[Link]/10.

14227/DT300323P162

Dissolution Method Development for Regulatory

Approval: A Comprehensive Review and Case Study
Pramod Parshuramkar1,*, Deepak Khobragade2, and Pranita Kashyap3
1Centaur Pharmaceuticals Pvt. Ltd., Hinjewadi, Pune, India.
2Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India.
3Dr. R. G. Bhoyar Institute of Pharmaceutical Education and Research, Wardha, Maharashtra, India.

e-mail: pramodudps@[Link]

ABSTRACT
In vitro dissolution testing is an important tool for any oral drug product. It is useful for product development and
to ensure the in vivo performance of drug products throughout their commercial life without conducting clinical or
bioequivalence studies after regulatory approval. It also plays a role in maintaining batch-to-batch consistency, providing
quality assurance, supporting biowaiver and post-approval changes, etc. Guidelines from regulatory agencies provide
expectations about the dissolution method and acceptance criteria; however, pharmaceutical manufacturers may fail
to comply with the requirements or the expectations of the agencies, resulting in dissolution deficiencies. Furthermore,
updates in dissolution testing may not be effectively communicated to non-industry scientists who are involved in
dissolution or drug delivery research. This article provides a comprehensive review of the current American and
European regulatory guidance for solid oral dosage forms followed by a case study to demonstrate how a dissolution
method should be developed, which can be used as a framework for any drug product.

KEYWORDS: Dissolution method development, dissolution specification, discriminatory power, dissolution

apparatus, dissolution medium

T
INTRODUCTION United States FDA Guidelines
his article focuses on the two main regulatory In 1997, the FDA published two guidances for industry
agencies, the United States Food and Drug that discuss the dissolution method and specifications for
Administration (FDA) and the European Medicine acceptance (1, 2):
Agency (EMA). In general, other health authorities
• Dissolution testing of immediate release solid oral
consider the development approach followed by these
dosage forms
two agencies appropriate and accept the same dissolution
methods with supporting rationale. Both agencies have • Extended-release oral dosage forms: development,
their own guidance and expectations about the dissolution evaluation, and application of in vitro/in vivo
method and acceptance criteria. The FDA and EMA correlations
guidance documents are non-binding recommendations
from the agencies, so alternative approaches can also be For generic product development, the FDA recommended
used and justified provided that the dissolution method to consider the United States Pharmacopeia (USP) and
has sufficient discriminatory power to assess the critical the dissolution method database maintained by the
quality attributes (CQAs) of a drug product. This article Office of Generic Drugs (3). The historical approach for
provides a comprehensive review of the requirements, dissolution method development for generic drugs was
expectations, significance, and rationale for selection of as follows (4). If the dissolution method is published in
dissolution test conditions and acceptance criteria. This the USP drug-specific monograph, then directly use the
article also provides a framework for dissolution method same dissolution method for the generic product. If the
development, including examples and case studies for dissolution method is not in the USP or no monograph
easy interpretation by pharmaceutical scientists. has been published, then refer and follow the method
*Corresponding author

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published in the FDA’s dissolution method database. If can be developed and validated if the USP and or FDA
the above-mentioned conditions are not suitable, then methods are not available or found inadequate. The
develop a new dissolution method. selection of the time point should be where not less than
(NLT) 80% of the drug is dissolved.
The FDA's perspective on developing the dissolution
method recently changed from a historical approach to Extended-Release Dosage Forms
a biopharmaceutical approach. Considering this, the FDA Irrespective of the method availability in the USP or
published the following guidance since 2017 (4–7): FDA dissolution method database, it is expected that
a product-specific discriminatory dissolution method
• Waiver of in vivo bioavailability and bioequivalence should be developed, thoroughly evaluated, and validated
studies for immediate release solid oral dosage for extended-release (ER) dosage forms. When setting the
forms based on a Biopharmaceutics Classification product specifications, a minimum of three time points
System (BCS) should be selected to cover the initial, middle, and final
phases of the dissolution profile. Dissolution acceptance
• M9 biopharmaceutics classification system-based
criteria for the initial and middle time points should be
biowaivers
based on a mean target value ± 10%. The last time point
• Dissolution testing and acceptance criteria for should cover at least 80% of the drug release. The target
immediate release solid oral dosage form drug value is based on the mean drug release of the lot/batch
products containing high solubility drug substances used in the clinical study.

Immediate-Release Dosage Forms Fixed-Dose Combination Products

For immediate-release (IR) drug products, the BCS should Fixed-dose combination (FDC) drug products can be
be considered when selecting the dissolution method the combination of two or more drug substances with
and acceptance criteria (4). The dissolution acceptance similar or different release mechanisms (IR and/or ER).
criteria should be 80% of drug release within 30 min. For FDC drug products, both USP and FDA databases
should be used as a starting point to see the conditions
For drug products containing highly soluble drug that have already been approved for the FDC or the single
substances, the following dissolution methods should be component drug products (9).
used (7).
The development of a dissolution method for FDC
• Method A: Basket apparatus; 0.1 N HCl medium, drug products is challenging due to the differences in
500 mL volume; 100 rpm agitation speed; without physicochemical properties of the drug substances.
surfactant. Individual dissolution methods can be developed for
each drug substance in the FDC product; however, it is
• Method B: Paddle apparatus; 0.1 N HCl medium,
expected to have a single dissolution method because of
500 mL volume; 50 rpm agitation speed; without
the analytical efficiency, time and cost savings, feasibility
surfactant. A sinker can be added as per the need,
during the commercial-release testing, and reduction
and agitation speed can be increased to 75 rpm with
in the burden during the stability study. Essentially, the
justification.
method should be robust and reproducible during routine
With appropriate justification, other test conditions can quality control testing.
be used and accepted by regulatory agencies. For IR drug
IR-FDC drug products comprising multiple highly soluble
products containing highly soluble drug substances, the
drug substances can be evaluated with a similar approach
dissolution test can be replaced with the disintegration
as an IR drug product containing a single component.
test in the finished product specifications with adequate
Similarly, the dissolution test can be replaced with the
justification (8).
disintegration test with adequate justification.
For drug products containing poorly soluble drug
In IR-FDC drug products comprising substances with
substances, both USP and FDA databases should be used
different solubilities, precedence should be given to
as a starting point to see what conditions have already
the poorly soluble component over the highly soluble
been approved. The selection of the dissolution method
component because its dissolution is rate-limiting in the
should be based on its feasibility and discriminatory
in vivo absorption. The selection of the time point should
power for the proposed drug product. A new method
be where NLT 80% of the drug is dissolved.

