A nice presentation ...

1. (In context To BCS,FDA prospective, Release kinetics)
PART-1
Presented by
SUBHAKANTA
A Brief concept To Dissolution Method
Development
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2. Dissolution:
• “ Dissolution is the amount of drug substance from a dosage form that goes
into solution per unit time under standard conditions of solid /liquid
interface, temperature and solvent composition.”
• Takes two steps one is liberation (drug release from dosage form) and
convection process ( drug transport within the dissolution media).
USP <1088>:
• “No product, including suspensions and chewable tablets, should be
developed without dissolution or drug release characterization where a solid
phase exists." and
• “Dissolution testing is required for all solid oral Pharmacopeias dosage
forms in which absorption of the drug is necessary for the product to exert
the desired therapeutic effect. Exceptions are for tablets meeting a
requirement for completeness of solution or for rapid (10 to 15 minutes)
disintegration for soluble or radiolabeled drugs.”
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3. Dissolution History:
• 1945–1950 Disintegration official in Brit Pharmacon and USP
• 1962 PMA Tablet Committee proposes 1% solubility threshold
• 1967 USP and NF Joint Panel on Physiological Availability chooses dissolution as a test
chooses an apparatus
• 1970 Initial 12 monograph standards official
• 1971–1974 -Variables assessment; more laboratories, three Collaborative Studies by PMA and
Acad. Pharm. Sci
• 1975 -First calibrator tablets pressed; First Case default proposed to USP
• 1978 Apparatus 2—Paddle adopted; two Calibrator Tablets adopted
• 1979 New decision rule and acceptance criteria
• 1981 Policy adopted January, includes the default First Case, monograph proposals published
in June
• 1982 Policy proposed for modified-release dosage forms
• 1984 Revised policy adopted for modified-release forms
• 1985 Standards now in nearly 400 monographs; field considered mature; Chapter <724>
covers extended-release and enteric-coated
• 1990 Harmonization: apparatus 4—Flow- through adopted; Apparatus 3 Apparatus 5, 6, 7 for
transdermal drugs
• 1995 Third Generation testing proposed—batch phenomenon; propose reduction in alibration
test number
• 1997 FIP Guidelines for Dissolution Testing of Solid Oral Products; pooled analytical samples
allowed
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4. Dissolution History: contu…
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5. Objective of Dissolution Studies:
To identify a QC
dissolution test method to
verify process and
product consistency.
At
Registration
and beyond
To identify a test method
that can provide an
IVIVR, IVIVC, or other
bio-relevant information.
II-III
To clearly establish the
mechanism of invitro
drug release and
solubilization.
0-I
ObjectivePhase
To confirm
manufacturing and
product consistency.
To evaluate the
quality of product
during its self life.
To assess post
approval changes and
for BE studies.
To evaluate the rate
of drug release.
Monitoring products’
release consistency.
Assessing
formulation changes.
Establishing IVIVC
or IVIVR.
During Commercial
stage
During development
stage
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6. What Does Dissolution Measure?
Solid drug particle stagnant layer (h) with a
concentration = Cs
bulk solution with a
concentration = CT
Bulk Solvent
)()( 1 tsts cckcc
vh
DS
kR −=−=
Modified Noyes and Whitney Equation
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7. Mechanism of Dissolution
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8. Mechanism of Dissolution
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9. Factor affecting dissolution
• A. PHYSICOCHEMICAL FACTORS
• Drug solubility and dissolution rate
• Particle size and effective surface area
• Polymorphism and amorphousim
• Salt form of the drug
• pKa of the drug and pH – (pH partition hypothesis )
• B. PHYSIOLOGICAL FACTORS
• .Gastric emptying time
• Intestinal transit time
• Gastrointestinal pH
• Disease states
• Blood flow through the GIT
• Gastrointestinal contents:
• Pre-systemic metabolism
• C. PHARMACEUTICAL FACTOR
• Manufacturing variables
• Pharmaceutical ingredients (excipients / adjutants)
• Nature and type of dosage form
• Product age and storage conditions
• Disintegration time (tablets / capsules)
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10. Factor affecting dissolution as GIT
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11. Factor affecting dissolution as GIT
all types of drugs are absorbed, about half of the absorbed drug
goes directly into the systemic circulation and the other half to
the liver
much smaller surface areaRectum
all types of drugs are absorbed but to a lesser extentsmall surface areaLarge intestine
major site for absorption of all types of drugs (lipophilic,
neutral, acidic or basic)
very large surface areaSmall intestine
lipophilic, neutral and acidic drugs absorbed but lesser than that
from intestine
not too large a surface areaStomach
lipophilic, neutral and basic drugs are absorbed directlysmall surface areaMouth
4-12 hr4-12 hr5.5-6.54-12 hr4-12 hr5.5-6.5proximal colon
60 min60 min7.5(7-8)60 min120 min7.5(7-8)lower.ileum
60 min60 min7.2(6.5-7.5)60 min60 min7.2(6.5-7.5)upper.ileum
60 min60 min6.8(6-7.2)60 min30 min6.8(6-7.2)lower jejunum
60 min60 min5.5(5.5-7)60 min30 min6.5(5.5-7)upper jejunum
< 10 min< 10 min5(4-7)< 10 min< 10 min6(4-7)duodenum
2-4 hr2-10 hr4(3-6)30 min60 min1.8(1-3)Stomach
MRT (pellets)MRT (Tablet)PHMRT (pellets)MRT (Tablet)PHsite
fed conditionfasting
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12. Method Development- Approach:
Drug Characterization
(Solubility,Permeability etc)
BCS Class Dosage form
GI Physiology
Dissolution method
Media Apparatus Test duration
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13. Intrinsic Drug Dissolution :
• It is the rate of dissolution of a pure pharmaceutical active when conditions such as surface
area, temp, agitation – stirring speed, pH and ionic strength of the dissolution medium are kept
constant.
Particle size:
Dissolution rate is typically influenced by particle size and wettability. The influence of
wettability on the dissolution rate of pharmaceutical powder was studied by Lippold and ohm.
Example: wetting agent: Polysorbate 80.
Ionization
• The amount of drug that exists in unionized form is a function of dissociation constant (pKa­)
of the drug and pH of the fluid at the absorption site.
for weak acid:
HA H+ + A-
acid base
pH = pKa + log
[A-]
[HA]
%
( )
( )
drugionized x
pH pKa
pH pKa
=
+
−
−
10
1 10
100
for weak base:
B + H+ BH+
pH = pKa + log
[B]
[BH+]
%
( )
( )
drugionized x
pKa pH
pKa pH
=
+
−
−
10
1 10
100
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Drug Characterization:

