BIOPHARMACEUTICS CONSIDERATION IN
DRUG PRODUCT DESIGN AND IN VITRO

DRUG PRODUCT PERFORMANCE

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CONTENTS

✓DISSOLUTION AND DRUG RELEASE TESTING

▪COMPENDIAL METHODS

▪ALTERNATIVE METHODS

▪MEETING DISSOLUTION REQUIREMENT

▪PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION
TESTING PERFORMANCE OF DRUG PRODUCT

▪DISSOLUTION PROFILE COMPARISONS

✓IN VITRO – IN VIVO CORRELATION

✓DRUG PRODUCT STABILITY

✓CONSIDERATION IN THE DESIGN OF A DRUG
PRODUCT

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DISSOLUTION AND DRUG RELEASE
TESTING

• DEFINITION :

• Dissolution and drug release test are in-vitro tests that measure
the rate and extent of dissolution or release of the drug substance
from the drug product usually in an aqueous medium under
specified conditions .

• OBJECTIVE:

• In-vitro studies used for monitoring the drug product stability &
manufacturing process control.

• Confirm batch-to-batch reproducibility and to show variability in
composition and manufacturing parameters.

• Relevant changes in the drug product formulation or changes in
the manufacturing process

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• It is important quality control components for the manufacture
of the drug products.

• Provide valuable information during formulation development
(i.e. salt form selection, excipient selection, etc).

• Each dissolution method is specific for the drug product and its
formulation & developing optimal dissolution parameters, a
variety of conditions (i.e. apparatus, media pH, etc) should be
explored.

• Major requirement for Scale-up and Post Approval Changes
(SUPAC). Establish drug product stability.

• Establish in vivo–in vitro correlations (IVIVC.)

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COMPENDIAL DISSOLUTION TEST APPARATUS
USP DESCRIPTOIN ROT. DOSAGE FORM
APP. SPEED

Type 1 Basket apparatus 50-100rpm Conventional, chewable, CR
formulation, capsules.

Type 2 Paddle apparatus 25-75rpm ʺ

Suspensions

Type 3 Reciprocating 6-35rpm CR, chewable.
cylinder

Type 4 Flow through cell N/A Implants , poorly soluble
apparatus API, powder, granules.

Type 5 Paddle over disk 25-75rpm Transdermal formulation

Type 6 cylinder N/A ʺ

Type 7 Reciprocating disk 30rpm CR( non disintegrating oral
formulation transdermal

formulation)
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APPARATUS 1- BASKET APPARATUS

➢Vessel- made up of borosilicate glass, hemispherical bottom.

➢Capacity-1000ml

➢Shaft –stainless steel 316,100 rpm

➢Temperature – 37±0.50 C

➢Use – tablets, capsules, delayed release suppositories

➢Advantages- Easily automated

➢Disadvantages- Basket screen clogged with gummy particles

Mesh gets corroded by HCl solution.

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APPARATUS 2 – PADDLE APPARATUS

➢Vessel –Same as basket apparatus

➢Shaft – The blade passes through the bottom of shaft

➢Stirring elements- Made of teflon, stainless steel 316

➢Temp – 37±0.50 C

➢Sinkers- used to prevent tablet/capsules from floating dosage

➢Advantage – Easy to use, robust, easily automated

➢Disadvantage- pH / media change is often difficult

Sinkers for floating dosage forms

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APPARATUS 3 – RECIPROCATING CYLINDER

➢ Vessel -set of cylindrical flat bottomed glass vessel with glass
reciprocating cylinders.

➢Stainless steel fittings, screens-

made of suitable non adsorbing

nonreactive material

(poly propylene)

➢Temperature- 37±0.50 C

➢Volume – 200-250ml

➢Agitation speed 5-35 dips/min

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➢The dosage unit is placed in reciprocating cylinder & the
cylinder is allowed to move in upward and downward
direction constantly. Release of drug into solvent within the
cylinder vessel.

➢ Use :Tablets, controlled release bead-type formulations.

➢ Advantages:

1) Easy to change the pH-profiles.

2) Hydrodynamics can be directly influenced by varying the
dip rate.
➢ Disadvantages:

1) Small volume (max. 250 ml).
2) Little experience.

