계면활성제 School of Pharmacy Sungkyunkwan University
Amphiphilic Surfactants * Amphiphile (greek 어원 ): Amphis(both) + philia(love, friendship) Sodium Lauryl Sulfate (SLS) or Sodium Dodecyl Sulfate (SDS or NaDS) (C 12 H 25 SO 4 Na) Amphiphilic surfactants contain a non-polar portion and a polar portion.
Free Energy Considerations 계면자유에너지 (ΔF): 내부에서계면으로분자를이동시키는데필요한에너지 계면에존재하는분자는내부 (bulk) 에존재하는것보다고 ( 高 ) 에너지상태 계면의 ΔF 는내부보다상대적으로높음 분자가내부에존재하려함 ( 표면적의최소화 ) ΔF = γ ΔA (ΔF : 계면자유에너지의증가분, ΔA : 표면적의증가분, γ : 서로다른계간의표면장력 ) ΔF 값이작을수록열역학적으로안정 계면활성제를가하면 ΔF 값이낮아짐 계면으로분자집중이가능함 γ 이작아져동일분자간의응집을막음 Air Oil Air Oil Water Water Water Water
Classification of Surfactants Anionic Cationic Sodium dodecylsulfate (SDS) Benzalkonium chloride Zwitterionic Nonionic O O O + OCH 2 CH 2 N(CH 3 ) 3 P O O - O Dipalmitoylphosphatidylcholine (lecithin) Polysorbate 80
Classification of Surfactants 1. 음이온성계면활성제 (anionic) 1) 비누류 가용성비누 : 고급지방산의알칼리 (1 가 ) 금속염, 수 - 가용성인비누 금속비누 : 수- 불용성, 지방에용해 ( 고급지방산의 2~3 가금속염 ) 유기아민비누 : 고급지방산및유기염기로구성된비누 2) 황산화물 ( 스테아린산트리에탄올아민 : 약알칼리성, 피부저자극성, 유화제로사용 ) 고급지방산또는고급알코올의황산화물 (R O SO 3- M + ) 3) 설폰화물 알킬설폰산염, 알칼아릴설폰산염등 (R SO 3- M + ) 2. 양이온성계면활성제 (cationic) 1) 제 4 급암모늄화합물 주로살균소독제용도 ( 염화벤잘코늄, 염화벤제토늄등 )
Classification of Surfactants 3. 양성계면활성제 (zwitterionic) : 분자내에음이온기와양이온기를함께가지고있음 1) 아미노산형양성계면활성제 2) 베타인형양성계면활성제 ( 예 : 레시틴 ) 4. 비이온성계면활성제 (nonionic) : 이온기를가지고있지않는계면활성제 1) 소르비탄에스텔류 (Span 류 ) 유상에용해 ( 분산 ) 하는계면활성제로 w/o 형유화제로사용 2) 폴리소르베이트류 (Tween 류 ) 수상에잘용해 ( 분산 ) 되는계면활성제로 o/w 형유화제등으로이용 Span 의유리 OH 기에다수의 ethylene oxide 를부가한것 5. 기타계면활성제 (Span 의 polyoxyethylene 유도체 ) 1) Pluronic 계, Poloxamer 계계면활성제 (PEO-PPO-PEO) : Block co-polymer surfactant
Structure of Surfactant and Micelle Micelle 형성 계면활성제는농도가매우낮은경우 분자단위로분산상태유지 농도가일정농도 (CMC) 이상일경우 소수기의내부에서다수회합하여 micelle ( 소수기를내측으로하고친 수기를외측으로향한수화상태의 분자집합체 ) 을형성. Micelle 형성은가역적인상태임 계면활성제농도가낮아지면다시 분자단위로적으로분산됨
Surfactant Aggregates Surfactants Micelle Rod-Shaped Micelle Neat Phase (Lamellar Phase) Middle Phase (Hexagonal Phase)
Critical Micelle Concentration (CMC) CMC Interfacia al tension CMC 14 12 10 Concentr ration 8 6 4 2 0 CMC unimers micelles Surfactant concentration 0 Surfactant concentration 1 Below CMC only unimers are present Above CMC there are micelles in equilibrium with unimers
Krafft Point ( 크라프트점 ) c CMC Crystals + solution Liquid crystals Micelles + solution Solution 이온성계면활성제는어떤특정의온도이상이되면물에대한용해도가급격하게증가한다. 이온도를크라프트점이라고한다. T 1 krafft T The temperature (more precisely, narrow temperature range) above which the solubility of a surfactant rises sharply. At this temperature the solubility of the surfactant becomes equal to the critical micelle concentration.
