Solid dosage forms and

Dissolution
Go into any pharmaceutical lab – will
see all sorts of dissolution testing and
apparatus
Starts at formulation steps all the way
through to finished product testing and
stability testing months and years later
Really important also for generic
manufacturers – demonstrate that their
product is bioequivalent to the branded
drug
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 Background
• Disintegration was the forerunner to the
dissolution test
• USP officially adopted dissolution requirements
for 12 monographs in 1970
• USP currently contains dissolution monographs
for approximately 600 articles
• Industry as well as regulatory agencies
worldwide have come to recognize the power
and importance of the dissolution test

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 Dissolution
• Purpose is to provide an indication of the
drugs potential bioavailability
• How much of the API present in the
product is likely to be available to the body
to absorb and utilize
• Dissolution Results provide only an
estimate or a guess as to the potential
bioavailability

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 Dissolution
• A number of formulations and manufacturing
factors can affect dissolution and
disintegration
• Eg
• Particle size of the drug substance in the
formulation
• Solubility and hygroscopicity of the
formulation
• Type and concentration of disintegrant,
binder, lubricant
• Manufacturing method
• Fairly complex relationships and factors 4
 Definition of Dissolution
• Dissolution (Webster’s Dictionary):
– Disintegrate; separation into component parts; the act
or process of dissolving

• Dissolution:
– A physico-chemical process whereby a solute
enters a solvent to form a solution

• Drug Product Dissolution:

– The amount of active ingredient in a solid dosage
form dissolved per unit time
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Diffusion Layer Model

R1 R2

Cs Cb

h
What if Cb > Cs?
What if Cb < Cs?
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 Dissolution
The three main factors affecting dissolution rates
and extents of solid dosage forms are:
– Physico-chemical properties of the drug compound
– Formulation related factors
– Dissolution apparatus and associated test parameters

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 What are the Purposes of the
Dissolution Test?
• To guide formulation development

• To monitor changes in product manufacturing

and identify critical variables
• To assure consistent batch to batch product
performance (quality control)
• To predict in-vivo performance
• Surrogate for bioavailability/bioequivalence
studies 8
 Dissolution
"Drug absorption from a solid dosage form after oral
administration depends on the release of the drug
substance from the drug product, the dissolution or
solubilization of the drug under physiological conditions,
and the permeability across the gastrointestinal tract.
Because of the critical nature of the first two of these
steps, in vitro dissolution may be relevant to the
prediction of in vivo performance. "

Guidance for Industry: Dissolution Testing of Immediate Release

Solid Oral Dosage Forms, U.S. FDA (CDER) 1997

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 Dissolution
Drug compound - Physico-chemical properties
affecting dissolution:
– Solubility
– Melting point
– Particle size, shape, form (surface area, crystalline,
amorphous, polymorphic)
– Hydrogen bonding potential (hydrophobicity, hydrates
versus anhydrous)
– Ionization potential (pKa)

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 Dissolution
Formulation factors affecting dissolution:
– Excipients (e.g., disintegrants, lubricants, diluents,
binders, fillers, granulating agents, dyes)
– Coatings, (e.g., shellac, cellulose acetate phthalate,
ethyl cellulose)
– Manufacturing variables (e.g., mixers, presses,
operators, site location)
– Granule size and distribution (wet granulation versus
direct compression?)

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 Dissolution
Dissolution test parameters:

– Apparatus type (e.g., paddles app#2, baskets app#1,)

– Medium (volume and type), pH of media, surfactants,
etc
– Agitation (rate i.e.rpm, hydrodynamics)
– Test duration – time
– Standard and sample preparation
– Reproducibility of the test – control all parameters –
this is extremely important since we need to test
products in a consistent way
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 The dissolution chemist should
remember:

• Dissolution is a process

• Physical and chemical characteristics of the

formulation will affect dissolution

• Dissolution is (should be) sensitive to test

parameters
• It is accepted that for a drug to be biologically
available, it must be in solution
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 Dissolution
Effective dissolution requires certain things

• We need to understand the drug – physical/chemical

characteristics

• We need to understand the formulation – effect of

excipients on disintegration and dissolution

• We need to understand the dissolution process

• We need to test and record accurately

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Recall that dissolution is a process