14. Nature of drug
Weakly acidic, weakly basic, free base, salt etc.
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Drug Characterization
0.199.9≥ 3
1992 to 3
1090≥ 1
50500
9010-1 to 2
991-2 to -3
99.90.1≥ -3
BasesAcids
Percentage of IonizationpH-pKa
Solubility of weak bases is often best in the stomach, that of weak acids in the
small intestine.

15. • Partition coefficient
The partition coefficient is the ratio of concentrations of un-ionized compound between the two
solutions. The logarithm of the ratio of the concentrations of the un-ionized solute in the
solvents is called log P.
• Higher the value, more the hydrophilic and faster the dissolution in aqueous fluids.
• If log p>4 then the drug is very lipophilic, which is practically estimated by shake flask method.
Usually intestinal permeability increases with liphophilicity but decreases with molecular weight
or H-bonding properties.
• Low LogP( below 0) injectable
• Medium (0-3) oral
• High(3-4) Transdermal
• Very High (4-7)toxic build up in fatty tissues.
• Drugs should be designed with the lowest possible Log P
• Effective surface area of the drug particles .
When the particle size of a certain mass of a drug is reduced the surface area is increased, hence,
if particle size is reduced dissolution rate increases .
Two types of surface area can be defined:
Absolute surface area: Which is the total area of solid surface of any particle, and
Effective surface area: Which is the area of solid surface exposed to the dissolution medium
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Drug Characterization