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APPARATUS 4 – FLOW THROUGH CELL

The assembly consists
➢ Reservoir – For dissolution medium
➢ Pump – holding a sample, pump forces the dissolution medium

upwards flow through the cell holding the test sample.
➢Flow rate – 4,8,16ml /min
➢Dissolution Medium -37 ± 0.50c.
➢Flow through cell –transparent

-mounted vertically with filter,
-Prevent –escape of undissolv particles
-Bottom cone- filled with small
glass beads(1mm)

➢Use – low solubility drugs,
micro particulates,
implants, suppositories

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APPARATUS 5 – PADDLE OVER DISK

➢Use the paddle and vessel assembly from Apparatus 2 with the
addition of a stainless steel disk assembly designed for holding
the transdermal system is placed at the bottom of the vessel.
➢ Useful for: Transdermal patches
➢ Standard volume: 900 ml

➢Advantages:

Less expensive

➢Disadvantages:

Disk assembly restricts the patch size.

17 mesh is standard (others available ).

Accommodates patches of up to 90mm.

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➢The disk assembly holds the transdermal system flat and
is positioned such that the release surface is parallel with
the bottom of the paddle blade.

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APPARATUS 6 – CYLINDER

➢Vessel- same as APP 1 in the place of basket, cylinder is used.

➢Temperature – 32°C ± 0.5°C

➢Sample – mounted to cuprophan (inner porous cellulosic
material)

➢Use – reservoir transdermal patches

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APPARATUS 7 – RECIPROCATING HOLDER

➢Vessel- flat bottomed cylindrical vessel

➢Sample – placed on the shaped holders

➢Temperature –32°C ± 0.5°C

➢Speed- 20-50 dpm

➢Advantage-

Sink conditions can be maintained

More sensitivity

➢Disadvantages- investment is high

because the design is totally different

from standard equipment.

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➢USE:

➢Used for transdermal patches and solid oral dosage forms.

➢It is particularly used for the drug release from osmotic
pumps and extended release tablets.

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ALTERNATIVE METHODS OF
DISSOLUTION TESTING

1.ROTATING BOTTLE METHOD

• Its mainly for controlled-release beads.

• The equipment consists of a rotating rack that holds the sample
drug products in bottles.

• The bottles are capped tightly and rotated in a 37°C temperature
bath.

• At various times, the samples are removed from the bottle,
decanted through a 40-mesh screen, and the residues are
assayed.

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• An equal volume of fresh medium is added to the remaining
drug residues within the bottles and the dissolution test is
continued.

• A dissolution test with pH 1.2 medium for 1 hour, pH 2.5
medium for the next 1 hour, followed by pH 4.5 medium for
1.5 hours, pH 7.0 medium for 1.5 hours, and pH 7.5 medium
for 2 hours was recommended to simulate the condition of the
gastrointestinal tract.

Disadvantage :

• It is manual and tedious.

• Less popular

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2.INTRINSIC DISSOLUTION METHOD :

• Most methods for dissolution deal with a finished drug
product sometimes new drug or substance.

• The dissolution of a drug powder by maintaining a constant
surface area is called intrinsic dissolution.

• Intrinsic dissolution is usually expressed as mg/cm2/min.

• 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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INTRINSIC DISSOLUTION METHOD APPARATUS

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3.PERISTALSIS METHOD :

• This method attempts to simulate – hydrodynamic conditions
of the gastrointestinal tract in an in vitro dissolution device.

• The apparatus consists of a rigid plastic cylindrical tube fitted
with a septum and rubber stoppers at both ends.

• The apparatus is placed in a beaker containing the dissolution
medium. The dissolution medium is pumped with peristaltic
action through the dosage form.

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4.DIFFUSION CELL (FRANZ
DIFFUSION CELL )

• Used to in vitro drug release and
drug permeation kinetics for
topically applied dosage form such
ointment, cream, transdermal drug
product.

• Used for characterizing drug
permeation through a skin model

• The source of skin – cadaver skin or
animal skin (eg.- hairless mouse
skin).

• Carried out at 32˚C.

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MEETING DISSOLUTION REQUIREMENTS

• Dissolution test times and specification are usually established
on the basis of an evaluation of dissolution profile data.

• USP-NF sets dissolution requirements for many products

Stage Number Acceptance criteria
tested

S1 6 Each unit is not less than Q+5%

S2 6 Average of12 unit (S1+ S2 ) is equal to or greater than Q &
no unit is less then Q – 15%

S3 12 Average of 24 units( S1, S2 & S3 ) is equal to or greater than Q,
not more then 2 unit are less than Q-15%,& no unit is less
than Q-25%

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• Q- the amount of drug dissolved within a given time period
& its expressed as a percentage of label content.

