DISOLUSI

As a tooll for QC and BE in vitro

Iyan Sopyan
Yoga Windhu Wardhana
Disolusi
Skema Wagner
Granul
Tablet/ Disintegrasi Deagregasi
Kapsul atau Partikel halus
Agregat

Disolusi Disolusi Disolusi

(kecil) (utama) (utama)

Obat dalam Larutan

(in vitro/in vivo)
Absorpsi

Obat dalam darah,

cairan biologis, dan
jaringan
 Mempengaruhi proses disolusi

 Hukum Fick: Koefisien D (difusi) mengikuti

hukum Stoke-Einstein :
dm
 k .S (Cs  C ) k '.T
dt D
6 .r.
 Hukum Noyes & Whitney: k’= tetapan Boltzman
T= suhu mutlak medium
dC D. A r= jari-jari molekul
 (Cs  C ) = kekentalan/viskositas
dt h medium
 Why dissolution ?

In Vitro Dissolution

Quality Control Bioavaibility/ Bioequivalence

IR Product BCS
 Product specification
Lower strength
 Batch Release
 Shelf Life IVIVC
ER Product Lower strength
BIOPHARMACEUTICAL CLASSIFICATION SYSTEM
Diperkenalkan oleh : Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R.
pada tahun 1995 dengan judul :
A Theoretical Basis for a Biopharmaceutic Drug Classification: The
Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability.
Pharm. Res. 12: 413–420. (FDA, 2000; European Agency for the Evaluation of
Medicinal Products, 2001).
 Teori Disolusi
 Disolusi merupakan suatu jenis spesifik dari
reaksi heterogen menghasilkan transfer
massa sebagai akibat dari pelepasan dan
pemindahan molekul solut dari permukaan
padat

 Kecepatan Disolusi didefinisikan sebagai

jumlah zat obat yang masuk ke dalam
larutan per unit waktu di bawah kondisi yang
dibakukan dari antarmuka cair-padat, suhu
dan komposisi pelarut.
Teori Disolusi yang terumum adalah

1. Teori Film
2. Teori Pembaharuan Permukaan
(Teori Penetrasi)
3. Teori Kecepatan Solvasi Terbatas
4. Gabungan Teori 1 dan 2
 TEORI FILM
Partikel padat dicelupkan ke dalam cairan, saat mulai melarut
partikel akan dikelilingi oleh film tak bergerak dari pelarut
dengan tebal h, yang bergantung pada kondisi pengadukan,
ketebalan lapisan film makin menipis oleh pengadukan yang
cepat.

C sat
Film tak bergerak

Solida

C sol

Conc
h
Persamaan Teori Film
Jika masa terlarut setara dengan m, volume
disolusi, v, dan luas permukaan zat padat, S,
maka persamaan Fick I dapat ditulis :
V dc (Csol  Csat)
 D
S dt h
atau
dm (Csat  Csol)
 K.S
dt h

 K adalah konstanta kecepatan disolusi

Teori Pembaharuan Permukaan
(Surface Renewal Theory)

Teori ini disebut juga Teori Penetrasi atau Model

Danckwert
Berbeda dengan teori
pertama (tradisional),
pada teori ini lapisan yg
berdekatan dengan
partikel tidak stagnan,
tetapi bergerak (selalu
diperbaharui) sehingga
konsentrasinya (CA)
lebih kecil dari CS

Hipotesis ini didukung oleh fakta bahwa molekul harus

tersolvasi sebelum melarut.
Persamaaan pada Model Danckwert :

dc dW
V   S D(Csat  Csol )
dt dt

 = Kecepatan Pembaharuan
permukaan segar
Teori Solvasi Terbatas
Teori ini menyatakan bahwa dalam proses disolusi
terjadi mekanisme solvasi dimana disolusi lebih
merupakan fungsi kelarutan dari pada fungsi difusi.
Persamaan :
G  ki(Csat  Csol)
jika konsep permukaan ini digabung dengan model
lapisan difusi, menjadi :
D (Csat  Csol)
G
h  D 
1  h.ki 

