Biowaiver Monograph for Ibuprofen Slide 1 of 31 Tehran University of

May 2014 Medical Sciences

School of Pharmacy
 Purpose and Scope
A monograph based on literature data is presented on
ibuprofen concerning its properties related to the
biopharmaceutics classification system (BCS)
To evaluate data available from literature sources about ibuprofen
To come to a conclusion whether or not to recommend a biowaiver
for immediate release (IR) solid oral dosage forms containing
ibuprofen, considering both the biopharmaceutical point of view and
public health risks.

Biowaiver Monograph for Ibuprofen Slide 2 of 31 Tehran University of

May 2014 Medical Sciences
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 Biowaivers
The term biowaiver is applied to a regulatory drug approval process
when the dossier (application) is approved based on evidence of
equivalence other than through in vivo equivalence testing.
A biowaiver means that in vivo bioavailability and/or bioequivalence
studies may be waived (i.e. not considered necessary for product
approval).
In 1995 the American Department of Health and Human Services, US
Food and Drug Administration (HHS-FDA) instigated the
Biopharmaceutics Classification System (BCS), with the aim of granting
so-called biowaivers for SUPACs.

Biowaiver Monograph for Ibuprofen Slide 3 of 31 Tehran University of

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 Biowaivers
At that time the biowaiver was only considered for SUPAC to
pharmaceutical products.
More recently, the application of the biowaiver concept has been
extended to approval of certain orally administered generic products
Scope:
Inside a product:
Scale up processes
Line extensions
Variation after marketing authorisation
between different products:
Application of generics without clinical data

Biowaiver Monograph for Ibuprofen Slide 4 of 31 Tehran University of

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 Biowaivers
According to the HHS-FDA definitions, the four possible categories for
an API according to the BCS are:
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.

high permeability low permeability

high HS/HP HS/LP
solubility Class I Class III
low LS/HP LS/LP
solubility Class II Class IV

In addition, IR solid oral dosage forms are categorized as having rapid or slow
dissolution.
Biowaiver Monograph for Ibuprofen Slide 5 of 31 Tehran University of
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 Biowaivers

BCS Class Boundaries: Objectives

October, 2010 PRESENTED BY DR. JAN WELINK

Prequalification of Medicines Programme, Abu Dhabi, 11-13
THIS SLIDE WAS TAKEN FROM: WHO Workshop on
Dissolution Very rapid/rapid dissolution - ensure
(Product) that in vivo dissolution is not likely to
be the rate determining step
Solubilit
High solubility- ensure that solubility
y (Drug)
is not likely to limit dissolution and,
therefore, absorption

Permeabili High permeability - ensure that drug

ty is completely absorbed during the
(Drug) limited transit time through the small
intestine
Biowaiver Monograph for Ibuprofen Slide 6 of 31 Tehran University of
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 Biowaivers
High Solubility Definition:
The highest single unit dose is completely soluble in 250 ml or less
of aqueous solution at pH 1 7.5 (37C)
250 ml: derived from typical BE study protocols that prescribe the administration
of a drug product to fasting human volunteers with a glass (approx. 250 ml) water

High Permeability Definition:

According to HHS-FDA, when 90 % or more of the orally administered dose is
absorbed in the small intestine.
Permeability can be assessed by pharmacokinetic studies (for example, mass
balance studies), or intestinal permeability methods, e.g. intestinal perfusion in
humans, animal models, Caco 2 cell lines or other suitable, validated cell lines.