Cloud Point ( 담점 ) and CMT c CMC Solution Micelles + solution CMT Cloud1 point Phase Separation T 폴리에틸렌계비이온성계면활성제에서는온도가상승하면물과의수소결합절단에의해수용성이감소하고, 어떤온도에서불투명해지는데이온도를담점이라고한다. The critical micelle temperature (CMT) is the lowest temperature at which micelles can form.
Phase Inversion Temperature (PIT; 전상온도 ) 비이온계면활성제의 HLB 가온도에의해변화하여온도가상승하면친수성으로부 터친유성으로변하는것을이용한것이다. 즉, 온도가상승하면수소결합이약해지기때문에일정온도에서친수성과친유성 이균형을이루는온도를전상온도 (phase inversion temperature) 라고한다. PIT 부근에서의안정도는매우 sensitive 하여 PIT 에의한계면활성제선택이 HLB 방 법보다더실제적이다. 오일 / 물계면의계면장력을측정하면전상온도에서유상, 계면활성제상, 수상의 3 상 영역으로되고계면장력이최저로된다. PIT 부근에서 minimum interfacial tension 을가지므로이를유화하면 finely dispersed emulsion 을얻을수있는데이를급냉하여 stable 한유화계를얻을수 있다. 이방법으로얻어진미세한유제입자라도전상온도에서장시간방치하면불안정화 되므로빠른시간내에급격히냉각시킬필요가있다.
Solubilization Normal micelles non-polar compound Reverse micelles polar compound amphiphilic compound
Solubility Effects Solubility of a poorly soluble compound increases as a result of solubilization in the micelles Solub bility CMC Surfactant concentration
Polymeric Micelles for Drug Delivery
Why Poly(ethylene glycol), PEG? Non-toxic Non-immunogenic/Non-thrombogenic i i Enhancement of drug solubility Listed in FDA inactive ingredient guide for currently marked drug products Clearance from the body in MW dependent Lower than 8 kda : rapidly excreted 8 kda-30 kda : governed by MW (recommended : less than 20 kda) Highly mobile Soluble in water and most organic solvents Partially biodegradable (cytochrome P450, oxidation)
Why Poly(lactic acid), PLA? Biodegradable Biocompatible Non-toxic and non-inflammatory degradation product Lactic acid Low toxicity Initially developed as biodegradable sutures Number of FDA-approved products in the market utilize PLA Nupron Depot (Leuprolide acetate, Prostate cancer) Zoladex (Goserelin acetate, Prostate cancer) Atridox (Doxycycline hyclate, Periodontal)
Why mpeg-pla? Detergent micelles Hydrophilic segment Hydrophobic segment *M Most widely used block copolymer micelles : PEO-PPO-PEO, PPO Pluronics HO(CH 2 CH 2 O) x (CH 2 CHO) y (CH 2 CH 2 O) x H CH 3 PEO-PPO-PEO x y MW L-61 3 30 1,950 L-121 F-68 (parenteral use, FDA) P-85 F-108 F-127 6 75 27 128 98 67 30 39 54 67 4,432 8,400 4,600 8,782 12,600 Limited usefulness (toxicity-immunogenic) Limited usefulness (toxicity-immunogenic) Risk of precipitation Low solubilizing power for hydrophobic drugs
mpeg-pla Diblock Copolymers Methoxy poly(ethylene glycol)-poly(lactide), mpeg-pla Synthesized by ring opening polymerization Hydrophilic segment-hydrophobic segment Micelles like structure depend on molecular weight ratio of hydrophilic and hydrophobic segment Biodegradable, Biocompatible Applicable to polymeric micelles & nanoparticles
