Pharmaceutical Quality Control

Chapter # 04

EVALUATION OF SUSTAINED
ACTION PRODUCTS (TABLETS
&
CAPSULES)

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 Pharmaceutical Quality Control

Evaluation of Sustained Release Drug Delivery Systems.

INTRODUCTION
In the conventional therapy aliquot quantities of drugs are introduced into the system at
specified intervals of time with the result that there is considerable fluctuation in drug
concentration level as indicated in the figure.

HIGH

Low

What is Sustain Release Dosage Form?

“Drug Delivery system that are designed to achieve prolonged therapeutic effect by
continuously releasing medication over an extended period of time after administration of
single dose.”

 The basic goal of therapy is to achieve steady state blood level that is therapeutically
effective and non toxic for an extended period of time.
 The design of proper dosage regimen is an important element in accomplishing this
goal.
However, an ideal dosage regimen would be one, in which the concentration of the drug,
nearly coinciding with minimum effective concentration (M.E.C.), is maintained at a constant
level throughout the treatment period. Such a situation can be graphically represented by
the following figure ;
CONSTANT LEVEL

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Types of Dosage forms Based on Drug Release

A. Immediate release
B. Modified release
I. Delayed release
II. Extended release
III. Sustained release
IV. Controlled-release
V. Modified release
Dosage forms can be designed to modify the release of the drug over a given time or after
the dosage form reaches the required location.

Delayed release
Delayed-release dosage forms can be defined as systems which are formulated to release
the active ingredient at a time other than immediately after administration. Delayed release
from oral dosage forms can control where the drug is released, e.g. when the dosage form
reaches the small intestine (enteric-coated dosage forms) or the colon (colon-specific dosage
forms).

Extended release
Extended-release systems allow for the drug to be released over prolonged time periods. By
extending the release profile of a drug, the frequency of dosing can be reduced.

Controlled-release
Controlled-release systems also offer a sustained-release profile but, in contrast to
sustained-release forms, controlled-release systems are designed to lead to predictably
constant plasma concentrations, independently of the biological environment of the
application site. This means that they are actually controlling the drug concentration in the
body, not just the release of the drug from the dosage form, as is the case in a sustained-
release system. Another difference between sustained- and controlled-release dosage forms
is that the former are basically restricted to oral dosage forms whilst controlled-release
systems are used in a variety of administration routes, including transdermal, oral and
vaginal administration.

Sustained release
These systems maintain the rate of drug release over a sustained period. For example, if the
release of the drug from the dosage form is sustained such that the release takes place
throughout the entire gastrointestinal tract, one could reduce Cmax and prolong the time
interval of drug concentration in the therapeutic range. This in turn may reduce the
frequency of dosing, for example from three times a day to once a day. Sustained-release
dosage forms achieve this mostly by the use of suitable polymers, which are used either to
coat granules or tablets (reservoir systems) or to form a matrix in which the drug is dissolved
or dispersed (matrix systems).

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Plasma concentration v/s time curve

Benefits of Sustained Release Drug Delivery System

 Improved patient convenience and compliance due to less frequent drug
administration.
 Reduction in fluctuation in steady-state level and therefore better control of disease
condition.
 Increased safety margin of high potency drug due to better control of plasma levels.
 Maximum utilization of drug enabling reduction in total amount of dose
administered.
 Reduction in health care cost through improved therapy, shorter treatment period.
 Less frequency of dosing and reduction in personnel time to dispense, administer
monitor patients.
 Better control of drug absorption can be obtained, since the high blood level peaks
that may be observed after administration of a dose of high availability drug can be
reduced.
Demerits of Sustained Release Drug Delivery System
 Decreased systemic availability in comparison to immediate release conventional
dosage forms; this may be due to incomplete release, increased first-pass
metabolism, increased instability, insufficient residence time for complete release,
site specific absorption, pH dependent solubility etc.,
 Poor in-vivo, in-vitro correlation.
 Possibility of dose dumping due to food, physiologic or formulation variable or
chewing or grinding of oral formulation by the patient and thus increased risk of
toxicity.
 Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reaction.