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Drug Characterization
Lipnski rule of 5 (an orally active drug has no more than one
violation of the following criteria)
• Not more than 5 hydrogen bond donors (nitrogen or oxygen
atoms with one or more hydrogen atoms)
• Not more than 10 hydrogen bond acceptors (nitrogen or oxygen
atoms)
• An octanol-water partition coefficient log P of less than 5
• A molecular weight under 500 daltons.
Exception toException to LipnskiLipnski rule of 5rule of 5
1. Compound classes that are substrates for biological transporters:
2. Antibiotics
3. Fungicides-Protozoacides -antiseptics
4. Vitamins
5. Cardiac glycosides.

17. BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)
IVIVC Level A
expected
VariableVariableBasic
Little or no IVIVCVariableVariableAcidic
Case by caseLittle or no IVIVCLow ,Dependent on site and
Narrow absorption window
Low & Site
Independent
4
permeabilityIVIVC
Level A expected
High & Site
Independent
HIGH, &
Site
Independent
3
dissolutionIVIVC
Level C expected
High, Dependent on site
and
Narrow absorption window
low & Site
Independent
2
Gastric
emptying
IVIVC Level A
expected
High & Site
Independent
High & Site
independent
1
Absorption
control
IVIVCPermeabilitySolubilityClass
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18. Solubility
A drug substance is considered highly soluble when the highest dose strength is soluble
in 250 ml or less of aqueous media over the pH range of 1-7.5.
A Drug is said to be very rapidly dissolving when NLT 85% is dissolved in 15 min using usp-1
at 100RPM (or 50 rpm )in volume 500mlin each media :0.1N Hcl OR SGF WITHOUT
ENZYME ,PH4.5,PH 6.8 OR SIF .
Permeability:
A drug substance is considered to be highly permeable when the extent of absorption
is at least 90% in comparison to an i.v. reference dose .
Methods used for determination of permeability include:
a. Mass balance studies, Absolute bioavailability studies and Intestinal perfusion methods
in human
b. In vivo or in situ intestinal perfusion in a suitable animal model
c. In vitro permeability methods using excised intestinal tissues
d. Mono layers of suitable epithelial cells e.g. Caco-2 cells or TC-7 cells .
BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)
CONT….
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19. .
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BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)
CONT….
ADDITIONALLY APPROACH OF BCS
The dose number (Do)- IT is the ratio of the dose to the amount of drug that will dissolve in
250 mL of range 1 to 8. Ideally, this ratio should be below 1 if full dissolution is to be
possible in principle.
• The absorption number (A n) -IT is the ratio of the transit time to the absorption time
(1/absorption rate constant). Ideally, this should exceed 1.
• The dissolution number (D n)-IT is the ratio of the transit time to the dissolution time
(1/dissolution rate constant). Ideally, it should exceed 1..

20. .
BIOPHARMACEUTICS CLASSIFICATION
SYSTEM (BCS) APPROACH FOR CLASS I/III…..
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21. .
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BIOPHARMACEUTICS CLASSIFICATION
SYSTEM (BCS) APPROACH FOR CLASS II/IV…..

