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1 콜로이드분산계 Colloid Dispersion i School of Pharmacy Sungkyunkwan University

2 콜로이드분산계 1nm 에서 05μm 0.5 미립자가기체또는액체중에응집하 거나침전하지않고분산된상태 (max : 1μm) 콜로이드라는명칭은 19 세기중엽에영국의그레이엄에 의해처음사용 물에잘녹아물속에확산하기쉬운것 ( 결정질 ) 과물에잘녹지않아확산하기어려운것 ( 콜로이드질 ) 결정질도콜로이드를이룰수있음 ( 예 >BaSO 4 )

3 콜로이드의분류 (I) 입자의구조에따라 1. 분자콜로이드 ( 단백질, 폴리비닐알코올등 ) 단백질이나고무와같은고분자가분산질이되기때문에, 용액이지만분자의크기가콜로이드차원이되어있어콜로이드의성질을띠게되는것 2. 미셀콜로이드 ( 會合콜로이드 ) ( 계면활성제류 ) 비누나염료 ( 染料 ) 같은것에서볼수있는것같이용액중에서분자또는이온이많이모여회합한상태 ( 미셀 ) 로콜로이드의성질을나타내는것 3. 입자콜로이드 ( 우유, 마요네즈, 흙탕물등 ) 단순히고체미립자가콜로이드차원이되어분산하고있는것

4 콜로이드의분류 (II) - 입자와매질의관계에따라 1. 친수 ( 親水 ) 콜로이드 분산질이녹말 단백질처럼물에대해친화성 ( 親和性 ) 인것 분산매가물이외의액체로서그액체에대해친화성이있으면친액 ( 親液 ) 콜로이드라고함 친수콜로이드에서는입자가물의얇은막으로덮여있기때문에소량의전해질을가하면전해질이물분자를끌어들이므로콜로이드입자에덮인수막 ( 水膜 ) 이소실하여 침전되며이현상을염석 ( 鹽析 ) 이라고함 2. 소수 ( 疎水 ) 콜로이드 ( 도료, 마요네즈등 ) 분산질이금속가루와같이물에대해친화성을갖지않는것 분산매가물이외의액체로서이에대해친화성을갖지않으면소액 ( 疎液 ) 콜로이드라고함 소수콜로이드에친수콜로이드를가하면, 일반적으로응석 (coagulation) 하기어렵게되어버리며, 이와같은작용을하는콜로이드를보호콜로이드라고함 ( 먹물에서는탄 소입자를아교질이보호하는상태의콜로이드가되어탄소입자를물속에분산시킴 )

5 콜로이드의특징 브라운운동 틴들현상 일반적으로전하를띠고있음 한외현미경내지전자현미경으로관찰가능하나광학현미경으로관찰불가함 여과지를통과하나반투막은통과하지못함 투석에의한정제가능

6 유제 (Emulsion) School of Pharmacy Sungkyunkwan University

7 Emulsion Definition Emulsion is a thermodynamically unstable pharmaceutical preparation consisting of at least two immiscible liquids (phases). Due to the lack of mutual solubility, one liquid is dispersed as tiny droplets (globules) in the other liquid to form an emulsion. Therefore, emulsions belong to the group of preparations p known as disperse systems

8 Determination of emulsion type 1. Miscibility or Dilution Test This method is based on the fact that an emulsion can be diluted freely with a liquid of the same kind as its external phase. Typically, a small amount of the emulsion is added to a relatively large volume of water and the mixture is stirred. If the emulsion disperses in water, it is considered to be an O/W type emulsion. If, however, the emulsion remains undispersed, it is a W/O type emulsion.

9 Determination of emulsion type 2. Staining or Dye Test This test is based on the fact that if a dye is added to an emulsion and the dye is soluble only in the internal phase, the emulsion contains colored droplets dispersed in the colorless external phase. An example of such a dye is scarlet red, which is an oil soluble dye. When added to an O/W type emulsion, followed by observation under the microscope, bright red colored oil drops in an aqueous phase can be seen clearly. oil soluble dye (Sudan III); Water soluble dye (methylene blue)

10 Determination of emulsion type 3. Electrical Conductivity Test This test is based on the fact that only the aqueous phase can conduct electrical current. when a voltage is applied across a liquid, a significant amount of electrical current will flow only when the path of the current is through a continuous aqueous phase. Since oil is a non-conductor of electricity, when tested for conductivity, a W/O type emulsion will show insignificant current flow.

11 Pharmaceutical Applications To disguise the taste or smell of oils or oil soluble drugs. These emulsions are normally O/W types with the aqueous phase containing sweeteners and flavoring agents to mask the poor taste of oils. An O/W type of emulsion also makes it easy to rinse off the residual dose from the mouth and does not leave an oily taste. Ex) Mineral oil, cod liver oil To improve the absorption of poorly soluble drugs. Oil soluble drugs may not be soluble enough to be absorbed efficiently. An example of such a drug is cyclosporin A, which is dispensed as a microemulsion. To deliver nutrients and vitamins by intravenous injection. To serve as a vehicle for the topical administration of a variety of drugs.