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Ionization and Solubility

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 Biopharmaceutics Classification
System: BCS
A classification of drug compounds based on their solubility
and biological permeability under the assumption that
rapidly disintegrating products with high degrees of
solubility and permeability will be bioequivalent

BCS Class I high solubility/high permeability

BCS Class II low solubility/high permeability
BCS Class III high solubility/low permeability
BCS Class IV low solubility/low permeability

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 Dissolution
Basic (general) steps in performing a dissolution
test
1) Preparation of dissolution medium (type?)
2) Set up of dissolution apparatus (i.e.paddles or
baskets, RPM, height adjustment, media
volume dispensed to vessels,etc)
3) Introduction of sample to vessels
4) Aquiring of sample at appropriate time and
preparation for analysis ( filter, dilute, prepare
standard,etc)
5) Perform analysis and calculate final results

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 Instrumental Analysis:
Calculations
Spectroscopic methods are based on the fundamental
principle that analytical response (response of the
analyte) is proportional to the concentration of that
analyte – Agreed ? In other words, Response = Conc

Hence if we know the concentration and responses

(absorbances) of our standards (which we will) and we
obtain a response for our sample (which we will) we
can mathematically determine the concentration of our
analyte in our sample – this assumes our solutions are
all made accurately and our detector is behaving in a
linear fashion

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 Instrumental Analysis:
Calculations
Why are we determining concentration of
analytes?
So we can determine how much of the
analyte is present! i.e. in analytical
chemistry we usually want to quantitate
1) Direct comparison (calculation)
Rspl = Cspl
Rstd = Cstd
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 Instrumental Analysis:
Calculations
Direct comparison (calculation)
Rspl = Cspl
Rstd = Cstd

This is the universal calculation used for

instrumental quantitation, since it is based
on the fact that our instrumental response
is proportional to the concentration of
analyte we measure 21
 Instrumental Analysis:
Calculations
2) Direct calculation based on label claim – this means we know
how much to expect and we’ll know our theoretical
concentration when we prepare our sample because the label
claim tells us how much analyte is theoretically inside the
sample (they key is that the sample in not pure analyte)

So, we really need three steps:

1) We do a direct comparison calculation to determine actual
sample concentration (ie using instrument data and Std conc
2) We calculate (on paper) what our theoretical sample
concentration is, based on the label claim
3) Then we compare the actual to theoretical to get the final
answer. Should they be the same?

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 Instrumental Analysis:
Calculations
We need to always account for the label
claim when performing Quantitative testing
on finished dosage forms.

If we account for (determine) the theoretical

concentration of our sample prior and
manipulate the direct calculation equation,
we obtain the following equation to use
when performing our final calculations
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 Instrumental Analysis:
Calculations
Rspl × C std × 100 = % amount dissolved
R std C spl per label claim (per
tablet)

- see “Pharmaceutical Calculations March

2101” – Kevin Kelly) – specifically
Dissolution calculation

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 Instrumental Analysis:
Calculations
Recall / notice that if we do a direct
calculation we still need to correct for
theoretical spl conc (if we have a label
claim to contend with)

Rspl = Cspl , solve for Cspl and compare to

Rstd = Cstd theoretical Cspl

Obtained (actual) ÷ theoretical × 100 = %25

 Instrumental Analysis:
Calculations – Example –Direct
Calculation- Dissolution Testing
Single point Dissolution testing was
performed on a batch of anti-inflammatory
tablets containing 400mg of Ibuprofen
active ingredient per tablet (as per the
label claim). Media volume was 1000mls.
The samples were then diluted by taking
25mls of sample filtrate and diluting to
100mls with dissolution media.
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 Instrumental Analysis:
Calculations
The samples were analyzed by UV analysis
at 254nm to determine the amount of
Ibuprofen dissolved from the tablets.

This means we are going to set the

spectrophotometer to select a wavelength
of 254 nm, pass this radiation through the
standard and the sample and observe the
absorbance. (this is called “reading” the
standards and samples) 27
 Instrumental Analysis:
Calculations
STANDARD:
An Ibuprofen stock standard solution was
then prepared by weighing 81.18mg of
reference standard material into a 200ml
volumetric flask and diluting to volume with
water. 5.0mls of this solution was then
taken and diluted to 20mls with water.