22. Method Development as per FDA
Prospective
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23. FDA ROLE in DISSOLUTION
Enforcement of USP
• Publishes Guidances
• Co-Sponsors workshops with AAPS
• Task force
– Gelatin working group
• Perform off shelf testing
• Perform validation on NDA methods
• Inspections
• Recalls
• Approve products
• Publishes the Orange Book
– Approved drug products with therapeutic equivalence evaluations
• AB….
• www.fda.gov/cder/ob/default.htm
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24. FDA Guidances
• Dissolution Testing of Immediate Release Solid Oral Dosage Forms - 1997
• Extended Release Oral Dosage Forms:Development, Evaluation, and Application of
In Vitro/In Vivo Correlations
• SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-
Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation
• SUPAC-MR: Modified-Release Solid Oral Dosage Forms: Scale-Up and Post-
Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation
• Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release
Solid Oral Dosage Forms Based on Biopharmaceutics Classification System -2000
• 483 warnings
– Failure to investigate Out of Specification results
– Do not have or follow SOP’s
– Inadequate calibration program or compliance
– Bubbles in vessel observed
– Unvalidated methods or computer programs
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25. FDA PERSPECTIVE
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26. Apparatus
United Sates of Pharmacopiea:
-Apparatus 1 Rotating basket Tablets/Capsules
-Apparatus 2 Paddle assembly Tablets/Capsules
-Apparatus 3 Reciprocating cylinder Escalating pH media
-Apparatus 4 Flow-through cell Low soluble drugs
-Apparatus 5 Paddle over disk Semisolids and transdermal
-Apparatus 6 Cylinder Transdermal patches
-Apparatus 7 Reciprocating holder Transdermal patches
European Pharmacopiea:/ British Pharmacopiea
-For solid dosage forms Paddle/basket/flow through cell
-For transdermal patches Disk assembly method/cell method/rotating cylinder
-For special dosage forms Chewing apparatus/Flow through apparatus
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27. STRATEGY FOR METHOD DEVLOPMENT
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28. a
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STRATEGY FOR METHOD DEVLOPMENT

29. STRATEGY FOR METHOD DEVLOPMENT
CONT…… Selection of Test Conditions
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30. a
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STRATEGY FOR METHOD DEVLOPMENT
CONT…… Selection of Test Conditions

31. Choices of Media
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Volume
Maximum Dissolvable Dose = V . CS / Sin k
V = Dissolution medium volume,CS = Saturated solubility of the co m pound in the
medium
Sink = Sink condition factor
Sink condition-It is volume of medium at least three times to required form saturated
solution of a drug substance.
Some sources recommend 5x or even 10x.
•If a medium fails to provide sink condition or said to be more discriminating Which
can be provide some surfactant to the medium.
•Sink condition is a must and is a volume (not a ratio) in which drug could easily and
accurately be dissolved . And be on the safe side, just increase the volume 20-30% than
the volume required .
•Sink condition is mandatory; however, ratio of 3:1 (medium volume used vs medium
volume required for saturation with drug) .

32. Choices of Media cont..
Volume: sink condition cont….
• Different techniques to improve sink
conditions.
Addition of organic solvents to aqueous medium,
Use of large dissolution volume,
pH changes
Addition of surfactants or their combinations Medium Volume
• 900 mL typical
• 500 mL for low dosage strengths
• 1000 mL for increased solubility, sink
• 2 L, 4 L, 200 mL - special needs
• Exceptions
• low solubility compound-2000 to 4000ml
• Highly potent drug -100 to 250ml.
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33. • Acid
–Hydrochloric acid (0.1--0.001 N)
• Buffers (use USP preparation instructions)
–Acetate (pH 4.1--5.5; 0.05 M)
–Phosphate (pH 5.8--8.0; 0.05M)
• Water
–Disadvantages
• No buffering capacity, can’t measure pH accurately
• Some regulatory bodies do not favor usage
• Different conductivity/pH depending on source
–Advantages
• Inexpensive, easy disposal
• Useful in correlations, provide good profile
Non-aqueous media
• -hydroalcholic media is used (e.g cortsone acetate tab)
•Measure pH before and after run
Medium Selection
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34. Surfactants
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•For low solubility compounds, adequate dissolution can not be obtained with aqueous solutions
within the physiologic pH ranges. That’s why compounds, aqueous solution containing a surfactant
may be used to enhance drug solubility.
•A surfactant can be used as either a wetting agent or when the critical Micelle concentration
(CMC)is reached, to stabilize the drug .
•Addition of surfactant – Air bubble trapping
EXAMPLE
Sodium lauryl sulfate,
Polyoxyethylenesorbitan monolaurate (Tween),
Cetyltrimethylammoniumbromide (CTAB ),
Polyoxyl castor oil (Cremophor),
Hexadecyltrimethylammonium bromide (HTAB),
Polyethylene glycol tert-octphenyl ether (Triton),
Media-enzymes
Need for enzyme- for cmc formation
Cross linkage of gelatin capsule shells
Example
Pepsin-SGF(PH-1.2)
Pancreatin –SIF (PH-6.8)

