Dissolution -final

Dissolution Technique in
Pharmaceutical Industry
By-Pushpendu Gaurav,
Karnataka Antibiotics and Pharmaceuticals Limited, Bengaluru

1. Introduction
- History
- Why dissolution test needs?
- Overview of Major Compendia
- FDA Database
2. Development of Dissolution Methods:
- Physiochemical characterization of API
- BCS Classifications
3. Method Development
- Instruments
- Media
- Agitations
- Sampling Time Points
4. Dissolution Method- Setting Specifications
5. Analytical Instrumental Qualifications
6. Validations – Dissolution test

1. Introductions
Dissolution
 a process in which a solid substance solubilizes in a given solvent i.e. mass
transfer from the solid surface to the liquid phase.
 Basically, it is controlled by affinity between the solid substance and the solvent
 To provide an overview on the general considerations and current practices for
development and validation of dissolution methods with focus on pharmacopeial
requirements.
 Dissolution rate: The dissolution rate of a drug from the solid state is defined as
the amount of drug substance that goes into solution per unit time under
standardized conditions of liquid/solid interface, temperature, and solvent
composition.

Introductions- Contd.
….History.
 19th Century- Bernard.S.Proctor
- Pill Dissolution is necessary for Drug Absorption
 1897-Noyes&Whitney
- Dissolution-related to rate of diffusion of saturated layer around the
solid
 1930- Attempt to relate invitro testing and In vivo availability
 1950’s – focus shifted from physicochemical aspects to effect on biological
activity.
 1951- Edward’ Therapeutic efficacy can be controlled by dissolution in GIT
 1960 to 1961- Levy & Hayes
- Correlated dissolution & Absorption Rates
 Late 1960’s
- Dissolution Testing became Mandatory requirement in USP
for Several Dosage form

Goals of Dissolution Test ….
 Predict the bioavailability – Surrogate the
parameter of the therapeutic efficacy
 Indicate the robustness of the dosage form
– drug product related safety
 Sensitive to variations in the manufacturing
process which have critical influence of the
dosage form performance

Dissolution / Drug release Test
Dosage form requiring dissolution and drug release test:
 Tablet
 Capsules
 Suspensions
 Ointments
 Creams
 Suppositories
 Transdermals
 Implants
 Medicated Gums
 And others

Why dissolution test needs ?
 Rate limiting steps
 Rate of dissolution controls rate of absorptions
 Bioavailability can be correlated with invitro dissolution
results
 Minimizing use of Human volunteers as test subjects.
 Ensure batch to batch quality equivalance
 In-vitro models can be used to screen potential drugs and
its formulations
 Post approval changes-effect of modification in Formula
Structure on bioavailability can be addressed.
 Minimize cost, Labor etc.
 Convenient
 STILL…….. The best model also may not be able to mimic
the fate of dosage form in biological system

Overview of Major Compendia…
USP < 701> Dissolution
USP < 1012> The Dissolution Procedure:
Development and validation
Ph.Eur.2.9.3 Dissolution Test for Solid dosage
form
J.P 6.10 Dissolution Test

USP < 701 > Dissolution..
•Descriptions of Apparatus 1, 2, 3 and 4
•Apparatus Suitability – Performance Verification Test
•Procedure
- Immediate release dosage forms
- Dissolution for a pooled sample
- Extended release dosage forms
- Delayed release dosage forms
Method A: change to buffer stage by media addition
Method B: change to buffer stage by media replacement
• Interpretation of results including acceptance table
-Immediate release dosage forms
-Immediate release dosage forms pooled sample
-Extended release dosage forms
-Delayed release dosage forms
- Acidic stage
- Buffer stage

Ph. Eur. 2.9.3 Dissolution Test
Ph. Eur. 2.9.3 Dissolution Test for Solid Dosage Forms
• Descriptions of Apparatus 1, 2, 3 and 4
– Apparatus suitability:
– Conformance to the dimensions
– monitoring of critical test parameters during use: volume and
temperatureof the dissolution medium, rotation speed (Apparatus
1 and 2, dip rate (Apparatus 3), and flow rate of medium
(Apparatus 4)
•Procedure
– Conventional-release solid dosage forms
– Prolonged-release solid dosage forms
– Delayed-release solid dosage forms
– Method A: change to buffer stage by media addition
– Method B: change to buffer stage by media replacement
• Interpretation
– Conventional release solid dosage forms
– Prolonged-release dosage forms
– Delayed-release dosage forms
– Acidic stage
– Buffer stage

JP 6.10 Dissolution Test
General Tests Processes and Apparatus
•Descriptions of Apparatus
- Apparatus for Basket (Apparatus 1)
- Apparatus for Paddle Method (Apparatus 2)
- Apparatus for Flow-Through Cell Method (Apparatus 3)
- Apparatus Suitability
– Conformance to the dimensions
– Monitoring of critical test parameters during use: volume and
temperature of the dissolution medium, rotation speed (Apparatus 1 and 2,
and flow rate of medium (Apparatus 3).
• Procedure and Interpretation including acceptance criteria
-Immediate-release dosage forms
- Extended-release dosage forms
- Delayed-release dosage forms
- JP specific requirements
- Dissolution test for delayed release dosage forms – only as a
separate stage test in acid and buffer medium
•Interpretation 2: NMT 2 dosage forms of 12 are outside the acceptance
requirements

Apparatus
USP Compendial Dissolution Testing
Apparatus 1: Rotating Basket
Apparatus 2: Rotating Paddle
Apparatus 3: Reciprocating Cylinder
Apparatus 4: Flow-Through Cell
Apparatus 5: Paddle over disk
Apparatus 6: Rotating Cylinder
Apparatus 7: Reciprocating Holder

Apparatus 1: Rotating Basket.

