KLASIFIKASI

BIOFARMASETIKA/
BIOPHARMACEUTICS
CLASSIFICATION SYSTEM
(BCS)
 CPMK
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berdasarkan aspek biofarmasetika

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Mahasiswa mampu menyimpulkan dan merancang sediaan farmasi
berdasarkan klasifikasi biofarmasetika/BCS dan aplikasinya dalam sediaan
farmasi serta menjelaskan korelasi in-vitro dan in-vivo sediaan
 INTEGRASI AIK
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• QS. Al-Mujadalah:11
• Al-Alaq:1-5
• Al-Maidah:11
• Pendahuluan
• Tinjauan tentang sistem
kalsifikasi biofarmasetika (BCS)
• Aplikasi
• Kesimpulan
• Referensi
 Pendahuluan
۞Biopharmaceutics Classification System
(BCS)
 Kerangka acuan untuk mengklasifikasikan
bahan obat berdasarkan kelarutannya dalam
air dan permeabilitas di usus
Apa pentingnya?
• Penting dalam menentukan
bioavaibilitas obat
 RUTE ORAL

♠ Penentuan rute pemberian bagi Formulator

 Continues to dominate the area of drug delivery technologies.
❖ Batasan
➢ Absorption and Bioavailability di lingkungan saluran cerna.
➢ Limitations more prominent (menonjol)
✓ with the advent of protein and peptide drugs
✓ compounds emerging as a result of combinatorial chemistry and
the technique of high throughput screening
 API structure
salt form and
excipients

Bioavailability of drug
is determined by
extent of drug solubility
and ➢drug
solubility
➢drug product
permeability quality
attributes
 Biopharmaceutics Classification System

Guidance provided by the U.S. Food and Drug

Administration for predicting the intestinal drug
absorption

The fundamental basis established by

Dr. Gordon Amidon (2005)
✓ Distinguished Science Award (Aug ’06 ,FIP)

❖ First introduced into regulatory decision-making process in the

guidance document on Immediate Release Solid Oral Dosage
Forms: Scale Up And Post Approval Changes
➢ Tiga faktor utama yang mempengaruhi absorpsi obat
dari bentuk sediaan padat oral lepas segera :

➢Dissolution
➢Solubility
➢Intestinal permeability.
The Biopharmaceutics Classification System (BCS)
(as defined by the FDA after Amidon)
 Basis of BCS
Disolusi obat in vivo SIMILAR IN VIVO
DISSOLUTION
menentukan

Konsentrasi obat SIMILAR IN VIVO ABSORPTION

Dalam membran
sebanding

SIMILAR SYSTEMIC
Intestinal Absorption AVAILABILITY
 SOLUBILITY DETERMINATION

(37±100C in aqueous medium with pH range of 1-7.5.)

A sufficient number of pH conditions

 Karateristik ionisasi zat uji

Minimal dilakukan pada 3 pH yang berbeda (pH 1,2;

pH 4,5; dan pH 6,8)
Larutan buffer (standar) sesuai Farmakope
Metode uji yang direkomendasikan
 Determination
of permeability

♣ Tidak hanya berdasarkan lipophilicity (termasuk abs. in

vivo)
A. Human studies
➢ Mass balance studies
➢ Absolute bioavailability studies
➢ Intestinal perfusion methods
B.In vivo or in situ intestinal perfusion in a suitable animal
model
C.In vitro permeability methods using excised intestinal
tissues
D. In vitro permeation studies across a monolayer of cultured
epithelial cells.e.g. Caco-2 cells or TC-7 cells
 DISSOLUTION DETERMINATION
➢ USP apparatus I (basket) at 100 rpm or USP apparatus
II (paddle) at 50 rpm.
➢ Dissolution media (900 ml): 0.1 N HCl or simulated
gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or
simulated intestinal fluid.
➢ Compare dissolution profiles of test and reference
products using a similarity factor (f2).

