This document discusses in vitro drug product performance characterization and dissolution testing of solid oral dosage forms. It describes the importance of in vitro testing in predicting in vivo drug absorption and performance. The key factors that can affect drug dissolution are described, including drug substance properties, formulation composition, manufacturing processes, and test conditions. Common dissolution apparatus, media, and acceptance tolerances used in testing immediate release solid oral drug products are also summarized.

1. 1
IN VITRO
DRUG PRODUCT PERFORMANCE
Department of Pharmaceutics

2. Introduction
 Importance & utilization of in vitro characterization –
solid orals
 Relation – factors affecting in vitro drug release
 Intrinsic characters of drug, drug product,
mfg process, dissolution test method
 Practical issues and applications
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3. Importance of in vitro drug product
characterization
 Modern solid orals – high quality, reliable performance
characteristics
 Careful selection, QC, GMP
 Variables – Pdt appearance, potency, stability and dissolution
 Application of research methodologies
 Use of latest instruments, equipments, techniques – Complex
 Characterization – API potency, uniformity, drug release rate
 Data – Imp for FD, comparability assessment, QA & QC
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4. Importance of in vitro drug product
characterization
 Tests – Based on monographs, general chapters, guidance
docs – FDA/CDER
 Content & consistency – Potency/assay, content uniformity/
wt variation
 After intake of solid orals
Disintegration, dissolution, solubilization
Permeability across membranes of GIT
Critical steps
In vitro dissolution predict in vivo performance
- Low solubility drugs, modified release drugs
- Drug release – RL Step for in vivo absorption
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5. Solid orals - Types
• Tablets
 Oral (Regular)
 Effervescent
 Chewable
 Orally disintegrating
 Sublingual
 Buccal
 Lozenges, troches, tablet tricurates
 Dispensing tablets, solution tablets etc
• Capsules
 Hard Gelatin Capsules
 Soft Gelatin Capsules
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6. Solid orals - Release
• Immediate release –Drug promptly released after administration
• Modified release
 Delayed release (Enteric coated)- retard the release of active until it
passes stomach
 Protect gastric mucosa – drug irritation
 Limit exposure in stomach – acid labile
 Have target release – enhance absorption
 Extended release (CR, SR) – active available for extended period of
time
 SR, CR and repeat action – lengthen dosing interval, reduce frequency
 Enhance patient convenience, compliance, increased therapeutic
effectiveness, minimize toxic effects
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7. Factors affecting
In vitro drug product dissolution
Steps
 Wetting & penetration of dissolution medium – Dosage form
 Disintegration/ deaggregation
 Solubilization of drug substance into solution
Factors
 Factors related to drug substance
 Formulation factors
 Manufacturing process factors
 Dissolution/ drug release test conditions
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8. FACTORS RELATED TO DRUG SUBSTANCE
 Dissolution - Solubilization of drug into dissolution medium
 Control – affinity b/n solid & disso lutionmedium, as diffusion of drug into
bulk liquid media
 Noyes and Whitney equation
dm/dt = K (Cs-Ct)
(Cs-Ct) – conc gradient b/n diffusion layer & bulk soln
 Brunner & Tolloczko incorporated S
dm/dt = K’ x S (Cs-Ct)
S – Surface area, K’ – constant to chemical subs
 Brunner expanded scope – included Nernst’s theory
Dc/dt = [DS/Vh] x (Cs-Ct)
D – Diffusion coefficient, h – thickness of diffusion layer, V –dissolution
volume
 Drug dissolution – inflUenced by solubility, diffusivity, SA and solution
hydrodynamics
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9.  Solubility of drug substance
 Dissolution associated with solubility
 High solubility – high dissolution rates
 Comp with “ionizable groups” – depend on pH of disso med and pKa
comp
 Solubility check – eq sol method
 Metastable polymorphs – converted – forms
 Dynamic method – kinetic solubility
 Dose/solubility ratio – fluid vol reqd
 If > 1L, in vivo disso – problem
 Eg: Griseofulvin- aq sol 15 µg/ml, 500 mg, ratio of 33.3 L
dissolution/solubility limited oral absorption
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10.  Polymorphism
 Drug – physical forms, solid-state polymorphism
 Polymorphism – more crystalline forms, hydrate forms,
amorphous phases
 Change in lattice energy- diff solubility & dissolution
 Differences in solubility
 crystalline polymorph – less or several folds
 hydrates – less solubility than anhydrous forms
 amorphous forms – > 100 times of cry comp
 Eg: CPM – A & B
B greater oral abs than A
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11.  Salt factor and pH of diffusion layer
 Organic salt > water soluble than unionized molecule –
increased dissolution
 Most drugs – salts of Na/K & HCl
 Considered during FD
 Salts of free bases > soluble than parent unionized molecule –
change in use.
