SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅰ. Introduction
Ⅱ. Dissolution of particles
Ⅲ. USP Dissolution testing
Ⅳ. Factors affecting drug dissolution
Ⅴ. Case study of dissolution testing
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅰ. Introduction
▪ Definition of dissolution
-Process by which a solid solute
with low solubility enters into a solution
in the presence of a solvent
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅰ. Introduction
▪ Dissolution, Absorption and Bioavailability
Dissolution → rate-limiting step
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅰ. Introduction
▪ Dissolution, Absorption and Bioavailability
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅰ. Introduction
▪ Dissolution, Absorption and Bioavailability
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅰ. Introduction
▪ Role of dissolution test
-Correlation between dissolution and bioavailability
-Evaluation of batch-to-batch uniformity of formulations
(Quality Control )
( 내용고형제의 품질을 일정한 수준으로 확보하고 현저한
생물학적 비 동등성의 방지를 목적으로 한다. 대한약전 8개정 p1687 )
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅱ. Dissolution of particles
▪ Diffusion layer model
Drug particle
Diffusion layer
(aqueous membrane)
Bulk solution
Cs
Cb
h
Cs; The conc. of drug at the surface of particle ( → the
saturated solubility of drug)
Cb; The conc. of drug in the bulk solution
h ; Thickness of diffusion layer
( Cs –Cb) /h ; Conc. Gradient ( → driving force)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅱ. Dissolution of particles
▪ Noyes-Whitney Relationship
dM/ dt = (DS/ h) (Cs- Cb )
↓
dC/ dt = (DS/ V h) (Cs- Cb )
M ; The amount of drug dissolved ( mg or mmol), t ; Time ( sec.)
D ; The diffusion coefficient of the drug ( cm2/s), h ; The thickness of diffusion layer ( cm)
Cs ; The conc. of drug at the surface of particle , Cb ; The conc. of drug in the bulk solution
S ; Surface area of the drug particles ( cm2),
V ; The volume of bulk solution ( cm3)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅱ. Dissolution of particles
▪ Noyes-Whitney Relationship
dM/ dt = (DS/ h) (Cs- Cb )
↓
dM/ dt = (DS Cs / h ) ← ∵Cs > > Cb
↓ integration
M = (DS Cs / h ) t
↓
C = (DS Cs / V h ) t
In sink condition
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅱ. Dissolution of particles
▪ Sink conditions and nonsink conditions
Amount
dissolved
Under nonsink conditions
Under sink conditions
What is sink condition ?
→ When the conc. of the
drug in the bulk
solution << the
saturated solubility,
we called sink condition.
Time
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅱ. Dissolution of particles
▪ Hixson-Crowell cube-root relationship
- Surface area of particle remains constant in the NoyesWhitney Relationship.
But, it will decrease as the drug dissolves.
( except something like trans dermal systems)
This decease changes the effective area.
⇒ Another relationship needed.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅱ. Dissolution of particles
▪ Hixson-Crowell cube-root relationship
M O1/3-M t1/3= K t
MO ; The amount of drug particles at time zero
Mt ; The amount of drug particles remaining at time t
K ; The cube-root dissolution rate constant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ⅱ. Dissolution of particles
▪ Higuchi ’s model relationship
M O -M t = K t ½
▪ Zero-order kinetics relationship
M O -M t = K t
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 1 (Rotating Basket)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 1 (Rotating Basket)
Consist : cylindrical stainless-steel basket, shaft
Use : capsules, suppositories and tablets that
have low density and tend to float on the
dissolution medium or dissolve very slowly.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 2 (Paddle)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 2 (Paddle)
Consist : very similar to that of apparatus 1 except
that a paddle and shaft are used.
- Rotational speed ( tablet ; 50rpm, suspension ; 25rpm)
- 검체는 반드시 잠겨있고 패들과 2cm 유지한다.
- capsule처럼 뜨는 검체의 경우 sinker를 사용한다.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 1 and Apparatus 2
www.distekinc.com
www.vankel.com
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Automated Dissolution System
www.distekinc.com
www.hansonresearch.com
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 3 (Reciprocating Cylinder)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 3 (Reciprocating Cylinder)
Consist: flat-bottomed cylindrical glass vessels
equipped with a reciprocating cylinder
Use: drug-containing microparticulate formulation
ex) sustain-released formulation
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 3 (Reciprocating Cylinder)
www.vankel.com
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 4 (Flow-through cell)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 4 (Flow-through cell)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 4 (Flow-through cell)
Consist : reservoir of dissolution medium that is
pumped into a flow cell containing the sample.
Use : sustained and controlled-release dosage
forms where the solubility of the drug in the
medium is very low. ⇒ maintenance of sink condition
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 4 (Flow-through cell)
www.distekinc.com
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 5 (Paddle over Disk)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 5 (Paddle over Disk)
Consist : sample holder or disk assembly that sits
at the bottom of the glass vessels
Use : topical and transdermal forms
ex) patch
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 6 (Cylinder Method)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 6 (Cylinder Method)
Consist : modified from apparatus 1 instead of a
basket, a stainless-steel cylinder is used as a
sample holder.
Use : transdermal patches
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 7 (Reciprocating Disk Method)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 7 (Reciprocating Disk Method)
Consist : motor drive assembly that reciprocates
the system vertically.