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 In FDC drug products comprising substances with different • Reflection paper on the dissolution specification for
release mechanisms, precedence should be given to the generic oral immediate release products
ER component, followed by the IR component if it is poorly
soluble. When setting the acceptance criteria, depending For all dosage forms, a product-specific dissolution
on the release mechanisms of each component, a similar method with discriminatory power should be developed
approach for IR or ER drug products containing a single and validated irrespective of method availability in any
component can be followed. public database.

Delayed-Release Dosage Forms Immediate-Release Dosage Forms

Delayed release (DR) dosage forms commonly have an For IR dosage forms, the dissolution method should
enteric coating. There can be other DR mechanisms based be developed irrespective of the drug solubility class.
on the rationale behind the product design (e.g., to protect Dissolution acceptance criteria should be 75–85% drug
against irritation of the stomach mucus membrane, to release in a given period of time. The target value is the
prevent acidic degradation of the drug, or for targeted mean drug release of the lot/batch used in the clinical
drug delivery in the gastrointestinal (GI) tract [i.e., colon study minus 10%.
targeting]). DR dosage forms can be non-disintegrating Extended-Release Dosage Forms
(coated tablets) and disintegrating (tablets or capsules When setting the product specifications for ER dosage
containing coated multiple-unit pellet systems). forms, a minimum of three time points should be
selected. The first time point is to eliminate dose dumping
In general for conventional DR dosage forms, a minimum
or to ensure the loading dose (20–30% drug release). The
of two time points is required to meet the specifications.
second time point is to define the drug-release pattern
The first point controls the drug release in the acid stage
(50% drug release), and the acceptance criteria should
(0.1 N HCl), usually NMT 10% in 2 h, and the second
be ± 10% to the mean target value. The last time point
time point controls drug release in the higher pH buffer
is to ensure at least 80% of the drug release. The target
stage (pH 6.8), usually NLT 80% in 45 min. If DR dosage
value is the mean drug release of the lot/batch used in
forms are designed for pulsatile, controlled release, or
the clinical study.
targeted delivery in the GI tract, the selection of a stage 2
dissolution medium, time points, and acceptance criteria Fixed Dose Combination Products
can be set as per the expectations for each release In FDC drug products comprising drug substances
mechanism (10, 11). with different solubilities and/or release mechanisms,
precedence should be given to the ER component and/
European Medicines Agency Guidelines
or poorly soluble components. Acceptance criteria can be
Just like the FDA follows the USP, the EMA follows the
derived using the same principles recommended by the
European Pharmacopeia (EP). However, EP only has
EMA or EP for individual IR or ER drug products containing
monographs for drug substances, and not drug products.
a single component.
Recently, EP has started to publish drug product
monographs, including dissolution methods for drug Delayed-Release Dosage Forms
products. For conventional DR dosage forms, expectations of the
EMA are the same as the FDA. USP general chapter <711>
The British Pharmacopoeia (BP) includes both drug and EP general chapter <2.9.3> have been harmonized.
substances and drug product monographs. Earlier BP For non-conventional DR dosage forms, selection of a
monographs were acceptable for developing drug stage 2 dissolution medium, time points, and acceptance
products for European territories; however, in February criteria can be set according to the expectations of the
2020, the UK withdrew from the European Union and EMA or EP for each release mechanism.
become a "third country" (12). So, drug products that
are developed for the European market must follow and DISSOLUTION METHOD DEVELOPMENT
comply with EP and EMA specifications and guidance. A product-specific dissolution method should be
developed in the sequence of activities given in Figure 1.
In addition to the general chapters by the EP for the
dissolution testing, EMA has published guidelines that Drug Solubility and Solution Stability
discuss dissolution method expectations and acceptance An analytical method should be developed for detecting
criteria (13, 14): the drug using suitable detection techniques. The
solubility of the drug should be determined in aqueous
• Guideline on quality of oral modified release products

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 Dissolu�on Method Development

Drug Sink Dissolution Evaluate Set product

solubility condition & apparatus & Method
discrimin- specifica-
and solution dissolution agitation validation
atory power tions
stability medium speed

Figure 1. Flow diagram of dissolution method development.