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 The physician has less flexibility in adjusting dosage regimens. This is fixed by the
dosage form design.
 Sustained release forms are designed for the normal population i.e. on the basis of
average drug biologic half-life. Consequently disease states that alter drug
disposition, significant patient variation and so forth are not accommodated.
 Economics factors must also be assessed, since more costly processes and equipment
are involved in manufacturing many sustained release forms.
Types of Sustained Release Dosage Forms based on Route of
Administration

1. Oral forms
2. Parenteral forms
3. Common sustained action dosage forms
a) Spansules
b) Slow core release tablets
c) Multilayer tablets
d) Repeat action tablets
e) Liquid products
f) Transdermal system

Types of Oral Sustained Drug Delivery systems based on mechanism

of Release
1. Dissolution: 1.Matrix
2. Encapsulation
2. Diffusion: 1.Matrix
3. Combination of both dissolution & diffusion.
4. Osmotic pressure controlled system
Matrix Type
 Also called as Monolith dissolution controlled
system.
 Controlled dissolution by:
1. Altering porosity of tablet.
2. Decreasing its wettability.

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3. Dissolving at slower rate.

 First order drug release.

 Drug release determined by dissolution rate of polymer.
 Examples: Dimetane extencaps, Dimetapp extent abs.
Encapsulation
 Called as Coating dissolution controlled system.
 Dissolution rate of coat depends upon stability
& thickness of coating.
 Masks color, odor, taste, minimizing GI
irritation.
 One of the microencapsulation method is used.
 Examples: Ornade spansules, Chlortrimeton
Repetabs

Matrix Diffusion Types

 Rigid Matrix Diffusion
Materials used are insoluble plastics such as PVP & fatty

acids.

 Swellable Matrix Diffusion

1. Also called as Glassy hydrogels.Popular for sustaining

the release of highly water soluble drugs.

2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides

Examples: Glucotrol XL, Procardia XL

Matrix system

Rate controlling step:

Diffusion of dissolved drug in
matrix.

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Reservoir System
 Also called as Laminated matrix device.
 Hollow system containing an inner core surrounded in water insoluble membrane.
 Polymer can be applied by coating or micro encapsulation.
 Rate controlling mechanism - partitioning into membrane with subsequent release
into surrounding fluid by diffusion.
 Commonly used polymers - HPC, ethyl cellulose & polyvinyl acetate.
 Examples: Nico-400, Nitro-Bid

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Dissolution & Diffusion Controlled Release system

 Drug encased in a partially soluble membrane.
 Pores are created due to dissolution of parts of
membrane.
 It permits entry of aqueous medium into core &
drug dissolution.
 Diffusion of dissolved drug out of system.
 Ex- Ethyl cellulose & PVP mixture dissolves in
water & create pores of insoluble ethyl cellulose
membrane.

Osmotic Pressure Controlled System

 Provides zero order release
 Drug may be osmotically active, or combined with an osmotically active salt (e.g.,
NaCl).
 Semipermeable membrane usually made from cellulose acetate.
 More suitable for hydrophilic drug.
 Examples: Glucotrol XL, Procardia XL,
Equation

(Q/t) z = Pw Am/ hm (πs-πe )

 (Q/t)= Rate of zero order drug release.
 Pw, Am & hm= water permeability, effective surface
 area & thickness of semipermeable membrane.
 πs= osmotic pressure of saturated solution of
 osmotically active drug or salt in system.
 πe = osmotic pressure of GI fluid.

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Osmotically active system

 Two compartments separated by movable
partition.
 Osmotically active compartment absorbs
water from GIT.
 Creates osmotic pressure.
 Partition moves upward & then drug
releases.
 Ex: Nifedipine.