G = Kecepatan disolusi per unit luas

ki = tetapan tranfer antarmuka efektif
FAKTOR-FAKTOR YANG MEMPENGARUHI
KECEPATAN DISOLUSI OBAT

A. FAKTOR ZAT AKTIF

B. FAKTOR TEKNOLOGI
C. FAKTOR FORMULASI
D. FAKTOR LINGKUNGAN UJI
DISOLUSI
Korelasi in vitro – in vivo (IVIVC)

FDA :

model matematik prediktif yang

menggambarkan hubungan antara
sifat in vitro dari bentuk sediaan
dengan respon yang relevan (in vivo)
 IVIVC Level
1. Level A
Korelasi paling baik
the most informative,
as it represents a generally
linear, point-to-point
relationship between in vitro
dissolution and in vivo
absorption profiles.
2. Level B
Korelasi kurang baik
the dissolution time is
compared with the mean
residence time or in vivo
dissolution time.
IVIVC Level
3. Level C
Sedikit ada korelasi
Establishes a single point
relationship of a dissolution
parameter (drug released at
one specific timepoint) and
one PK parameter.
4. Level C Multiple
Hampir tiada korelasi
PARAMATER PADA IVIVC Level
IVIVC vs BCS
Rate-Limiting Step to Absorption and Requirements for
Dissolution According to BCS Classification
of the Drug Substance
BCS Solubility Permeability Major rate Requirement for
class limiting step dissolution
I High High Gastric Fast over physiological range,
emptying 85% in 30 min in all media

II Low High Dissolution Specifications set on the basis

of IVIVC
III High Low Uptake cross Very fast over
the intestinal physiological range,
mucosa 85% in 15 min

IV Low Low Dissolution and Case by case

uptake evaluation; poor
chance of IVIVC
 IN VITRO BIOEKIVALEN
Dua kondisi tersebut dapat ditentukan jika profile
disolusi kedua produk/bets pada setiap
pengujian dengan medium disolusi memiliki
kesamaan :
1. Jika kedua hasil uji dan produk referen (baku)
menunjukkan lebih dari 85% disolusi selama
15 min, profile demikian dipertimbangkan
memiliki kemiripan
• Tidak diperlukan perhitungan
jika tidak seperti diatas, gunakan poin 2
2. Hitung nila f2 (faktor similaritas):
• Jika f2 ≥ 50, Profile pada normalnya
memiliki kemiripan (similar)
Glossary
Solid oral dosage forms

Immediate release typically means that

75% of the API is dissolved within 45
minutes
◦ Rapidly dissolving: ≥ 85% in ≤ 30 minutes
◦ Very rapidly dissolving: ≥ 85% in ≤ 15 minutes
Not part of presentation
Modified-release dosage forms (consult Int.Ph., BP, USP)
◦ Formulation deliberately changes release (slows down)
 Extended-release (prolonged-release)
Slower release throughout the GI tract
 Delayed-release (enteric coated tablets)
Resists gastric fluid & disintegrates in intestinal fluid
 IN VITRO BIOEKIVALEN
KONDISI PERCOBAAN
Apparatus • Paddle, 50 (75) rpm or
(choice) • Basket, 100 rpm
Dissolution media 1. Buffer pH 6.8 or simulated intestinal fluid
without enzymes
All three media 2. Buffer pH 4.5
for full 3. 0.1 M HCl or buffer pH 1.2 or simulated
comparison gastric fluid without enzymes
Volume of media 900 ml or less
Temperature 37°C ± 0.5°C
Sampling points 10, 15, 20, 30, 45, (60, 120) min. (typical)
Units (individual) 12 for “official” studies
Similarity Factor (f2)

n = number of time points

R(t) = mean % API dissolved of reference product at time point x
T(t) = mean % API dissolved of test product at time point x
 Minimum of 3 time points (zero excluded)
 12 units (each in own dissolution vessel) for each product (for
“official” purposes)
 Only one measurement should be considered after both products
have reached 85 % dissolution
 RSD at higher time points ≤ 10%
 Example
Lamivudine 150 mg & zidovudine 300 mg tablets
Source, WHO publication:
 Ongoing Monitoring of Antiretroviral Products as Part of
WHO’s Prequalification Project. Journal of Generic
Medicines (accepted for publication, January 2006
edition)
 Samples from PQ project or bought/requested