What is Polymeric Micelles? Amphiphilic Block Copolymer Hydrophilic segment Hydrophobic segment Hydrophobic drug Internal compartment; contains hydrophobic drugs Preparation methods forms core-shell structure in aqueous environment 20 ~ 100 nm Hydrophobic segment Hydrophilic segment Major driving force: hydrophobic interaction
Dissociation Behavior of Micelles Polymeric Micelles (association number : 200-400) slow (> hr) Surfactant Micelles (association number : 30-50) fast (~ms)
Properties of Polymeric Micelles Small size (ca., 10-100 nm) High water solubility and structural stability Apparent thermodynamic stability (i.e., low CMC) Solubilization of hydrophobic h drugs Low RES uptake (i.e., stealth properties) Modified biodistribution of drugs Size of micelles precludes renal excretion but may allow for direct extravasation of the carrier; single polymer chains may be renally cleared Simple sterilization by microfilteration Prolonged storage in freeze-dried state Low viscosity
Micelle 생체분포의 hurdles 신장의사구체에서의분비작용 High m.w. 의 micelle 이혈관을따라순환하다가사구체의입구에서걸려혈 관을따라이동을하지못하기때문임 간의세망내피계 (RES) uptake 시스템 200 nm 사이즈로 micelle 을디자인해야함 고밀도의 shell 을지니며 hydrophilic 한생체적합성고분자 (ex. PEG) 를통해 입자표면개질하여문제해결 비장과폐 Micelle 은바로분해가되지않고동역학적성질에따라천천히분해돰 그러므로혈관을따라이동하다가목표조직에다가가축적됨 체내에서장기적인축적으로인한위험성이적어야하며안전성확보요함 Tissue Engineering and Regenerative Medicine, Vol. 5, No. 1, pp 70-75 (2008)
Chemical & physical incorporation of drugs within micelles micellization a) chemically bound drug hydrophilic segment hydrophobic segment chemically bound drug physically bound drug b) physically bound drug
Mechanisms of micelle-forming polymeric drugs 1. Direct interaction with cells drug action cell 2. Drug release from micelles release drug action 3. Dissociation control dissociationi drug action
Drug release from block copolymer micelles (1) diffusion (2) dissociation of micelles
Drug loading for polymeric micelles Stirring in water phase micellization vial Dialysis in selective solvent micellization solvent evaporation Dialysis using molecular porous membrane tubing Emulsion li selective solvent for core-forming segment Hydrophilic segment Hydrophobic segment Drug
