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Asian Journal of Biochemical and Pharmaceutical Research Issue 1 (Vol.

1) 2011 ISSN: 2231-2560


Review Article
1
Asian Journal of Biochemical and Pharmaceutical Research

Dissolution Testing of Formulations: A Regulatory, Industry and Academic
Perspective
*1, 2
Sachin Kumar Singh,
1
Dev Prakash and K.K. Srinivasan
3
1
Faculty of pharmacy, Karpagam University, Coimbatore 641021, Tamilnadu, India.
*
2
Department of Pharmaceutical Analysis, Bharathi College of Pharmacy, Bharathinagara, Mandya Dist., Karnataka- 571422, India
3
Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Dist.- Udupi, Karnataka, India.
Received: 28 February 2011; Revised: 5 March 2011; Accepted: 8 March 2011
Abstract: Drug dissolution testing plays an important role as a routine quality control test, for
characterizing the quality of the product, for accepting product sameness under SUPAC (Scale-Up and
Post-Approval Changes) related changes, in waiving bioequivalence requirements for lower strengths
of a dosage form, and in supporting waivers for other bioequivalence requirements. The guidance of
dissolution developed by the regulating agencies provides recommendations on the development of
dissolution test methodology, on how to set the specifications for dissolution testing. As the time is
passing away, the in vitro dissolution testing is relied on to assure product performance, therefore one
must design an appropriate dissolution test procedure which should be simple and economical method
that can be utilized effectively in developing countries to assure acceptable drug product quality. The
dissolution testing is enjoying a resurgence of interest on an academic as well as on industrial and
regulatory levels. Provided the groundwork continues to be focused on the development of dissolution
tests and testers that are both bio relevant and can be adapted to routine quality control, it is likely that
dissolution testing will become an even more powerful tool for the assurance of product quality, in its
broadest sense in the years to come.
Keywords: Drug dissolution, SUPAC, bioequivalence, regulating agencies, bio relevant
INTRODUCTION:
Dissolution testing over the last quarter century has emerged as a highly valuable in vitro test
to characterize drug product performance. For a useful dissolution test: it must be simple, reliable and
reproducible and must be able to discriminate among different degrees of product performance.
Dissolution test value is significantly enhanced when product performance is evaluated as a function
of time (drug release profile with respect to time), which means that, when the dissolution profile is
determined rather than a single point determination, which is a standard compendia for batch release.
Drug dissolution testing plays an important role as a routine quality control test, for
characterizing the quality of the product, for accepting product sameness under SUPAC (Scale-Up and
Post-Approval Changes) related changes, in waiving bioequivalence requirements for lower strengths
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of a dosage form, and in supporting waivers for other bioequivalence requirements [1].Dissolution
from the dosage form involves mainly two steps: liberation of the drug from the formulation
matrix(disintegration) followed by the dissolution of the drug(solubilisation of the drug particles) in
the liquid medium. The overall rate of dissolution depends on the slower of these two steps. In the first
step of dissolution, the cohesive properties of the formulated drug play a key role. For solid dosage
forms, these properties include disintegration and erosion. If the first step of dissolution is rate-
limiting, then the rate of dissolution is considered disintegration controlled. In the second step of
dissolution (i.e., solubilisation of drug particles), the physicochemical properties of the drug such as its
chemical form (e.g., salt, free acid, free base) and physical form (e.g., amorphous or polymorph and
primary particle size) play an important role. If this latter step is rate-limiting, then the rate of
dissolution is dissolution controlled [2]. This is the case for most poorly soluble compounds in
immediate-release (IR) formulations whose solubility is less than 12 mg/L in the pH range of 28.
Recent advanced technologies like combinatorial chemistry and high-through put screening are
effective in the discovery of new drugs with good pharmacological activities [3]. About 3540 % of
the drugs discovered with these technologies have poor aqueous solubility [4]. Dissolution testing of
poorly soluble compounds in immediate-release (IR) solid dosage forms poses many challenges. These
challenges include developing and validating the test method, ensuring that the method is
appropriately discriminatory, and addressing the potential for an in vivoin vitro relationship (IVIVR)
or correlation (IVIVC). Satisfying all of these challenges and developing a meaningful dissolution
method is a large task, because the extent of release is too low (i.e., one cannot get 100% of the dosage
form dissolved) and secondly, the rate of release is too slow (i.e., one cannot get dissolution fast
enough for a convenient test) [5].