Eg: Naproxen
Parent unionized – rheumatoid/osteo arthritis
Na Salt – More soluble - Post partum pain
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12.  Surface area and particle size
 Dissolution – related to SA
 Decrease in particle size – increased SA, increased dissolution
 Micronized drugs – better dissolution
Eg: Glyburide, Griseofulvin
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13. FORMULATION FACTORS
 Excipients – have effects on formulation
ADVANTAGES
 Immediate release – excipients enhances dissolution
 Disintegrants – Crosscarmellose Na, Na starch glycolate –
deaggregation, more SA
 Surfactants – SLS, polysorbates – increase disso rates
Micelle formation – increase sol of hydrophobic drugs
Facilitates wetting, decreases ST, inc large drug-solvent surface interface
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14. FORMULATION FACTORS
DISADVANTAGES
 Drug shouldn’t bind to excipient – insoluble metal chelate – alters
dissolution
 Lubricants – stearates – hydrophobic (<1%) – reduces wetting &
disso
 Gelatin cap –prone to cross link – free aldehydes or keto groups –
pellicle forms – decreases dissolution
Modified release forms
 Absorption windows – hydrophobic/philic, ion exchange resin,
osmotic pump, coating
 Factors – properties of API, type of release device, excipients,
desired drug release profile
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15. MANUFACTURING PROCESS FACTORS
 Mfg variables affect dissolution rates
 Spray dried/ melt extrusion of API with PVP – stable –
enhanced disso
 Method of granulation – API character
Problems of mfg process
 Over mixing of lubricants, more compression pressure
 Modified release – Process- defined, robust, reproducible
batches
 Each process to have well defined end points
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16. DISSOLUTION/ DRUG RELEASE TEST CONDITIONS
 Variables
Dissolution medium
Volume
pH
Rotation speed
 Others
Instrumentation
Assay methods
Valid measurements & actual, accurate representation
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17. In vitro drug performance evaluation
DISINTEGRATION TEST
 Described in USP General chapter <701> Disintegration
 Its appropriate – if relation established with dissolution
 Or, DIS is discrimination with dissolution
 Official apparatus – USP basket rack assembly – Immediate release
 ICH Q6A – decision tree for applying disintegration test
 If dissolution is rapid (NLT 80% in 15 min at pH 1.2, 4.0 & 6.8) & drug
soluble in physiological range – disintegration test meaningful
 Drug – highly soluble – if highest dose soluble in 250ml or less aq.
Media over pH 1.2-6.8
 250 mL – typical BE study protocol – fasting subjects (8 fl. oz)
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18. Dissolution test
Immediate release solid oral dosage forms
 Quantitative measure of drug that dissolve from dosage form to
dissolution medium under std apparatus & procedure
 FDA – Dissolution testing of Immediate release solid oral dosage
forms
 Reqd for all solid oral dosage forms for pdt approval
 ICH Q6A – Dissolution test conditions, tolerances
 Test conditions – sensitive & discriminatory measure of drug pdt
performance
 Dissolution data – support – PA changes (mfg/ form), waive BE
studies*
* certain conditions only
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19. Dissolution test
Immediate release solid oral dosage forms
 Apparatus
 Media
 Tolerance
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20. Dissolution test - APPARATUS
Immediate release solid oral dosage forms
 USP General chapter <711> Dissolution
 Apparatus I (basket), II (paddle)
 Basket – 100 rpm (cap), 50 rpm (tab)
 Rotation rate increases, dissolution rate increases
 ICH Q6A – decision tree for deviation of suitable dissolution
test conditions and tolerances
 USP apparatus III – for immediate release excluding extended
release forms
 Apparatus 4 & 7 – extended release products (tab/cap)
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21. Dissolution test
Immediate release solid oral dosage forms
USP APPARATUS
USP
Apparatus
Description Rotational
speed
Dosage form
1 Basket 50-120 IR, DR, ER
2 Paddle 25-100 IR, DR, ER
3 Reciprocating
cylinder
6-35 dpm IR, ER
4 Flow through cell N/A ER & poorly soluble
API in IR
7 Reciprocating
disk
30 cpm ER
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22. Dissolution test – MEDIA
Immediate release solid oral dosage forms
 Media – based on physico chemical properties of drug & dosage
form
 Mimic physiological conditions
 pH range from 1.2 to 6.8 selected
 Common media – 0.1 N HCl, pH 4.5 acetate buffer, pH 6.8
phosphate buffer
 API
 Weak acids – DR increases with increases in pH
 Weak bases – DR decreases with increases in pH
 Poor aq. solubility – Large dissolution medium
 Surfactants may be used – sink conditions, inc solubility, DR – by
reducing interfacial tension, micelle formation
 Adding ionic salts – increases DR
 Hydroalcoholic solns adding – not preferred