HLB of Surfactant and RHLB of Oil HLB Hydrophilic-Lipophilic Balance (HLB): a relative ratio of polar and nonpolar groups in the surfactant Provide a scale of surfactant hydrophilicity that simplified emulsifyer selection and blending No indication of emulsion behavior or stability RHLB It has been found that various oils and lipid materials form stable emulsions with surfactants that have a certain HLB value. This HLB value is called the required HLB of the oil or lipid. Selected on the basis of physical stability The creaming characteristics of the system Useful starting point for the preparation of a variety of emulsion
HLB and Use of Surfactants HLB 1-3.5 3.5-8 7-9 8-16 13-16 15-40 Applications Antifoams Water-in-Oil Emulsifiers Wetting and spreading agents Oil-in-Water Emulsifiers Detergents Solubilizers Lipophilic Hydrophilic 0 3 6 9 12 15 18 Antifoams Wetting/spreading Detergents agents Solubilizers W/O emulsifiers O/W emulsifiers
HLB Estimation Approximation i of HLB based on water dispersibilityibili HLB range Water Dispersibility 1-4 Not dispersible 3-6 Poor dispersion 6-8 Milky dispersion only after vigorous agitation 8-10 Stable milky dispersion 10 13 Translucent to clear dispersion >13 Clear solution Calculation of HLB (1) HLB = (% of polyoxyethylene moiety) / 5 (2) HLB = Sum of hydrophilic group number - Sum of lipophilic group number + 7
Calculation of HLB (1) (1) HLB = (mol% of hydrophilic moiety) / 5, POE = 20 Surfactant 1 HLB=70/5= = 14 70% 30% Surfactant 2 20% 80% HLB = 20 / 5 = 4 Hydrophilic moiety Lipophilic moiety
Calculation of HLB (2) (2) HLB = Sum of hydrophilic group number - Sum of lipophilic group number + 7 CH 3 -CH 2 -CH 2 -CH 2 -SO 4- Na + Hydrophilic moiety CH 3 -CH 2 -CH 2 -CH 2 SO 4- Na + Lipophilic moiety * HLB = (38.7) - (0.475 + 0.475 + 0.475 + 0.475) + 7 = 43.8
HLB Group Numbers Hydrophilic guoups SO 4- Na + COO - K + COO - Na + N (tertiary amine) Ester (sorbitan ring) Ester (free) COOH Hydroxyl (free) O Hydroxyl (sorbitan ring) Lipophilic groups CH CH 2 H 3 C =CH - Derived groups (CH 2 CH 2 O) (CH 2 CH 2 CH 2 O) Group Numbers 38.7 21.1 19.1 9.4 6.8 2.4 21 2.1 1.9 1.3 05 0.5 0.475 0.33 0.15
Calculation of HLB (3) (3) HLB of Surfactant Blend : HLB blend = f HLB A + (1-f) HLB B Surfactant t blends are commonly used to obtain desired d emulsifying properties. What is the HLB of the mixture of 40 % Span 60 (HLB = 4.7) and 60 % Tween 60 (HLB = 14.9)? HLB of mixture : 47 4.7 x 04 0.4 + 149 14.9 x 06 0.6 = 108 10.8 In what proportion should Span 80 (HLB = 4.3) and Tween 80 (HLB = 15.0) be mixed to obtain required HLB of 12.0? 4.3. (1-x) + 15. x = 12 x = 0.72 72 % Tween 80 and 28 % Span 80
