Mufti

Schematic for Dissolution

of Solid Dosage Forms

Dari skema disimpulkan :

Kecepatan disolusi obat merupakan tahap
pembatas kecepatan sebelum obat berada dalam
darah
Apabila suatu sediaan padat berada dalam
saluran cerna, ada dua kemungkinan yang akan
berfungsi sebagai pembatas kecepatan
Bahan berkhasiat dari sediaan padat tersebut pertamatama harus terlarut
obat yang berada dalam larutan melewati membran
saluran cerna

Dissolution Rate-limited
Absorption
Possible Consequences
Delayed peak plasma concentration
Therapeutic level not reached
Large fraction unabsorbed

Griseofulvin (Cs = 1 mg/100mL)

Diffusion Layer Model

Noyes-Whitney/Nernst- Brunner

Diffusion Layer Model

Diffusion Layer Model

Noyes-Whitney/Nernst- Brunner

Where w = mass of solute dissolved at time, t, and dw/dt =

the rate of dissolution.
Note: rate = -dw/dt if w is the weight of the undissolved
solid.
D = diffusion coefficient (cm 2/sec)
S = effective surface area of the solute (cm 2)
h = the thickness of the diffusion layer (cm)
CS= solubility of the solute (g/cm 3)
C = concentration in the bulk phase (g/cm 3)

Sink Conditions The Biologically

Relevant Case

Since D, CS, and h can be considered

constant under a given set of conditions
of temperature, stirring, etc.

Intrinsic Dissolution Rate (G )

(Dissolution rate per unit of S)

G is a constant for a given compound under a given set of

experimental conditions.
In drug development, G has been used as a preformulation
screening test for early indication of likelihood of dissolution
rate -limited absorption.

Example of Use of G in Preformulation

Screening*
G < 0.1 mg/min/cm2 - suspect and usually
exhibit dissolution rate-limited absorption
G > 1.0 mg/min/cm2 - usually not prone to
dissolution rate-limited absorption
G >0.1<1.0 Borderline and require more
information
*Measured in the physiologic pH range of 1-7 at 37o,
500 mL dissolution fluid, 50 rpm stirring speed; S.A. Kaplan,
Drug Metab. Revs, 1, 15-34.

Dissolution of Tablets and Capsules

Hixson-Crowell Cube-Root Law

Example
Given a tablet containing 300 mg drug. The tablet
disintegrates in 2 minutes. If 60% of the drug is
released in the first 15 minutes in a standard USP
dissolution test, how long would it take for 90% to
be released, assuming dissolution follows the
cube root law closely enough?
W0 = 300 mg
After 15 min, 60% dissolves, thus w t = 120 mg.
When 90% dissolves, w t = 30 mg.

Solution

Dissolution Test
First adapted in USP XVII (1970) in 12
monographs.
In 1976, USP adopted policy favoring the
inclusion of a dissolution standard in essentially
all tablet and capsule monographs.
Currently, there are more than 600 monographs
requiring dissolution testing in USP XXVI.

Apparatuses 1 and 2
The Originals

Apparatus 1 (Rotating Basket Method)

First official apparatus
Standard is a 40 mesh basket
100 RPM unless otherwise specified (may range 50
150 RPM)

Apparatus 2 (Paddle Method)

Developed 1973-78
High popularity
Wire helix to prevent capsules from floating
Default speed is 50 RPM unless otherwise specified
(may range 25-100RPM)

Tablet Dissolution

USP Apparatus I (Basket) and II (Paddle)

Round bottom flasks containing dissolution media
at 37C
Dosage form placed in the basket or in the flask
Media mix by paddle or basket
Samples withdrawn at specific time intervals and
analyzed to determine concentration
UV spectrophotometer
HPLC

USP Apparatus 1 and 2

Dissolution Expressions and USP

Requirements
T with an associated % value (Unofficial)
Ex. T -50% or T 50% means time required for 50% of the
drug to dissolve from the dosage form
Q the USP designation used in monographs for the
percent dissolved by a specified time.
Ex. Not less than 80% (Q) of the labeled amount is
dissolved in 30 minutes.
Always used in conjunction with the appropriate USP
Acceptance Table.
Usually single point; multiple points may be required for
drugs with narrow therapeutic indices or toxicity problems;
at least 3 time points are required for modified release
dosage forms.