Apparatus 2: Rotating Paddle

Apparatus 3: Reciprocating Cylinder

Apparatus 4: Flow-Through Cell

Apparatus 5: Paddle over disk

Apparatus 6: Rotating Cylinder

Apparatus 7: Reciprocating Holder

2. Development of Dissolution Methods
Drug Product Performance and Bioavailability
 Drug product performance is the release of the active pharmaceutical
ingredient (API) from the drug product leading to bioavailability of the API and
achieving a desired therapeutic response.
 Biopharmaceutics is the science that examines the interrelationship of the
physical and chemical properties of the drug substance, the dosage form and
the route of administration on the rate and extent of systemic drug absorption.
 Bioavailability (BA) studies focus on determining the process by which a drug
is released from the dosage form and moves to the site of action.
 Bioavailability is the rate and extent to which the drug substance or Active
Pharmaceutical Ingredient (API) is absorbed from the drug product and
becomes available at the site of action

Development of Dissolution Methods - Contd.
 exemplified for disintegrating immediate release solid dosage
forms:
Solid oral
dosage form
Solid
particles
Drug in
solution
Drug in Body
Disintegration Dissolution Absorption
 Prerequisite for absorption: drug in solution

Factors to Consider
 API has to be released from the dosage form and has to dissolve in the
physiological fluid in order to be available for absorption
 Factors influencing dissolution
Active pharmaceutical ingredient
– Solubility
– Intrinsic dissolution
– Stability
Pharmaceutical dosage form
– Site of release
– Mechanism of release
– Formulation characteristics

Active Pharmaceutical Ingredient
 Physical properties
– particle size
– structure (amorphous, crystalline)
 Physico-chemical properties
– solubility
– pKa
– intrinsic dissolution
 Chemical properties
– salt form
– stability
 Biopharmaceutical properties
– BCS classification
Formulation
 Site of drug dissolution
– gastrointestinal tract
– skin
 Type
– solid
– liquid
 Release characteristics
– immediate release
– modified release
 Excipients
 Manufacturing process
 Marketing considerations

Physicochemical Characterization of API
Solubility in various aqueous media in the physiological pH range
 pH dependent solubility
– Buffer solutions with different pH values, e.g. pH 1 to pH 8
 Influence of salt composition
– Different composition of buffer solution at the same pH value
 Use of solubilizing agents
– To improve wettability
– To improve solubility
 Effect of various surfactants (if applicable)
– Different surfactant types (e.g. non-ionic, anionic, cationic)
– Different concentrations of the same surfactant
 Simulation of direct food effect (if applicable)
– FaSSIF
– FeSSIF

BCS Classification
FDA
High Solubility: Highest strength should be soluble in 250 ml or less of aqueous
media over the pH range of 1- 7.5 (at 37°C ± 1°C)
High Permeability: 90% or greater absolute bio, or urinary recovery, or;
permeability greater than the reference compound(s)
WHO
High solubility: the highest dose is soluble in 250 ml or less of aqueous media
over the pH range of 1.2 – 6.8 (at 37°C ± 1°C)
High permeability: Extent of absorption in humans is 85% or more based on a
mass balance determination or in comparison with an intravenous comparator
dose

Biopharmaceutics Classification Scheme
 Categorized into 4 basic classes based on its solubility & permeability
 Class 1. High Solubility-High permeability Drugs
 Class 2. Low Solubility-High Permeability Drugs
 Class 3. High Solubility-Low Permeability Drugs
 Class 4. Low Solubility-Low Permeability Drugs
 Covers two potential rate limiting factors
. Solubility through upper GIT
. Drug Transport through Gut Wall
 Used as basis for setting dissolution specifications
 Basis for predicting successful IVIVC

CLASS I DRUGS
 Stability in GIT
 Secreted directly from the Gut Wall
 Dosage Form Characteristics
 Ensure that drug is released rapidly from the dosage form
CLASS II DRUGS
Rate Limiting Step – Dissolution
Limitation Equilibrium- insufficient volume of fluid in GI to dissolve
e.g. Grisiofulvin Dose: 500 mg
Solubility: 15 µgml Dose -solubility ratio: 33 Lts
Kinetic- Drug dissolve too slowly
e.g. Digoxin Dose: 0.25 mg
Solubility: 20 µgml Dose -solubility ratio: 12.5 ml
 Testing at different dissolution medium
 Formtion of insoluble complexes
 First Pass Metabolism

CLASS III DRUGS
 Rate Limiting Step – Permeability
 Rapid Dissolution from Dosage form is desirable
 Increased Contact time between dissolved drug & absorbing mucosa.
 Gastric Emptying Time
 Duration of Dissolution Testing should be as stringent as Class I
CLASS IV DRUGS
 Rate Limiting Step – Dissolution & Permeability
 Poor formulation have additional negative influence in Class IV
 Present significant problem for oral drug delivery

BCS – Solubility
Methods to evaluate solubility
 pH solubility profile of test drug in aqueous media with a pH range of 1.0 to 8.0
considered
 Shake flask or Titration method
 Analysis by a validated stability-indicating assay
BCS – Permeability
Methods to evaluate Permeability
 Intestinal perfusion study in humans - directly measure the rate of mass
transfer of a drug substance in humans across human intestinal membrane
 In vitro permeation studies on intestinal tissue from humans
 In vitro permeation study - non-human systems capable of predicting the extent
of drug absorption in humans can be used: in vitro epithelial cell culture
methods, CaCo2 cells
 Study of absolute bioavailability with the absorption of the drug evaluated in
comparison with the absorption of a reference substance.

3. Method Development – Selection of Test conditions
 A method must be developed which is both
a) discriminating, and
b) rugged and reproducible enough for day-to-day operation, and capable of
transfer between labs.
The acceptance criteria should be representative of multiple batches with the
same formulation/manufacturing process, including key batches (eg BE).
The method should be discriminating enough:
The procedure should be capable of distinguishing significant changes in
composition or manufacturing process that might be expected to affect in
vivo performance.
The method should not be overly sensitive:
Assessing the results from multiple batches that represent typical variability in
composition and manufacturing parameters may assist this evaluation.

Steps of method development
 Literature Survey
 Selection of Apparatus
 Selection of Dissolution medium
 Selection of Volume of Dissolution medium
 Selection of Agitation Rate and Temperature
 Sampling Time Points
 Selection of Analytical Methods
Method Development - Contd.