media with a pH in the range of 1–6.8 at 37 ± 1 °C. FDA (7). In other cases, the choice of the medium should
Solution stability in each medium should be ensured be based on the ability to maintain the sink condition and
using the stability-indicating assay or impurity method stability of the solution. If the drug substance has pH-
of the analysis. Drug solubility and stability are useful independent solubility and stability, then the preferred
for determining the solubility class and for the selection dissolution medium can be 0.1 N HCl or purified water.
of dissolution medium. If the highest dose of the drug If a drug substance has poor solubility in all pH ranges,
substance is soluble in 250 mL of the aqueous medium then the solubility study can be conducted by adding
with a pH in the range of 1–6.8, then that drug is the minimum effective concentration of the surfactant.
considered highly soluble (5, 6, 7). The choice and concentration of surfactant should be
based on the evaluation and appropriate justification.
For FDC drug products, an in-depth evaluation of the Commonly, sodium lauryl sulfate, polysorbate 20, and
physicochemical properties of each drug substance, polysorbate 80 are used as surfactants in the dissolution
like pH solubility, solution stability, and drug-to-drug medium. If adequate solubility to satisfy sink conditions
interaction in the physiological pH range should be exists only over a narrow pH range, then an appropriate
performed. In general for FDC drug products, an analytical buffer should be selected to maintain the pH range.
method with high performance liquid chromatography
(HPLC) is preferred over UV-visible spectroscopy to If FDC drug products contain drug substances with
avoid interference in the absorbance at a particular different solubilities, a pH should be selected that meets
wavelength. However, UV-visible spectroscopy methods the sink condition for the low soluble drug. If FDC drug
are acceptable with the appropriate demonstration products contain multiple poorly soluble drug substances
of specificity and lack of interference for the active with different pH solubilities or pH-dependent solution
ingredients. stabilities, then multiple pH media and buffers should
be evaluated (even within narrow pH ranges) to
Sink Conditions and Selection of Dissolution Media accommodate the sink condition and solution stability of
To use any aqueous medium as a dissolution medium, it multiple drug substances.
should be capable of maintaining the sink condition and
have sufficient solution stability to cover the duration of Dissolution of conventional DR dosage forms can be
time required to perform the dissolution test and analyze performed in 0.1 N HCl followed by a pH 6.8 phosphate
the sample aliquots. The sink condition is at least three buffer. The acid-stage dissolution ensures or validates
times the volume needed to obtain a saturated solution the efficiency of enteric-coating polymers to avoid
based on the highest strength of the drug product (10, drug release or degradation beyond the specified limit,
15, 16). The preferred dissolution media volume for USP commonly no more than (NMT) 10%. If the drug is
apparatus 1 and 2 (basket and paddle, respectively) is 500 insoluble in 0.1 N HCl, then the acid-stage dissolution
900, or 1000 mL, and in the worst case, 1800 mL. For the performance can be checked by developing the acid
USP apparatus 3 (reciprocating cylinder), media volume medium with the addition of surfactants. In some cases,
can be in the range of 200–300 mL per vessel. the drug can be degraded in 0.1 N HCl, where the acid
stage dissolution can be performed by detecting the
For IR dosage forms containing highly soluble drugs, 500 degradant products alone or along with the parent drug
mL of 0.1 N HCl should be directly used according to the substance.
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 Selection of Dissolution Apparatus and Agitation or unit-to-unit variation. The agitation speed is also
Speed important to achieving the discriminatory power of the
There are seven compendial dissolution apparatus used dissolution method. An increase in agitation speed often
in the pharmaceutical industry, depending on the dosage reduces the discriminatory capacity of the dissolution
form (10, 11): method, with a low agitation speed causing the variation.
• USP apparatus 1 (basket): used for tablets, capsules, USP apparatus 3 (reciprocating cylinder) can be used
suppositories, and floating dosage forms for IR, ER, and DR dosage forms like matrix tablets
or formulations containing coated multi-particulate
• USP apparatus 2 (paddle): used for tablets, capsules
systems, which may not completely disintegrate into fine
(with or without sinkers), and suspensions
particles in the earlier rows and pass through the mesh of
• USP apparatus 3 (reciprocating cylinder): used for IR, the cylinder. Apparatus 3 can be useful when drug release
ER, and DR tablets is pH-dependent, in which case it becomes appropriate to
adjust pH over the course of the dissolution run. Agitation
• USP apparatus 4 (flow-through cell): used for implants for apparatus 3 is considered in the form of dips per
or when sink conditions cannot be achieved using minute (dpm). When developing a dissolution method
another apparatus using apparatus 3, it is necessary to optimize the dips,
which generally range from 5–30 dpm.
• USP apparatus 5 (paddle over disc): used for
transdermal delivery systems USP apparatus 4 (flow-through cell) is used for products
containing drugs that have limited solubility. For USP
• USP apparatus 6 (rotating cylinder): used for
apparatus 4, the media flow rate is critically controlled.
transdermal delivery systems
Standard flow rates are 4, 8, and 16 ml/min. Other
• USP apparatus 7 (reciprocating disc): used for flow rates and modified flow-through cells can be
transdermal delivery systems and ER tablets used depending on the need and with justification, for
example, powder dosage forms.
USP apparatus 1 and 2 (baskets and paddle, respectively)
is widely used for dissolution testing of solid oral dosage USP apparatus 7 is useful for ER dosage forms containing
forms, as they are feasible and easily available. In some coated multi-particulate systems or for osmotic-
cases, where a basket or paddle apparatus is not feasible, controlled release delivery systems.
another USP apparatus can be used. Evaluation of the
For handling the sequential dissolution in the case of DR
dissolution apparatus should consider the product design
dosage forms, two methods are commonly discussed in
initially, then further considerations should be made
USP <711> and EP <2.9.3>.
based on the observations during the evaluation. The
paddle apparatus can be used for IR and ER dosage forms. Method A: Perform the acid-stage dissolution using 750
Sinkers can be used for dosage forms that float or stick to mL of 0.1 N HCl with a paddle or basket apparatus for 2
vessel walls. The basket apparatus can be used for dosage h followed by sampling and testing for acid-stage drug
forms that tend to float. In certain cases, drug products release. After 2 h, add 250 mL of 0.20 M tribasic sodium
in the dissolution vessel form a cone or hip if there is a phosphate to each vessel to make 1000 mL of pH 6.8
significant amount of insoluble material. In those cases, buffer. If required, the pH adjustment can be done using
the agitation speed can be increased or apex vessels can 2 N HCl/NaOH.
be used with appropriate justification. A non-compendial
low-volume apparatus with mini paddles and baskets Method B: Perform the acid-stage dissolution using 1000
can be adequately qualified and used with appropriate mL of 0.1 N HCl with a paddle or basket apparatus for
justification (e.g., low-dose drug products). 2 h followed by the sampling and testing for acid-stage
drug release. After 2 h, drain the 0.1 N HCl from each
The recommended agitation speed is 100 rpm for the vessel with careful attention so that the drug product
basket apparatus and 50 rpm for the paddle apparatus. under study should not be lost, and pour 1000 mL of pH
A paddle with an agitation speed of 75 or 100 rpm can 6.8 buffer (previously equilibrated at 37 ± 0.5 °C) in each
be used with an optimization study and the justification. vessel.
Sometimes, 50 rpm agitation does not create sufficient
hydrodynamics to uniformly disintegrate or dissolve Another option is to directly replace each vessel of 0.1
the drug product, resulting in incomplete drug release N HCl with another vessel containing 1000 mL of pH 6.8