Stability Studies of sustained Release Dosage Forms

INTRODUCTION

STABILITY – THEORITICAL CONSIDERATION

Definition:-
The capacity of a drug or product to remain within established specifications of identity ,
quality, purity in a specific period of time.
OR
The capacity or the capability of a particular formulation in a specific container to remain
with in particular chemical , microbiological , therapeutically , and toxicological
specifications.
USP defines stability of pharmaceutical product as , “extent to which a product retains with
in specified limits and throughout its period of storage and use ( i.e. shelf life).

SHELF LIFE
It is defined as the time required for the concentration of the reactant to reduce to 90% of
its initial concentration .Represented as t90 and the units of time /conc.
t90 = (a-0.9a) = 0.1 a
ko ko

 Where , a = initial concentration .

o ko = specific rate constant for zero order reaction.
 (the time from the date of manufacture and packaging of the formulation until its
chemical or therapeutic activity is maintained to a predetermined level of labeled
potency and ,

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 its physical characteristic have not changed appreciably or deleteriously ).

TYPES OF STABILITY THAT MUST BE CONSIDERED FOR ANY DRUG

CHEMICAL
Each active ingredient retains its chemical integrity and labeled potency within the specified
limit.

PHYSICAL
The physical stability properties includes appearance, palatability ,uniformity ,dissolution
and suspend ability are retained.

MICROBIOLOGICAL
Sterility or resistance to microbial growth is retained according to specified requirement.

THERAPEUTIC
Therapeutic activity remains unchanged .

TOXICOLOGIC
No significant increase in toxicity occurs

REGULATORY REQUIREMENTS
 Stability study requirement and expiration dates are covered in the current GMP ,
USP and FDA
 GMP (Good Manufacturing Practice) states that there will be written testing program
design to access the stability characteristics of drug products . And result of such

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stability testing will be used to determine appropriate storage condition and

expiration dates
ICH GUIDELINES FOR STYABILITY TESTING

ICH GUIDELINES TITLE

Q1A Stability testing of new drug substances and products (second revision)
Q1B Stability testing : photo stability testing of new drug substance and
products.
Q1C Stability testing for new dosage forms
Q1D Bracketing and matrixing designs for stability testing of drug substances
and products
Q1E Evaluation of stability data
Q1F Stability data package for registration application in climatic zones III
and IV

LONG TERM STABILITY STUDIES :

According to WHO, long term stability testing during and beyond expected shelf life under
storage conditions in the intended market.

RECOMMENDED CONDITIONS FOR LONG TERM STABILITY

STORAGE CONDITIONS
TEMPERATURE (‘C) RELATIVE HUMIDITY% MINIMUM TIME
25’C+/- 2’C 60 +/- 5% 12 MONTHS
30’C +/- 2’C 30+/- 5% 6 MONTHS

ACCELERATED STABILITY STUDIES:

STORAGE CONDITIONS
TEMPERATURE (‘C) RELATIVE HUMIDITY% MINIMUM TIME
40’C +/- 2’C 75 +/-5% 6 MONTHS
 In , general the accelerated stability conditions must be at least 15’C above the
actual storage temperature and appropriate relative humidity . Substances and drugs
products intended to be stored in a refrigerator . the accelerated stability studies
should be carried out at 25+/-2’c and 60+/-5% relative humidity.
STABILITY IDENTIFYING ASSAYS
It is a quantitative analytical method which is based on the characteristic structural,
chemical, biological, properties of each active ingredient of drug product and that can
differentiate between active pharmaceutical ingredient and its degradation product
accurately.

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STABILITY INDICATING ASSAY DEVELOPMENT

Developing a stability indicating assay requires consideration of three aspects of the
method :

 Obtaining a representative SAMPLE.

 Choosing the separation techniques .
 Selecting the detectors .
OBTAINING A REPRESENTATIVE SAMPLE
Pure drug compound degrades into toxic compound.

Formulation ----degradation drug (toxic) + inert (non-toxic).