0
 Batasan
HIGHLY SOLUBLE jika the highest dose
strength is soluble in < 250 ml water over a pH range
of 1 to 7.5.
The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of

absorption in humans is determined to be > 90% of
an administered dose

RAPIDLY DISSOLVING when > 85% of the

labeled amount of drug substance dissolves within 30
minutes using USP apparatus I or II in a volume of <
900 ml buffer solutions.
BCS Class Boundaries: Objectives

Dissolution
Rapid dissolution - ensure that in vivo
(Product)
dissolution is not likely to be the
“rate determining” step

Solubility
High solubility- ensure that solubility
(Drug)
is not likely to limit dissolution and,
therefore, absorption

Permeability High permeability - ensure that drug

(Drug) is completely absorbed during the limited
transit time through the small intestine
 • menunjukkan penyerapan
yang tinggi dan disolusi yang
Kelas I : tinggi.
Metoprolol, • Senyawa ini umumnya sangat
Diltiazem, baik diserap.
Verapamil, • diformulasikan sebagai produk
dengan pelepasan segera, laju
Propranolol. disolusi umumnya melebihi
pengosongan lambung

hampir 100% penyerapan (setidaknya 85% dari produk larut dalam 30

menit dalam pengujian disolusi in vitro dalam berbagai nilai pH), oleh
karena itu data bioekivalensi in vivo tidak diperlukan untuk menjamin
perbandingan produk
 Kelas II :
Fenitoin, • memiliki daya serap yang tinggi
tetapi laju disolusi rendah.
Danazol, • Dalam disolusi obat secara in vivo
Ketokonazol, maka tingkat penyerapan terbatas
asam kecuali dalam jumlah dosis yang
mefenamat, sangat tinggi.
Nifedipine.

• Penyerapan obat untuk kelas II biasanya lebih lambat

daripada kelas I dan terjadi selama jangka waktu yang lama
• Korelasi in vitro-in vivo (IVIVC) biasanya diterima untuk obat
kelas II.
 Kelas III: • Permeabilitas obat berpengaruh
pada tingkat penyerapan obat,
Simetidin, namun obat ini mempunyai laju
Acyclovir, disolusi sangat cepat
Neomycin B, • Obat ini menunjukkan variasi yang
tinggi dalam tingkat penyerapan
Captopril obat.

• pelarutan yang cepat, variasi ini disebabkan perubahan

permeabilitas membran fisiologi dan bukan faktor bentuk
sediaan tersebut.
• Jika formulasi tidak mengubah permeabilitas atau waktu durasi
pencernaan, maka kriteria kelas I dapat diterapkan
 • Senyawa ini memiliki
bioavailabilitas yang buruk.
Biasanya tidak diserap dengan
Kelas IV : taxol, baik dalam mukosa usus.
hydroclorthiaziade, • Senyawa ini tidak hanya sulit
furosemid. untuk terdisolusi tetapi sekali
didisolusi, sering menunjukkan
permeabilitas yang terbatas di
mukosa GI.

Cenderung sangat sulit diformulasikan

 BCS -Implications for drug development
ЖApplication in early drug development and then in
the management of product change through its life
cycle
ЖAids fundamental understanding of the
biopharmaceutical and physical properties of the drug
ЖAids discriminatory dissolution method development
ЖCan help guide the development of in-vitro/in-vivo
correlations
ЖCan be used to obtain a biowaiver
ЖDevelopment of poorly soluble drugs
This classification is associated with drug
dissolution and absorption model, which
identifies the key parameters controlling
drug absorption as a set of dimensionless
numbers viz
BCS defines 3 numbers (no units)

❖An ~ absorption number

❖Do ~ dose number
❖Dn ~ dissolution number
 Absorption Number
A function of GI Permeability to Drug Substance

Effective permeability Residence time in GI

P  T
An =  (T ) = eff GI

R T
GI

ABS

Radius of GI
Time required for
complete absorption
 Dose Number
A function of solubility of drug substance

Highest Dose Unit

D  250 mL

 V 
Do =  Water


 C 
Solubility

 
S
 Dissolution Number
A function of drug release from formulation

Solubility
mg/mL
Residence time in GI
Diffusivity 180 min
5x10-6 cm2/s

 3 D  C  T 
Dn =  
S
(T ) =   GI

 r    T 
2 GI

DISS

Particle Radius
25 mm
Density Time required for
1.2 mg/cm3 complete dissolution
 Applications of BCS in oral drug
delivery technology
Class I - High Permeability,
High Solubility