Biowaiver Monograph for Ibuprofen Slide 7 of 31 Tehran University of

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 Biowaivers
Dissolution:
In three different media: pH 1.2 HCl, pH 4.5 Acetate buffer and pH
6.8 Phosphate buffer, composition in a paddle (50 rpm) or basket
(100 rpm) apparatus at 37 C and a volume of 900 ml
Very Rapid Dissolution:
An IR drug product is considered VERY RAPIDLY DISSOLVING
when >85% of the labeled amount of drug substance dissolves
within 15 minutes
Rapid Dissolution
An IR drug product is considered RAPIDLY DISSOLVING when
>85% of the labeled amount of drug substance dissolves within 30
minutes
Biowaiver Monograph for Ibuprofen Slide 8 of 31 Tehran University of
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 Biowaivers
To be considered bioequivalent according to the HHS-FDA
biowaiver procedure, a pharmaceutical product:
Should contain a Class I API
Should be rapidly dissolving, in three different media
First Option: Very rapidly dissolving and no further profile comparison
Second Option: Rapidly dissolving and Proving similarity of dissolution profiles
of T and R (e.g. using f2-test)
Should not contain excipients which could influence the absorption
of the API (affecting motility or permeability)
Should not contain an API with a narrow therapeutic index
Should not be designed to be absorbed from the oral cavity.
Biowaiver Monograph for Ibuprofen Slide 9 of 31 Tehran University of
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 Biowaivers
It is clear that the HHS-FDA requirements for the classification of APIs
and eligibility criteria for the biowaiver are very strict.
Several publications and continuing scientific discussions have
suggested that the original HHS-FDA criteria for application of the
biowaiver procedure could be relaxed without substantially increasing
the risk to public health or to the individual patient.
On the basis of these publications and dialogue, WHO has proposed
revised BCS criteria and additional considerations for the eligibility of a
pharmaceutical product for the biowaiver procedure

Biowaiver Monograph for Ibuprofen Slide 10 of 31 Tehran University of

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 Biowaivers
WHO revisions to the criteria for BCS classification
WHO high-solubility definition: (Dose:Solubility) ratio of 250 ml or
lower at 37C over a pH range of 1.26.8
The decrease in pH from 7.5 reflects the need to dissolve the drug
before it reaches the mid-jejunum to ensure absorption from the
gastrointestinal tract.

Image belongs to nature

The dose that is to be used for the calculation is the highest dose
indicated in the Model List of Essential Medicines (EML).
WHO permeability definition: API is absorbed to an extent of 85% or
more, it is considered to be highly permeable.
The permeability criterion was relaxed from 90% in the FDA
guidance to 85% in the WHO Multisource document.

Biowaiver Monograph for Ibuprofen Slide 11 of 31 Tehran University of

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WHO extensions to the scope of application of the biowaiver

HHS-FDA WHO

Biowaiver Monograph for Ibuprofen Slide 12 of 31 Tehran University of

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 Back to Ibuprofen Case: Literature Data
Ibuprofens chemical name is
(RS)-2-(4-Isobutylphenyl)propionic acid.

Usually administered as the racemic compound,

but the S(+)-enantiomer (dexibuprofen) are available.
Usually given as the free acid but various salts, esters, are also used:
lysine and sodium salts, guaiacol and pyridoxine esters,
isobutanolammonium and meglumine derivatives.
In this monograph, ibuprofen is understood to be the free acid in the
racemic form, unless otherwise indicated.

Biowaiver Monograph for Ibuprofen Slide 13 of 31 Tehran University of

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 Literature Data
Ibuprofen is a well-known and widely used nonsteroidal
antiinflammatory drug (NSAID).
Ibuprofen is regarded one of the safest NSAIDs available
The S(+)-enantiomer was found to be a selective COX-1
inhibitor while R(-)-ibuprofen has little pharmacodynamic
efficacy.

Biowaiver Monograph for Ibuprofen Slide 14 of 31 Tehran University of

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 Literature Data : Physicochemical Properties
Solubility:
In the literature only data at 20C or room temperature were found.
BCS classification requires data on the solubility at 37C, these values
were experimentally determined. for each media in triplicate.
Ibuprofen drug substance was suspended in medium and stirred for 24
h at 37C and then stored for a further 24 h without agitation. In each
case sediment on the bottom of the flask was observed. The ibuprofen
concentration in the clear supernatant was determined by UV-analysis.