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buffer (previously equilibrated at 37 ± 0.5 °C) followed essential for developing a control strategy by controlling
by the transfer of drug product from the stage 1 vessels Critical Material Attributes (CMAs), fixing the processing
to the stage 2 vessels. In each case, stage 2 dissolution equipment, and defining acceptable ranges for the
can be performed commonly up to 45 min or on a case- Critical Process Parameters (CPPs). So, with this rationale,
by-case basis as per the adopted dissolution time point, the selected dissolution method should be capable of
considering the release mechanism or design of the drug detecting acceptable and unacceptable characteristics
product. that can be possible during the commercial life of the
product.
Dissolution of DR dosage forms can also be performed
using apparatus 3 and 4. The use of apparatus 3 makes Once a tentative dissolution method (including medium,
it easier for the sequential dissolution as the 0.1 N HCl volume, apparatus, and agitation speed) has been chosen,
can be added in the first row and the pH 6.8 buffer in the then the method should be evaluated for discriminatory
second row using media volumes in the range of 200–300 power by preparing different formulations with
mL. meaningful changes to the composition and/or process.
The term ‘meaningful change’ here signifies any change
Discriminatory Power Evaluation and Method
Validation in the raw material, composition, or manufacturing
Discriminatory power is the ability of the dissolution process that is possible during routine operation that
method to detect changes in the drug product. The may affect the in vivo performance of the product (e.g.,
rationale behind the requirement for discriminatory differences in particle size or polymorphic forms of the
power is as follows. drug substance, differences in lot-to-lot polymer viscosity,
changes in functional excipient level like polymer,
For a new drug product or a new generic drug product, in disintegrant, binder, lubricant level, etc). Manufacturing
vivo clinical or bioequivalence (BE) studies are conducted process changes can be granulation parameters, milling
after the completion of the formulation, analytical, parameters, tablet hardness, polymer coating spray
and process development (which are submitted in rate, coating weight build-up, curing temperature, curing
the dossier to the agency for marketing approval). time, etc. Complete removal of any excipient or change
Dissolution specifications are finalized based on the in the process design to prove the discrimination is not
dissolution data of batches used in the in vivo clinical/ supported.
BE studies. Throughout the commercial life of the drug
product, batches are expected to have the same in vivo To check the discrimination, a dissolution profile of the
performance, which is indirectly ensured by using the final formulation should be compared to a formulation
in vitro dissolution test as a quality control tool (13, 14). with meaningful changes. The comparison of dissolution
Dissolution is identified as a CQA for most formulations profiles may be done using similarity factor analysis,
(exceptions can be IR dosage forms containing highly i.e., difference factor (f1) or similarity factor (f2). An f1
soluble drugs) and is often utilized to determine the value above 15 or an f2 value below 50 signifies that the
Proven Acceptable Ranges (PAR) and generate the design dissolution profiles are different (18). A difference in the
space. The study of any individual unit operation or dissolution profile indicates the discriminatory power of
parameter while keeping other parameters constant will the method. Discriminatory power can also be proved if
give the PAR. By changing more than one factor at a time, the optimized formulation complies with the proposed
multidimensional combinations and interactions of input dissolution acceptance criteria while formulations
variables and process parameters can be evaluated. If a with meaningful changes fail to comply with the same.
factor demonstrates the ability to assure quality, then The choice of any one method should be based on
that factor generates design space (17). For example, the the method's comparative discriminatory capacity. To
factors that can affect dissolution are the granulation achieve maximum discriminatory power, the dissolution
process (input raw materials attributes, granulating method can be evaluated by varying the media volume,
fluid quantity, particle size distribution of the granules, agitation speed, apparatus, etc. Not all formulation or
etc.), lubrication process (lubricant level, lubrication process changes are expected to result in a significant
time, etc.), compression process (compression force, dissolution profile difference, but the dissolution test
tablet hardness, etc.), coating process (weight build-up, should be able to discriminate expected differences due
spray rate, curing temperature, curing time, etc.), and to the underlying drug release mechanism(s).
stability measures (temperature, humidity, hold time, There is a possibility of the dissolution method being over-
etc.). Therefore, the discriminatory dissolution method is discriminatory and leading to the rejection of batches
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 that may not have a concern for in vivo performance. If Setting Product Specifications
the manufacturing process is in a state of control that is The dissolution profile of the test batch used in the
capable of consistently producing a product that meets clinical or BE study should be used to determine the drug
specifications, an overly discriminating dissolution test product's final specification. In case of IR products where
may be justified. a BCS-based biowaiver is applied, the Q value can be
set between 15 and 30 mins. Table 1 and 2 provides the
If there is a concern that the process may produce batches understanding for setting the dissolution specifications
that are out of specification, then the best approach to for the American and European market, respectively (2, 4,
reducing this risk is to establish the IVIVC by performing 7, 13, 14, 20). Hypothetical examples are included in Tables
an in vivo study on the batches produced with the most 1 and 2 to make it easy to understand the expectations of
extreme dissolution profiles, followed by the setting the regulatory agencies.
of in vitro dissolution acceptance criteria based on the
acceptable and non-acceptable in vivo behavior of the Briefly, the best possible approach to setting the
formulation. dissolution acceptance criteria for an IR drug product is
mean drug release of the clinical/BE batch at a given time
The finalized discriminatory dissolution method should point minus 10% (Q). For an ER drug product, the target
be validated as per ICH Q2 guidance and USP <1092> (10, value is the mean drug release of the clinical/BE batch ±
19). 10% for early time points and minus 10% for the last time

