1. Chapter 13. Dissolution Phenomena

2. Content Ⅰ. Introduction Ⅱ. Dissolution of particles
Ⅲ. USP Dissolution testing
Ⅳ. Factors affecting drug dissolution
Ⅴ. Case study of dissolution testing

3. Ⅰ. Introduction ▪ Definition of dissolution
-Process by which a solid solute
with low solubility enters into a solution
in the presence of a solvent

4. Ⅰ. Introduction ▪ Dissolution, Absorption and Bioavailability
Dissolution → rate-limiting step

5. Ⅰ. Introduction
▪ Dissolution, Absorption and Bioavailability

6. Ⅰ. Introduction
▪ Dissolution, Absorption and Bioavailability

7. ▪ Role of dissolution test
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 )

8. Ⅱ. Dissolution of particles
▪ Diffusion layer model
Diffusion layer
(aqueous membrane)
Drug particle
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)

9. 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)

10. Ⅱ. Dissolution of particles
▪ Noyes-Whitney Relationship
dM/ dt = (DS/ h) (Cs- Cb ) ↓
dM/ dt = (DS Cs / h ) ← ∵Cs > > Cb In sink condition
↓ integration
M = (DS Cs / h ) t
C = (DS Cs / V h ) t

11. Ⅱ. Dissolution of particles
▪ Sink conditions and nonsink conditions
Under nonsink conditions
What is sink condition ?
→ When the conc. of the drug in the bulk solution << the saturated solubility,
we called sink condition.
Amount dissolved
Under sink conditions
Time

12. Ⅱ. Dissolution of particles
▪ Hixson-Crowell cube-root relationship
- Surface area of particle remains constant in the Noyes-Whitney Relationship.
But, it will decrease as the drug dissolves.
( except something like trans dermal systems)
This decease changes the effective area.
⇒ Another relationship needed.

13. 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

14. 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

15. III. USP Dissolution Testing
▪ Apparatus 1 (Rotating Basket)

16. 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.

17. III. USP Dissolution Testing
▪ Apparatus 2 (Paddle)

18. 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.

19. III. USP Dissolution Testing
▪ Apparatus 1 and Apparatus 2

20. III. USP Dissolution Testing
▪ Automated Dissolution System

21. III. USP Dissolution Testing
▪ Apparatus 3 (Reciprocating Cylinder)

22. 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

23. III. USP Dissolution Testing
▪ Apparatus 3 (Reciprocating Cylinder)

24. III. USP Dissolution Testing
▪ Apparatus 4 (Flow-through cell)

25. III. USP Dissolution Testing
▪ Apparatus 4 (Flow-through cell)

26. 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

27. III. USP Dissolution Testing
▪ Apparatus 4 (Flow-through cell)

28. III. USP Dissolution Testing
▪ Apparatus 5 (Paddle over Disk)

29. 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

30. III. USP Dissolution Testing
▪ Apparatus 6 (Cylinder Method)

31. 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

32. III. USP Dissolution Testing
▪ Apparatus 7 (Reciprocating Disk Method)

33. 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.

34. III. USP Dissolution Testing
▪ Apparatus 7 (Reciprocating Disk Method)

35. III. USP Dissolution Testing
▪ Acceptance Criteria
Stage
Number tested
Acceptance Criteria S1 6
Each unit is not less than Q + 15% S2
Average of 12 unit (S1+S2) is equal to or greater than Q, and no unit is less than
Q - 15% S3 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%
Q (%) ; the percentage of the
labeled amount
USP XXⅣ / National Formulary XIX

36. III. USP Dissolution Testing
▪ KP Dissolution testing
제 1 법 (회전검체통법)

37. III. USP Dissolution Testing
▪ KP Dissolution testing
제 2 법 (패들법)

38. III. USP Dissolution Testing
▪ KP Dissolution testing
제 3 법 (Flow-Through Cell 법)

39. Ⅳ. Factors affecting drug dissolution
▪ 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)]

40. Ⅳ. Factors affecting drug dissolution
▪ 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

41. Ⅳ. Factors affecting drug dissolution
▪ 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.

42. Ⅳ. Factors affecting drug dissolution
▪ Formulation factors

43. Transdermal DDS (TDDS)
Drug Delivery System which delivers a drug well-controlled rate into the circulating blood through skin

44. 약물 경피흡수 in vitro 평가
Determination of permeation rate through skin using Diffusion Cells
Franz
Keshary-Chien
Valia-Chien

45. 약물 경피흡수 in vitro 평가(2)

46. Drug-in-Adhesive Single-Layer
Types of Patches
Backing Drug Membrane Adhesive Liner/Skin
Matrix
Reservoir
Drug-in-Adhesive
Multi-Layer
Drug-in-Adhesive Single-Layer

47. Ⅳ. Factors affecting drug dissolution
▪ 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

48. Ⅴ. Case study of dissolution testing
- 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.
▪ Dissolution test for nifedipine tablet

49. Ⅴ. Case study of dissolution testing
▪ 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/ K ; mg/ hr1/2
- Zero-order kinetics relationship
M O -M t = K t K ; mg /hr

50. Ⅳ. Factors affecting drug dissolution
- 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
▪ Dissolution test for nifedipine tablet
Int. J. Pharm. 21, (1984)

51. Ⅳ. Factors affecting drug dissolution
▪ Dissolution test for nifedipine tablet
TIME (hr)
%Released
M0-Mt
M01/3-Mt1/3
Time1/2 1
4.40
28.68
2.974 2
8.83
27.32
2.82
1.41 3
12.89
26.13
2.70
1.73 4
16.54
24.91
2.58 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

52. Ⅳ. Factors affecting drug dissolution
▪ Dissolution test for nifedipine tablet

53. Ⅳ. Factors affecting drug dissolution
▪ Dissolution test for nifedipine tablet
Zero-order kinetics
Cube-root relationship
Higuchi ’s model
k = 1.22 (mg/hr)
r =
k = 0. 05(mg1/3/hr)
r =
k = (mg/hr1/2)
r =

54. Drug Release: Higuchi Model