Biowaiver Monograph for Ibuprofen Slide 15 of 31 Tehran University of

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Literature Data : Physicochemical Properties

Biowaiver Monograph for Ibuprofen Slide 16 of 31 Tehran University of

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 Literature Data
Polymorphism:
Ibuprofen does not exhibit genuine polymorphism.
Partition Coefficient
Calculation of the octanol-water distribution coefficient gave log D values of 3.7,
3.6, 2.1, and 1.2 at pH values of 1, 4, 6, and 7, respectively.
Log p(n-octanol/water) and Clog p values of 3.68 and 3.14 were estimated,
respectively.
for the highly permeable marker drug metoprolol, using the same methodology,
log p and Clog p values of 1.72 and 1.35 were calculated.
pKa
The pKa of ibuprofen is in the range of 4.54.6
Dose Strength of Marketed Drug Products
The WHO List of Essential Medicines includes strengths of 200 and 400 mg

Biowaiver Monograph for Ibuprofen Slide 17 of 31 Tehran University of

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 Literature Data: Pharmacokinetic Properties
Absorption and Permeability:
Following oral administration of ibuprofen, Cmax = 12 h in humans
with an absolute bioavailability(BA) of about 100%
Antacids accelerate the rate of absorption due to pH changes
However, the extent of absorption,AUC0, was not affected.
Food intake also affects the absorption rate (likely due to food
induced pH elevation) resulting in earlier in vivo dissolution.
Rapid and complete absorption suggests a high permeability
through the GI membrane.
Scintigraphic studies with sustained release products indicate that
absorption occurs throughout the GI tract following oral
administration, which again supports a high permeability.

Biowaiver Monograph for Ibuprofen Slide 18 of 31 Tehran University of

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 Literature Data: Pharmacokinetic Properties
Similar to other NSAIDs, high permeability of ibuprofen and its
enantiomers has been observed in rats, where increased GI
permeability was observed because NSAIDs promote their own
transport.
High permeability of ibuprofen and its enantiomers has been also
observed in Caco-2 cell cultures. In a radiolabeled Caco-2 cell culture
study, P-app of ibuprofen and propranolol were 53E-6 and 27.5E-6
cm/s, respectively.

Biowaiver Monograph for Ibuprofen Slide 19 of 31 Tehran University of

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 Literature Data: Pharmacokinetics
Linear pharmacokinetics in the dose range of 200400 mg.
At doses higher than 400 mg nonlinearity has been reported, but this is
more likely due to changes of plasma protein binding than reduced
absorption.
Ibuprofen is extensively bound to plasma proteins (>99%)
R(-)-ibuprofen undergoes systemic unidirectional inversion to S(+)-
ibuprofen, which is known to be the main pharmacodynamically active
moiety.
Hepatic biotransformation results in two inactive main metabolites
which are excreted either free or as conjugates in urine.
Total urinary recovery of ibuprofen and its metabolites is 70-90%
About 10% of the administered dose is eliminated via feces.
Biowaiver Monograph for Ibuprofen Slide 20 of 31 Tehran University of
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 Dosage Form Performance
The pharmacokinetic properties of two ibuprofen preparations were
compared in a randomized crossover study on ten healthy volunteers;
there was no statistically significant difference in the extent of
absorption but ibuprofen peak plasma concentrations differed between
the two preparations.
In another study, the pharmacokinetic properties of a soft gelatin
capsule and a film coated tablet were compared to liquid prepared from
effervescent tablets. The fastest absorption was observed with soft
gelatin capsule; liquid and film-coated tablet produced longer
absorption half-lives, lower Cmax in serum and greater tmax values, but
also in this study, the AUCs were close to similar for all products.

Biowaiver Monograph for Ibuprofen Slide 21 of 31 Tehran University of

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 Dosage Form Performance
In another study, ibuprofen containing capsules prepared either from
hypromellose or gelatin were investigated in vitro and in vivo.
There were no differences found in the extent of absorption.
Some regulatory authorities classified ibuprofen as an active
pharmaceutical ingredient (API) for which in vivo BE testing is not
always necessary, in view of its wide therapeutic index and non critical
therapeutic use.

Biowaiver Monograph for Ibuprofen Slide 22 of 31 Tehran University of

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 Dissolution
The current USP 34 specification for in vitro dissolution
requires not less than 80% (Q) dissolved within 60 min in 900
mL phosphate buffer pH 7.2 at 50 rpm using the paddle
apparatus.

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 Discussion: Solubility
The several reports on the solubility at 20C are in reasonable
agreement with each other and also support our experimental
values at 37C, being somewhat higher than the values at
20C, as can be expected.
Solubility for biowaiver purposes should be determined at 37C
and at that temperature, at pH values below pH 5.5 their
dose/solubility ratio exceeds the critical value of 250 mL for
both strengths considered.
So, ibuprofen is insoluble in acid and consequently not highly
soluble as defined according to the present BCS guidances.