STABILITY INDICATING ASSAYS

PREPRATION OF SAMPLE
 Forced degradation .
 Purposeful degradation .
 Drug is subjected to acid , base , heat , light , or oxidation .
 Goal is to degrade the drug.
 It should include 10-20% degradation & greater than 10—20% could result in
secondary
 degradants that will complicate the development process.
 Dissolving portion of sample in 0.1 N hydrochloric acid for acid degradation and
collect sample at interval of 1,2,4,8,24 hrs.
 Similarly reaction is quenched in BASE .
 FOR OXIDATION (with peroxides), collect sample.
 Resulting sample is analyzed by measuring loss of parent drug .
 Auto sampler vials can also be used, injections at regular interval of 1hr.
 Observe sample change in time.
SEPERATION
 REVERSE PHASE CHROMATOGRAPHY is the method of choice for stability indicating
assays because the samples are generated in aqueous solutions . (non polar
stationary phase).
 We should choose gradient elution for sample screening.
 Most commonly used solvent type are - acetonitrile , methanol.
 Low and intermediate PH are generally obtained by use of phosphate buffer in the
PH 2.5 – 6.5 range.
 If method involve mass spectroscopy (MS) detector at same point ,select buffer that
are MS compatible such as 0.1 %trifluoroacetic acid .
 Column temperature (35—50’C).
 Core set of experiments should be 4runs for each sample.
 After the screening runs are completed .Now match the peaks between runs so that
each compound can be tracked as the conditions change.

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 Although each sample might contain only 4 or 6 significant degradants ,different

40degradation conditions can produce some of the same compounds in addition to
unique degradation.
THE DETECTORS
 The mass spectrometer is detector of choice for many liquid chromatography
methods ,particularly for biological.
 UV detector remains the detector of choice for stability indicating assay.
 Assay must be capable to determine sample within at least 1000 fold conc. . Range
from 0.1 to 0.05 % of the parent drug.
 MS detector can be very useful in identifying unknown peaks in the final method.
 DIODE ARRAY UV detector
 Often are used during the development of a stability indicating assay .
 Each compound could be detected at its absorbance maximum by using individual
maxima for routine detection.
 By collecting a UV SPECTRUM for each peak in the chromatogram , peak tracking
can be simplified.
 In addition to the specific stability tests that are required for the particular dosage
form, the stability study should include assays for the release pattern of the active
ingredient. Because of the nature of these types of drugs, drug release patterns or
rates should be measured by dissolution tests. When microencapsulated sustained-
release dosage forms are to be studied, measurement of the capsule particle size
range distribution, including ratios of core to wall thickness, may be necessary.
Evaluation of Sustained Release Drug Delivery System
 Drug release is evaluated based on drug dissolution from dosage form at different
time intervals.
 Specified in monograph.
 Various test apparatus and procedures – USP, Chapter <724>.
Two types
 In vitro evaluation
 In vivo evaluation
In vitro evaluation :
 Acquire guidelines for formulation of dosage form during development stage before
clinical trials.
o Kinetics or rate of drug release from the dosage form can be measured in
simulated gastric and intestinal fluids.
 Necessary to ensure batch to batch uniformity in production of a proven dosage
form.
o Obtain in vitro / in vivo correlation
In vitro quality control tests include:
 Rotating basket (apparatus 1)
 Paddle (apparatus 2)
 Modified disintegration testing apparatus (apparatus 3)

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 At a specified time intervals measurement of drug is made in simulated gastric fluid /

intestinal fluid.
- 2 hrs in gastric fluid and 6 hrs in intestinal fluid

Data is analysed to see

 Dose dumping i.e., Maintenenance dose is released before the period is completed.
 Dose that is unavailable is not released in G.I.T.
 Release of loading dose.
 Unit to unit variation, predictability of release properties.
 Sensitivity of the drug to the process variables
 Composition of the simulated fluid
 Rate of agitation
 Stability of the formulation
 Ultimately does the observed profile fit expectations.
Other apparatus specific for SR evaluations
 Rotating bottle
 Stationary basket / rotating filter
 Sartorius absorption and solubility simulator
 Column-type flow through assembly
Rotating bottle method:

Samples are tested in 90 ml bottles containing 60 ml of fluid which are rotated end over end
0
in a 37 C bath at 40 rpm.