Table 1. Dissolution Specifications for the USA Market (2, 4, 7)

Type Conditions Acceptance Criteria (US FDA) Hypothetical Examples
Mean drug release of Acceptance criteria
test lot used in clinical/
BE study
IR Highly soluble drugs Single point specification: 15 min: 82% 30 min: NLT 80%
NLT 80% in 30 min 30 min: 93%
IR Complete drug release ≤ 60 min Single point specification: 15 min: 65% 45 min: NLT 80%
NLT 80% in specified time interval 30 min: 82%
45 min: 93%
60 min: 99%
IR Complete drug release > 60 min Minimum 2 time points: 15 min: 35% 60 min: NLT 60%
1st time point: < 60 min 30 min: 42% 90 min: NLT 80%
2nd time point: > 60 min & 80% release 45 min: 63%
60 min: 72%
75 min: 85%
90 min: 96%
ER Conventional ER Minimum 3 time points (initial, middle, 1 h: 18% 1 h: NMT 30%
and final phase) & 80% releasea 5 h: 52% 5 h: NLT 42% & NMT 62%
10 h: 93% 10 h: NLT 80%
ER Modified ER with bi-phasic or multi- Minimum 3 time points (initial, middle, 0.5 h: 25% 0.5 h: NLT 15% & NMT 35%
phasic release and final phase) & 80% releasea 4 h: 55% 4 h: NLT 45% & NMT 65%
8 h: 96% 8 h: NLT 85%
DR Conventional enteric-coated drugs Minimum 2 time points: Acid stage: 2 h: 4% Acid stage, 2 h: NMT 10%
Acid stage: usually NMT 10% in 2 h Buffer stage: Buffer stage, 45 min: NLT 80%
Buffer stage: usually NLT 80% in given 15 min.: 65%
time interval 30 min.: 82%
45 min.: 93%
60 min.: 99%
DR DR with ER mechanism Minimum 1 time point in acid stage and Acid stage: 2 h: 4% Acid stage, 2 h: NMT 10%
3 time points in buffer stage. Buffer stage: Buffer stage:
Acid stage: NMT 10% in 2 h 1 h: 22% 1 h: NLT 12% & NMT 32%
Buffer stage: Initial, middle, and final 2 h: 52% 2 h: NLT 42% & NMT 62%
phase & 80% releasea 6 h: 93% 6 h: NLT 80%
aAcceptance based on mean target value ± 10%; mean target value is the mean drug release of the test lot used in the clinical/BE study.
FDA: Food and Drug Administration; IR: immediate release; ER: extended release, DR: delayed release; BE: bioequivalence; NLT: not less than; NMT: not
more than.

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Table 2. Dissolution Specifications for the Europe Market (13, 14, 20)
Type Conditions Acceptance Criteria (EMA) Hypothetical Examples
Mean drug release of test Acceptance criteria
lot used in clinical/BE study
IR Complete drug release ≤ 45 min Single point specification: 15 min: 92% 15 min: NLT 80%
Q value = bio batch mean drug release – 30 min: 99%
10%. 15 min: 79% 30 min: NLT 80%
Q value is usually 75–85%. 30 min: 93%
Q value above 85% is considered irrelevant.
15 min: 65% 45 min: NLT 85% i
30 min: 82%
45 min: 99%
IR Complete drug release > 45 min Minimum 2 time points: 15 min: 35% 45 min: NLT 50%
1st time point: < 45 min 30 min: 42% 90 min: NLT 85%
2nd time point: > 45 min & 80% release 45 min: 63%
60 min: 72%
75 min: 85%
90 min: 96%

ER Conventional ER drug products Minimum 3 time points: 2 h: 22% 2 h: NLT 12% & NMT 32%
1st time point: 20–30 % release 6 h: 52% 6 h: NLT 42% & NMT 62%
2nd time point: 50% release 12 h: 93% 12 h: NLT 80%
3rd time point: ≥ 80% releasea
ER Modified ER with bi-phasic or Minimum 3 time points: 0.5 h: 25% 0.5 h: NLT 15% & NMT 35%
multi-phasic release 1st time point: 20–30 % release 4 h: 55% 4 h: NLT 45% & NMT 65%
2nd time point: 50% release 8 h: 96% 8 h: NLT 85%
3rd time point: ≥ 80% releasea
DR Conventional enteric-coated Minimum 2 time points: Acid stage: 2 h: 4% Acid stage, 2h: NMT 10%
drugs Acid stage: usually NMT 10% in 2 h. Buffer stage: Buffer stage, 45 min: NLT
Buffer stage: usually NLT 80% in given time 15 min: 65% 80%
interval. 30 min: 82%
45 min: 93%
60 min: 99%
DR DR with ER mechanism Minimum 1 time point in acid stage and 3 Acid stage: 2 h: 4% Acid stage, 2 h: NMT 10%
time points in later buffer stage. Buffer stage: Buffer stage:
Acid stage: usually NMT 10% in 2 h. 1 h: 22% 1 h: NLT 12% & NMT 32%
Buffer stage: 2 h: 52% 2 h: NLT 42% & NMT 62%
1st time point: 20–30 % release 6 h: 93% 6 h: NLT 80%
2nd time point: 50% release
3rd time point: ≥ 80% releasea
a
Acceptance based on mean target value ± 10%; mean target value is the mean drug release of the test lot used in the clinical/BE study.
EMA: European Medicines Agency; IR: immediate release; ER: extended release, DR: delayed release; NLT: not less than; NMT: not more than.

