프리포뮬레이션의 이해 1

(1)

3

Introduction of Preformulation I

프리포뮬레이션의 이해 1

(2)

Introduction

사전제제설계(preformulation) 특성평가 원료의약품

(Active Pharmaceutical Ingredient, API) (Active Ingredient)

첨가제 (ref. 부형제)

(Pharmaceutical Additives) (Pharmaceutical Excipients) (Inactive Ingredient)

제조 공정

(Good Manufacturing Practices, GMP)

품질 관리(Pharmaceutical Quality Control)

확인시험, 함량시험, 순도시험

붕해시험, 용출시험, 함량균일성시험…

(3)

Introduction

Drug-like properties

Absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties (e.g., physicochemical, metabolic, toxicity) of compounds in addition to pharmacology (e.g., efficacy, selectivity)

(4)

Introduction

물리화학적 특성: Physicochemical properties

Molecular formula Boiling point

Molecular weight Vapor pressure Physical state

Concentration at saturation Appearance

Vapor density

Surface properties Polymorphism

Hygroscopy

Coefficient of water/oil distribution Density

pH

Freezing point Solubility

Stability

Melting point Particle size

…

(5)

Introduction

용출속도(dissolution rate)

- Noyes-Whitney 식

- Hixson-Crowell cube-root

- Higuchi equation

- Kosmeyer peppas equation

(6)

Introduction

Intrinsic dissolution rate (내인성 용출속도, 고유용출속도)

IDR (unit: amount/area/time, mg/cm²/min)

(7)

Introduction

융점(melting point)

모세관(Thiele arrangement)에 충진된 물질의 용융을 육안으로 관찰하는 방법

고온 현미경법(hot stage microscopy) -편광

시차 주사 열량계법(differential scanning calorimetry) - tg, tm

(8)

Introduction

pH에 따른 수성 용해도(aqueous solubility as a function of pH)

- the concentration of solute in a saturated solution at a certain temperature

- Solvent with solvent - Solute with solute - Solvent and solute

Solubility (S)

S=f (Crystal Packing Energy + Cavitation Energy + Solvation Energy)

(9)

Introduction

KP: the number of mL of solvent in which 1 gram of solute will dissolve Ex) 1 g boric acid dissolved in 18 mL of water, in 18 mL of alcohol, in 4 mL of glycerin

The gram of solute that can be dissolved in 100 mL of solvent Molarity of saturated solution

Molality of saturated solution Percentage of saturated solution

(10)

Introduction

pH

Log S

Acid

pH

Log S

Base

(11)

Introduction

용해도(solubility)

SOLVENT-SOLUTE INTERACTIONS

“like dissolves like”

Non-polar molecules are soluble in non-polar solvents

Polar molecules are soluble in polar solvents

Ionic compounds are more soluble in polar solvents

(12)

Introduction

Semipolar solvents

- Solvents with intermediate dielectric constants.

- Semipolar solvents can induce polarity in nonpolar solvent molecules - Examples of semipolar solvents: acetone, propylene glycol, propanol

- Acetone increases the solubility of ether in water.

- Propylene glycol increases the solubility of oil in water.

(13)

Introduction

Kamlet-Taft linear solvation energy relationship model (KAT-LSER)

the relationship between some properties and the Gibbs free energy (XYZ) of a solvent-solute system

XYZ = XYZ0 + cavity formation energy + solvent-solute interaction energy

(14)

Introduction

- Particle size

The solubility of the fine particles

The solubility of the solid consisting of

relatively large particles

The surface tension of the particles The molar volume

(cm³ per mole of particles)

The gas constant (8.314×10⁷ ergs/deg mole) The absolute temperature

The final radius of the particles

(15)

Introduction

Thermodynamic (equilibrium) solubility (shake-flask solubility method)

Excess of solid drug is dispensed into aqueous solution

Analysis (UV, HPLC etc) Saturation

Equilibrium (several hours or days, even months) Filtration or centrifugation

(16)

Introduction

흡습성(hygroscopicity)

흡착수 vs 결정수

수분 흡수량의 측정

고체를 여러 다른 습도에서 평형상태에 이르게 한 후 중량 측정법 Karl Fischer 적정 또는 건조시 손실량 분석법에 의해 측정하는 방법

(17)

Introduction

흡습성(hygroscopicity)

Dynamic vapor sorption (DVS) is a gravimetric technique a dry powder absorbing water.

- Very hygroscopic : > 15% (w/w)

- Moderately hygroscopic : 2-15% (w/w) - Slightly hydroscopic : 0.2-2% (w/w) - Nonhydroscopic : 0-0.12% (w/w)

(18)

Introduction

결정다형(polymorphic forms) 결정성(crystallinity)

- 항바이러스성 약물인 리토나비어 사례

: 반고형 캅셀제 제조 => 물리적 불안정성과 용출 저하

: 원인 반고형탑셀제의 매트릭스 중의 약물이 새로운 결정형으로 전환 : 용해도 저하 용출저하 약효 저하

: 새로운 제형 (연질)로 변경

(19)

Introduction

결정다형(polymorphic forms) Crystalline Solids

The structural units of crystalline solids, such as ice, sodium chloride, and menthol, are arranged in fixed geometric patterns or lattices.

1. Cubic (sodium chloride) 입방정계

2. tetragonal (urea) ^정방정계

3. hexagonal (iodoform) 육방정계

4. rhombic (iodine) 사방정계

5. monoclinic (sucrose) 단사정계

6. riclinic (boric acid) 삼사정계

(20)

Introduction

결정다형(polymorphic forms) 무정형

Amorphous Solids vs Crystalline Solids

Irregular shape: molecules are arranged in a random manner No definition melting point Isotropic

Ex) glass, synthetic polymers etc.

Regular shape: fixed geometric patterns

Definite melting point Diffract X-rays

Anisotropic

Ex) diamond, graphite etc.