Importance of visual observations in dissolution testing
Kavita Singh, Aditya Marfatia and Amrita
Bajaj give an outlook about various aspects of dissolution testing
Dissolution testing is a critical methodology which is widely utilised in the
development of a new pharmaceutical product. The test, in its simplest form,
consists of placing the formulation in a dissolution apparatus containing suitable
dissolution medium, allowing it to dissolve over a specified period of time
and then assaying the resultant solution using appropriate analytical method
to determine the amount of drug. Dissolution tests are relevant for an array
of investigations like drug degradation profiles, stability and shelf life studies,
physical and mechanical testing of dosage forms, incoming quality control (QC)
testing on raw materials etc.
The dissolution test is a vital tool for formulation optimisation, method development,
formulation changes, manufacturing changes, process modifications to comply
with regulatory requirement, US Pharmacopoeia (USP) compliance, in-vitro in-vivo
correlation (IVIVC) and Scale Up and Post Approval Changes (SUPAC). As the drug
moves into production, dissolution test becomes a QC test, which helps to understand
outcomes of process and manufacturing changes on dissolution profile. When a
new supplier for a certain excipient needs to be selected or when a new lot
of excipient is used in the formulation the dissolution profile is investigated.
Dissolution test helps in determining whether a drug lot passes or fails as
per pharmacopeial standards. Finally as the drug moves into generic arena, dissolution
test is one test, which helps to prove bio-equivalence of the generic drug with
the patent protected innovative drug in the market. During all these stages,
formulation scientists are always looking for ways to find a correlation between
the in-vitro dissolution test and in-vivo drug concentration profile (IVIVC).
Dissolution studies also provide means to control the quality of many of the
parameters of a solid oral dosage form for both batch release and stability
testing. This test can provide a much greater amount of value, in addition to
providing a metric for quality control and stability testing. The test can be
used to investigate a number of critical processing and formulation properties,
in order to develop and produce a more robust and better quality drug product.
A number of metrics like disintegration time, time for 50 per cent drug release,
Q10, Q90 etc. are available to improve the information obtained from dissolution
test. One commonly overlooked metric that can provide a host of information
about the dosage unit under study is a visual observation of façade of
dosage form during dissolution process. The stature of the dosage form is a
simple physical observation, which may be followed by the notebook documentation
of the photograph. A digital image captured to support the observation, or even
live video obtained with a dedicated visual imaging system will enhance the
value of the results.
USP considerations for visual observations of dissolution
USP 34 chapter <1092> on Dissolution Procedure, Development and Validation,
states the significance of visual observation for disintegration studies of
both immediate release and extended release formulations. For immediate-release
dosage forms, the duration of the procedure is typically 30 to 60 minutes. In
most cases, a single time point specification is adequate for pharmacopoeial
purposes. Industrial and regulatory concepts of product comparability and performance
may require additional time points, which may also be required for product registration
or FDA approval. A sufficient number of time points should be selected to adequately
characterise the ascending and plateau phases of the dissolution curve. According
to the Biopharmaceutical Classification System referred in several FDA guidelines,
highly soluble and highly permeable drugs formulated with rapidly dissolving
products need not be subjected to a profile comparison if they can be shown
to release 85 per cent or more of the active drug substance within 15 minutes.
In such cases visual assessment plays a key role in understanding the pattern
of dosage form dissolution pattern.
Dissolution profiles of immediate-release products typically show a gradual
increase reaching 85 per cent to 100 per cent at about 30 to 45 minutes. Thus,
observation for the dissolution time points in the range of 15, 20, 30, 45,
and 60 minutes are usual for most immediate-release products. For rapidly dissolving
products, including suspensions, useful information may be obtained from earlier
points, e.g., five to 10 minutes. For slower-dissolving products, time points
later than 60 minutes are useful.
For an extended-release dosage form, at least three test time points are chosen
to characterise the in vitro drug release profile for pharmacopeial purposes.
