvent and solvent-solvent interface.
Dissolution Methods:
 two methods:-
Official methods Non official methods
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OFFICIAL METHODS:
Apparatus are used according to standards specified. The USP includes
seven apparatus design for drug release and dissolution testing of immediate
release and for oral dosage form, for extended release, enteric coated,
transdermal drug delivery system.
Methods are listed below:
Rotating basket method
Paddle method
Flow-through method
Reciprocating cylinder method
Paddle over disk method
Rotating cylinder method
Reciprocating disk method
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ADVANTAGES:
Infinite sink condition can be achieved hence low soluble
drugs studies can be done.
It is easy to change pH of media during test, avoiding
hot spots as seen in basket method.
Minimum dwell time, avoiding problems of degradation
of drug during process.
Ease of sampling and automation of data reduction.
Adaptability to current USP calibrators.
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DIS-ADVANTAGES:
Large volume of media is required.
Control of constant flow rate is difficulty.
Clogging results in damage to equipment.
Pump should produce pulse free flow.
Pressure may build up due to clogging hence
pressure transducer should used to regulate
pressure and to maintain constant flow rate.
9

NON- OFFICIAL METHODS:
Tracking of dissolution from different dosage form is
some times is not possible with the existing official
methods. So several non-official methods are designed for
dissolution testing. These includes,
Percutaneous absorption technique.
 Rotating bottle method for sustained release
dosage form.
 Dialysis system.
13

PERCUTENOUS ABSORPTION TECHNIQUE:
Percutaneous absorption is related to the absorption across the skin.
Percutaneous absorption methods are currently used to study transfer
kinetics through membranes.
These are useful in testing membrane characteristics and studying
absorption through skin.
These are generally use for patches, the patches generally mounted
in same position as the simulated skin membrane and serves as the
donor side of the system.
Some of the tech. that are used in percutaneous absorption
measurement includes side-by-side, the Franz cell, and flow through
cell design.
14

ROTATING BOTTLE METHOD:
This is probably the oldest method used for sustained
release dosage forms .
The system consists of 12 small bottle attached to a
horizontal shaft that rotates at a slow rate of 6-50 rpm.
The whole assembly is placed in a constant water bath.
Each bottle consists of 60 ml of dissolution fluid that is
decant through a 40-mesh screen after each sampling
period and is replaced by fresh fluid.
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DIALYSIS SYSTEM:
In this case very poorly soluble drugs, where perfect sink
condition would necessitate a huge volume of solvent with
conventional methods, a different approaches utilizing
dialysis membranes, was tried as a selective barrier
between the fresh solvent and the cell compartment
containing the dosage form .
It has been used with some success in case of other
dosage form such as suspensions, creams and ointments.
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# According to Food & Drug administration:
IVIVC is a predictive mathematical model describing the
relationship between an in-vitro property of a dosage
form and a relevant in-vivo response.
# According to FDA 1977 on bioavailability &
bioequivalence stated that dissolution test the preferred
in-vitro test should be correlated with in-vivo data.
17

 The in-vitro property is the rate or extent of drug
dissolution or release while the in-vivo response is the
plasma drug concentration or amount of drug absorbed.
 It establishes relationship between biological property
(pharmaco-dynamic effect & plasma drug concentration)
and physicochemical property of drug substance such as
dissolution rate.
 The in-vitro dissolution characteristics are dependent on
the physical properties of active pharmaceutical
ingredients, the drug dissolution, hydrodynamics of
dissolution apparatus & dissolution media.
 UNLESS THE INVITRO DISSOLUTION REFLECTS
THE INVIVO PERFORMANCE THE RESULTS
OBTAINED WILL HAVE NO RELEVANCE.
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1) To ensure batch to batch uniformity in physiological
performance by utilizing in-vitro experimental data.
2) To serve as a tool in developing new, efficacious and
safe dosage form.
3) It assumes great imp. Especially for such formulations
which contains drugs having narrow therapeutic
window (Eg: Diltiazem , carbamazepine& Nifedipine )
or variable therapeutic response (Eg: Theophylline,
digoxin etc.,)
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A) Pharmacological correlations based on
clinical observations.
B) Semi-quantitative correlation based on drug
blood level or urinary excretion data.
C) Quantitative correlation arising from
absorption kinetics & calculation of an in-
vivo absorption rate constants.
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 Simple point type
 Comparison of Profiles
 Simple Point Type: The percentage of drug
dissolved in a given time is correlated with the
bioavailability of the Drug product.
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In vivo Data
 Plasma concentration time profile.
 Pharmacokinetic parameters.
 Percent drug absorbed time profile.
 Statistical movement analysis.
In vitro Data
 Percent drug dissolution profile.
 Kinetic parameters.
 Percent drug dissolved time profile.
 Statistical movement analysis.
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In vivo Data In vitro Data
Plasma concentration time profile
Pharmacokinetic parameters.
Percent drug absorbed time profile.
Statistical movement analysis.
Percent drug dissolution profile.
Kinetic parameters.
Percent drug dissolved time profile.
Statistical movement analysis.