Use : release of drug from transdermal system.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Apparatus 7 (Reciprocating Disk Method)
www.distekinc.com
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ Acceptance Criteria
Stage
Number
tested
Acceptance Criteria
S1
6
Each unit is not less than Q + 15%
6
Average of 12 unit (S1+S2) is equal to or
greater than Q, and no unit is less than
Q - 15%
12
Average of 24 unit (S1+S2+S3) is equal to
or greater than Q, and no more than 2
units are less than Q- 15%
S2
S3
Q (%) ; the percentage of the
labeled amount
USP XXⅣ / National Formulary
XIX
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ KP Dissolution testing
제 1 법 (회전검체통법)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ KP Dissolution testing
제 2 법 (패들법)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
III. USP Dissolution Testing
▪ KP Dissolution testing
제 3 법 (Flow-Through Cell 법)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Physicochemical Properties of the Drug
- Ionized vs. unionized forms
; Salt forms >> Weak electrolytes ( about dissolution rate)
∵ ↓Ionic strength → ↑ dissolution rate
With weakly basic drugs, the dissolution may occur
in the stomach, and those drugs are absorbed more
effectively from the upper intestine.
Weak base (codeine, pilocarpine)
 % ionized = 100 / [1+antilog (pH-pka)]
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Physicochemical Properties of the Drug
- Particle size ; ↓ particle size ⇒ ↑ surface area
- Crystalline state ; crystalline states tend to dissolve more
slowly than do the amorphous forms.
- Drug complexes ; drug-polymer,
hydrophobic drug-hydrophilic material
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Formulation factors
- Solid dosage forms ; Dissolution is affected by compression
force and addiction of binding agents, diluents,
or lubricants.
- Suspensions and Emulsions ; Settling, aggregation, crystalline,
viscosity, and partition of drug( emulsions).
- Semisolid dosage forms ; Performed by diffusion cell
like Franz cell.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Formulation factors
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Drug Delivery System which delivers a drug well-controlled
rate into the circulating blood through skin
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Determination of permeation rate through skin
using Diffusion Cells
Franz
Keshary-Chien
Valia-Chien
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Matrix
Reservoir
Drug-in-Adhesive
Multi-Layer
Backing
Drug
Drug-in-Adhesive
Single-Layer
Membrane
Adhesive
Liner/Skin
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Physiologic factors
- Gastric emptying and Intestinal transit times
- Variability of pH
; The pH of fasted stomach ⇒ 1.2
The pH of fed stomach ⇒ 3.5 , approximately
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Dissolution test for nifedipine tablet
- KP 제 2법
- medium ; 10% 인산 완충액, 1% 라우릴 황산 나트륨을 이용한 용액
(pH 6.8, 37± 0.5 ℃)
- sampling ; 1, 2, 3, 4, 6, 8, 12시간에 각각 5 ㎖씩 취하고,
즉시 동일 조건의 medium을 보충한다.
- Analysis ; 0.45 ㎛ nylon membrane filter로 여과한 후에 HPLC를
이용하여서 분석한다.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Dissolution test for nifedipine tablet
- Dissolution parameter
K ⇒ 약물 방출 상수
- Cube-root relationship
M O1/3-M t1/3= K t
K ; mg1/3 /hr
- Higuchi ’s model relationship
M O -M t = K t 1/2
K ; mg/ hr1/2
- Zero-order kinetics relationship
M O -M t = K t
K ; mg /hr
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Dissolution test for nifedipine tablet
- Dissolution parameter
- Cube-root relationship ⇒ 약물 방출이 용출액의 침투로 약물의
실제 용해에 의한 경우
- Higuchi ’s model relationship ⇒ 용출액의 다공성 침투에 의한 경우
- Zero-order kinetics relationship ⇒ 약물의 방출이 정제의 팽창에 의한 경우
Int. J. Pharm. 21, 317-329 (1984)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Dissolution test for nifedipine tablet
TIME (hr)
%Released
M0-Mt
1
4.40
2
1/3
M0
1/3
1/2
-Mt
Time
28.68
2.974
1
8.83
27.32
2.82
1.41
3
12.89
26.13
2.70
1.73
4
16.54
24.91
2.58
2
6
24.83
22.50
2.33
2.45
8
32.80
20.12
2.08
2.83
12
49.56
15.24
1.55
3.46
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Dissolution test for nifedipine tablet
100
% r eleased
80
60
40
20
0
0
3
6
9
12
time
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
▪ Dissolution test for nifedipine tablet
3.5
35
35
3
30
30
2.5
25
M0-Mt
20
15
2
M 0 -M t
M01/3 -Mt1/3
25
1.5
20
15
10
1
10
5
0.5
5
0
0
2
4
6
8
10
12
14
time
Zero-order kinetics
k = 1.22
(mg/hr)
r = 0.9997
0
0
0
2
4
6
8
10
12
14
time
Cube-root relationship
k = 0.
05(mg1/3/hr)
r = 0.9973
0
0.5
1
1.5
2
time
2.5
3
3.5
4
1/2
Higuchi ’s model
k = 5.66
(mg/hr1/2)
r = 0.9523
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실