 Apparatus: paddle at 75 rpm

 Medium: 900 ml 0.1 M hydrochloric acid, 37°C
 Sample times: 5, 10, 15, 20, 30 and 45 minutes
 Analysis: HPLC
 Data presented for individual APIs in next tables
 Example
Lamivudine 150 mg & zidovudine 300 mg tablets

Time % Lamivudine of label claim dissolved

(min) Combivir® Gen-1 Gen-2 Gen-3 Gen-4
5 85 25 92 65 45
10 96 46 96 85 81
15 97 65 98 95 92
20 97 80 98 98 95
30 97 97 98 98 96
45 97 97 98 98 97
≥ 85 in ✔ no ✔ ✔ ✔
15 min ? Reference
f2 21
Example 3
Lamivudine 150 mg & zidovudine 300 mg tablets (4)

 Conclusion (considering only 0.1 M HCl as medium)

1. 3 products show profile similarity with
Combivir®
(≥ 85% in 15 minutes)
2. The profiles of Combivir® and Gen-1 are not
similar
 The products may still show bio-equivalency

 The dissolution profiles of the APIs in a particular

product are similar (true for all 5 products)
◦ Examples: see profiles of Combivir® and Gen-
1
 Time % Zidovudine of label claim dissolved
(min) Combivir® Gen-1 Gen-2 Gen-3 Gen-4
5 85 22 74 68 45
10 97 44 90 88 83
15 98 64 97 96 95
20 98 81 99 100 98
30 98 100 101 99 99
45 99 100 100 99 100
≥ 85 in ✔ no ✔ ✔ ✔
15 min ? Reference
f2 20
 120
120

100 100

Dissolution (%)
Dissolution (%)

80 80

60 60
Lamivudine Lamivudine
40 40
Zidovudine
Zidovudine
20 20

0 0
0 10 20 30 40 50 0 10 20 30 40
Time (minutes) Time (minutes)

Combivir ® dissolution profile Gen-1 dissolution profile

0.1 M hydrochloric acid 0.1 M hydrochloric acid

Note the similarity of the API profiles of each product

APIs highly soluble = dissolution controlled by disintegration time
Is particle size of APIs expected to be critical ?
Reporting
Comparative dissolution data
Full report, including
1. Purpose of study
2. Products/ batches information
 Batch number, manufacturing/expiry date, packaging, etc.
 CoA & size for “own” batches (and BMR for bio-studies report)
3. Dissolution conditions and method
4. Analytical method or reference to part of
dossier
5. Results (% API dissolved)
 Tabulated
 Graphically
 Similarity determination / calculation
6. Conclusion
 Some conclusions
 Comparative dissolution
◦ should form an essential part of R&D of solid oral dosage
forms (including suspensions),
◦ supports bio-studies,
◦ is required for comparison of pharmaceutical release
properties of pivotal batches,
◦ is used to set dissolution specifications, and
◦ assists in post-approval changes

 It is thus important
◦ to conduct the studies under controlled conditions in the 3
media, all as required by the guidelines,
◦ to take samples for analysis at meaningful intervals and
◦ to be able to determine similarity of profiles
 Peralatan Disolusi
Apparatus Classification in the USP :
Apparatus 1 (rotating basket)
Apparatus 2 (paddle assembly)
Apparatus 3 (reciprocating cylinder)
Apparatus 4 (flow-through cell)
Apparatus 5 (paddle over disk)
Apparatus 6 (cylinder)
Apparatus 7 (reciprocating holder)
 Peralatan Disolusi
Apparatus Classification in the European
Pharmacopoeia

For solid dosage forms Paddle apparatus

Basket apparatus
Flow-through apparatus
For transdermal patches Disk assembly method
Cell method
Rotating cylinder method
For special dosage forms Chewing apparatus
Flow-through apparatus