Sartorius device

Includes an artificial lipid membrane which separates the dissolution chamber from
simulated plasma compartment in which the drug concentration are measured or dialysis
membrane may be used.

Advantages:

Measure release profile of disintegrating dosage units such as powder materials,

suspensions, granular materials, if permeability is properly defined

Column flow through apparatus

 Drug is confined to a relatively small chamber in a highly permeable membrane
filters.
 Dissolution fluid might be re-circulated continuously from the reservoir allowing
measurement of cumulative release profile.
 Duration of testing 6-12hrs.
Media used:

 Simulated gastric fluid or pH 1.2

 Simulated intestinal fluid pH 7.2
 Temperature 37oC

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 If required bile salts, pancreatin and pepsin can be added.

Example-
Specifications for Aspirin Extended- release Tablets
Time (hr) Amount Dissolved
1.0 Between 15% and 40%
2.0 Between 25% and 60%
4.0 Between 35% and 75%
8.0 Not less than 70 %

Mathematical Models to Explain Release from SR Drug

Delivery System Models
• ZERO-ORDER
• FIRST-ORDER
• HIGUCHI ORDER
• HIXSON-CROWELL
• WEIBULL ORDER
• KORSMEYER-PEPPAS ORDER
• CONCLUSION
• REFERENCES

 Drug release: It is a process by which a drug leaves a drug product and is

subjected to ADME and eventually becoming available for pharmacological
action.
 Mathematical models are based on different mathematical functions, which
describe the dissolution profile.
 It includes the zero, first, higuchi, korsmeyer-peppas, hixson-crowell, weibull etc

ZERO ORDER MODEL

Drug dissolution from dosage forms that do not disaggregate and release the drug slowly
can be represented by equation:

QO-QT=Kot
QO=initial amout of drug in the pharmaceutical dosage form.

QT= amout of drug in the pharmaceutical dosage form in time t

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Ko=zero order release constant

t= time period

ft=Kot

Ft=fraction of drug release time t &ko apparent

relsease constant.

Application –modified

release pharmaceutical

dosage form
Like coated form, osmotic system, transdermal system etc.
Example: Ibuprofen sustain release
Graph is plotted between cumulative % drug release on Y-axis and time on X-axis

FIRST ORDER MODEL

 This model is used to describe absorption and/or elimmination of some drug,
although it is difficult to conceptualize this mechanism on a theoretical basis.
 The release of drug which followed first order kinetics can be expressed by
equation:
k1t
Q =Q e-
t o

Qt=amount of drug release in time t.

Qo=initial amount of drug
k rate constant.
1
Drug release proportional to amount of drug remaining

 Application-water soluble drug in porous matrix (mule&turco,1995.)

 Graph is plotted between log % drug remaining vs time

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HIGUCHI MODEL
First example of mathematical model aimed to
describe drug release from a matrix system was
proposed by huguchi in 1961.
Model based on hypotheses that-
 Intial drug concentration in matrix is much higher than drug solubility
 Drug diffusion takes place only one dimension
 Drug particles are much smaller than system thickness
 Drug diffusivity is constant.
 Perfect sink conditions are maintained
 Higuchi describe drug release as a diffusion process based in fick’s law,squre root
of time denpendent.
According to model expression:

f =Q=A√D(2C-Cs)Cst
t
where,
 Q is the amount of drug released in time t by surface unity,
 C is the initial concentration of the drug,
 Cs is drug solubility in matrix media
 D is diffusivity of drug molecules in matrix substances
To study the dissolution from a planar heterogeneous matrix system, where the drug
concentration in the matrix is lower than its solubility and the release occurs through
pores in the matrix, the obtained relation was the following
f =Q=√Dє(2C-єCs)Cst/Ґ
t