An early time point, usually one to two hours, is chosen to show that there
is little probability of dose dumping. A visual inspection can give a fair idea
of uncontrolled release pattern in such cases. During the intermediate and a
final time points the in-vitro release profiles show the essentially complete
release of the drug, which could be visually ensured by the complete disintegration
of the dosage form. When using an automated system operated by the software,
we need to be confident that the instrument is functioning the way it is programmed
especially during the overnight studies where constant monitoring is practically
Conditions entailing visual observation of dissolution
One of the most useful tools for identifying sources of error is close observation
of the test. A trained analyst can pinpoint many problems because he understands
the consequences and effect of certain observations. Accurate, meaningful dissolution
occurs when the product dissolves without disturbance from barriers to dissolution,
or disturbance of vessel hydrodynamics from any source. The particle disintegration
pattern must show freely dispersed particles. Some of the conditions where visual
observations could be valuable are listed below:
1. Physical state of dosage form in dissolution medium:
Dissolution of drug in the medium depends on some basic physical states like
dancing or spinning of the dosage unit or the dosage unit being hit by the paddle,
such miniscule behaviour is critical when assessing IVIVC. Large floating particles
or chunks of the dosage unit present should be noted and correlated with the
analytical data obtained. Observations must be made during complex disintegration
of the coating of modified or enteric-coated products. For example, the partial
opening and splitting apart or incomplete opening of the shell accompanied by
the release of air bubbles and excipients, needs to be monitored. It's important
to observe the adhesion of particles to the paddle or the inside of the basket
upon removal of the stirring device at the end of the run. The percentage reduction
in size of the dosage unit within a certain time frame is evidently recorded
through visual monitoring and imaging.
2. Dissolution testing of MUPS: There is a growing
interest in the area of multi unit particulate (MUPS) delayed release systems
but carrying out dissolution studies for MUPS to obtain clinically relevant
data is a tedious job. The observation of coarse and fine particles emitting
during the dissolution of MUPS could give a unique insight into production of
the dosage form. Dissolution process from MUPS follows diffusion on contact
with aqueous fluids causing water diffusion into the interior of the particle.
Drug dissolution occurs and the drug solutions diffuse across the release coat
to the exterior. Some coatings can be designed to erode gradually with time,
thereby releasing the drug contained within the particle. Further it follows
osmosis, which allows water to enter and osmotic pressure can be built up within
the interior of the particle. The drug is forced out of the particle into the
exterior through the coating. Therefore it is very important to monitor these
Figure 1: Screenshot of iDisso showing magnified jar 1 along
with the view of remaining five jars
3. Characteristic pattern shown by the dosage form during
dissolutioprocess: Along with good documentation, familiarity with the dissolution
behaviour of a product is essential in quickly identifying changes in stability
or changes associated with a modification of the formulation. One may notice
a change in the size of the dissolving particles, excipients floating upward,
or a slower erosion pattern. Changes in the formulation or an increase in strength
may produce previously unobserved basket screen clogging. If contents of the
basket immediately fall out and settle to the bottom of the vessel, a spindle
assembly surge might be indicated. All such issues may be identified and rectified
using data capturing and imaging system.
4. Visual observations of light sensitive drugs: Recordings
of product dissolution and disintegration behaviour are very useful because
dissolution and disintegration patterns can be indicative of variables in the
formulation or manufacturing process. To accomplish visual observation, suitable
lighting of the vessel contents and clear visibility in the bath are essential.
Drugs like Furosemide, Cisplatin and Nifedipine, which are photosensitive require
appropriate consideration so that the photo degradation can be minimised. Currently,
light sensitive drugs are processed for dissolution testing either by making
the whole room dark and/or by use of sodium vapour lamps that consume high energy
and are inconvenient. Sometimes the dissolution bath is covered with foil or
any other adhoc design, which limits the observation of the dosage form in the
vessel. For light sensitive drugs amber colour light is recommended for reducing
the photo degradation.
Figure 2: Screenshot of iDisso with simultaneous view of all
the six jars
5. Dissolution studies with multiple time points: Extended
release formulations are subjected to dissolution testing from minimum of 24
hours to several days depending on the type and purpose of the dosage form.
For extended release formulations multiple dissolution time points are analysed
for drug concentrations. During the long dissolution hours the particles have
high probability of clinging to the sides of the vessel, there could be coning
or mounding directly under the apparatus, particles might float at the surface
of the medium, film-coated tablets tend to stick to the vessel, and/or off-centre
mounds might be formed. While designing a study with number of time points,
visual observation is a strong indication of the dissolution process and it
would be highly advantageous to keep track of uneven distribution of particles
throughout the vessel.