Literature Survey
 Official in Pharmacopoeia
 FDA Database (Orange Book)
 Journals, Published papers
 Pharmacopoeia (USP, EP, JAPAN Pharmacopoeia……)

 FDA Database (Orange Book)

Selection of Apparatus
 API solubility and stability characteristics
– High solubility
– Low solubility
 Dosage form
– Solid oral dosage forms
– Semisolid dosage forms, etc
 Physiological conditions at the site of drug dissolution
– Gastro-intestinal tract
– Skin, etc
 Release mechanism
– Immediate release
– Modified release, etc
 Regulatory expectations
– Compendial instruments
– Modifications if needed

Selection of Dissolution Apparatus
 The choice of apparatus is based on
– Dosage form and formulation design
 For solid oral dosage forms
– Apparatus 1 and Apparatus 2 are used most frequently
 Some changes can be made to the apparatus when the need is clearly
documented by supporting data
– A basket mesh size other than the typical
40-mesh basket (e.g.; 10, 20 mesh)
– Use of a sinker
– Apparatus 5 (Paddle over disk)
 Agitation can be adjusted as needed

FIP/AAPS Guidelines for Dissolution/In Vitro
ReleaseTesting of Novel/Special Dosage Forms

USP <711> Dissolution
Procedure for Apparatus 1 and 2
 Immediate-Release Dosage Forms
– volume of medium ±1%
– temperature ±0.5ºC
– pH ±0.05 if buffered
– dissolved gases
– sampling position
– sampling time ±2%
– replacement medium or correction
– verification of automated equipment or modified apparatus
– pooled Samples
 Extended-Release Dosage Forms
– as above

Procedure for Apparatus 1 and 2
 Delayed-Release Dosage Forms
 Method A
– medium addition
Ex.- In 250 mL 0.1 N HCl for 1 hrs
then add 500 mL of phosphate
Buffer (pH of media 6.8) upto 2 hrs
 Method B
– medium replacement
Ex.- In 900 mL 0.1 N HCl for 2 Hrs then replaced with 900 mL of pH 6.8
phosphate buffer for further time points.

Problems associated with USP Apparatus 2-paddle in some
formulations
 Cone Formation
 Floating of dosage unit
 Cone Formation
 is a typical problem for disintegrating products
– especially if hydrophobic
 fluid interchange only at surface
– center of cone may be saturated solution
 increasing rotation speed may overcome problem
– a PEAK vessel with an inverted
cone molded into the bottom was
developed to eliminate the potential
for cone formation (non-compendial)

 Floating of dosage unit – to avoid sinkers are used
 Sinkers
– 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
– Alternative sinker device
(compendial)
– Other not compendial sinkers

Paddle/ Basket Dissolution Apparatus
 Advantages
– Widely accepted apparatus for dissolution testing
– Apparatus of first choice for solid oral dosage forms
– Easy to operate
– Standardized
– Robust
– Broad experience
 Disadvantages
– Fixed (limited) volume
– Simulation of gastrointestinal transit conditions, i.e. media/pH change not easily
possible

USP Apparatus 3 - Reciprocating Cylinder
 Vessels
– Cylindrical flat-bottomed glass
– About 325 ml capacity
 Glass reciprocating cylinders
– Inert fittings
– Screens at the top and bottom of the cylinders
 Reciprocating agitation
– Usual speed 5 to 35 dips/min
– Through 10 cm vertical distance
 Dosage form is placed in the cylinder
 Cylinder moves horizontally to different rows

 Drug products
– Solid dosage forms
(mostly nondisintegrating)
– Single units (e.g. tablets)
– Multiple units (e.g. encapsulated beads)
– Originally used for extended release
products, particularly beads in capsules
 Generates fractionated dissolution results
 Dissolution profile versus pH profile

Procedure for Apparatus 3
 Immediate-Release
– similar to 1 and 2
– reciprocation through 10 cm
 Extended-Release
– as above
 Delayed-Release
– as Method B for Delayed-Release
with App. 1 and 2
– use two rows

 Advantages
– Programmable to run dissolution in different media and at different
speeds at various times
– Attempt to simulate pH changes in the GI tract e.g. pH 1, pH 4.5, pH 6.8
 Disadvantages
– Not suitable for dosage forms that disintegrate into small particles
– Surfactants cause foaming
– Small vessel volume
– Media evaporation for tests of long duration

USP Apparatus 4 - Flow Through Cell

USP Apparatus 4 - Flow Through Cell used for :
Drug products
 Solids: tablets, capsules, implants, powder, granules
 Semisolids: suppositories, soft gelatin capsules, ointments
 Liquids: suspensions
 Advantages
– Volume of media not limited
– Suitable for poorly soluble drugs
– Gentle hydrodynamic conditions
 Disadvantages
– Limited experience with use of the apparatus*
– Pump precision influences the results

USP Apparatus 5 - Paddle Over Disk
 Uses paddle and vessel assembly from
Apparatus 2 with the addition of a stainless
steel disk assembly
 Temperature: 32°C
 Speed: typically 50 rpm
 Drug Products
– Transdermal patches
– Matrix transdermal patches can be
cut to the size of the disk assembly
(only if stated in the instruction for
patients)

USP Apparatus 6 – Cylinder
• Uses vessel assembly from App. 1
– Replaces basket and shaft with
a stainless steel cylinder stirring element
• Temperature: 32°C
• Dosage unit is placed on the cylinder with
release side out
• Drug products
– Any kind of Transdermal Drug Delivery
Systems (TDS)

USP Apparatus 7 - Reciprocating Holder
 Similar to Apparatus 3 but with different
dimensions
 Temperature: 32°C (for transdermal
dosage forms)
 Various devices to hold transdermal patches,
tablets, capsules, implants
 Speed: 20-50 dpm
 Reciprocation through 2cm

Selection of Dissolution Medium
Based on physical and chemical data for
 Drug substance
– Solubility of drug substance
– Sink conditions maintained
– Chemical stability of drug substance
 Drug product
– Immediate release, delayed release, extended release, transdermal patch,
etc.
– Theoretical drug release mechanism, if known
For development of Extended Release dosage forms more than one medium is
required
– for topographical characterization
– To prove the robustness of dosage form

 Aqueous buffer solutions pH 1.2 – pH 6.8
– Modified-release formulations up to pH 7.5
– To reflect the pH conditions at the dissolution site
 Addition of surface active agents
– Natural surfactants: bile salts (sodium cholate, sodium taurocholate…)
– Synthetic surfactants: sodium lauryl sulfate, polysorbates…
– Enzymes (pepsin, pancreatin)
 Sink-conditions are desirable
 Use of aqueous-organic solvent mixtures are allowed in specific cases
(e.g. investigation of the dosage form robustness)
 Purified water as dissolution medium is not recommended

Suggested media for comparative dissolution studies:
 pH 6.8 buffer
 pH 4.5 buffer
 pH 1.2 buffer or 0.1N HCl
Water may be used as an additional medium, especially when the API is unstable
in buffered media to the extent that data is unusable.