point. For a DR drug product, the target in the acid stage between the batch with changes vs. the batch used in the
is NMT 10% after 2 h, and the buffer stage target depends early clinical/BE studies (13).
on the release mechanism (IR or ER) or design of the drug
product. CASE STUDY
A dissolution method development case study is presented
Any deviation from the range specified above can be in the subsequent sections for a better understanding of
justified by performing the additional clinical/BE studies each element. The case study considers a model drug and
using the batches with extreme dissolution profiles. ER tablet dosage form; however, the same procedure can
During the stability study, it is expected that the product be applied to any dosage form.
should meet the acceptance criterion that was derived
Materials
based on the batches linked to the clinical/BE studies, any
Metformin hydrochloride ER tablets (50 mg) was
change in the dissolution behavior during the stability
selected as a model drug for this study. Metformin
study can trigger an out-of-specification value followed
hydrochloride (Harman Finochem), lactose monohydrate
by an investigation. If needed, to support the change in
(DFE), povidone (BASF), colloidal silicon dioxide (Evonik),
dissolution data, acceptance criteria can be revised by
magnesium stearate (Petergreven), hypromellose (Lotte),
demonstrating additional BE (i.e., dissolution profile)

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 ethylcellulose (DuPont), triethyl citrate (Stearinerie Shimadzu) was used with 1-cm quartz cuvettes. Drug
Dubois), talc (Emerys), and isopropyl alcohol (Runa standard solutions with a final concentration of 10 µg/
Chemicals) were obtained from Centaur Pharmaceuticals mL were prepared using various buffer solutions (0.1 N
Pvt Ltd. Hydrochloric acid (37%), sodium hydroxide, HCl, pH 4.5 acetate, pH 6.8 phosphate buffer, and water).
potassium dihydrogen phosphate, disodium hydrogen Absorbance was measured for each standard solution
phosphate, sodium acetate, glacial acetic acid were of using the UV spectrophotometer at a wavelength ranging
analytical grade. from 200 to 400 nm. The pattern of the spectrum and
absorbance maxima was evaluated in each medium. The
Optimized Formulation Development
UV spectrophotometer method was found to be feasible.
A formulation was optimized with a reservoir system,
Spectra with 0.1 N HCl showed a solvent effect, giving a
and the target was to achieve an ER profile. The tablet
sharp peak close to 200 nm. The absorbance maximum
core was prepared using granules manufactured using
was 233 nm in pH 4.5 acetate, pH 6.8 phosphate buffer,
an aqueous wet granulation process, compression using
and water. A concentration of 10 µg/mL was finalized to
8.2 mm round punches, and B-tooling tablet press with
achieve an absorbance of not more than 1.0.
a target tablet weight of 250 mg. To smooth the core
surface and to serve as a barrier between the core and the Drug Solubility Study and Solution Stability
controlled-release polymer coating, a 3% w/w subcoating The pH-solubility profile of the drug was determined in
was layered over the core tablets. After subcoating, triplicate at 37 ± 1 °C in aqueous media with a pH in the
controlled-release polymer coating (15% w/w) was range of 1–6.8 using the shake-flask method. The drug
performed using a hydrophilic-hydrophobic polymer was added to the 10 mL of the corresponding buffer
combination. The last film coating used an Opadry premix solution until a saturated solution was formed. Saturated
(3% w/w). The formulation composition is listed in Table solutions were kept in a shaker maintained at 37 ± 1 °C
3 (formulation #1). for 24 h. After 24 h, each solution was filtered (0.45-µ
nylon syringe filter, Millipore), followed by dilution using
Analytical Method Development
the same buffer solution, and the concentration was
An ultraviolet (UV) spectrophotometer (1800 series,

Table 3. Case Study: Composition of Optimized Formulation

Components Function Value (mg)
Intragranular
Metformin Hydrochloride Drug substance 50
Povidone K 30 Binder 15
Lactose Monohydrate Diluent 181.25
Purified water Solvent q.s.
Extragranular
Colloidal Silicon Dioxide Glidant 1.25
Magnesium Stearate Lubricant 2.5
Subcoating
Hypromellose – 5 CPS Film former 7.5
Purified water Solvent q.s.
Controlled-release polymer coating:
Ethyl cellulose – 10 CPS Release controlling polymer 16.22
Hypromellose – 5 CPS Pore former and film former 19.7
Triethyl Citrate Plasticizer 2.7
Isopropyl Alcohol Solvent q.s.
Purified water Solvent q,s,
Film Coating
Opadry Premix Film former with color 8.88
Purified water Solvent q.s.
Film coated tablet weight 305
CPS: Centipoise; q. s.: quantity sufficient

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determined using UV spectrophotometry. Mean drug required. Although the agitation speed increased with
solubility was 199, 167, 250, and 200 mg/mL in the 0.1 N the paddle, the release rate was similar, which could be
HCl, pH 4.5 acetate buffer, pH 6.8 phosphate, and purified due to the design of the drug product by the reservoir
water, respectively. The stability of the standard solution system. The discriminatory capability of the method can
in each medium at 37 ± 1 °C was checked for up to 72 h. be reduced by increasing the agitation speed; hence,
a paddle at 50 rpm and a basket with 100 rpm was
Sink Condition and Dissolution Medium
considered appropriate for comparison.
The drug has pH-independent, high solubility, and the sink
condition can be maintained in 500 mL, allowing 3 times
the unit dose (150 mg) to be sufficiently dissolved. The
drug solution with each medium was found stable for up
to 72 h. Considering the solubility data, any medium can
be taken forward as a dissolution medium. As the drug
has pH-independent solubility, water was preferred as
the dissolution medium, which was also proven to have
discriminatory capacity, as discussed in the later sections.

A standard calibration curve was prepared in purified

water with the drug concentration ranging from 2–12 Figure 2. Dissolution profiles (evaluation of test apparatus).