• Q -specified in the monograph for drug product pass the
dissolution test.

• Three stages (S1, S2 & S3) of testing are allowed by USP.

• Initially 6 tablet or capsules are tested for the dissolution test.

• If the dissolution test fail to meet the criteria for S1, then six
more units are tested.

• Dissolution test continues until the dissolution criteria are met
or until three stages are exhausted.

• New product, setting the dissolution specification requires a
through consideration of the physical & chemical properties
of the drug ensure consistent bioavailability of the product.

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PROBLEMS OF VARIABLE CONTROL IN
DISSOLUTION

• Dissolution process is complex -steps such as

➢solid–liquid mass transfer,

➢particle erosion, possible particle disintegration,

➢particle suspension, and particle–liquid interactions

• other factors such as shear stress distribution as a function of
tablet location within the apparatus. Variations may occur with
the same type of equipment and procedure.

• The centering and alignment of the paddle is critical in the
paddle method.

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• Turbulence can create increased agitation, resulting in a higher
dissolution rate.

• Wobbling and tilting due to worn equipment should be
avoided.

• The basket method is more sensitive to clogging due to
gummy materials

• 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, the selection of diss method is
based on the type of drug product to be tested. eg:low density
prep may be poorly wetted in the basket method, gummy prep
–clog up the basket so paddle preferred

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• Small variations in the location of the tablet on the vessel
bottom-result in significantly different velocities and velocity
gradients near the tablet.

• Experiments were conducted using paddle apparatus by
placing (aligned to the walls) a metal strip (1.7 mm thick ×
6.4 mm wide) to evaluate the effect of variable
mixing/stirring and flow pattern in a drug dissolution vessel.

• Significantly higher dissolution results with vessels
containing metal strip than without.

• Floating dosage form (suppository)- placed – stainless steel
coil sinkers-so that it remain –bottom of flask.

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IN VITRO IN VIVO CORRELATION

• In vitro in vivo correlations (IVIVC) play a key role in the
drug development and optimization of formulation

• IVIVC can be used in the development of new
pharmaceuticals to reduce the number of human studies
during the formulation development.

• Thus, the main objective of an IVIVC is to serve as a
surrogate for in vivo bioavailability and to support
biowaivers.

FDA Definition:

• In vitro-in vivo correlation is defined as the predictive
mathematical model that describes the relationship between
in vitro property ( rate and extent of dissolution ) of dosage
form and an in vivo response (plasma drug conc. Or amount
of drug absorbed).

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PARAMETERS FOR CORRELATION

In vitro dissolution In vivo plasma data

Time for specific amount of AUC, Cmax

drug to dissolve

Percentage drug dissolution
Plasma conc, Time profile

profile

Mean dissolution time MRT,MAT,MDT

Parameter estimated after Concentration at time t,
modeling the dissolution amount absorbed at time t.
process

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LEVELS OF IVIVC

• Five correlation levels have been defined in the IVIVC
FDA guidance .

• The concept of correlation level is based upon the ability
of the correlation to reflect the complete plasma drug
level-time profile .

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LEVEL A

• The highest category of correlation.

• It represents a point-to-point relationship between in vitro
dissolution & in vivo absorption.

• The in vitro dissolution and in vivo absorption rate curves are
super imposable.

• Utilizes all the dissolution and plasma level data available to
develop correlation.

• Most informative and useful from a regulatory perspective

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LEVEL B CORRELATION:

• Utilizes the principles of statistical moment analysis.

• The mean in-vitro dissolution time (MDT) is compared either to
mean in-vivo residence time (MRT) or the mean in vivo
dissolution time (MDT).

• It does not reflect the actual in vivo plasma level curve

• It is not considered as a point-to-point correlation .

• Reason : because a number of different in vivo curves will
produce similar MRT values.

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Limitations

• Level B correlation is not unique, because MRT remains
same, though the shape of in vivo curves are different.

• Therefore it fails to justify the formulation modifications.

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LEVEL C CORRELATION:

• It is single point correlation.

• In this level of correlation, one dissolution time point (t50%,
t90%, etc.) is compared to one mean pharmacokinetic
parameter such as AUC, tmax or Cmax

• This is the weakest level of correlation as partial relationship
between absorption & dissolution is established.

• This level does not reflect the complete shape of the plasma
concentration-time curve.

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• Useful in early formulation development and in-process
quality control procedure.