35. STRATEGY FOR METHOD DEVLOPMENT
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36. Selection of Test Apparatus
• Basics for Apparatus
– Need low variability
– Good profile
– Should pick up changes
– Hydrodynamic aspects-
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37. Typical Apparatus Speeds
Paddles
– 50 rpm preferred-speed for BCS
– 75 rpm to eliminate coning, variability
– 25 rpm or more used for suspensions
– Used with tablets or capsules with sinkers
– 100 rpm or higher needs justification
– 100 rpm used frequently with ER
• Basket
– 50-100 rpm preferred
– Over 100 rpm sometimes necessary
– Used for floating dosage forms
– Used for slowly disintegrating dosage forms
• Reciprocating cylinder
-15 rpm(capsule,tablet,suspension)
• Paddle over disk
-25rpm (TDS)
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38. Temperature
• Oral dosage forms -37 ± 0.5°c
• Suppositories- 38 ± 0.5°c
• TDS- 32 ± 0.5°c
• Chewing gum- 37 ± 0.5°c
Hydrodynamic Issues
• Fluid Flow
– Basket mesh size
– Coning with paddle
– In-residence
probes/automation
– Vessel irregularities
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39. Deaeration
• Troubles from non-de -aerated
medium
– Slow down (barrier) or speed up
(buoyant)
– Bubbles adhere to screens
– Particles adhere to bubbles that
may be clinging to the vessel
walls
– Basket carries down the bubble on
surface
– Can break up cone
– Surfactants not practical due to
foaming
• Additionally air bubbles- cling to
apparatus & vessel wall.
• Bubbles on the dosage unit→
buoyancy (↑) → dissolution (↑)
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Methods

40. Sinkers
• USP -- ”such as not more
than a few turns of a wire
helix…”
• Uniformity is critical,
especially when transferring
method
• Sinker should be validated
• Method should Compared
with sinker vs non sinker
• Sinkers can be barriers to
dissolution.
2
0.55
8#3 and #4
3
0.7
10#1 and #2
4
0.8
12#0, elongated
Cork Bore
Number
Diameter
Size
(cm)
Length of Wire
(cm)
Capsule Shell Type
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41. Test Duration and sampling interval
• Rapidly Dissolving product (IR PRODUCT)
- profile generated at 5-10 min,interval may necessary.
• Extended release product
- At least 3 point of dissolution
• IR PRODUCT
Highly soluble (class-I & III)
-A single point NLT 85% in 60 min.
Poorly soluble (class-II & IV)
-2 Point dissolution specification ,one at 15 min, other at 30,45,60 min
• When avg. dissolution from reference product does not reach 85% ,at
testing time would be T/4,2T/4,3T/4,T
• INFINITY POINT FOR DEVLOPMENT STUDY
- Help during formulation study at 150rpm for 1 hr or 2 hr depending
on type of dosage form.
.
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42. Observations
• Particle disintegration
pattern/must disperse freely
• Floating (chunks), spinning
• Coning, mounding
• Gumming, swelling
• Capping, clam shell
• Erosion pattern
• Center/off-center, sticking
• Particles adhering to
apparatus/vessel
• Ballooning, rubbery mass, pellicles
• Particle size (snowflake, fine)
• Look on surface around shaft
• Disintegration and shell dissolution
rate
• BUBBLES
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Observations