ROLE OF DISSOLUTION TESTING IN REGULATING PHARMACEUTICALS:
Dissolution tests are meant for assessing batch to batch quality, where the approach makes the
basis for specification (test, methodology and acceptance criteria) to allow batch release. It is also used
to provide process control and quality assurance and assess the need for further bioequivalence studies
relative to minor post approval changes, where it can function as a signal of bioinequivalence.
If an in vivo absorption characteristic has to be defined for the different product formulations,
then the in vitro dissolution studies for all product formulations are investigated (including proto type
formulations). These effects may allow an in vitro / in vivo correlation. The in vitro test can serve not
only as a quality control specification for the manufacturing process, but also as an indicator of how
the product will perform in vivo.
The guidance of dissolution developed by the regulating agencies provide recommendations on
the development of dissolution test methodology, on how to set the specifications for dissolution
testing [6, 7]. A recent FDA guidance draft on bio waiver based on the Bio pharmaceutics
classification system suggests that documentation of bioequivalence for highly soluble, highly
permeable and rapidly dissolving orally administered immediate release drug products via dissolution
studies may be an appropriate approach [8].
At least a two point determination should be used to characterize the in vivo performance of an
orally administered immediate release drug products. The only reason behind this is that, a modified
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release dosage form is a more complex formulation and not less than four dissolution time points are
needed to characterize the drug product.
In the presence of Scale Up and Post Approval Changes (SUPAC), the dissolution profile
comparison has been extensively used in assessing product sameness. In order to avoid subjective
evaluation of dissolution profile comparison, FDA has adopted a simple method to compare
dissolution profiles, which is termed as similarity factor, f
2
[9].
The art and science of dissolution testing have come on long way since its inception about 25
years ago. This procedure is well established, reliable and reproducible.
As the time is passing away, the in vitro dissolution testing is relied on to assure product
performance, therefore one must design an appropriate dissolution test procedure which should be
simple and economical method that can be utilized effectively in developing countries to assure
acceptable drug product quality.
The SUPAC initiatives were started to provide scientific rationale to expedite the processes of
post approval changes of drug products so that FDA can assure their safety and effectiveness and at
the same time lower the regulatory burden for industry. Problem areas were identified and research
was performed at academia, industry and FDA laboratories to support changes in (1) components and
composition (2) manufacturing (process and equipment) (3) scale of manufacture; and (4) site of
manufacture. The specifications for the drug product include sterility, dissolution rate, containers and
closure systems. It was the intent of the research to improve specification requirements and modify
testing procedures for the product quality aspects of drug production. The changes may shorten the
application process for industry and facilitate the approval process with the FDA.
Investigators at University of Maryland/Baltimore, FDA and pharmaceutical industry gathered
data on the impact of scale-up, formulation, and other manufacturing changes on product quality,
resulting in the release of a number of guidance by FDA, including: (1) 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-IR). (2) 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 (SUPAC-MR).
(3) Semi-solid dosage forms scale-up and post approval changes: chemistry, manufacturing and
controls, in vitro dissolution testing, and in vivo bioequivalence documentation (SUPAC-SS). (4)
Intermediates in drug substances synthesis/bulk actives post approval changes: chemistry,
manufacturing, and controls documentation (BACPAC I) and ( 5) SUPAC-IR/MR manufacturing
equipment addendum. Several other SUPACs are at various stages of development including one for
transdermal delivery systems (SUPAC-TDS) and one for sterile aqueous solutions (PAC-SAS). As can
be deduced, the guidances have been developed on the basis of types of dosage forms.
The guidance provide specific recommendations on documentation of equivalence in post
approval changes of drug products in component-composition, batch size, manufacturing process and
site of manufacture. Each category is divided into 2 or 3 levels based on the degree and type of
changes in the approved product. Post-change product batch is considered the same as the pre-change
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product batch when there are no discrepancies in their dissolution profiles or the release rates. The
similarity in the physicochemical properties of the batches from the release test or dissolution profile
can be used to infer that the pre-change products and post-change products are also the same in terms
of safety, efficacy or bioequivalence.