USP Dissolution Apparatuses

Apparatus
No.

Description

General
Application*

Rotating Basket

Oral IR and MR

Rotating Paddle

Oral IR and MR

Reciprocating Cylinder

Oral MR

Flow Through Cell

Oral MR

Paddle over disk

Transdermal DS

Cylinder

Transdermal DS

Reciprocating Holder

Transdermal DS
or non
disintegrating oral
MR

USP Apparatus 3

USP Apparatus 4

USP Apparatus 5

USP Apparatus 6

USP Apparatus 7

Role/Uses of Dissolution Testing

To help assure lot-to-lot uniformity
USP requirement applies even if there is no correlation
with in vivo data because it is a very discriminating and
useful control over manufacturing variables.
To guide formulation development
To help establish stability/expiration dates
To demonstrate to FDA that products after scaleup and
post-approval changes are bioequivalent to the originally
approved product
When correlated with in vivo data, dissolution may be used
instead of human biostudies.
Used without in vivo correlation for minor changes.

The Biopharmaceutical Classification

(BCS) for Drugs
Provides a logical basis for estimating the
risk of bioavailability problems based on
the drugs solubility in relationship to its
permeability.
Provides an understanding of when in
vitro-in vivo correlations are likely to be
found with IR products.

Solubility and Permeability

A drug substance is considered to have High
Solubility when the highest dose strength is
soluble in < 250 mL water over a pH range of 1
- 8 at 37o. If 250 mL or more are required, then
its Low Solubility.
A drug substance is considered to have High
Permeability when the extent of absorption in
humans is determined to be > 90% of an
administered dose, in the absence of evidence
suggesting instability in the GI tract.

Example
Given a drug with a dose of 1 mg and a
minimum solubility at pHs 1- 8 of 0.02
mg/mL. For BCS purposes, is it considered
to have High Solubilityor Low Solubility?

Solution
Dose/Solubiliy = Dose Volume
1 mg/ 0.02 mg/mL = 50 mL
Since 50 mL< 250 mL, it is considered High
Solubility

Biopharmaceutic Classification System

High Solubility

Low Solubility

(Dose Vol. < 250

mL)

(Dose Vol. >250mL)

High Permeability e.g. propranolol, e.g. piroxicam,

(Fract. Abs. > 90%)
Metoprolol,
Naproxen,
Verapamil
ketoprofen,
karbamazepin
Low Permeability e.g. ranitidine,
(Fract. abs. <90%)
Cimetidine,
atenolol

e.g. furosemide,
hydrochlorothiazide
taxol

Expectations for Immediate Release

Products Based on BCS
Class

InVitro-InVivo
Correlation (IVIVC)
Expectation

Oral IR SDF
Implications

Formulation

Limited or none expected;

I
HS/HP abs is gastric emptying rate

Few formulation problems.

Absorption is expected to be
II
LS/HP dissolution rate- limited; IVIVC

A target for IR formu lators is to make

dw/dt is so rapid that absorption is no
longer dissolution rate-limited.

Absorption (permeability) is
III
HS/LP rate determining and limited or

Currently, little or no ability to influence

permeability. At least, dw/dt should be
fast enough to ensure permeability ratelimited absorption

limited if dissolution is rapid.

expected.

no IVIVC expected.

Limited or no IVIVC expected H i g h l e v e l o f d i f f i c u l t y i n

IV
developing successful dry solid oral
LS/LP on case-by-case basis.

dosage forms; parenteral administration

may be indicated.

Implications of Low Solubility

Must optimize particle size
Must have rapid disintegration
Appropriate selection and use of excipients
Soluble fillers vs insoluble fillers
Watch hydrophobic lubricants
Wetting agents

Other approaches?