Selection of the Volume of Dissolution Medium
 Basket/ Paddle Apparatus
– generally: 500 ml – 1000 ml
– special cases: 2 or 4 liter
 Reduced volume Basket/ Paddle Apparatus
– low dose: 150 ml - 250 ml (not compendial)
 Reciprocating Cylinder Apparatus
– up to 250 ml/vessel
– use of up to 6 vessels for testing
 Flow-through Cell Apparatus
– generally: 4 ml/min – 16 ml/ml
– for implants: 1.0 ml/min – 2 ml/min
– special cases: up to 50 ml/min

Role of Sink Condition for Selection of the Volume of
Dissolution Medium
 The volume of dissolution medium to be used is defined considering "sink
condition."
 One of the requirements to conduct an appropriate drug dissolution test is to use a
sufficient volume of dissolution medium, which should be able to dissolve the
expected amount of drug released from a product. This ability of the medium to
dissolve the expected amount of drug is known as a “sink condition”.
 The solubility of the drug substance is quantitatively determined in several
dissolution media within the physiological pH range at 37 °C. Using this value, the
volume of dissolution medium necessary to obtain a saturated solution of the
highest dose of the product to be marketed is calculated.
 Sink condition is considered as at least 3 times this volume. Some companies work
with 5 times or 10 times this value.
 There are some instances where the dissolution test is more discriminative if sink
condition is not followed.
 The volume of dissolution medium has no relationship with the volume of gastric
fluids in humans. According to information available in the literature, a realistic
volume to simulate the total fluid available in the stomach in the fasted state is in
the range of 250-300 mL.

Selection of Agitation Rate and Temperature
Stirring rate
 Basket Apparatus: 50 - 100 rpm
 Paddle Apparatus: 50 rpm - 75 rpm, above 100 rpm with proper justification
– Suspensions: 25 – 50 rpm
– Extended release formulations: 100 rpm
 Reciprocating Cylinder Apparatus: 5 dips/min – 35 dips/min
 Flow-through Cell Apparatus: variation of cell diameter
– 22.6 mm diameter
– Alternative flow-through cell types
Temperature
 Most dosage forms: 37°C
 Dosage forms applied on the skin: 32°C

Sampling Time Point
 Immediate-release formulations
- Development: profiles to characterize the dissolution pattern
(e.g. 10, 15, 20, 30, 45 and 60 min)
- Quality Control: single time point, e.g.15 or 30 min
 Modified release formulations
- Delayed release formulations
– Acidic stage: 1 h or 2 h
– Buffer stage: similar to IR formulations
- Extended release formulations, at least
– One early time point: 1 or 2 hours
– Intermediate time point: 4 or 5 hours
– Final time point e.g. 8, 12 or 24 hours
 “Infinity” Time Point
–May provide useful information about formulation characteristics during
initial development

Additional Sampling for Method Development
Infinity Time Points
 The paddle or basket speed is increased at the end of the run for a sustained
period (typically 15 to 60 minutes), after which time an additional sample is taken
– no requirement for 100% dissolution in the profile
 Provides data that may supplement content uniformity data
 May provide useful information about formulation characteristics during initial
development
 Not required for routine testing

Analytical Method Selection for Dissolution Testing
Based on
 Drug chemical properties
 Compatibility with Dissolution Media
Analytical Methods used for Dissolution Testing
 UV-Vis Spectrophotometry
- For drug compounds with one or more chromophoric group
- Faster, Simpler, Fewer solvent use.
- Chances of intereference in dissolution media with surfactants (Tween 80, SLS)
 HPLC
- Less Chances of intereference in dissolution media with surfactants(Tween 80,
SLS)
- Improve Analytical sensitivity, can be automated.
- in cases where direct or separation-based UV detection is deemed unsuitable
 GC
- Complex compounds not detected by UV and HPLC.

4. Dissolution Method- Setting Specifications
 In vitro dissolution specifications are established to ensure batch to batch
consistency and to signal potential problems with in vivo bioavailability
Establishing Tolerances/Specifications
 Dissolution/drug release specifications based on:
– Manufacturing experience
– Formulation screening experience
– Pivotal clinical trial batches
– Other bio-batches
– Production batches
 Specifications and dissolution method are linked to each other
– Modifications of methods require revalidation and re-verification of specs

Dissolution Method- Setting Specifications - Contd.
Setting Dissolution Specifications – NDAs
For New Drug Applications
 The dissolution specifications should be based on acceptable clinical, pivotal
bioavailability, and/or bioequivalence batches
 The NDA dissolution specifications should be based on experience gained during
the drug development process and the in vitro performance of appropriate test
batches
 Once a dissolution specification is set, the drug product should comply with that
specification throughout its shelf life
 Generic products - usually same as that of RLD

Dissolution Test Specifications for IR Drug Products
 Single-point specifications
– Entire kinetic process of dissolution reduced to one coordinate
– As a routine quality control test (for highly soluble and rapidly dissolving drug
 Two-point specifications
– Entire kinetic process of dissolution reduced to two coordinates
– Gain of safety by closer control of dissolution process
– For characterizing the quality of the drug product
– As a routine quality control test for certain types of drug products (e.g.; slowly
products)
dissolving or poorly water soluble drug product like carbamazepine)

Dissolution Specifications For A New Chemical Entity
 The dissolution characteristics of the drug product may be developed based on
consideration of the pH solubility profile and pKa of the drug substance
 Excipients may mask physicochemical properties of API
 Dissolution testing should be carried out under appropriate test conditions
– Rule of thumb: basket method at 50/100 rpm or paddle method at 50/75 rpm
 Generate a dissolution profile by sampling at <15-minute intervals
– For rapidly dissolving products, sampling at 5- or 10-minute intervals may be
necessary to obtain an adequate profile

Dissolution Specifications For A New Chemical Entity
IR formulation: Specifications for quality control test
 BCS Class1 and BCS Class 3 Drugs
– a single-point dissolution test
– specification of NLT 85% (Q=80%) in 60 minutes or less
 Slowly dissolving or poorly soluble drugs
(e.g.; BCS Class 2 or BCS Class 4)
– a two-point dissolution specification is recommended to characterize the quality
of the product
– at 15 minutes to include a dissolution range (a dissolution window)
– at a later point (30, 45, or 60 minutes) to ensure 85% dissolution