HLB value of surfactants Anionic HLB value Triethanolamine oleate 12 Sodium oleate 18 Potasium oleate 20 Cationic Oleic acid 1 Sorbitan trioleate 1.8 Sorbitan monooleate (Span 80) 4.3 Sorbitan monolaurate (Span 20) 8.6 POE(5) Sorbitan monooleate (Tween 21) 10.0 POE(20) Sorbitan monostearate (Tween 60) 14.9 POE(20)Sorbitan monooleate (Tween 80) 15.0
Required HLB (RHLB) Oil or Liquid Stearic acid W/O - O/W 17 Cottonseed oil Mineral oil - 4 7.5 10-1212 Beewax Paraffin wax 5-10-16 9 Cetyl alcohol Lanolin anhydrous - 8 13 15
Required HLB (RHLB) HLB needed for emulsification of the oil phase. If there are several oil ingredients, the required HLB is calculated as a sum of their respective required HLB multiplied by the fraction of each. Calculate the required HLB for the oil phase of the following o/w emulsion: cetyl alcohol 15 g., white wax 1g. Lanolin 2 g, emulsifier (q.s.), glycerin 5 g. water 100 g. Required HLB Fraction (from reference) Cetyl alcohol o 15 x 15/18 12.5 White wax 12 x 1/18 0.7 Lanolin 10 x 2/18 1.1 Ttl Total required dhlb 14.3
에어로솔제제 School of Pharmacy Sungkyunkwan University
에어로솔제제의분류 분사제제제방식제형주용도 액화가스 3 상계시스템 공간용 : 살충제, 공기정화제 2 상계시스템 분사제 표면용 : 외용제, 화장품, 살충제 2 액층시스템분무제외용제, 제취제 유화시스템 w/o형 o/w형 분무제포말제 외용제, 살충제외용제, 피임제, 화장품 현탁시스템분무제흡입제, 외용제 압축가스 가용성가스시스템분무제화장품, 클리너 불용성가스시스템파스타제치약, 식품
에어로솔제제의분류 액화가스시스템 1) 2 상계시스템 주약함유액체 ( 분사제액화가스 + 주약용액 ) / 상부액화가스의 2 상으로구성됨 공간분사체 : 공기중에주약을미세입자로서분무 표면분사체 : 대상면에원액을부착도포하는형태 2) 3 상계시스템 유층 ( 액화가스 ) / 수층 ( 원액 ) / 상부액화가스로구성되거나 또는유층 ( 액화가스 )+ 수층 ( 원액 ) 의유제 / 상부액화가스로구성됨 유화시스템 : w/o 형, o/w 형 분사제 : 액화석유가스 ( 물에안정 ) 3) 현탁시스템 액화가스에녹지않는주약의입도를 10 μm이하로조절하고이를액화가스중에현탁시킴 분사와동시에주약입자의에어로솔을얻음
에어로솔제제의분류 압축가스시스템 1) 가용성가스류 탄산가스사용 표면분사제에주로사용함 2) 불용성가스류 질소가스사용 가스압력에의하여내용물인페이스트가압출됨
분사제 1. 액화가스분사제 : 가압상태로부터대기압에감압되었을때의순간적인기압팽창에따라액화가스와함께용해또는유화하고있던원액이미세한입자로됨 1) 불화탄화수소류 : 프레온 2) 액화석유가스류 : n- 부탄, 이소부탄, 프로판으로압력조정한혼합물이이용 3) 디메칠에텔 2. 압축가스분사제 1) 가용성가스 : 주로탄산가스가쓰이고있고, 그용해계수는온도의상승에따라감소 2) 불용성가스 : 질소가스
제조방법 1. 액화가스계에어로솔제제조법 용기의세정 원액의충전 밸브의장착 분사제의충전 Under cup 식충전 : 탈기, 충전및밸브장착을한공정으로행하는방식 냉각충전 온수조테스트 기타 : 온수조통과후온풍건조, 충전량검사, 분사테스트, 캡장치및포장의공정 2. 압축가스계에어로솔제의제조법 가용성가스 : 이산화탄소원액에충분히흡수용해시킨후에충전 불용성가스 : 질소가스주입
포장재료 1. 밸브 스템에장착된단추가눌러지면가스켓고무로닫혀져있던스템의구멍이내부와통하도록됨 ( 축의구멍지름 - 0.2~0.5mm)
포장재료 2. 누름단추 Nozzle 의구멍지름 : 0.2~0.5mm Break-up nozzle: 액류에회전력을부여 분사각확대, 입자미세화 3. 용기 금속용기 : side seam, seamless, monoblock can 의 3 종류 주로 8 cm 이하내경의함석또는알루미늄재질로된용기이용함 내용적이 100 ml 이하이면표면을수지피복한유리용기또는플라스틱용기가 허용
제제시험법 1. 내압 (internal pressure): 시료를항온수조중에 30 분간이상완전히침적한후, 밸브스템에압력계를기밀하게꽂아넣어측정 2. 내용액의용량: 금속용기의경우내용액용량을외관으로알수없음 내용액중량 ( 전량배출후의중량차 ) / 비중 3. 분사량 (g/sec) : 주약의용량을정하는데중요하며밸브 / 노즐구경에따라조절 4. 용기내압 : 용기내를물로치환한후서서히압력을가해 13 kg/cm 2 으로 30 초 간유지시켜압력저하나변형이없는것으면적합함 5. 제제분석 분사제분석 : 가스크로마토그래피이용 주약의분석 : 분사제를방출시킨후원액을정량분석