Plasma concentration time profile:
•Plasma concentration at time t.
•Peak plasma concentration (Cmax).
•Time taken for Cmax (tmax).

AUC0
t
, AUC0
∞
Time for a certain percentage of drug to reach
the blood such as t30%, t50%, t90%, etc.
Percent drug dissolution profile:
•Percent drug dissolved at time t.
•Maximum drug dissolved at tmax.
•Time taken for maximum amount of drug
to dissolve.
•Total amount of drug dissolved.
•Time for a certain percentage of drug to
dissolve such as t30%, t50%, t90%, etc.

Pharmacokinetic parameters:
•Absorption rate constant.
•Elimination rate constant.
•Absorption half life.
•Elimination half life.

Kinetic parameters:
•Dissolution rate constant.
•Dissolution half life.

Percent drug absorbed time profile:
•Percent drug absorbed at time t.
Percent drug dissolved time profile:
•Percent drug dissolved at time t.

Statistical movement analysis:
•Mean Residence Time (MRT).
Statistical movement analysis:
•Mean Dissolution Time (MDT). 23

 If a drug is absorbed completely after dissolution, a linear
correlation may be obtained and by comparing the percent drug
absorbed to the percent drug dissolved.
 In choosing the dissolution medium and use a slow dissolution
stirring rate so that invivo dissolution is approximated.
 Eg: The drug Aspirin is absorbed rapidly and completely from
GIT. Therefore a change in the dissolution rate from a dosage
form may be reflected in a change in the amount and rate if drug
absorption during the period of observation.
 Differences in the dissolution rates of dosage forms will be
reflected in the rate and extent of the drug only if the drug
absorption is dissolution rate limited.
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 If dissolution of the drug is rate limiting, a faster dissolution
rate may result in a faster rate of appearance of drug in the
plasma. It may be possible to establish a correlation
between rate of dissolution and rate of absorption of the
drug.
 The absorption is more difficult to determine then peak
absorption time. Therefore, the absorption time may be
used in correlating dissolution data to absorption data.
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 In the analysis of invitro invivo drug correlation rapid drug
absorption may be distinguished from the slower drug
absorption by observation of the absorption time for the
preparation.
 Eg: In study involving three sustained released Aspirin
products, the dissolution time for the preparations were
linearly correlated to the absorptions times for various
amounts aspirin absorbed.
 The results from this study demonstrated that aspirin was
rapidly absorbed and it was very much depended on the
dissolution rate for absorption.
26

Stage 1 IVIVC:
represents a point-to-point relationship between in
vitro dissolution rate and in vivo rate of the drug
from the dosage form.
 Superimposable absorption rate curves and
mathematical descriptions are similar
Alternative to in vivo method
Manufacturing method changes, formula
modification performed without in vivo data
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Stage 2 IVIVC
level B IVIVC utilizes the principles of statistical
moment analysis.
In this level of correlation, the mean in vitro
dissolution time (MDTvitro) of the product is
compared to either mean in vivo residence time
(MRT)
Not point to point correlation
This level is not reliable to justify changes in
manufacturing or formula changes
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Stage 3 IVIVC:
Single point correlation
Relates dissolution time with pharmacokinetic
property like AUC (AREA UNDER CURVE)
Helps to develop formulations
Stage 4 IVIVC: (multiple stage 4)
Amount of drug dissolved at different time intervals
can be correlated with many pharmacokinetic
parameters
Scale up and post approval changes(SUPAC) can
be made to the formulation
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 Subrahmanyam CVS ; Biopharmaceutics
pharmacokinetics; Delhi, Vallabh prakashan:2010.
 Brahmankar DM, Sunil B.Jaiswal;
Biopharmaceutics & Pharmacokinetics; Delhi,
Vallabh prakashan: 2015.
 Patrick J.Sinko, Martins; physical pharmacy &
pharmaceutical science; 5th
edition: 2006.
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Dissolution method and ivivc by ranjeet singh

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