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

8

개정 p1687 )

SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실

Ⅱ

. Dissolution of particles

▪ Diffusion layer model Diffusion layer Drug particle (aqueous membrane) Cs Bulk solution C b h Cs; The conc. of drug at the surface of particle ( → the saturated solubility of drug) C b ; 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) (C

s - C b

) ↓ dC/ dt = (DS/ V h) (C

s - C b

) M ; The amount of drug dissolved ( mg or mmol), t ; Time ( sec.) D ; The diffusion coefficient of the drug ( cm 2 /s), h ; The thickness of diffusion layer ( cm) Cs ; The conc. of drug at the surface of particle , C

b

; The conc. of drug in the bulk solution S ; Surface area of the drug particles ( cm 2 ), V ; The volume of bulk solution ( cm 3 )

SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실

Ⅱ

. Dissolution of particles

▪ Noyes-Whitney Relationship dM/ dt = (DS/ h) (C

s - C b

↓ ) dM/ dt = (DS C

s

/ h ) ←

∵

C

s > > ↓ integration M = (DS C

s

/ h ) t ↓ C = (DS C

s

/ V h ) t

C b In sink condition

SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실

Ⅱ

. Dissolution of particles

▪ Sink conditions and nonsink conditions 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 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.

SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실

Ⅱ

. Dissolution of particles

▪ Hixson-Crowell cube-root relationship

M

O 1/3

-M

t 1/3

= K t

M O

; The amount of drug particles at time zero

M t

; 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

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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

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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 . - capsule 처럼 뜨는 검체의 경우 sinker 를 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

Stage S1 S2 S3

III. USP Dissolution Testing

▪ Acceptance Criteria

Number tested Acceptance Criteria 6 Each unit is not less than Q + 15% 6 12 Average of 12 unit (S1+S2) is equal to or greater than Q, and no unit is less than Q - 15% 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 XX Ⅳ / 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 Drug-in-Adhesive Multi-Layer Reservoir Drug-in-Adhesive Single-Layer Backing Drug Membrane Adhesive Liner/Skin

SKKU

Physical Pharmacy Laboratory

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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 2 법 - medium ; 10% 인산 완충액 , 1% 라우릴 황산 나트륨을 이용한 용액 (pH 6.8, 37 ± 0.5

℃

) - sampling ; 1, 2, 3, 4, 6, 8, 12 즉시 동일 조건의 시간에 각각 5 ㎖씩 취하고 , medium 을 보충한다 . - Analysis ; 0.45 ㎛ nylon membrane filter 로 여과한 후에 이용하여서 분석한다 .

HPLC 를

SKKU

Physical Pharmacy Laboratory

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물리약학연구실

▪

Dissolution test for nifedipine tablet

- Dissolution parameter K

⇒

약물 방출 상수 Cube-root relationship

M

O 1/3 -M t 1/3 = K t K ; mg 1/3 /hr Higuchi ’s model relationship

M

O -M t = K t 1/2 Zero-order kinetics relationship K ; mg/ hr 1/2

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) 1 2 3 4 6 8 12 %Released 4.40

8.83

12.89

16.54

24.83

32.80

49.56

M 0 -M t 28.68

27.32

26.13

24.91

22.50

20.12

15.24

M 0 1/3 -M t 1/3 2.974

2.82

2.70

2.58

2.33

2.08

1.55

Time 1/2 1 1.41

1.73

2 2.45

2.83

3.46

SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실

▪

Dissolution test for nifedipine tablet 100 80 60 40 20 0 0 3 6 time 9 12 SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실

▪

Dissolution test for nifedipine tablet 35 30 25 20 15 10 5 0 0 2 4 6 time 8 10 12 14 Zero-order kinetics k = 1.22 (mg/hr) r = 0.9997

3.5

3 2.5

2 1.5

1 0.5

0 0 2 4 6 time 8 10 12 14 Cube-root relationship k = 0. 05(mg 1/3 /hr) r = 0.9973

35 20 15 30 25 10 5 0 0 0.5

1 1.5

2 time 1/2 2.5

3 3.5

4 Higuchi ’s model k = 5.66 (mg/hr 1/2 ) r = 0.9523

SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실

SKKU

Physical Pharmacy Laboratory

성균관대학교

물리약학연구실