Specifications For Generic Products (ANDAs)
 USP drug product dissolution test is available
 USP drug product dissolution test is not available
– Dissolution test for reference listed NDA drug product is publicly available
 USP drug product dissolution test not available
– Dissolution test for reference listed NDA drug product is not publicly available
USP drug product dissolution test not available
 Dissolution test for reference listed NDA drug product not publicly available
– Comparative dissolution testing using test and reference products under a
variety of test conditions is recommended
– Test conditions may include different dissolution media (pH 1 to 6.8), addition of
surfactant, etc.
– Apparatus 1 and 2 with varying agitation
 In all cases, profiles should be generated
 The dissolution specifications are set based on the available bioequivalence and
other data

Setting Dissolution Specifications – ANDAs
For Abbreviated New Drug Application
 The dissolution specifications should be based on the performance of acceptable
bioequivalence batches of the drug product
 The dissolution specification is generally the same as the reference listed drug
(RLD)
 The specification is confirmed by testing the dissolution performance of the generic
drug product from an acceptable bioequivalence study
 If the dissolution of the generic product is substantially different compared to that of
the reference listed drug and the in vivo data remain acceptable, a different
dissolution specification for the generic product may be set
 USP Monograph - Generic manufacturer may request an additional dissolution test
 Once a dissolution specification is set, the drug product should comply with that
specification throughout its shelf life

Setting Dissolution Specifications Without an IVIVC
 Specifications should be established on clinical or bioavailability lots
 Recommended range at any dissolution time point specification is ±10% deviation
from the mean dissolution profile obtained from the clinical/bioavailability lots
 Deviations from the ±10 % range can be accepted
– Provided that the range at any time point does not exceed 25%
– Specifications greater than 25% may be acceptable based on evidence that side
batches with mean dissolution profiles that are allowed by the upper and lower limit
of the specifications are bioequivalent
 A minimum of three time points is recommended
 The time points should cover the early, middle, and late stages of the dissolution
profile
 The last time point should be the time point where at least 80% of drug has
dissolved
– If the maximum amount dissolved is less than 80%, the last time point should be
the time when the plateau of the dissolution profile has been reached

Setting Dissolution Specifications Without an IVIVC
 Specifications based on average dissolution data for each lot under study, equivalent
to USP Stage 2 testing
 Specifications allow that all lots to pass at USP Stage 1 testing may result in lots with
less than optimal in vivo performance
– This specification may be too wide and not discriminating in batch-to-batch
differences
 USP acceptance criteria for dissolution testing are recommended unless alternate
acceptance criteria are specified in the ANDA/NDA

Setting Dissolution Specifications With an IVIVC
 Optimal approach
– All batches that have dissolution profiles within the upper and lower limits of the
specifications are bioequivalent
 Less optimal approach
– All batches that have dissolution profiles at the upper and lower dissolution limits are
bioequivalent to the clinical/bioavailability lots or to an appropriate reference
standard
 Level A IVIVC Correlation established
 Specifications based on average data
– A minimum of three time points
− the early, middle and late stages of the dissolution profile
– Last time point is at least 80% of drug has dissolved or at the time where the
plateau of the dissolutionprofile is reached

Setting Dissolution Specifications With a Level C IVIVC
 Level C is a one time point correlation
 This one time point may be used to establish the specification such that there is not
more than a 20% difference in the predicted AUC and Cmax
 At other time points, the maximum recommended range at any dissolution time point
specification should be ± 10% of label claim deviation from the mean dissolution
profile obtained from the clinical/bioavailability lots
 Reasonable deviations from ± 10% may be acceptable if the range at any time point
does not exceed 25%

Setting Specifications Based On Release Rate
 A specification may be established to describe the dissolution characteristics of that
formulation
– If the release characteristics of the formulation can be described by a zero order
process for some period of time (e.g.; 5%/hr from 4 to 12 hours)
– The dissolution profile appears to fit a linear function for that period of time
 A release rate specification established on
– On the cumulative amount dissolved at the selected time points
–When at least 80% of drug has dissolved
Alteration of Dissolution Specifications
 The product is expected to comply with dissolution specifications throughout its shelf
life
 If the dissolution characteristics of the drug product change with time
– Any alteration in specifications will depend on demonstrating bioequivalence of
the changed product to the original bio-batch or pivotal batch

5. Analytical Instrumental Qualifications
Dissolution Test – Sources of Variability
Variability in the formulation or due to variability in the manufacturing process may
lead to:
 Poor content uniformity
 Poor disintegration homogeneity
 Poor dissolution homogeneity i.e.; highly variable results
– Within one run
– Between runs
 Examples for variable dissolution results:
– Hard gelatin capsules
– HPMC containing tablets
– Buoyant dosage forms

Analytical Instrumental Qualifications - Contd.
Dissolution Test – Variability of Results
 High variability in results can make it difficult to identify trends or effects of
formulation changes
 High variability caused by the test make it impossible to describe differences in
product quality
 Dissolution results may be considered highly variable if the relative standard
deviation (RSD) is greater than 20% at time points of 10 minutes or less and greater
than 10% at later time points
 Most dissolution results exhibit less variability
 The source of the variability should be investigated when practical, and attempts
should be made to reduce variability of the testing procedure / method whenever
possible

Sources of Apparatus and Method Variability
Sources of Variability:
The Dissolution Apparatus (instrument qualification)
 Vessels - perturbation studies provide proof
 Cover of water bath
 Driving unit
 Others
The Method (method validation)
 Physical
– deaeration
– evaporation
– Adsorbance
 Physicochemical
– Precipitation
 Chemical
– decomposition
– complexation

Dissolution Test – Causes Of Artifacts
Artifacts associated with the test procedure
 Coning, tablets sticking to the vessel wall or basket screen
 Any time the dosage contents do not disperse freely throughout the vessel in a
uniform fashion, aberrant results can occur
– Reactions taking place at different rates during dissolution:
– excipient interactions or interferences
 Visual observations are often helpful for understanding the source of the variability
and whether the dissolution test itself is contributing to the variability
 film coatings (pellicule forming)
 aged capsule shell (“cross-linking”)
 secondary inclusions of drugs in excipients (“dead extraction”)

Dissolution Test – Decreasing Variability
Usual remedies during method development include:
 Changing the apparatus type, speed of agitation, or deaeration
 Consideration and/or examination of sinker type
 Changing the composition of the medium
 Changing other parts of instrumentation
– Sinkers
– Probes
– Vessels (size, material)
 Modifications to the apparatus may also be useful, with proper justification and
validation
– Caveat: modified instrument no longer pharmacopeial standard!