SUPAC-IR uses in vitro dissolution tests to indicate product sameness. Dissolution profile
comparison on post-change batch and pre-change batch is indicated by the similarity factor, f2.
log = logarithm to base 10
n = number of sampling time points
Rt = dissolution at time point t of the reference (pre-change batch)
Tt = dissolution at time point t of the test (post-change batch)
In vitro-in vivo correlation is an important measure for SUPAC-MR involving development,
validation and application and dissolution profile comparison. In vitro release test is used in SUPAC-
SS as a measure of product quality and sameness. The equivalence approach based on a standard
confidence interval procedure is utilized to verify that the lots are close enough for product sameness
between pre-change and post-change batches.
The International Society for Pharmaceutical Engineers (ISPE) collaborated with FDA to
provide equipment equivalence lists which clearly define classes and subclasses of equipment by unit
operation. The Equipment Addendum Guidance documents provide assistance for changes in
equipment.
Further updating of the SUPACs is possible based on the approach delineated in FDAMA
Section 116 to permit pre-approved supplements, change-being-effected supplements and annual
report filings. The concept of SUPAC on drug product is being extended to drug substance (BACPAC
I and II). The general approach works to achieve continuing pharmaceutical equivalence and
bioequivalence after approval for NDAs and ANDAs, as well as other approved FDA products.
There were 1,039 SUPAC supplements submitted for generics and 263 for new drugs from
1995 to 1998. Immediate release and alternate site changes dominated the topics for SUPAC
supplements with 582 and 431 submissions, respectively, for generic drugs and 142 and 66,
respectively, for new drugs. Semi-solids and modified release dosage forms accounted for less than 30
submissions for both types of drugs during the three year period. Based on qualitative estimates
provided by pharmaceutical company representatives, consulting experts, and the number of SUPAC-
IR submissions during 1997, the Office of Planning and Evaluation, FDA, estimated savings for 1997
chemistry, manufacturing and control changes to be $70.7 million. The savings generated by SUPAC
were realized through shorter waiting times for site transfers, more rapid implementation of process
and equipment changes, more rapid implementation of batch size increase, production of fewer
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unmarketable stability test batches, and reduced stability tests and reduced administrative cost. For
example, there was documentation that the times taken for one company in submissions and reviews of
supplements on packaging and manufacturing were 600 and 111 months, respectively, before and after
the adoption of SUPAC guidance [10].
Overall, several industrial representatives at the workshop stated that there were no major
issues with SUPAC. The coordination at CDER was excellent. After the initial learning period,
pharmaceutical companies and the review divisions and district offices of FDA were comfortable with
the processes involved in SUPAC.
It was the consensus of the scientists at the SUPAC workshop that there are several issues that
need to be addressed for future SUPAC applications. The topics that need to be addressed are dosage
form independent issues, SUPAC IR/MR/SS issues, site transfer, and equipment process changes.
Dosage form independent issues include multiple changes, packages, and sizes. SUPAC-IR/MR issues
include: 1) mechanism to control changes to specification and in-process control; 2) capsules (size,
shapes, color); 3) tablet weight; 4) shape, size, scoring, energizing; 5) need to simplify Case C
dissolution; 6) product-specific selection of media; and 7) f 2 specification/profile. Site transfer issues
include:1) harmonization of IR/MR site transfer requirements for stability; 2) transfer of experiment
date to new site, and 3) the need for a bioequivalent test for level 3 SUPAC-MR. Equipment process
change issues include 1) the use of biopharmaceutical classification system to justify changes being
effected (CBE) and 2) clarification of deposition of other types of level 2 and 3 changes. SUPAC-SS
issues include preservatives and in vitro release testing.
As stated by Larry Augsburger, President of AAPS, the range of dissolution profiles of
products found bioequivalent in the Maryland study may be broad enough to encompass many major
changes. Consideration should be given to: 1) reducing the dissolution requirement for Class I drugs.
