12. Jenis Sediaan yang memerlukan uji
disolusi
Tablet/Kaplet
Oral suspensi/emulsi
Sistemik semisolid (suppositoria)
Trandermal sistemik (patch)
Sediaan yang pelepasnya terkendali (ER)
S2 FTF 12
13. Disolution Test
Disolusi partikulat
Disolusi intrinsik
Disolusi-permeasi/disolusi usus terbalik
S2 FTF 13
14. 14
1. Pemindahan
molekul dari fase
solut pada suhu
tertentu.Penerima-
an energi potensial
atau usaha netto
untuk proses
tersebut : w22:
Proses pemindahan molekul tersebut terjadi dalam 3 tahap
2. Pembentukan lubang
dalam solven yang cukup
besar agar dapat
menerima molekul solut.
Usaha: w11.
3. Molekul solut
ditempatkan dalam
lubang dalam
solven, dan usaha
yang diperolah atau
penurunan energi
potensial adalah -
w12
Lubang dalam solven sekarang tertutup dan terjadi tambahan penurunan
energi, -w12 , bersangkutan dengan usaha neto dalam langkah terakhir ini
adalah -2 w12 .
Usaha total adalah (w22 + w11 -2 w12 ).
S2 FTF
15. (37±100C) in aqueous medium with pH range of 1-7.5.)
P a d a p H y a n g s e s u a i
Melihat ionisasi dari bahan obat yang di uji
minimal 3 replicate penentuan kelarutan pada
masing2 pH
Standard buffer solutions dijelaskan di pharmacopoeias
Methods other than shake flask method (with
Justification). e g. acid or base titration methods
SOLUBILITY DETERMINATION
S2 FTF 15
17. 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.
S2 FTF 17
19. Mempengaruhi proses disolusi
Hukum Fick:
Hukum Noyes & Whitney:
. ( )
dm
k S Cs C
dt
.
( )
dC D A
Cs C
dt h
Koefisien D (difusi) mengikuti
hukum Stoke-Einstein :
k’= tetapan Boltzman
T= suhu mutlak medium
r= jari-jari molekul
= kekentalan/viskositas
medium
'.
6 . .
k T
D
r
S2 FTF 19
20. Why dissolution ?
In Vitro Dissolution
Quality Control Bioavaibility/ Bioequivalence
Product specification
Batch Release
Shelf Life
IR Product BCS
Lower strength
ER Product IVIVC
Lower strength
20S2 FTF
22. 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).
S2 FTF 22
23. 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
S2 FTF 23
24. 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.
Solida
C sat
Film tak bergerak
C sol
h
Conc
S2 FTF 24
25. Persamaan Teori Film
Jika masa terlarut setara dengan m, volume
disolusi, v, dan luas permukaan zat padat, S,
maka persamaan Fick I dapat ditulis :
atau
K adalah konstanta kecepatan disolusi
h
Csat)(Csol
D
dt
dc
S
V
h
Csol)(Csat
K.S
dt
dm
S2 FTF 25
26. 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.
S2 FTF 26
27. Persamaaan pada Model Danckwert :
)(
dt
dc
V CsolCsatDS
dt
dW
= Kecepatan Pembaharuan
permukaan segar
S2 FTF 27
30. 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)
S2 FTF 30
31. 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
S2 FTF 31
32. IN VITRO BIOEKIVALEN
Apparatus
(choice)
• Paddle, 50 (75) rpm or
• Basket, 100 rpm
Dissolution media
All three media
for full
comparison
1. Buffer pH 6.8 or simulated intestinal fluid
without enzymes
2. Buffer pH 4.5
3. 0.1 M HCl or buffer pH 1.2 or simulated
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
KONDISI PERCOBAAN
S2 FTF 32
33. 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%
Similarity Factor (f2)
S2 FTF 33
34. 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 tablesS2 FTF 34
36. 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
S2 FTF 36
38. 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 ?
0
20
40
60
80
100
120
0 10 20 30 40 50
Time (minutes)
Dissolution(%)
Lamivudine
Zidovudine
0
20
40
60
80
100
120
0 10 20 30 40
Time (minutes)
Dissolution(%)
Lamivudine
Zidovudine
S2 FTF 38
39. 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
S2 FTF 39
40. 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
S2 FTF 40
44. 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
S2 FTF 44
48. 2. 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)
S2 FTF
48
49. 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.
S2 FTF 49
50. 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
S2 FTF 50
55. Rate-Limiting Step to Absorption and Requirements for
Dissolution According to BCS Classification
of the Drug Substance
BCS
class
Solubility Permeability Major rate
limiting step
Requirement for
dissolution
I High High Gastric
emptying
Fast over physiological range,
85% in 30 min in all media
II Low High Dissolution Specifications set on the basis
of IVIVC
III High Low Uptake cross
the intestinal
mucosa
Very fast over
physiological range,
85% in 15 min
IV Low Low Dissolution and
uptake
Case by case
evaluation; poor
chance of IVIVC
S2 FTF 55