Where,
 Q is the amount of drug released in time t by surface unity,
 C is the initial concentration of the drug,
 є is the matrix porosity,
 Ґ is the toruosity factor of the
capillary system,
 C is the drug solubility in the
matrix / s excipient media and D
the difussion constant
 Application: Water soluble drugs
 Low soluble drug incorporated
in semi solid /solid polymer
matrix.
A graph is plotted between
cumulative % drug release vs √T

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WEIBULL MODEL
Describes for different dissolution process as equation

m=1-exp b
[-(t-T ) /a]
i

Where,
M=amount of drug dissolved
Mo=total amount of drug being released
t = time
T =lag time
a = scale parameter describes,time dependence
b = shape of dissolution curve progession
Application: useful for comparing the release properties of matrix type drug delivery.
Limitations:
 there is not any kinetic fundament and could only describe, but does not
adequately characterize the dissolution kinetics properties of drug.
 There is not any single parameter related with the intrinsic dissolution rate of the
drug.
 It is not limited use for establishing in-vivo in-vitro correlation.
 A graph is plotted between log drug release vs log tine
HIXSON-CROWELL MODEL
• Hixson-crowell recognised that the particles regular area is proportional to the
cube root of its volume
They derived the equation:
1/3 1/3
W0 – Wt =K t
s

Where, Wo is the initial amount of drug in

dosage form,
• Wt is the remaining amount of
drug t in the dosage form at
time t and Ks is a constant
incorporating the surface–
volume relation.
It describes the drug release by dissolution
and considers the surface area and
geometrical shape of dissolving entity.

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This model used to describes the release profile keeping in mind the diminishing surface of
drug particles during dissolution.
 A graph is plotted between cube root of drug % remeaining vs time

KORSMEYER-PEPPAS MODEL
 Koremeyer et all derived a simple relationship which described drug release from
a polymeric system equation.
 To find out the mechanism of drug release, first 60% drug release data were
fitted in peppas model

According to model the equation:

n
M /M =kt
t ∞
Where,
n is the release exponent, indicative of the drug release mechanism, and the function of t is
M /M fractional release of drug.
t ∞
Application-This model is generally used to analyse the release of pharmaceutical polymeric
dosage forms, when the release mechanism is not well known or when more than one
type of release phenomena could be involved.
A graph is plotted between log cumulative % drug release vs log time

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In this model, n value characterizes the release mechanism of drug

Release exponent Drug transport mechanism Rate as function of time
(n)
0.5 Fickian t -0.5

0.45<n=0.89 Non-Fickian t n-1

0.89 Case 2 Zero order release

>0.89 Super case 2 t n-1

RELEASE KINETIC MODELS

In vivo evaluation
 A clinical trial, testing the availability of the drug being used in the form prepared by
noting its effect versus time.
 Preliminary in vivo testing of formulation carried out in a limited number of carefully
selected subjects based on
- Similar body built, size, occupation, diet, activity and sex.
- A single dose administered and effect measured over time (24hrs)
- Test may or may not be blind and cross over design.
Evaluation of In-Vivo Bioavailability Data
 A properly designed in-vivo bioavailability study is performed. The data are then
evaluated using both pharmacokinetic and statistical analysis methods. The
evaluation may include a pharmacokinetic profile, steady-state plasma drug
concentrations, rate of drug absorption, occupancy time, and statistical evaluation of
the computed pharmacokinetic parameters

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Pharmacokinetic Profile
 The plasma drug concentration–time curve should adequately define the
bioavailability of the drug from the dosage form. The bioavailability data should
include a profile of the fraction of drug absorbed (Wagner–Nelson) and should rule
out dose dumping or lack of a significant food effect. The bioavailability data should
also demonstrate the extended-release characteristics of the dosage form compared to
the reference or immediate-release drug product.
IN VITRO IN VIVO CORRELATIONS FOR SUSTAINED RELEASE DOSAGE
FORMS
 In vitro dissolution: It’s a process of release of drug from dosage form as measured in
an in vitro dissolution apparatus
 In vivo dissolution: process of dissolution of drug in the GI tract.
 Correlation: relationship between in vitro dissolution rate and in vivo absorption rate
as used in bio-equivalence guidance
 IVIVC has been defined as “a predictive
 mathematical model describing the relationship between an in-vitro property of a
dosage form and an in-vivo response”
Significance of ivivc
 The main objective of developing and evaluating an IVIVC is to enable the dissolution
test to serve as a surrogate. It reduces the number of bio-equivalence required for
approval as well as during scale up and post approval changes (SUPAC).
 IVIVC shortens the drug development period, economizes the resources and leads to
improved product quality.
 A means of assuring the bioavailability of active ingredients from a dosage form.
 Supports and or validates the use of dissolution methods and specifications
 IVIVC assists in supporting biowaivers.
Parameters for correlations