Conc = 0.101475mg/ml
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 Instrumental Analysis:
Calculations
Responses obtained from the corresponding
readings:

Standard Absorbance : 0.250

Sample Absorbance: 0.242 (from one tablet
sample)

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 Instrumental Analysis:
Calculations
• What was the percentage Ibuprofen found
in one tablet sample compared to label
claim? Based on the label claim, how
many milligrams Ibuprofen are in the
tablet? By how many percent do the
tablets deviate from their label claim?

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 Instrumental Analysis:
Calculations - Example
Remember, Absorbance is proportional to
Concentration, therefore:
Aspl = Cspl
Astd Cstd
If we know three of these values, we can
solve for the fourth (Cspl)

We know std and spl response and we can

determine the standard concentration. 31
 Instrumental Analysis:
Calculations - Example
Std conc = 81.18mg into 200mls ( 81.18/200
= conc = 0.4059mg/ml) and then 5mls into
20mls
(0.4059mg/ml × 5/20 = conc =
0.10148mg/ml standard concentration)
So….
Aspl = Cspl → 0.242 = Cspl
Astd Cstd 0.250 0.10148mg/ml
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 Instrumental Analysis:
Calculations - Example
Solving for Cspl ,
0.242 * 0.10148mg/ml = 0.09823mg/ml
0.250
0.09823mg/ml is the sample conc according
to the instrument. It represents what was
in the dissolution vessel when we took the
sample. If response is proportional to
concentration, this is what the sample
(tablet) actually contains
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 Instrumental Analysis:
Calculations
• But what is the sample concentration
supposed to be? i.e what does the label
claim say?

• How did we prepare the sample and what

is its concentration based on what the
label tells us? (ie theoretical)

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 Instrumental Analysis:
Calculations - Example

Theoretical sample (tablet) concentration:

400mg × 25mls = 0.100mg/ml
1000mls 100mls
So if all the Ibuprofen professed to be in the
sample (tablet) dissolves in our dissolution
media, and we dilute it, we’re supposed to
get the above concentration
35
 Instrumental Analysis:
Calculations - Example
We need to compare what we actually
obtained from the analysis to the amount
we were supposed to get (based on label
claim) and convert to a %
So ,
Actual amount obtained = 0.09823mg/ml
Theoretical amount 0.1000mg/ml

Multiply by 100 to get %, we get 98.2% 36

 Instrumental Analysis:
Calculations - Example
98.2% - this is the potency of the tablet and
is the amount Ibuprofen found in the tablet
tested in the dissolution experiment,
relative to the label claim

So, how many mgs of Ibuprofen does this

particular tablet contain?
400mg * 98.2% = 392.8 or 393mgs
Ibuprofen in this particular tablet
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 Instrumental Analysis:
Calculations - Example
The amount that we obtained in the tablet is
not 100% of what the label says. Is this a
problem? Why?? Why not??
The amount of Ibuprofen actually in the
tablets and the amount that the label claim
says is in the tablets will never be exactly
the same. Why not? That’s ok , providing
the % Ibuprofen found in the tablet (or
tablets) is within specifications. E.g. 90% -
110% 38
 Instrumental Analysis:
Calculations - Example
Method #2 - Performing a direct calculation
based on label claim, recall the formula:

Rspl × C std × 100 = % amount dissolved

R std C spl per label claim (per
tablet)

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 Instrumental Analysis:
Calculations - Example
Substituting our responses and our
calculated concentrations into the formula
we get:

0.242 × 0.10148mg/ml * × 100 = 98.2%

0.250 0.1000mg/ml **
same result !
* (from slide #32)
**(from slide #35) 40
 Instrumental Analysis:
Calculations - Example
The previous example was demonstrated for
one (1) tablet.

Usually, we would be testing at least six (6)

tablets during a dissolution experiment.
How does this change the procedure? It
doesn’t. We just prepare all six samples
the same way, do six separate
calculations, and report six final results.
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