12 Components of formulation 1. Drug 2. Oil Phase 3. Aqueous Phase 4. Thickening Agent 5. Sweetener 6. Preservative 7. Flavor 8. Color 9. Antioxidant 10. Emulsifier

13 유화제 * 고형미립자가유화시키는사례 1. Silica ( 물에 wetting 용이 ) O/W 유제에적합함 2. Carbon Black (oil에 wetting 용이 ) W/O 유제에적합함 3. Sodium dodecanoate로표면처리한황산바륨 (θ= 90 ) O/W 유제에적합함 4. SDS로표면처리한황산바륨 (θ=120 ) W/O 유제에적합함

14 유화방법 (p55) 1) Agent-in-water method ( 수중유화제법 ) : 유화제를수상에가한다음유상을서서히가하면서유제를만듬 o/w가생성되지만유상이많으면 w/o로 phase inverse 됨 2) Agent-in-oil method ( 유중유화제법 ; 대륙법 ) : 유화제를유상에혼합한후이를수상에가하면 o/w형유제가생성됨 반대시에는 w/o형유제생성 3) Nascent soap method ( 비누형성법 ) : 지방산을유상에용해시키고알칼리부분을수상에용해하고이를혼합하면계면에 o/w 또는 w/o 유제 콜드크림, 비누.. 4) Alternate addition method ( 교호첨가법 ; 영국법 ) : 유화제에수상과유상을번갈아조금씩섞어만듬 유화제를두배중량의물과연화함 이에소량의유상을가해서점조액이될때까지연화함 ( 초유제 ; primary emulsion) 나머지첨가물을가하여번갈아가하면서완성함

15 Emulsifying device Homogenizer Colloid mill Ultrasonic homgenizer Microfluidizer SPG membrane

16 Physical Stability of Emulsion (potential energy, Diffusion, Brownian motion, DLVO) (attractive force) (gravitational Stokes' law) v. Phase Inversion vi. Ostwald ripening (solubility of dispersed phase)

17 Physical Stability of Emulsion Creaming Coalescence separation Primary emulsion li (o+w+ 계면활성제 ) Creaming 흔들면원상태로감 Flocculationl Coalescence Separation X X Breaking

18 Creaming (sedimentation) <Stoke s Law> Particle size Density difference - Since ρ2(droplet density)<ρ1(external dednsity), for most oil phases in o/w type, then sedimentation will be negative, the oil droplets will rise forming a creamy white layer. The gravitational constant, g

19 Creaming (sedimentation) Viscosity Increase the concentration of the internal phase Increase the viscosity of the internal phase by adding waxes or waxy solids to the oil phase. Increase the viscosity of the external phase by adding a viscosity building agent. Creaming does not usually occur in a semi-solid emulsion.

20 Flocculation and coalescence of emulsion Flocculation 두개의 droplet 가서로접해있지만얇은 film 으로분리된상태임 더많은droplet가첨가되면 aggregate가형성되어덩어리를이룸 Coalescence 두개의droplet 사이의얇은액체 film이사라지고큰 droplet로서결합된다. 점점더큰 droplet가됨 coalescing emulsion의특징 : droplet size 다양성, cluster는발견되지않음

21 Flocculation and coalescence of emulsion V T = V R + V A R : electrostatic energy of repulsion A : van der Waals energy of attraction

22 Phase inversion 유화제에따라 올레인산나트륨이함유된유제에 Ca +2, Mg +2 등의금속이 온도에따라 온을가한경우 고온에서제조된 w/o 유제가냉각시에유화제의수화정 도가높아지면서 o/w 로변화되는경우 상용적비에따라:

23 Ostwald ripening

24 유제의물리적안정화에영향을주는인자 1) 계면장력을저하시킨다. 2) 계면막을형성시킨다. 3) 내상의농도를조절한다. ( 상용적비조절 ) 4) 유제의점도를조절한다. 5) 유제의분산입적를미소화한다. 6) 내 / 외상간계면에전하를발생시켜입자간상호반발을유 발한다. 7) 유제의 ph 를조절한다. 8) 내 / 외상간비중차를최소화한다.