Sources of Variability
For an integrated dissolution testing system in general, the sources of variability may
come from:
 the dissolution testing apparatus that generates the test solutions – including its
environment
 The devices used for
– Sampling
– Processing
– Filtration
– Dilution
– Transfer
 the details of the testing procedure
 the analytical instruments and method used to quantify the dissolved drug substance
in the test solution
 the analyst
 Remember: the specimen under investigation and their intrinsic variability

Sources of Variability
Test Assembly:
 Mechanics and fluid dynamics
 Instrumental and environmental vibrations
 Vessel dimensions, asymmetry and surface irregularities
 Vessel or shaft verticality
 Wobble, height, centering, rotation speed
 Paddle or basket dimensions
 Levelness
 Temperature control

The Dissolution Apparatus
 The basic concepts of the dissolution apparatus were established by empirical
means rather than sound scientific and engineering considerations
 The design of most modern dissolution testers has evolved to precisely control
physical parameters, test conditions and alignment to ensure that the release of drug
from a dosage form will be determined consistently from one tester to another and
from one laboratory to another
 However, apparatus found around the world are not all equivalent the Dissolution
Apparatus

Qualification of Dissolution Apparatus
USP Chapter <711>
 Formerly apparatus suitability test
 Now performance verification test (PVT)
– Use of reference i.e.; standard tablet
– Tablet qualified by collaborative trial including labs of
– USP
– FDA
– HPB….and about 30 others
– Spec‘s established for each new lot individually
– The how-to are part of the USP education course titled “Dissolution: Theory and
Best Practices”
 Mechanical Qualification is a prerequisite
– May be more detailed in the future
– May not replace PVT as demonstrated by the “perturbation studies“

Sources of Variability for Apparatus 1 and 2
 Mechanical variables easily controlled
– Dimension of stirring elements
– Shaft verticality vertical
– Vessel eccentricity ±2mm
– Stirring element depth 25±2mm
 Operational variables
– Stirring rate ±4%
– Temperature ±0.5°C
– Medium Volume ±1%
– pH value ±0.05
– Sampling time ±2%

Sources of Variability for Apparatus 1 and 2
 Mechanical variables not precisely defined
Vessel verticality vertical
Shaft wobble without significant wobble
Vessel dimensions cylindrical with a hemispherical bottom 1L
vessels: diameter: 98mm - 106mm
height: 160mm - 210mm
Vibrations not significant
 Variability due to the “sample preparation”
Amount of dissolved gasses/air

Dissolution Vessels
USP <711> vessel definition
– covered vessel made of glass or other inert, transparent material
– is cylindrical with a hemispherical bottom
– for a nominal capacity of 1 liter, the height is 160mm to 210mm and its inside
diameter is 98mm to 106mm
– its sides are flanged at the top
The vessel is usually made by traditional glass-blowing techniques
 Each vessel is more or less unique since they are effectively handmade
 They may have individual flaws which add to hydrodynamic variability
 diameter: 98mm - 106mm
 height: 160mm - 210mm

Summary of Calibration test and Acceptance Criteria
 Physical Parameters - Frequency: Monthly ± 3 days of scheduled date
 Chemical Parameters - Frequency: Half Yearly ± 3 days of scheduled date
Prednisone Tablets 10 mg used
Acceptance Criteria : As specified in certificate for calibrator tablets
Calculation by putting results in performance verification test calculation tool
for geometric mean and % CV.
Refer USP website www.usp.org/uspnf/pvtcalculationtool
Test By means of Acceptance Criteria
Centering of vessels Two Hemisphere Blocks Shaft of Paddle is easily
fitted and aligned at Centre
Shaft Wobbling Wobble Meter Basket ± 1.0 mm
Paddle ± 0.5 mm
Distance Depth guage 25 mm ± 2 mm
Temperature Calibrated Temperature
Probe
37ºC ± 0.5ºC
RPM Calibrated Tachometer ± 4% of set RPM

6. Validation – Dissolution Test
Validation – Definition
 ICH Q2 (R1): “... The objective of validation of an analytical procedure is to
demonstrate that it is suitable for its intended purpose”
 Analytical Procedure: “…The analytical procedure refers to the way of performing
the analysis”
 “…It should describe in detail the steps necessary to perform each analytical test
...” (e.g.; sample, reference standard, reagent preparation, use of apparatus,
generation of the calibration curve, calculations)
USP General Chapters
 <1092> The Dissolution Procedure: Development and Validation
 <1224> Transfer of Analytical Procedures
 <1225> Validation of Compendial Procedures
 <1226> Verification of Compendial Procedures

Validation – Dissolution Test - Contd.
Validation of Dissolution Procedures
Dissolution method
 Apparatus
 Testing conditions
 Deaeration of dissolution medium
 Sampling
 Selection of filters, sinkers
Analytical method
 Specificity - placebo interference
 Linearity and range
 Accuracy/Recovery
 Precision and Intermediate Precision
 Robustness
 Solution stability
 Filter Compatibility and Filter Saturation

Specificity - Placebo Interference
Determination:
 Prepare a blank solution (diluent), placebo solution; standard solution and sample
solutions to check for interference.
 Sample solution will be prepared by spiking the drug substance containing placebo
powder equivalent to one dosage unit to obtain solutions at 100 % level of target
concentration by using the method under validation.
Acceptance criteria:
 For HPLC method:
No peak should be observed due to blank solution and placebo solution at the
same retention time of the principle peak as observed in the standard solution
and sample solution.
 For UV - Spectrophotometry method:
Interference due to placebo solution should not be more than 2.0% with respect
to that of standard absorbance.

Linearity and Range
Determination:
 Prepare linearity solutions from the stock solution of standard to obtain solutions
from 30 % to 150 % of the working concentration with respect to sample by
preparing minimum 5-concentration level.
 For multiple strength dosage form, 30 % of lower strength up to 150% of the higher
strength will be covered by preparing minimum 5 concentration levels.
 Inject single injection of all the prepared solutions.
 Plot a graph of corrected concentration (ppm) vs. peak areal absorbance.
 Determine and report the slope, y-intercept, and correlation coefficient of the
regression line and residual sum of squares.
 For range, inject six replicates each of lower and higher concentration levels and
calculate the mean and relative standard deviation and also record the concentration
levels over which the results are linear.