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MULTIPLE LEVEL C CORRELATION:

• Relates one or several pharmacokinetic parameters to the
amount of drug dissolved at several time points.

• Based on at least three dissolution time points covering the
early, middle, and late stages of the dissolution profile.

LEVEL D CORRELATION:

• It is a qualitative analysis and rank order correlation and is not
considered useful for regulatory purpose.

• It is not a formal correlation but serves as an aid in the
development of a formulation or processing procedure.

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BCS & IVIVC

• The BCS is a fundamental guideline for determining the
condition under which IVIVC are expected.

• According to BCS, in vivo bioavailability & bioequivalence
studies not be conducted for drug product under following
circumstances

➢Rapid & similar dissolution.

➢High solubility.

➢High permeability.

➢Wide therapeutic window

➢Excipients used in dosage form are same as those present
in approved drug product

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Class Solubility Perme IVIVC expectation for Predicting
-ability immediate release product IVIVC from

dissolution data

I High High If dissolution rate is slower than Yes
gastric emptying rate, otherwise
limited or no correlation

II Low High IVIVC is expected if in vitro Yes
dissolution rate is similar to in
vivo dissolution rate, unless dose
is very high

III High Low Absorption (permeability) is rate No
determining & limited or no
IVIVC with dissolution rate

IV Low Low Limited or no IVIVC is expected No
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DISSOLUTION PROFILE COMPARISONS

• Dissolution profile comparisons are used to assess the similarity of
the dissolution characteristics of two formulation or different
strengths of the same formulation to decide whether in vivo
bioavailability/ bioequivalence studies required.

Method for comparison of dissolution profile:

• A model independent method for comparison of two dissolution
profiles is based on determination of difference factor f1 and
similarity factor f2 which are calculated using following formula:

 n 
 Rt −Tt 

f  t=1 1 = × 100
 n 
 Rt 
 t=1 

 −0.5 
 1 n  

f2 = 50 × log 1+  ( − )  100
 wt Rt Tt 
 n r=1  

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where,

n = number of dissolution time points

Rt =dissolution value of reference drug product at time t

Tt = dissolution value of test drug product at time t

Difference factor Similarity factor Inference
f1 f2

0 100 Dissolution profile
are identical

≤15 ≥50 Similarity or
equivalence of two
profiles

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• Similarity factor : comparison of closeness of two formulation

• The similarity factor (f2) is determined by comparing the
dissolution profiles of 6–12 units each of the test and reference
products.

• Value 100 – two groups are identical

value 0 – dissimilarity increases

• For this calculation, three to four or more dissolution time
points should be available.

• The dissolution measurements of the test and reference batches
should be performed under exactly the same conditions.

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DRUG PRODUCT STABILITY

• It defines as extent to which a product retains with in specified
limits and throughout its period of storage and use.

• It defines time period for which product quality, safety, and
effectiveness are assured and product still meets its specification.

• It is usually determined by testing a variety of stability indicating
attributes – drug potency, impurities, dissolution, and other
relevant physicochemical measures.

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• Stability studies are generally performed under well-controlled
storage and testing conditions.

• Provide evidence – how the quality of a drug product varies
with time under the influence of a variety of environmental
factors such as temperature, humidity, oxygen, and light

• The time period during which a drug product is expected to
remain within the established product quality specification
under the labeled storage conditions is generally termed shelf
life or expiry date

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GENERAL CASE

Study Storage Condition Minimum Time period
covered by data at
submission

Long-term 25 °C ± 2 °C/60% RH ± 5% RH or 12 months or 6
30 °C ± 2 °C/65% RH ± 5% RH or months
30 °C ± 2 °C/75% RH ± 5% RH

Intermediate 30 °C ± 2 °C/65% RH ± 5% RH 6 months

Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months

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Proposed criteria and long-term testing conditions

Climatic zone Definition Long-term testing
pressure conditions

I Temperate climate 21 °C / 45% RH

II Subtropical and 25 °C / 60% RH
Mediterranean
climate

III Hot and dry climate 30 °C / 35% RH

IVA Hot and humid 30 °C / 65% RH
climate

IVB Hot and very humid 30 °C / 75% RH
climate

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CONSIDERATION IN THE DESIGN OF A DRUG
PRODUCT

1.Pharmacodynamic considerations

• Therapeutic objective

• Toxic effects

• Adverse reactions

2.Drug considerations

• Chemical and physical properties of drug

3.Drug product considerations

• Pharmacokinetics of drug

• Bioavailability of drug

• Route of drug administration

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• Desired drug dosage form

• Desired dose of drug

• Dosing frequency

4.Patient considerations

• Compliance and acceptability of drug product

• Cost

5. Manufacturing considerations

• Cost

• Availability of raw materials

• Stability

• Quality control

• Method of manufacturing Patents

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1.PHARMACODYNAMIC CONSIDERATIONS

• It is the study of the effect of a drug in the body and its
mechanism of action.