SL. No. IN VITRO INVIVO

1. Dissolution rate Absorption rate (or absorption

time)
2. Percent drug dissolved Percent of drug absorbed
3. Percent drug dissolved Maximum plasma
concentration, C
max

4. Percent drug dissolved Serum drug concentration, C

p

Dissolution rate versus absorption rate

If dissolution of drug is rate limiting step, the faster the dissolution rate, the faster is the rate
of appearance of drug in the plasma. Therefore, absorption time and dissolution time may be
considered for correlation

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Figure 1: In vitro-in vivo correlations-Dissolution

time Vs absorption time of three sustained
release products

Percent of drug dissolved versus percent of

drug absorbed:
. Appropriate dissolution medium and a slow stirring rate
during dissolution should be considered to mimic in vivo
dissolution.
. If the drug is absorbed completely after dissolution, a
linear correlation may be obtained by comparing the
percent drug absorbed to the percent drug dissolved.

Percent of drug dissolved versus maximum plasma concentration:

 A poorly formulated drug may not be completely dissolved and released, resulting in
lower plasma drug concentration.
 The percentage of drug released at any time interval will be greater for more
bioavailable drug product, the peak serum concentration will be higher for the drug
that shows highest percent of drug dissolved.

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Serum drug concentration versus percent of drug dissolved

 In a study on aspirin absorption, serum concentration of aspirin was correlated to
percent of drug dissolved using an in vitro dissolution method
 Dissolution of drug is rate limiting step, and various formulations with different
dissolution rates has difference in serum concentration of aspirin

Levels of correlation
 Level A Correlation
 Level B Correlation
 Level C Correlation
 Multiple Level C Correlation
1. Level A correlation
 It is estimated by two step method,
deconvolution followed by comparison of
fraction of drug absorbed to the fraction of
drug dissolved.
 Defines a direct relationship between in vivo
data such that measurement of in vitro
dissolution rate alone is sufficient to determine
the biopharmaceutical rate of the dosage
form.
 An in vitro dissolution curve can serve as a
surrogate for in vivo performance

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2. Level B correlation:
 Level B correlation utilizes the principles of
statistical moment analysis.
 Mean in vitro dissolution time (MDT ) of the
vitro
product is compared to mean in vivo
residence time (MRT).
 MRT may be calculated as the ratio of the
area under the first moment curve (AUMC) to
the AUC, where AUMC is the area under the
curve observed for the product of time and
concentration versus time.

3. Level C correlation
 Level C correlation represents a single point correlation.
 One dissolution time point (t , t , etc.) is compared to one mean pharmacokinetic
50% 90%
parameter such as AUC, t or C .
max max
 Weakest level of correlation as partial relationship between absorption and dissolution
is established.

Multiple level C correlations

 Multiple Level C correlation relates one or several pharmacokinetic parameters of
interest (C , AUC, or any other suitable parameters) to the amount of drug dissolved
max
at several time points of the dissolution profile.
 Its correlation is more meaningful than that of Level C as several time points are
considered.

Development of in vivo/ in vitro correlation

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 Pharmaceutical Quality Control

Refrences:-
Sir, Fahad Pervaiz Lectures.
Compiled by:-
Faizan Akram
4th Prof (Eve)

Keep Praying & Keep Reading with Smiling……

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