Achieve a target release profile associated with a

particular pharmacokinetic and/or pharmacodynamic
profile.
Formulation approaches include both control of release
rate and certain physicochemical properties of drugs
like pH-solubility profile of drug.
 Class II - High Permeability,
Low Solubility

Micronisation,
Addition of surfactants,
Formulation as emulsions and microemulsions
systems,
Use of complexing agents like cyclodextrins
 Class III - Low Permeability,
High Solubility

Require the technologies that address to

fundamental limitations of absolute or
regional permeability.

Peptides and proteins constitute the part of

class III and the technologies handling such
materials are on rise now days
 Class IV - Low Permeability,
Low Solubility

♫Major challenge for development of drug

delivery system and the route of choice
for administering such drugs is parenteral
(solubility enhancers.)

♫Fortunately, extreme examples are the

exception rather than the rule and are
rarely developed and reach the market
IVIVC-BCS
Definition of IVIVC
• In vitro dissolution: It’s a process of release of drug from
dosage form as measured in an in vitro dissolution
apparatus
• In vivo dissolution: process of dissolution of drug in the GI
tract.
• Correlation: relationship between in vitro dissolution rate
and in vivo absorption rate as used in bio-equivalence
guidance
• IVIVC has been defined as “a predictive mathematical
model describing the relationship between an in-vitro
property of a dosage form and an in-vivo response”
 Significance of ivivc

• The main objective of developing and evaluating an IVIVC is

to enable the dissolution test to serve as a surrogate. It reduces
the number of bio-equivalence required for approval as well as
during scale up and post approval changes (SUPAC).
• IVIVC shortens the drug development period, economizes the
resources and leads to improved product quality.
• A means of assuring the bioavailability of active ingredients
from a dosage form.
• Supports and or validates the use of dissolution methods and
specifications
• IVIVC assists in supporting biowaivers.
IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption IVIVC expectations for

rate
Immediate release product
control

High High Gastric IVIVC expected, if dissolution rate is

I slower than gastric emptying rate,
emptying
otherwise limited or no
correlations
Low High Dissolution IVIVC expected, if in vitro
II dissolution rate is similar to in
vivo dissolution rate, unless
dose is very high.
High Low Permeability Absorption (permeability) is rate
III determining and limited or no
IVIVC with dissolution.
Low Low Case by Limited or no IVIVC is expected.
IV
case
 High Solubility Low Solubility

Class 1 ImipramineI Class 2

Ketorolac Itraconazole S,I
Abacavir Ketoprofen Amiodarone I
Acetaminophen Atorvastatin I
S, Ketoconazole I
Labetolol S LansoprazoleI
Acyclovirb LevodopaS Azithromycin ,I
AmilorideS,I Carbamazepine S,I Lovastatin S,I
Levofloxacin S Mebendazole
Amitryptyline S,I LidocaineI Carvedilol
Antipyrine Chlorpromazine I Naproxen
Lomefloxacin S Nelfinavir S,I
Atropine Meperidine Cisapride
c Ofloxacin
Buspirone Metoprolol Ciprofloxacin S
High Permeability

Caffeine Cyclosporine I
S, Oxaprozin
Metronidazole Phenazopyridine
Captopril MidazolamS,I Danazol
ChloroquineS,I Dapsone PhenytoinS
Minocycline Piroxicam
Chlorpheniramine Misoprostol Diclofenac
Cyclophosphamide Diflunisal Raloxifene S
Nifedipine S Ritonavir S,I
Desipramine Phenobarbital Digoxin S
Diazepam Erythromycin S,I Saquinavir S,I
Phenylalanine Sirolimus S
Diltiazem S,I Prednisolone Flurbiprofen
Diphenhydramine Glipizide Spironolactone I
PrimaquineS Tacrolimus S,I
Disopyramide Promazine GlyburideS,I
Doxepin Griseofulvin TalinololS
Propranolol I Tamoxifen I
Doxycycline Quinidine I
S, Ibuprofen
Enalapril Indinavir S Terfenadine I
Rosiglitazone Warfarin
Ephedrine Salicylic acid Indomethacin
Ergonovine Theophylline
Ethambutol Valproic acid
Ethinyl Estradiol Verapamil I
FluoxetineI Zidovudine
Glucose
 High Solubility Low Solubility