• Therapeutic consideration desired:

Pharmacodynamic and pharmacological properties of the drug,
(including the desired therapeutic response, type and frequency
of adverse reactions to the drug).

• The therapeutic objective influences -design of the drug product
to be manufactured.

• In the case of acute illness –drug release – rapid, quick absorb

• Eg: nitroglycerin and chronic disease-asthma

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2. DRUG CONSIDERATION

• The physicochemical properties of the drug substance -major
factors -controlled or modified by the formulator.

• Such as solubility, stability, chirality, polymorphs, solvate,
hydrate, salt form, ionizable behavior, and impurity profile.

influence

type of dosage form, formulation, manufacturing process.

• Physical properties of the drug

intrinsic dissolution rate, particle size, and crystalline form

Influenced by

methods of processing and manufacturing.

• If the drug has low aqueous solubility – intravenous injection
(salt form)

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3.PATIENT CONSIDERATION

• The drug product and therapeutic regimen -acceptable to the
patient.

• Poor patient compliance

result from

poor product attributes, (difficulty in swallowing,

disagreeable odor, bitter taste, unusual dosage requirement)

• Pharmacodynamic factors (side effects or allergic reaction)

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4.DRUD PRODUCT CONSIDERATION

Pharmacokinetics of the drug:

• Knowledge of the pharmacokinetic profile :

➢important to estimate the dose and dosage regimen of the drug
product & release rate, that will maintain a desired drug level in
the body.

• Therapeutic window determines the desired plasma drug
concentration that will effect with minimal adverse effect.

• Drug concentration higher than therapeutic window (MEC) –
cause more intense pharmacodynamic or toxic response.

• Drug concentration lower than therapeutic window- may be sub
therapeutic.

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Bioavailability of the drug:

• Penicillin G – unstable in acid medium stomach . Addition of
buffering in formulation or use of an enteric coating on the
dosage form will protect the drug from degradation at a low
pH

• If oral drug bioavailability is poor due to metabolism by
enzymes in the gastrointestinal tract or liver, – need higher
dose or alternative route of drug administration. Eg.
Nitroglycerin, insulin.

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Dose consideration:

• The size of the dose in the drug product -based on the inherent
potency of the drug & its apparent volume of distribution –
which determine the target plasma drug concentration.

• In the presence of renal or liver impairment, the drug
metabolism or excretion process may be altered requiring
smaller dose.

• Eg. Phenobarbitone, Morphine.

• The size and the shape of a solid oral drug product are
designed for easy swallowing. Eg. capsule-shaped tablet
(caplet) easier to swallow than a large round tablet.

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Dosing frequency

• Related clearance of the drug & target plasma drug concentration.

• Drug has rapid clearance from the body – the drug given more
frequently.

Route of drug administration

• The route of drug administration affects bioavailability of the
drug, thereby affecting the onset, duration, and intensity of the
pharmacological effect (efficacy and safety).

• In the design drug dosage form, the pharmaceutical manufacturer
must consider:

➢ intended route of administration, size of the dose.

➢ anatomic and physiologic characteristics such as membrane
permeability and blood flow) physicochemical properties(pH,
osmotic pressure, and presence of physiologic fluids).

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REFERENCES

• D. M. Brahmankar, Sunil B.Jaiswel, Biopharmaceutics and
Pharmacokinetics.

• Somnath sakore,Bhaswat Chakraborty. invitro –in vivo
correlation(IVIVC).A strategic tool in Drug
Development.Journal of Bioequivalence and
Bioavailability.2011.pg.1-12

• Cardot J m,Beyssac E,Alric M.invitro-invivo
correlation:Importance of dissolution in IVIVC.Dissolution
technologies.Feb 2007.Pg.1-4.

• Leon Shargel,Susanna wu-pong,Andrew B.C.Yu.Appiled
Biopharmaceutics & Pharmacokinetics.Fifth
edition.USA.McGrawHill;2015.pg 404 – 430.

• www.pharmaciestsblogspot.com

• www.ich.org

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THANK YOU

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