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Discussion: Absorption and Permeability
The BA of about 100% already classifies ibuprofen as highly
permeable according to the present BCS Guidances.
A P-app exceeding 10E-6 cm/s is considered to imply high permeability.
The results reported from Caco-2 studies exceed this value, in line with
the higher P-app found for ibuprofen than for propranolol.
(propranolol is recommended as a high permeability reference substance for Caco-2
permeability in the FDA guideline.)

The partition coefficient of ibuprofen, being higher than of metoprolol,

supports its high permeability.
(metoprolol was chosen as the reference compound for permeability since 95% of the
drug is known to be absorbed from the GI tract.)

Biowaiver Monograph for Ibuprofen Slide 25 of 31 Tehran University of

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 BCS Classification
According to the present regulations, ibuprofen is a BCS
class II drug, showing high permeability and pH-dependent
solubility, that is, a high solubility according to BCS
requirements only above a certain pH value.
This is supported by an in vitro in vivo correlation (IVIVC) where a rank
order was found between dissolution characteristics and the rate of
absorption, since IVIVCs are predicted for BCS Class II drugs.
Current BCS Guidances allow the possibility for a biowaiver exclusively
for BCS class I drugs.
The limited solubility of ibuprofen at acid pH thus excludes it from the
present biowaiver criteria.

Biowaiver Monograph for Ibuprofen Slide 26 of 31 Tehran University of

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 BCS Classification
At pH values near neutral, the solubility of ibuprofen is
sufficient to comply with criterion for high solubility.
As these pH values are closer to those at the absorption sites
in the small intestine they are therefore more relevant in
terms of systemic absorption of ibuprofen.

Accordingly, ibuprofen may also fit in the newly proposed

intermediate solubility class suggested for acids and bases
that are highly soluble at either physiologically relevant pH
1.2 or 6.8.

Biowaiver Monograph for Ibuprofen Slide 27 of 31 Tehran University of

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 Criteria from: TRS 937 Annex 8 part 6.3
For pharmaceutical products containing APIs with high
solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high
permeability (Class II with weak acidic properties)
These are eligible for a biowaiver provided that the
multisource product:
Is rapidly dissolving, i.e. 85% within 30 minutes in standard
media at pH 6.8 /paddle/ 75 rpm basket/ 100 rpm; and
The multisource product exhibits similar dissolution profiles,
to those of the comparator product in buffers at all three pH
values (pH 1.2, 4.5 and 6.8).
Biowaiver Monograph for Ibuprofen Slide 28 of 31 Tehran University of
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 Patients Risks Associated with Bioinequivalence

When considering a biowaiver for a drug substance, its

therapeutic index also needs to be taken into account.
Ibuprofen has a wide therapeutic range between 10 and 50
mg/L, the toxic concentration being>100 mg/L and has no life
threatening indication.
So, the use of in vitro methodology as a surrogate for in vivo
BE studies involves little therapeutic risk.

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 Conclusion
A biowaiver for IR ibuprofen solid oral dosage form is
scientifically justified, provided that:
The dosage form is rapidly dissolving (85% in 30 min or less) in pH
6.8 buffer
The test product shows dissolution profile similarity to the reference
product in pH 1.2, 4.5, and 6.8
The test product contains only the non-critical excipients, in
amounts that are usual for IR solid oral dosage forms.

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 References
WHO Technical Report Series No. 937, May 2006
Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration
requirements to establish interchangeability

Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List
of Essential Medicines immediate release, solid oral dosage forms

FDA - Guidance for Industry: Waiver of in vivo bio-equivalence studies for

immediate release solid oral dosage forms containing certain active
moieties/active ingredients based on a Biopharmaceutics Classification
System (2000)
EU-guidance: Note for Guidance on the Investigation of Bioavailability and
Bioequivalence CPMP/EWP/QWP/1401/98; paragraph 5.1
A systematic approach to the biowaiver decision: International Pharmaceutical
Federation (FIP) published in the Journal of Pharmaceutical Sciences.
Biowaiver Monograph for Ibuprofen Slide 31 of 31 Tehran University of
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