Implications of Low Permeability

Incomplete absorption
Rapid, complete dissolution needed
Release may need to be modified
Increase exposure to an absorption window
Possible retarded release if a saturable
transport phenomenon exists

PIROXICAM - A Capsule Case Study

Formulation Variables
Lubricant [MgSt] Level (0.5 1.5%)
Wetting Agent [SLS] (0 - 1%)
Filler Level [% Lactose] (0 100%) (Binary Lactose/MCC
Filler)
Piroxicam Part. Size (0 100% milled) (Binary Mixture
of Milled/ Umilled Drug)
Process Variable
Lubricant Blend Time (10 - 18
min.)

Data from UM-FDA Research

When is Drug Particle Size Most Critical?

Specific Particle Number?

Specific Surface Area?

Faktor- faktor yang mempengaruhi laju disolusi

Faktor yang berkaitan dengan sifat fisikokimia

obat

kelarutan, bentuk kristal, bentuk hidrat solvasi dan

kompleksasi
mempengaruhi Cs

ukuran partikel

mempengaruhi S

kekentalan

mempengaruhi D

keterbasahan

mempengaruhi S

 Faktor yang berkaitan dengan formulasi sediaan

bentuk sediaan
Pengaruh bentuk sediaan pada laju disolusi tergantung
pada kecepatan pelepasan bahan aktif yang terkandung
didalamnya
Secara umum laju disolusi akan menurun menurut urutan
sebagai berikut : larutan, suspensi, kapsul, tablet dan tablet
salut, tablet modified release

bahan pembantu
Penggunaan bahan pembantu sebagai bahan pengisi,
pengikat, penghancur dan pelicin dalam proses formulasi
mungkin akan menghambat atau mempercepat laju disolusi
tergantung pada bahan pembantu yang dipakai

cara pengolahan (prosesing)

Cara pengolahan dari bahan baku, bahan pembantu dan
prosedur yang dilaksanakan dalam formulasi sediaan padat
peroral juga akan berpengaruh pada laju disolusi

 Faktor formulasi yang dapat mempengaruhi laju disolusi

kecepatan disintegrasi

mempengaruhi S

interaksi obat dengan eksipien

kekerasan

mempengaruhi S

porositas

mempengaruhi S

mempengaruhi Cs

Faktor yang berkaitan dengan alat uji disolusi dan

parameter uji

Faktor ini sangat dipengaruhi oleh lingkungan

selama percobaan
kecepatan pengadukan (berpengaruh pada h)
suhu medium (berpengaruh pada D dan Cs)
pH medium (berpengaruh pada Cs)
metoda uji yang dipakai

Faktor formulasi dan teknologi yang

dapat merubah karakteristik disolusi
Metode yang paling banyak dikembangkan adalah dengan
Meningkatkan kelarutan dan luas permukaan efektif

Meningkatkan luas permukaan efektif obat

Mengurangi ukuran partikel

penambahan senyawa aktif permukaan dan solubilizer

Teknik dispersi padat

Kompleksasi
Polimorfi
Titik eutektik

Pembentukan kompleks

Kompleks inklusi dengan siklodekstrin

Kompleks dengan N-metilglukamin

Bahan yang dapat mengubah tetapan dielektrik cairan

Kelarutan dari senyawa merupakan fungsi dari tetapan

dieleltrik cairan
pada nilai tetapan dielektrik tertentu diperoleh satu
kelarutan optimum

Bahan Penglarut Miseler

Contoh : Gliserin, polioksi-etilenglikol, propilenglikol

Terjadinya penurunan tegangan permukaan

Surfaktan dengan zat aktif dapat membentuk
kompleks yang lebih larut lemak dan lebih dapat
diserap
Surfaktan juga dapat berpengaruh langsung pada
proses fisiologik yang memperpanjang waktu
pengosongan lambung, menghambat pengeluaran
getah lambung dan memperlambat gerakan usus

Penyalutan dengan senyawa hidrofil