Class 3 Class 4
Acyclovir Fexofenadine S Amphotericin B
Amiloride S,I Folinic acid Chlorthalidone
Amoxicillin S,I Furosemide Chlorothiazide
Low Permeability

Atenolol Ganciclovir Colistin

Atropine Hydrochlorothiazide Ciprofloxacin S
Bisphosphonates Lisinopril Furosemide
Bidisomide Metformin Hydrochlorothiazide
Captopril Methotrexate Mebendazole
Cefazolin Nadolol Methotrexate
Cetirizine Pravastatin S Neomycin
Cimetidine S Penicillins
Ciprofloxacin S Ranitidine S
Cloxacillin Tetracycline
Dicloxacillin S Trimethoprim S
Erythromycin S,I Valsartan
Famotidine Zalcitabine
 Parameters for correlations
SL. No. IN VITRO INVIVO

1. Dissolution rate Absorption rate (or absorption time)

2. Percent drug dissolved Percent of drug absorbed

3. Percent drug dissolved Maximum plasma concentration,

Cmax

4. Percent drug dissolved Serum drug concentration, Cp

 Level
IVIVC
• Tiga level:
– A
– B
– C
 Comment
1. In vitro in vivo correlations (IVIVC) play a key role in the
drug development and optimization of formulation.
2. IVIVC as surrogate for in vitro dissolution study and to
support biowaivers (Time and cost saving).
3. IVIVC is a mathematical relationship between in vitro
properties of a dosage form with its in vivo performance.
4. IVIVC produce regulatory burden.
5. IVIVC can be used in the development of new
pharmaceuticals to reduce the number of human studies during
the formulation development.
 Biowaiver
A biowaiver is an exemption from conducting human
bioequivalence studies when the active ingredient(s)
meet certain solubility and permeability criteria in vitro
and when the dissolution profile of the dosage form
meets the requirements for an "immediate" release dosage
form.

Obat2 yang hanya memerlukan uji BE in vitro (Uji Disolusi

Terbanding) → BCS kelas 1 dan 3
 Waiver of In Vivo Bioequivalence Study
based on

➢Pharmaceutical Dosage Form

(Solutions)
➢Biopharmaceutics Classification
System
➢Dose. (Highest Strength should be tested)
 BCS BIOWAIVER
Biowaiver for
Rapid and similar dissolution.
High solubility &High permeability.
Wide therapeutic window.
Excipients used in dosage form used
previously in approved immediated
released solid dosage forms.
REQUEST FOR BIOWAIVERS

Data Supporting :-

Rapid and Similar Dissolution

High Permeability
High Solubility
 Limitations of BCS as a Predictor
of Drug Disposition
Ω Permeability (90% absorption) is difficult to
determine, and difficult to convince the regulatory
agency .

Ω There is little predictability for BCS classification

drugs beyond Class 1 primarily due to the difficulty of
determining and proving 90% absorption.
➢ many drugs are misclassified (e.g. HIV protease inhibitors
as Class 4 compounds)).
 Conclusion
BCS aims to provide a regulatory tool for replacing
certain BE studies by accurate in-vitro dissolution
tests..
This increased awareness of a proper biopharmaceutical
characterization of new drugs may in the future result
in drug molecules with a sufficiently high permeability,
solubility and dissolution rate, and that will
automatically increase the importance of the BCS as a
regulatory tool over time
 References
• Krishna, R. and Yu, L. (2008). Biopharmaceutics
Applications in Drug Development, Springer.
• Paradkar, A.R. , dan Bakliwal, S.R. (2008).
Biopharmaceutics & Pharmacokinetics.
• Wagner, J.G. (2008). Biopharmaceutics and Relevant
Pharmacokinetics. Drug Intelligen Publications. 2008