For the examples studied, the requirement of 85% dissolution in 15 minutes was not justified, 2)
reducing the filing requirements for a change in technical grade of excipient at least to CBE
classification in accordance with 21 CFR 314.70(c). Though limited in the number and classes of
excipients tested, the Maryland data do not support Level 2 (PAC), 3) shifting of levels downward by
an increment of one for compositional changes, 4) removing reference to 10X in re scale changes, and
5) reducing the media required in Level C dissolution tests to two or three.
ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL INDUSTRY:
Dissolution testing in pharmaceutical industry is a very important tool in drug development and
in quality control. While traditionally developed for solid oral dosage forms, in the last years, the use
of dissolution testing has been widened to a variety of dosage forms, such as semi-solid or parenteral
(e.g. implant) preparations.
Scientifically, a lot of progress has been made through more than three decades. Also, from the
perspective of (pharmacopoeia) standardization, international harmonization of regulations, and thus
consistent concepts and test methods being applied around the world, we have reached a high level.
But, does that mean that we have no more questions, no more issues to be addressed? No, definitely
not! The burning questions and issues are not necessarily new but, it is a set of aspects coming up
again and again whenever experts meet and discuss in vitro dissolution:
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Is there a value or need for calibrator tablets?
Is there a scientific justification for further standardization of dissolution media?
Is there a scientific rationale for standardization of dissolution specifications (e.g. 75% in 15
min; 75% in 45 min), or do we need to treat each product on a case-by-case basis?
How important is stage 3 testing (especially when being strict in post-marketing stability
studies)?
Are we really having a good understanding of which criteria would allow us to use in vitro
dissolution as a surrogate for bioequivalence studies- Where are we too strict? Where are we
not conservative enough?
What level of in-vitro-in-vivo-correlation requirement is justified for validation of test
method and specifications? For which type of products?
Is the basic concept of searching for the most discriminating in vitro method justified, when
at the same time we continue to: face difficulties when applying low rotation speeds with
apparatus 2 (and 1)? Learn that typically, differences in vitro are more pronounced than
those in bioavailability, when comparing similar products?
Is their value in dissolution testing, when an in-vivo-in-vitro-comparison has proven a non-
correlation (for any test condition considered reasonable)?
The use of bio relevant media is how much justifiable as it is very costly [For example, one liter of
FeSSIF can cost as muchas US$700, whereas the price of one liter of medium containing synthetic
surfactants (mixed micelles) is only around US$1] (11). Whether this problem can be overcome by
the use of mixed micelles?
Which concepts for comparison of in vitro dissolution profiles are truly scientifically sound
and still pragmatic-to-handle in terms of being easily applied and meaningful?
This list is not at all meant to be complete. Interesting enough, we are collecting more and
more examples, many of them supporting established concepts, many other data sets raising these
questions again. Sometimes we tend to question the basic concepts of dissolution testing (completely
abstract, conventional method which we still believe to reflect gastro-intestinal processes?).
What are we really looking for? Maybe we need further scientific studies and investigations.
But definitely, we need pragmatic approaches to make sure that we are staying on scientific ground,
have sufficiently (adequately!) standardized tests in place, and still allow for enough flexibility to
handle specific products or situations. Industry needs to focus on speed in registration of new products
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and in implementing post approval changes/variations. The objective is the safety and efficacy of our
products for the patient. As long as regulatory requirements are illustrated in guidelines rather than
bureaucratic directives, we will manage to the benefit of the patient, scientifically sound, and still
economically feasible.
The SUPAC approaches and the FIP-Guideline are going into the right direction. Not
necessarily all other recent proposals are obviously consolidating all available experience. Reoccurring
same or similar questions may also be an indicator that, in some areas, we could be turning in circles
rather than adding value.
FUTURE DIRECTIONS FOR ACADEMIC RESEARCH IN DISSOLUTION TESTING:
A quarter of a century ago, it was already recognized that particle size of the active substance
could have a great influence on the dissolution rate and also on the bioavailability of the compound.
Efforts to establish in vitro/in vivo correlations (IVIVC), for example with digoxin products containing
different particle size of the active ingredient, met with success. Subsequently, IVIVC was tried for
many other products, but good correlations could mostly only be obtained on an a posteriori basis and
dissolution testing for IVIVC purposes became less popular.