µg/mL. The linear relationship between the drug

concentration and absorbance makes water suitable for Evaluation of Discriminatory Power
determining the drug concentration by measuring the The discriminatory power was evaluated by preparing the
absorbance. To obtain the drug concentration within different formulations with meaningful changes in the
the linear calibration range during dissolution analysis, composition like polymer ratio, coating weight build-up,
the dilution factor was adjusted to achieve a final and changes in the manufacturing process like coating
concentration of 10 µg/mL. spray rate. Dissolution profiles of the formulation with
these changes were compared with the dissolution profile
Dissolution Apparatus and Agitation Speed
of the optimized formulation through f1 and f2 calculation.
The dissolution apparatus was evaluated by conducting
The difference in dissolution profiles is not only measured
the dissolution test with the optimized formulation using
through these calculations, but also based on the overall
a basket apparatus at 100 rpm and paddle apparatus at
dissolution profile. The reason for this is that the f1 and
50, 75, and 100 rpm. The dissolution data are presented
f2 values are driven by multiple time points, which may
in Table 4 and Figure 2.
not be necessary to show discrimination. Sometimes,
Both apparatus were found feasible and showed uniform the data can be evaluated by identifying differences at
drug release. Floating or sticking of the tablet was not particular time points that are critical to controlling the
observed in the case of the paddle, so a sinker was not in vivo performance (i.e., part of the acceptance criteria).

Table 4. Case Study: Dissolution of Optimized Formulation

Time Point USP Apparatus 2, USP Apparatus 2, USP Apparatus 2, USP Apparatus 1,
(h) 50 rpm 75 rpm 100 rpm 100 rpm
0 0 0 0 0
1 3 (1 – 4) 3 (2 – 5) 4 (3 – 7) 2 (1 – 5)
2 5 (3 – 8) 4 (3 – 7) 7 (6 – 10) 5 (4 – 8)
3 28 (23 – 31) 26 (24 – 29) 31 (28 – 35) 28 (25 – 31)
4 51 (46 – 54) 48 (46 – 51) 52 (47 – 56) 50 (48 – 53)
6 81 (75 – 83) 78 (76 – 81) 85 (84 – 88) 83 (81 – 85)
8 93 (90 – 95) 92 (89 – 94) 97 (95 – 100) 95 (91 – 99)
10 95 (93 – 98) 96 (94 – 99) 100 (98 – 102) 96 (94 – 99)
12 96 (95 – 99) 98 (97 – 100) 99 (97 – 101) 99 (99 – 102)
Values are mean (range), n = 12. Dissolution medium was 500 mL of water.
USP: United States Pharmacopeia.

AUGUST 2023 171

[Link]
 To evaluate the discriminatory power of the dissolution Results and Discussion
test methods (paddle apparatus at 50 rpm versus The results are presented in Table 5 and Figure 3. Both
basket apparatus at 100 rpm), three formulations trials dissolution methods successfully discriminated the slight
were developed by changing formulation variables changes in polymer-to-pore former ratio (Fig. 3A and 3B),
(formulation #2 and #3) or process variables (formulation polymer coating weight build-up (Fig. 3C and 3D), and
#4). Formulation trial #2 was manufactured by changing polymer spray rate (Fig. 3E and 3F). Although f2 values
the release-controlling polymer-to-pore former ratio were above 50, there were differences in the release at
(ethylcellulose: hypromellose) from 42:51 to 39:54 and some early and middle time points.
keeping the coating weight build-up, other components,
and process parameters constant with the optimized Although both the dissolution methods are discriminatory
formulation. Formulation trial #3 was manufactured and equally feasible, the paddle apparatus method is
by keeping the same coating composition and process comparatively more discriminatory than the basket
parameters but increasing the CR polymer coating weight apparatus. Thus, the preferred dissolution method for
build-up from 15% to 17% w/w. Formulation trial #4 was metformin hydrochloride ER tablets is USP apparatus 2
manufactured by keeping the composition same and (paddle) at 50 rpm with 500 mL of purified water (37 ±
only increasing the spray rate to 10–16 g/min from the 0.5 °C).
optimized spray rate of 5–8 g/min, which affects the film If the optimized formulation (#1) is the same as that
property. used in the clinical or BE study and no in vitro-in vivo

Table 5. Case Study: Dissolution of Optimized Formulation (#1) vs. Formulation Trialsa

Time Point (h) Formulation #1 Formulation #2 Formulation #3 Formulation #4

USP Apparatus 2, 50 rpm
0 0 0 0 0
1 3 (1–4) 5 (2–7) 0 8 (6–11)
2 5 (3–8) 13 (10–15) 2 (1–4) 14 (11–16)
3 28 (23–31) 37 (34–39) 17 (14–21) 42 (38–45)
4 51 (46–54) 68 (66–71) 40 (36–42) 59 (56–62)
6 81 (75–83) 87 (86–91) 77 (76–81) 89 (86–91)
8 93 (90–95) 97 (94–99) 92 (89–95) 99 (96–101)
10 95 (93–98) 99 (97–101) 93 (90–99) 100 (98–101)
12 96 (95–99) 100 (99–102) 96 (92–100) 102 (99–104)
f1 Ref 32 17 28
f2 Ref 51 58 52
USP Apparatus 1, 100 rpm
0 0 0 0 0
1 2 (1–5) 3 (2–3) 1 (0–3) 6 (3–8)
2 5 (4–8) 11 (8–13) 3 (1–6) 12 (10–13)
3 28 (25–31) 34 (30–36) 18 (16–23) 37 (35–39)
4 50 (48–53) 65 (61–67) 39 (35–44) 56 (53–59)
6 83 (81–85) 88 (83–90) 79 (74–82) 89 (83–90)
8 95 (91–99) 99 (98–101) 94 (90–96) 101 (98–101)
10 96 (94–99) 100 (99–102) 99 (98–102) 100 (99–102)
12 99 (99–102) 99 (98–102) 100 (99–103) 101 (98–102)
f1 Ref 26 15 21
f2 Ref 55 60 59

Values are mean (range), n = 12. Dissolution medium was 500 mL of water.
USP: United States Pharmacopeia.