Linearity and Range
Acceptance criteria (For HPLC and UV Spectrophotometry methods):
 Correlation Coefficient should not be less than 0.995.
 % Y-Intercept should be within ± 5.0.
 For Range the relative standard deviation should not be more than 2.0 % or as
specified in the methodology for six replicate injections.

Linearity and Range
Example : Carbimazole Tablets 5 mg and 20 mg
Sample preparation : 1 Tablet ------------ 900 mL Dissolution media
Concentrations : For 5 mg -------- 5.56 ppm
For 20 mg ------- 22.22 ppm
For Linearity we have to consider levels from 30 % of lower strength to 150 % 0f higher
Strength. (i.e. 30 % of 5.56 ppm to 150 % of 22.22 ppm).

Linearity and Range
Level
Conc
(ppm)
Corrected
conc (ppm)
Area
8% 1.67 1.69 61498.521
38% 8.33 8.39 304142.025
100% 22.22 22.38 801256.204
125% 27.78 27.97 1009427.931
150% 33.33 33.57 1203735.639
SLOPE 35865.0422
Y-INTERCEPT 1749.2703
CORRELATION COEFFICIENT 1.0000
RESIDUAL SUM OF SQUARE 37453553.2860

Accuracy/ Recovery
Determination:
 Prepare recovery solutions by spiking the drug substance in to the dissolution vessel
(or volumetric flask) containing placebo powder equivalent to one dosage unit, to
obtain solutions from 50 % to 120 % of target concentration with respect to sample
by preparing minimum 3-concentration levels in triplicates.
 Analyse the solutions as described in the method under validation.
 If the amount of drug substance to be spiked to each dissolution vessel is less than
10 mg or if the drug substance floats in the dissolution medium or if the drug
substance is poorly soluble, then prepare a stock solution of drug substance for
spiking into the dissolution vessels.
 Calculate the recovery in mg and also the % recovery for each level and mean
recovery of all solutions.
Acceptance criteria (For HPLC & UV - Spectrophotometry methods):
 All the individual recoveries should be within 95.0% to 105.0%.

Accuracy/ Recovery
Example: Carbimazole Tablets 5 mg and 20 mg
Level
API Spiked
(mg)
Area
Recovered
(mg)
% Recovery
50 %
2.5028 94217.308 2.4137 96.4
2.5028 96337.326 2.4680 98.6
2.5028 96086.486 2.4616 98.4
100 %
20.0224 773012.202 19.8034 98.9
20.0224 775298.789 19.8620 99.2
20.0224 772675.731 19.7948 98.9
120 %
22.0100 924508.030 21.9655 99.8
22.0100 924314.340 21.9605 99.7
22.0100 974828.848 21.9737 99.8
Mean % Recovery 98.9

Precision
Determination:
 For multiple strengths precision study will be performed for both lower and higher
strengths.
 The dissolution test will be performed in the dissolution vessel by spiking the drug
substance containing placebo powder equivalent to one dosage unit to obtain
solutions at 100 % level of target concentration by using the method under validation
and analysed by the same analyst, on same equipment, on the same day.
Calculate the dissolution results. Determine the mean, standard deviation, relative
standard deviation and 95 % Confidence interval of the dissolution results (six
dosage units).
 Relative standard deviation (for six sample preparations) should not be more than
5.0 % and should meet the specifications.

Precision
Example: Carbimazole Tablets 20 mg
Sr. No.
Carbimazole
Peak Area % Dissolution
1 769947.053 98.3
2 770327.497 98.3
3 766067.295 97.8
4 770572.414 98.3
5 772050.742 98.5
6 767944.310 98.0
Mean 98.2
% RSD 0.26

Precision
Example: CarbimazoleTablets 5 mg
Sr. No.
Carbimazole
1 189903.174 97.1
2 189753.815 97.0
3 189239.097 96.8
4 189292.445 96.8
5 189804.093 97.0
6 190366.848 97.3
Mean 97.0
% RSD 0.20

Intermediate Precision
Determination:
 For multiple strengths intermediate precision study will be performed for both lower
and higher strengths.
 The dissolution test will be performed in the dissolution vessel by spiking the drug
substance containing placebo powder equivalent to one dosage unit to obtain
solutions at 100 % level of target concentration by using the method under validation
and analyse by a different analyst, on different equipment, on different day by a
different column (if the estimation method is by HPLC).
 Calculate the dissolution results. Determine the mean, relative standard deviation
and 95 % Confidence interval of the dissolution results (six sample preparations)
 Calculate the absolute difference in the results obtained in Repeatability (mean
value) and lntermediate precision (mean value).

 Relative standard deviation (for six sample preparations) should not be more than
5.0 % and should meet the specifications.
 The absolute difference in the dissolution results obtained in Repeatability (Mean
result) and Intermediate precision (Mean result) should not be more than 5.0.
Example: Carbimazole Tablets 20 mg
Sr. No.
Carbimazole
1 774611.046 98.4
2 779292.853 99.0
3 787668.068 100.0
4 794438.113 100.9
5 783974.261 99.6
6 776095.547 98.6
Mean 99.4
% RSD 0.95

% Dissolution of Sample
Mean Dissolution in
Repeatability
98.2
Mean Dissolution in
99.4
Absolute Difference 1.2

Robustness
Determination:
 Under normal conditions perform the dissolution test for six test solutions using the
method under validation Calculate the dissolution results. Determine the mean,
standard deviation, relative standard deviation and 95 % Confidence interval.
 Individual small deliberate changes in the analytical procedure. Robustness shall be
carried on using (3 or 6) dissolution vessels. Robustness study shall be performed
on any two critical parameters on sample and standard solutions. Select the
changes to be made in the analytical procedure from the below list, as applicable
Change in dissolution parameter
 Change in dissolution medium volume (± 1 %).
 Change in RPM (± 4%).
 Change in pH of dissolution medium (pH specified in dissolution medium ± 0.2).
 Change in strength of the dissolution medium (specified morality ± 0.02 M).