6. Dearation of the dissolution medium: Dissolution
medium showing air bubbles can prevent proper wetting of the dosage and hinder
the drug dissolution process. It's reported that presence of air bubbles around
the paddle, dosage form and side walls of vessel result in reduction of per
cent drug released up to 10-20 per cent. When the dissolution medium has not
been properly deaerated, the analyst may see air bubbles and particles clinging
to vessel walls. To assess the need of deaerating the dissolution media, a drug
analyst must make careful visual observation of the vessel, apparatus or dosage
unit, sheen on the apparatus is also a sign of air bubbles.
7. Anomalous behaviour of dosage forms: Sometimes anomalous
dissolution behaviour may be observed because of floating chunks of tablet,
spinning, coning, mounding, gumming, swelling, capping, 'clam shell' erosion,
off-centre position, sticking, particles adhering to apparatus or vessel walls
or clear particles. Of primary concern is coning, which results in a cone shaped
mass of disintegrated, insoluble solids at the bottom of the Apparatus 2 vessel.
Pellicles or analogous formations, such as transparent sacs or rubbery, swollen
masses surrounding the capsule contents indicate the drug losses that need to
be accounted for achieving maximum efficacy.
Figure 3: Screenshot of jar 1 with magnified view of the tablet
8. Aid to current documentation systems: Documenting
observations by drawing sketches and taking photographs or videos can be instructive
and helpful for those who are not able to observe the real time dissolution
test. Observations are especially useful during method development and formulation
optimisation. It is important to note that only analytical method results are
no longer sufficient for record keeping purposes.
In today's time of automation of dissolution instruments
from the stage of dissolution sampling to dilution, mixing and analysis of collected
samples; all the steps could be machine monitored based on the pre-programmed
software. In such a state it is very critical to have a camera - based visual
monitoring to ensure that the processes like dissolution and disintegration
are functioning as programmed by the software. Just a glimpse of captured images
can give the confidence for the data collected and reduce the human effort of
visual inspection at various intervals for future reference. Any discrepancy
obtained on analysis of dissolution aliquots can be easily cross verified from
the video file recorded during the study. An integrated solution with a user
friendly interface to observe and record the drug dissolution and disintegration
is highly desirable by research scientists since it can provide live view of
in-vitro analysis process whenever necessary. A convenient visual monitoring
and recording can help the QC analyst and formulator in better understanding
of release kinetics and formulation aspects like selection, concentration and
behaviour of excipient explored in the formulation.
Study carried out for visual characterisation during dissolution
We have used a dissolution tester (EDT-08Lx, ELECTROLAB) coupled with iDisso-06
(ELECTROLAB) for quantitative, as well as visual evaluation of osmotically controlled
bilayered extended release tablets. It was possible to regulate and monitor
each and every fraction of dissolution testing throughout the entire study;
since the software has a default imaging facility, which captures images at
pre-programmed intervals. Uninterrupted video recording of the dissolution test
was utilised during experimentation. Documenting observations by taking photographs
and videos was quite instructive and helpful in recording and analysing the
data. While visual monitoring we could remotely view the dissolution process
via browser enabled network PC. It proved to be a helpful tool in evaluation
of out of specification (OOS) and out of trend (OOT) data. Some of the screenshots
taken during the study are shown in Fig 1, 2 and 3.
It is evident from the Fig 1, 2 and 3 that data could be viewed from various
angles and magnified dosage form images could also be captured. Such data will
be valuable to assess the changes in surface characteristics during dissolution
testing. The imaging was helpful in selecting right excipients while dosages
form development and formulation optimisation.
It is imperative to visually observe the behaviour of the dosage form throughout
the dissolution testing run. It could provide important insight to drug development
processes and dissolution evaluation. Visual monitoring, recording and documentation
of dissolution process are most critical parameters specified by USP 34 under
the heading of Dissolution Testing validation. Hence, visual imaging techniques
have potential applications in assessment of dissolution behaviour of novel
drug delivery systems. Moreover, R&D, QC and QA departments could periodically
record the dosage forms undergoing dissolution for record keeping purposes as
a supplement to the analytical results.
Acknowledgement: Authors would like to express their
sincere gratitude to ELECTROLAB for providing the facility to carry out the
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(The authors can be contacted at firstname.lastname@example.org Kavita
Singh is from CU Shah College of Pharmacy, SNDT Women's University, Mumbai,
Aditya Marfatia is from ELECTROLAB, Goregaon (East ), Mumbai and Amrita Bajaj
is with SVKM's Dr Bhanuben Nanavati College of Pharmacy, Mumbai)