172 AUGUST 2023

[Link]
 A B

Paddle, 50 rpm Basket, 100 rpm

100 100
80 80
% Drug release

% Drug release
60 Formulation # 1 Formulation # 1
[Optimum] 60 [Optimum]
40 40
Formulation # 2 Formulation # 2
20 [with change in [with change in
polymer ratio] 20
polymer ratio]
0 0
0 5 10 0 2 4 6 8 10 12
Time Point (h) Time Point (h)

C D

Paddle, 50 rpm Basket, 100 rpm

100 100

80 80
% Drug release

% Drug release

Formulation # 1 Formulation # 1
60 [Optimum: 15% 60 [Optimum: 15%
CR polymer CR polymer
40 coating] 40 coating]
Formulation # 3 Formulation # 3
20 [17% CR polymer 20 [17% CR polymer
coating] coating]
0 0
0 2 4Time Point
6 (h)8 10 12 0 5 10
Time Point (h)

E F

Paddle, 50 rpm Basket, 100 rpm

105 105
90 90
75 75
% Drug release
% Drug release

60 Formulation # 1 60 Formulation # 1
[Optimum: spray [Optimum: spray rate:
45 rate: 5 - 8 g/min] 45 5 - 8 g/min]
30 Formulation # 4 30 Formulation # 4
[Increased spray [Increased spray rate:
15 rate: 10 - 16 g/min.] 15 10 - 16 g/min.]
0 0
0 5 10 0 5 10
Time Point (h) Time Point (h)

Figure 3. Dissolution of formulations with changes in polymer ratio (A and B), CR polymer coating weight build-up (C and D), and coating spray
rate (E and F) using apparatus 2 (A, C, E) and apparatus 3 (B, D, F).

AUGUST 2023 173

[Link]
 correlation (IVIVC) is established, then the final dissolution and application of in vitro/in vivo correlations; Guidance for
specification for the commercial life of the product can be Industry. U.S. Department of Health and Human Services,
proposed as given in Table 6. The same acceptance criteria Food and Drug Administration, Center for Drug Evaluation and
can be applied in the American and European markets. Research (CDER), 1997.
3. Dissolution methods. U.S. Department of Health and Human
If the dissolution profiles of formulation #1 and #4 (see Services, Food and Drug Administration, Center for Drug
Table 5) are compared with the derived specifications Evaluation and Research (CDER), Office of Pharmaceutical Quality,
(Table 6), then the batches are out of specification. Office of New Drug Products, Division of Biopharmaceutics,
This indicates that the dissolution method is capable 2022.
of discriminating batches with acceptable and non- 4. Anand, O. Decrease RTR, IR, and CR Regulatory Actions Due
acceptable release characteristics. to Dissolution Deficiencies, and Increase Approval During First
Table 6. Case Study: Derived Specifications for the Optimized
Review Cycle: A Biopharmaceutics Perspective. Presented at
Formulation Regulatory Education for Industry (REdI): Generic Drug Forum
April 3-4, 2019.
Time Point Mean Drug Proposed Acceptance Criteria
(h) Release (%) 5. Waiver of In Vivo Bioavailability and Bioequivalence Studies
Option 1 Option 2
for Immediate-Release Solid Oral Dosage Forms Based on a
1 3 -- --
Biopharmaceutics Classification System; Guidance for Industry.
2 9 NMT 20% -- U.S. Department of Health and Human Services, Food and
3 28 -- NLT 18%, NMT 38% Drug Administration, Center for Drug Evaluation and Research
4 51 NLT 41%, NMT 61% NLT 41%, NMT 61% (CDER), 2017.
6 81 -- -- 6. M9 Biopharmaceutics Classification System-Based Biowaivers;
8 93 NLT 80% NLT 80% Guidance for Industry. U.S. Department of Health and Human
10 95 -- -- Services, Food and Drug Administration, Center for Drug
12 96 -- -- Evaluation and Research (CDER), 2021.
7. Dissolution Testing and Acceptance Criteria for Immediate-
NLT: not less than; NMT: not more than.
Release Solid Oral Dosage Form Drug Products Containing
SUMMARY High Solubility Drug Substances; Guidance for Industry. U.S.
This review showcases the importance of the dissolution Department of Health and Human Services, Food and Drug
test and the specifications for oral solid dosage forms, Administration, Center for Drug Evaluation and Research (CDER),
including a concise summary of regulatory requirements 2018.
and expectations in the US and Europe. The discussion on 8. Specifications: Test procedures and acceptance criteria for new
dissolution method development, including a case study, drug substances and new drug products: chemical substances,
provides handy guidance to academics, research scholars, Q6A; ICH Harmonised Tripartite Guideline. International
and industry scientists to develop a dissolution method Conference on Harmonisation of Technical Requirements for
for any new or generic solid oral dosage form. Registration of Pharmaceuticals for Human Use, 1999.
9. Zhang, L.; Fiske J.; Zhao, H.; Patel, H.; Jennings S. Dissolution
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The authors thank Centaur Pharmaceuticals Pvt. Ltd., – challenges and strategies. Am. Pharm. Rev. Published November
Pune, India, for supporting the research work. 30, 2015. [Link]
Featured-Articles/181886-Dissolution-Method-Development-
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10. <1092> The Dissolution Procedure: Development and Validation.
CONFLICT OF INTERESTS In USP 43–NF 38. The United States Pharmacopeial Convention,
The authors disclosed no conflicts of interest related to Inc., 2022.
this article. 11. <711> Dissolution. In USP 43–NF 38. The United States
Pharmacopeial Convention, Inc., 2022.
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