25 Multiple Emulsion

26 마이크로에멀젼 Micromulsion i School of Pharmacy Sungkyunkwan University

27 Microemulsion 의정의 마이크로에멀젼은계면활성제와분자량이크지않은알코올류 (short chain alcohol), 아민류및약한양쪽성분자 (weak amphiphilic molecule) 와같은보조계면활성제와연계하여열역학적으로안정화된유상과수상을갖는계 (system) 이다. - Aboofazeli et al. Int. J. Pharm. 111, (1994) SMEDDS (Self-Microemulsifying Drug Delivery System) 유상, 계면활성제, 보조계면활성제로구성되는상온에서액체또는고체상태의균질한혼합물로서위장관운동같은약한힘만으로도수상과만나서섞이면순식간에유화되는약물운반체를말한다. 약물의용해도를증가시키며생체이용률을증가시킨다.

28 Structure of Microemulsion Water Oil Surfactant (S) 10~200 nm Cosurfactant (CoS) S: Forms the interfacial film CoS: Reduces the interfacial tension, therefore reduces the droplet size

29 Microemulsion 의특징 Thermodynamic stability Low interfacial tension (γ o/w 0.01 dynes/cm) Spontaneous formation (no mechanical energy required) High solubilizing power Microemulsions are well tolerated Transparency: very small particle size (10 to 200 nm) Newtonian fluid Low viscosity Isotropy

30 Benefits of Microemulsion Spontaneous formation at room temperature: easy process reduces manufacturing ac u costss incorporation of thermosensitive components at any step during manufacturing process Thermodynamic stability: no phase separation over time returns to initial structure, even after freezing or heating high solubilizing properties surface area increased absorption enhancement of active ingredients

31 Emulsion 과 Microemulsion Emulsion 과 Microemulsion 의중요한차이 : droplet 의크기 Microemulsion 0.15μm이하 외관은투명 열역학적으로안정 (γ o/w 0.01 dynes/cm) 제조중즉시형성되어야함 ( 안정제의비와성질이중요 ) 계면활성제의양이많다 ( 전체무게의 6-8%) Emulsion 수μm의크기 외관은불투명 ( 계면활성제의양은 2-3%) 열역학적으로불안정 Co-surfactant micellar solution 을 microemulsion 으로변화시키기위해첨가 보통 alcohol을사용함 hydrocarbon이중앙에있는 microemulsion droplet를만들수있음 반대로 water soluble substance 를 w/o microemulsion 내에용해가능

32 Emulsion 과 Microemulsion Property Emulsions Microemulsion Particle diameter Thermodynamic stability 1000 to nm - < 150 nm + Spontaneous formation Dilution High viscosity it Surfactant percentage Optical aspect + a few % Milky, opaque - from 15 to 70% Isotropic, transparent Solubilization power Preservation + Preservative ++ Preservative Up-scaling Manufacturing process - - or heat or filtration + +

33 Components of Microemulsion Drug Surfactant (Primary) Large polar head, high HLB ( typically 13 to 14) Co-Surfactant Small polar head, low HLB (typically 4 to 6) Alcohols ethanol propylene glycol dimethylisosorbide Lipidic idi phase Hydrophilic phase

34 The Phase Diagram : Quaternary system At room temperature S S / CoS Water CoS Oil

35 Preparation of Microemulsion S+CoS The ratio S/CoS 100% must be fixed. The temperature must be fixed. P Water 100% Oil phase 100% % of water phase

36 Titration method (I) S+CoS 100% S/CoS and temperature fixed A A = 60% of Oil phase Water 100%Oil 40% of S+CoSS 100% phase

37 Titration method (II) S+CoS 100% S/CoS and temperature fixed A = 60% of Oil phase 40% of S+CoS B = 20% of Water 80% of Mixture A B A A 80% A-B Water 100% 100%Oil phase B

38 Titration method (III) C S+CoS 100% B A S/CoS and temperature fixed A = 60% of Oil phase 40% of S+CoS B = 20% of Water 80% of Mixture A C = 50% of Water 50% of Mixture A B Water 100% 100%Oil phase C

39 Titration method (IV) The same experiment is conducted many times on various primary mixtures (Oil + S + CoS) S/CoS S and temperature fixed S+CoS 100% S/CoS and temperature fixed A 1 A 2 A 3 A 4 A 5 Water 100% 100%Oil phase

40 Titration method (V) S+CoS 100% S/CoS and temperature fixed Microemulsion existence field Water 100% 100%Oil phase

41 Characterization of Microemulsion Transparency : to the naked eye Isotropy : under a polarized light microscope Newtonian behaviour : with a rheometer Thermodynamic stability : aging test, centrifugation Particle size : laser spectroscopy

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- 1 - - 1 - - 2 - - 3 - - 4 - - 5 - - 6 - ι κ λ β β β β β - 7 - - 8 - - 9 - - 1 - - 11 - 마. - 12 - - 13 - - 14 - - 15 - - 16 - - 17 - - 18 - - 19 - - 2 - - 21 - - 22 - - 23 - - 24 - ι κ λ β β - 25 - - 26 - -