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23. Dissolution test – MEDIA
Immediate release solid oral dosage forms
 HGC/SGC – enzymes may be added – prevents pellicle
formation
 Air bubbles – removed by deaeration method described in
USP <dissolution> or other methods
 Temperature – 37 + 0.5°C
 New research, bio-relevant media
 Predict dissolution of poorly soluble drugs, plasma levels of
lipophilic drugs
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24. Dissolution test – TOLERANCE
Immediate release solid oral dosage forms
 DT acceptance (tolerance) – Quantity (Q) that is dissolved within
a specified time interval
 Given as % of labeled claim (not assay) of API in dosage form
 75-80% of drug to be dissolved in set time (15-60 min)
 Dissolution test results evaluated by acceptance table in USP
<711>
 711 describes criteria for mean and individual sample
dissolution results
 S1, S2, S3 specifying 6, 12 & 24 samples tested
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25. Dissolution test – TOLERANCE
Immediate release solid oral dosage forms
 Q should be used “as is”, not confused with “Q + 5%” as
specified in stage I (S1)
 BE purpose – stage II (S2) used – 12 samples
 Dissolution tolerances established based on profiles obtained
from drug product on which BA/BE studies were done
 Generic immediate release product – meets USP specs
 If no USP specs – product to meet or exceed in vitro disso
performance of RLD
 Drug solubility, permeability, DR, pharmacokinetics –
considered for dissolution test specs – for product similarity/
equivalence
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26. Dissolution test
Modified release solid oral dosage forms
 Described in USP General chapter <724> Drug release
 Drug release test same as dissolution test, but applied for
modified release dosage forms not for IR
 FDA’s recommendations
BA & BE studies for orally administered drug products- General
considerations and extended release oral dosage forms:
Development, evaluation and application of in vitro/ in vivo
corelation
 Sample size – 6 to 24 units
 BE studies – 12 dosage units
 Different drug/ mfr – unique drug release, but need not use the
tests approved for testing RLD/ other mfr
 Unjustified tests are not encouraged
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27. Dissolution test - APPARATUS
Modified release solid oral dosage forms
 USP <724> – equipment specs, operational std for
app 3, 4 & 7 in addition to app 1 & 2
 App 1 & 2 – preferred
 If specific advantage over app 1 & 2 – others can be
used
 Non official apparatus - discouraged
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28. Dissolution test – MEDIA
Modified release solid oral dosage forms
 Same as used in immediate release dosage forms
 No provision for adding enzymes
 2 stage testing – For DR (enteric coated), solid orals
 1st in 0.1 N HCl for 2 hr, next in pH 6.8 buffer
 Acid stage and buffer stage – acceptance as per USP
<724>
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29. Dissolution test – TOLERANCE
Modified release solid oral dosage forms
 Release tolerance – based on in vitro drug release
performance on the bio-study lots
 Tolerance – minimum of 3 time points within labeled
dosing interval
 1st tolerance – set at 1 h ensure against “dose
dumping”
 Subsequent time points – set as ranges, final time
point – min value of label claim (NLT -80%)
 Tolerances as per acceptance table 4 in <724>
 3 levels described as for immediate release drug
products
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30. Dissolution/ drug release profile comparisons
 FDA guidance request submission of comparative multi-
point dissolution profile data in addition to meeting a
single point tolerance (Q)
 Profile comparison approaches – developed & evaluated
by agency
• Model-dependent
• Model-independent-multivariate
• Model-independent-index
 Useful to compare dissolution profiles of drug product
lots, evaluate effects of scale-up and PA changes
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31. Model dependant approach
 Profile similarity evaluated using suitable mathematical
model to describe dissolution data
 Recommended for dissolution “data rich” conditions
 Similarity region
 Statistical distance
 Confidence region
 Compare confidence region & similarity region
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32. Model independent
“Multivariate” approach
• Dissolution values are directly compared – no model /
creating parameters
• Each dissolution measurement – considered as variable,
corelated to adjacent time point
• Statistical distance – accounted for mean dissolution
differences and their variance, covariance matrix
• Later, confidence region is calculated around the
statistical distance.
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33. Model-independent-index approach
 Profiles are compared wrt prior defined index
 Several indices
 Rescigno (1992) & Rho, Rho-m, Delta-a, Delta-s.