Robustness
Determination:
Robustness study shall be performed on any two critical parameters on standard
solutions. Select the changes to be made in the analytical procedure from the below
list, as applicable if chromatographic condition are different from assay
 Change in pH of mobile phase / buffer (pH specified in method ± 0.2).
 Change in mobile phase composition (Absolute 2 % or 30% relative whenever 2%
absolute is not possible for e.g. 98: 02).
 Change in flow rate (Flow rate specified in method ± 0.2 mL. In case, flow rate
Specified ≥ 1 .0 mL, change flow rate ± 0.2 mL and for < 1 .0 mL, change flow rate
± 0.1 mL.)
 Change in column oven temperature (Temperature specified in method ± 5°C).
 Change in Wavelength (± 2) only for UV- Visible spectrophotometry method.
Calculate the dissolution results for each set of analysis. Determine the absolute
difference between the results obtained in Robustness study (Mean dissolution) and
Mean Precision (i.e. carried out in robustness study only).

Robustness
 Relative standard deviation (for six sample preparations) should not be more
than 10.0 %.
 The absolute difference in the results obtained in Robustness study (Mean
dissolution) and Repeatability study (Mean dissolution) should not be more than
5.0.

Solution Stability
Determination:
 Prepare the standard solutions and sample solutions equivalent to target
concentration (i.e. 100 % of test concentration) as mentioned in the methodology.
Sample solution will be prepared by spiking the drug substance containing placebo
 Keep the prepared solutions tightly closed and store at controlled room temperature
(20°C to 25°C) and analyse the standard and sample solution upto 24hrs (if
estimated method is by UV spectrophotometry) or store the solutions at either
controlled room temperature (20°C to 25°C) or at a temperature below controlled RT
(as per STP recommend like 2-8°C, 10°C or 15°C). Analyse the standard and
sample solution upto 48hrs (If the estimation method is by HPLC) if the drug product
tends to be stable in solution. (Based on the information obtained from development)
Analysis may also be done at intermediate time intervals. Report the results of initial
and actual time interval conditions. Determine the absolute difference in % assay /
dissolution / release for standard solution and test solution at the particular time point
with respect to initial.

Solution Stability
 The absolute difference in assay for standard solution and % release for test
solution at each time point should not be more than 2.0. If it is out of the set
criteria, make appropriate recommendations.
Example : Carbimazole Tablets
Time
(hours)
Standard Solution
Time
(hours)
Sample Solution
10 º C 10 º C
Area
%
Assay
Absolute
Diff.
Area
%
Release
Absolute
Diff.
Initial 877194.515 98.9 - Initial 770253.502 98.3 -
2 Hrs 876842.902 98.9 0.0 2 Hrs 768385.573 98.1 0.2
8 Hrs 871070.261 98.2 0.7 8 Hrs 763537.244 97.5 0.8
14 Hrs 866402.925 97.7 1.2 14 Hrs 759129.014 96.9 1.4
24 Hrs 862083.733 97.1 1.8 24 Hrs 752550.557 96.0 2.3
26 Hrs 862816.934 97.3 1.6 - - - -
32 Hrs 856508.296 96.6 2.3 - - - -

Filter Compatibility
Determination:
 At the filtration stage, filter the sample solution through a specific filter only as
described in the standard test procedure or as recommended from developmental
studies (i.e. filters iike GF/C or 0.45µm nylon or 0.45µm PVDF could be used).
Discard about 5 mL sample solution or as described in the methodology from the
specific filter and collect the sample solution for further analysis. Centrifuge the same
(unfiltered) sample solution.
 Analyse all the solutions as described in the test procedure and calculate the %
release results.
 Determine the absolute difference between the results obtained from the filtered
sample and centrifuge sample.
 If methodology itself contains sample to be centrifuged then consider the centrifuge
sample as 'as is sample' and then the same sample solution will to be filtered
through the specific filter as described in the methodology.

Filter Compatibility
 Absolute difference in the results obtained between the filtered sample and
centrifuged sample should not be more than 2.0.lf it is out of the set criteria then
make appropriate recommendations.
Filter Type Area % Dissolution
Absolute Diff.
w.r.t. Centrifuge
Centrifuged 764881.004 97.6 -
GF/C Filter 770253.502 98.3 0.7

Filter Saturation
Determination:
 At filtration stage, discard the volume of 1.0 mL , 3.0 mL and 5.0 mL through
the filter of choice followed by filtration of 10 mL aliquots or as described in the
methodology. Collect the filtrate from the specific filter as recommended from Filter
compatibility study and collect the filtrate in separate test tube.
 Analyse the obtained solutions as described in the method to be validated and
calculate the % release results.
 Absolute difference in the results obtained between two subsequent filtered solutions
should not be more than 2.0.lf it is out of the set criteria then make appropriate
recommendations.

Filter Saturation
Volume
Discarded
Area % Dissolution
Absolute
Difference
1.0 mL 765679.357 97.7 -
3.0 mL 770633.344 98.4 0.7
5,0 mL 770644.042 98.4 0.0
As absolute difference of subsequent filtered solutions of 3.0 mL and 5.0 mL is
0.0. So 5.0 mL discard volume is selected.

REFERENCES
 Dissolution <711>. United States Pharmacopeia and National Formulary USP 38-NF
33; United States Pharmacopeial Convention
 Dissolution <1092>. United States Pharmacopeia and National Formulary USP 38-
NF 33; United States Pharmacopeial Convention
 Dissolution Test J.P 6.10 Japanese Pharmacopoeia
 Dissolution Test for Solid dosage form Ph.Eur.2.9.3 European Pharmacopoeia
 Qingxi Wang,Decheng Ma, and John P. Higgins, Analytical Method Selection for
Drug Product Dissolution Testing. Dissolution Technologies AUGUST 2006, 6-13
 Evaluation And Recommendation of Pharmacopoeial Texts For Use In The ICH
Regions on Dissolution Test General Chapter Q4B ANNEX 7(R2) ICH Harmonised
Tripartite Guideline
 Dissolution Testing of Immediate Release Solid Oral Dosage Forms Guidance for
Industry U.S. Department of Health and Human Services Food and Drug
Administration Center for Drug Evaluation and Research (CDER) August 1997
(Internet) http://www.fda.gov/cder/guidance.htm
 Specifications: Test Procedures and Acceptance Criteria ICH Q6A ICH Harmonised

REFERENCES
 Validation Of Analytical Procedures: Text And Methodology Q2(R1) ICH Harmonised
 Developing and Validating Dissolution Methods, U.S.Pharmacopoeial Convention
Global Education and Training, 2013.

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