44. Sampling
• Syringe
– Plastic or glass
• Needle
– Stainless steel
– Bent or straight
• Filter - end of probe, in line,
after sampling
• Pipettes-not good unless filter at
tip
• Pore size of filter
– 0.2 micron - 70 micron
– Depth filters, full flow
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45. Maintenance Schedule
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46. Discriminating dissolution media
Discriminating
Its ability of method to detect changes in the drug product performance, lot –to lot
variation, process changes (SUPAC) and to discriminate between dosage forms that are
not bioequivalent.
-if similarity of batch------go for Discriminating Method
-for BA,BE,IVIVC---------------Go for Bio-relevant Media
Development of a Discriminating Method
• A method must be developed which is both (test as well as reference)
a) discriminating, and
b) 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 (e.g. BE).
• The procedure should be capable of distinguishing significant changes in
composition or manufacturing process that might be expected to affect in vivo
performance
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47. Development of a Discriminating Method cont…..
•Factors to consider:
-Formulation point of view
Qualitative and quantitative Excipient changes
Manufacturing parameters (examples):
Lubrication
Blend time
Compression force
Drying parameters
-Method development point of view
-Biorelevant media
-Rpm challenge
-apparatus challenge
-media volume challenge
-Effect of bile salt (if any effect on product)
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48. Bio-Relevant Media
OBJECTIVES
1. The biorelevant method should be able to stimulate the in vivo environment
where the majority of drug being released.
2. Biorelevant dissolution media, apparatus and test conditions Should be
discussed with emphasis on their relevance to the physiological factors,
including the pH, composition of the GI fluids, volume, GI
hydrodynamics/motility, and food effect.
Choice Biorelevant medium
• Fed and fasted media
• pH at site of absorption
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49. Gastric
Emptying
Transit Permeation
Dissolution
Metabolism
DISSOLUTION
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50. Biorelevant for Gastric condition
Gastric condition : a view
-The fasted state of young healthy subjects, values of gastric pH are generally between 1.4
and 2.1
-The surface tension of gastric fluid .
- Addition, surfactants, such as SLS, should be added into the medium.
-To simulate the fed state in the stomach, the use of milk (Macheras et al., 1987) and Ensure
R_ (Ashby et al., 1989) may be appropriate, since these media offer appropriate ratios of fat
to protein and fat to carbohydrate.
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51. Possible targeted Biorelevant gastric Dissolution Media
• Pre-prandial stomach
1. SGF USP (pH 1.2) without enzyme
2. SGF USP plus surfactant (e.g. 0.1% Triton X)-PH-1.8 plus perhaps pepsin
• Post -prandial stomach
1. Ensure Plus
2. Bovine milk 3.5% fat
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1L1Lwater
1gTriton x 100
7g3gHcl con.
2g2gSodium chloride
SGF PH 1.2FASGF PH 1.8