With the advent of the Bio pharmaceutics Classification System (BCS) it became evident that
IVIVC cannot be expected for drugs with certain properties. At the same time, dissolution tests that
attempt to be closer model, the physiological conditions were developed, for example the flow-through
tester and certain more bio relevant media. As a result, we now have the tools necessary to determine
when an IVIVC is reachable, and what in vitro tests we need to do to achieve an IVIVC on an a priori
basis. To further improve the predictive capability of dissolution testing, there needs to be further
refinement of the media used, use of appropriate volumes, and hydrodynamic designs that can provide
better flow patterns in the gut.
These points will continue to be a focus of academic research in the coming years, with the
greatest challenges being associated with the development of suitable tests for controlled release
products and the translation of the dissolution tests used for IVIVC into workable tests for quality
control purposes.
A further challenge is to establish suitable dissolution tests for non-conventional oral dosage
forms, for example chewable tablets, swell able dosage forms and wafers that are designed to dissolve
on the tongue. The classical methods do not provide suitable agitation conditions on the one hand, and
the volumes used are unrealistic for wafer-type dosage forms on the other hand. Likewise, the
suitability of current methods for non-oral dosage forms continues to be an area of controversy and
research.
The evaluation of results is also an area of continued interest for the academic as well as the
regulatory community. The utility of the recently proposed f
2
factor and its benefits and disadvantages
compared to other evaluation methods (both model dependent and independent) will need to be
carefully scrutinized using a wide variety of data sets, including drug products from each of the BCS
categories and data sets for controlled release products.
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Finally, the controversy related to calibration of dissolution testers continues. Alternatives to
the current USP calibrator tablets need to be developed, with the most desirable approaches being
those that avoid the batch to batch reproducibility problems associated with the current tablets, those
that are efficient in terms of time and effort required and those that can be applied in a wide variety of
laboratory settings.
In summary, dissolution testing is enjoying a resurgence of interest on an academic as well as
on industrial and regulatory levels. Provided the groundwork continues to be focused on the
development of dissolution tests and testers that are both bio relevant and can be adapted to routine
quality control, it is likely that dissolution testing will become an even more powerful tool for the
assurance of product quality, in its broadest sense in the years to come.
REFERENCES:
1. Dissolution Testing of Immediate Release Solid Oral Dosage Forms; Guidance for Industry; U.S.
Department of Health and Human Services, Food and Drug Administration, U.S. Government
Printing Office: Washington, DC, 1997.
2. C. Brown, H. Chokshi, B. Nickerson, R. Reed, B. Rohrs, P. Shah; Pharm. Technol.; 2004, 28 (12),
56.
3. T. Ohara, S. Kitamura, T. Kitagawa, K. Terada; Int. J. Pharm.; 2005, 302, 95.
4. C. Lipinski; Poor aqueous solubilityan industry wide problem in drug discovery. Am. Pharm.
Rev.; 2002, 5, 82.
5. B. Rohrs; Dissolution Technol.; 2001, 8 (3), 1.
6. Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Form, August
1997.
7. Guidance for Industry: Extended Release Solid Oral Dosage Forms: Development, Evaluation and
Application of In Vitro/In Vivo Correlations, September 1997.
8. Draft Guidance for Industry: In Vivo Bioavailability and Bioequivalence Studies for Immediate
Release Solid Oral Dosage Forms Containing Certain Active Drug Ingredients/Active Moieties
Based on a Biopharmaceutics Classification System, January 1999.
9. V. P. Shah, Y. Tsong, P. Sathe and J.P. Liu.; Pharm. Res.;1998, 15, 889.
10. D. C. Pang.;AAPS Workshop on SUPACs: Where are We Going? Have We Reached the Limit?
Dissolution Technol.; 1999, 6, 16.
11. T. Zoeller, S. Klein, Dissolution Technol.; 2007, 14, 8.
*Corresponding author: Sachin Kumar Singh: Department of Pharmaceutical Analysis, Bharathi
College of Pharmacy, Bharathinagara, Mandya, India