 Fit factors – f1 & f2 – Moore & Flanner (1996)
 “FDA guidances” recommend f2, known as “similarity factor”
 f1 & f2 – measure overall difference and similarity b/n two
profiles
 Greater the value of f2 or smaller the value of f1 – more
similar are the 2 profiles
 f2 value b/n 50 to 100 suggests less than 10% global or
overall diff b/n 2 disso profiles
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34. Applications of in vitro dissolution
1. Product development
 IVD aids in guiding the selection of prototype
formulations, optimum level of ingredients to
achieve drug release profiles (ER)
 Guides in selection of “market image” product
to be used in BA/BE studies
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35. Applications of in vitro dissolution
2. Quality assurance
 Dosage form should possess acceptable in vitro, in
vivo BA/BE characters
 Dissolution test method and acceptance criteria
devised based on dissolution testing of bio-lots
 Depends of drug characteristics
 For future lots, dissolution used to assess lot-to-lot
performance of drug pdt – continued assurance
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36. Applications of in vitro dissolution
3. Product stability
 IVD – assess pdt quality, stability & shelf life
 Aged pdt – characteristics changed, hence IVD also
changes
Eg: Change in moisture level – alters hardness of
tablet – also IVD
 In polymorphs – transformations to stable
polymorphs – less soluble, IVD
 HGC – aldehyde-amino cross linking – pellicle
formation – altered IVD
 IVD done throughout the shelf life – provides
assurance of product performance till the expiry
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37. Applications of in vitro dissolution
4. Comparability assessment
 IVD used to assess the impact of pre and PA
changes to product
 “SUPAC guidelines” – nature and extent of
changes, describes the use of either a single
point or disso profile comparison to evaluate
changes
 Required to ensure continued performance
equivalency and pdt similarity
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38. Applications of in vitro dissolution
5.Waivers of in vivo BE requirements
 May be used to waive in vivo BA/BE in following
5.1 Formulation proportionality
 BA/BE studies conducted on 1 strength, BA/BE on other lower
strengths of same products – waived, if
 Proportionally similar – active & inactive, same dissolution
profiles
Formulation proportionality – 2 types
 1. constant proportion – A & IA changed proportionally across
strength
 2. constant weight – total weight is held constant across
strengths – for low dose drugs
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39. Applications of in vitro dissolution
5.2 Biopharmaceutics classification system (BCS)
 I – High solubility, high permeability
 II - Low solubility, high permeability
 III- High solubility, low permeability
 IV - Low solubility, low permeability
 Highly soluble drug – highest dose in < 250 ml aq media, pH 1.2 to 6.8
 Highly permeable – extent of abs (AUC) is > 90% of an administered
dose
 Rapidly dissolving product – IR, NLT 85% of labeled amount dissolves
within 30 min in type I-100 rpm or type-II-50 rpm, vol 900 ml or less in
each of these: acidic media, pH 4.5, pH 6.8
 Class I – HS, HP, rapidly dissolving – RLS is gastric emptying
 For class I BE studies can be waived
 Absorption calculated based on solubility, trans-intestinal absorption
rate constant, SI water volume and transit time
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40. Applications of in vitro dissolution
5.3 In vitro/ In vivo correlations
 Correlation done by techniques like de-convolution
 Technique predicts in vivo dissolution and absorption and
establishes the IVIV relation
 Levels of correlation – A, B or C
 Done for BCS Class II drugs & ER pdts
 If IVIVC established, BE may be waived
 Models to be identified based on objective criterion for in
vitro/ in vivo correlation analysis
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41. Limitations of in vitro dissolution
 Has several utilities & advantages, but limitations cant be
overlooked
Precision, accuracy of DT depends on several subtle operational
controls
 Stirring element eccentricity, agitation alignment, torsional
vibration, dosage form position, sampling position, dissolved
gases, flow patterns, heat transfer etc
 Recent study – diff tab positions – diff results
 Strict control on these subtle factors – assure reliable &
reproducible test results
Relevance – imp limitation of dissolution
 In absence of suitable IVIVC, dissolution # in vivo
 IR ptds – Class I & II, DT is overdiscriminating, bcoz oral
absorption is limited by gastric emptying or int permeation
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42. Limitations of in vitro dissolution
 IR pdts –Class III & IV, single point DT is non-discriminating-
unable to detect lots with poor in vivo performance
 If IVIVC – est for pdt, limited value as “Product specific” - cant
extend to other pdts
 Despite of limitations – DT is most imp and useful in vitro test
for assuring pdt quality
 Limitations – help in judicious conclusion about the
significance/ insignificance of DT results – pdt performance
 Recognize and develop meaningful and useful DT
methodology
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43. Glance…….
 In vitro characterization – essential for in vivo performance of
product
 In vitro testing – useful during pdt development, QA &
control, pdt stability testing, assess comparibility
 Useful in getting waivers for pdts meeting BCS Class I
requirement or when meaningful IVIVR is established
 Modern developments for in vitro testing – fiber optics
(detect drug concn. in disso med), application of artificial
neural network for disso prediction and Process Analytical
Technology (PAT)
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