52. Biorelevant for Intestinal condition
Intestinal condition : a view
• The dissolution of drug products in the small intestine is influenced by physiological factors
pH, endogenous secretions from the pancreas and gall bladder (e.g., bile salts, lecithin, and
digestion enzymes), and food effects.
• The pH values of intestinal conditions are considerably higher.
• one apparent difference between the SGF and FaSSIF is that this simulated intestinal medium
contains bile salts and lecithin .
• The dissolution rate of poorly soluble, lipophilic drugs may be improved greatly in this
medium in comparison to the dissolution rate observed in simple aqueous solutions .
• The volume of the fasted state simulated intestinal medium, pharmacokinetic studies in the
fasted state show that by ingesting 200–250mL of water with the dosage form, a total volume
of 300–500mL will become available in the proximal small intestine. Hence volume of 500mL
is recommended for the FaSSIF
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53. Biorelevant for Intestinal condition contue..
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54. PH OF DIFFERENT CONDITION OF MEDIA FOR REMEMBER
5.8SCOF
5SIF FED
6.5SIF FAST
6.8SIF with enzyme
2.1SGF without enzyme
1.2SGF with enzyme
2.12.1with SLS
30.001 N Hcl
2.10.01 N Hcl
1.20.1 N Hcl
PHMedia
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55. DIFFERENT CONDITION OF MEDIA FOR REMEMBER
Dissolution media for ( Class I and Class III)
• simple medium is sufficient
• USP media or aqueous buffers
1. SGFsp pH 1.2
2. Acetate buffer pH 4.5
3. SIFsp pH 6.8
Dissolution media for ( Class II and Class IV)
FaSSIFpreprandialSmall intestine
Ensure® Plus ,MilkpostprandialStomach
FaSSGF
SGFsp (USP) plus surfactant (Triton X 100)
preprandialStomach
Medium
pre-/post
prandial
postprandia
Location
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56. DIFFERENT CONDITION OF MEDIA FOR MR PRODUCT
• For extended-release drug products, the dissolution method must capture, at
minimum, the changes in composition, pH, and residence times along the GI tract,
since absorption of these dosage forms takes place throughout the entire intestine.
• The reciprocating cylinder and flow-through cell systems can be used, in conjunction
with different biorelevant dissolution media, to assess the in vivo release behavior of
extended-release dosage forms
Biorelevant Media for Studying Food Effects on Release
from MR Dosage Forms
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57. Dissolution testing and alcohol-induced dose-
dumping of generic MR oral drug products
• Some modified-release oral dosage forms can contain drugs and
excipients which are highly soluble in ethanol.
• Even moderate amount of alcohol may cause problem (dose-
dumping) in vivo.
• The Office of Generic Drugs recommends assay
1. Designed to compare dissolution performance of the generic
(test) product and the corresponding reference listed drug.
2. 0.1 N HCl media with differing amounts of ethanol(v/v) added
to give the following percentages of ethanol in the media:
0%, 5%, 20%, and 40%
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58. Alcohol-induced dose-dumping of generic MR oral drug
products continue…
Methods.
• The assay was implemented for several MR drug products under review at the Office of
Generic Drugs (OGD). The assay employs USP Apparatus I or II and 900 mL of 0.1 N HCl
media containing ethanol (v/v) at: 0%; 5%; 20%; and 40%, sampling every 15 minutes until 2
hours. Applicants conduct these studies on all drug product strengths.
The dissolution results are categorized as
• Case I: If at 2 hours, % dissolved of the generic product in 40% ethanol is ≤ in 0%
ethanol, the generic product is considered robust (does not dose-dump); if not
• Case II: at 2 hours, % dissolved of the generic product in ethanol solution is less or
comparable to that of the reference, the potential for dose-dumping is similar for the two
products and the generic product is acceptable; if not
• Case III: the generic product releases more drug in ethanol than the reference and is
unacceptable.
• Results.
To date, the OGD reviewed 22 submissions, representing 7 different drugs, containing
results of in vitro dose-dumping in alcohol studies. Of these 22 studies, 12 (54.6%), 9
(40.9%), and 1 (4.5%) were categorized as Case I, II, and III, respectively.
Similar trends in study outcome were observed for the various strengths of each drug
product line tested.
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59. Dissolution Method Development
At a glance
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Selection of test conditions
•classify the drug substance according to the BCS as
characterize the drug solubility over the pH range 1.2 to
6.8
• Run dissolution tests with the pure drug to determine
whether there are any wetting problems.
• choose appropriate media (pH, composition) and
volumes

60. Dissolution Method Development
At a glance
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ALKEM
R & D

61. May God bless you….
Thank You
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ALKEM
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