Disperse System Definition Dispersing phase Interface Dispersed phase Disperse Systems Pharmaceutical Unit size property agent Properties Surfactant Stability potential -amphiphakc rheology HLB value Xiaohui Wei Mochanism: Solubilization System micelle:CMC xhwei@sjtu.edu.cn Safety Three pharmaceutical suspension drug delivery systems emulsion 2 Formulation Study: liposome 4. Evaluation Mothod: 1.Introduction 2.Fundamental properties: 2.1.Classification Definition: 1.The Types of the dispersed phase /the dispersing Dispersed phase and Dispersing phase phase. The significance: 2. Molecular/Micellar dispersions be widely used in oral,tropical,parenteral drug delivery. 3 Spherical/Linear target delivery 1
1 Disperse Systems Xiaohui Wei xhwei@sjtu.edu.cn Disperse System Definition Dispersing phase Dispersed phase Interface Pharmaceutical Properties Unit size Stability rheology Zeta Safety, potential Effectiveness, Reliability; Given route Surfactant Electric property Stabilizing agent Three pharmaceutical systems suspension emulsion liposome amphiphilic HLB value Mechanism: micelle;CMC Safety 1. Vehicle properties for drug delivery 2. Formulation Study; 3. Preparation Method; 4. Evaluation Method; Solubilization System 1. Introduction Definition: Dispersed phase and Dispersing phase The significance: be widely used in oral, tropical, parenteral drug delivery. target delivery 2.Fundamental properties: 2.1.Classification 1. The Types of the dispersed phase / the dispersing phase. 2. Molecular / Micellar dispersions 3 Spherical/ Linear
Classification based on the types of the dispersed phase Classification of Dispersed systems based on Particle Size the dispersing phase. Class Particle Size Examples S-L L-L G-L Molecular 0.5μm R.B.C.,Pharmaceutical Dispersion emulsions,suspensions Questions 2.2 Fundamental Properties: Particle Size Distribution The size of the dispersion unit? Expression: Eguivalent Spherical Diameter 。The stable period? Determination Method: QELS(PCS)Method Coulter Counter Method For the liquid dispersion system,what kind of rheological properties it has Data Presentation: by volume/number/intensity polydispersion index 2
2 Classification based on the types of the dispersed phase / the dispersing phase. S-L L-L G-L S-S L-S G-S S-G L-G G-G Suspensions: S-S, L-S (OR S-L), G-S Emulsion: L-L Class Particle Size Examples Molecular 0.5 µm(µ) R.B.C., Pharmaceutical Dispersion emulsions, suspensions Classification of Dispersed systems based on Particle Size Questions z The size of the dispersion unit? z The stable period? z For the liquid dispersion system, what kind of rheological properties it has ? 2.2 Fundamental Properties: Particle Size & Distribution Expression: Equivalent Spherical Diameter Determination Method: QELS(PCS) Method Coulter Counter Method Data Presentation: by volume/number/intensity polydispersion index
2.3.Fundamental Properties: The Surface Properties Crystal Growth Significance: Nal AgNO3 physical stability excess →Agll+Nat+NO Zeta potential: definition:unit charge from infinity to the fixed layer; negatively charged charge:adsorption or ionization:crystal lattice extension ⊙g个g colloidal particle diffuse double layer:fixed layer and mobile diffuse layer Determination:electrophoresis method From "CoMloidal Systems"by R Gary Hollenbeck,Ph.D. Particle Surface Stern Layer(fixed layer) Shear plane Gouy-Chapman Layer Particle Surface ⊙ 1 ⊙ Bulk Solution ⊙ @ ⊙ Equal concentration ⊙ of similions and counterions o NO NO Di折se Double Layer From "Colloidal Systems"by R.Gary Hollenbeck,Ph.D. Diffuse Double Layer FromColloidal Systems"by R Gary Hollenbeck,Ph.D. 卡 Distance from particle surface Distance from particle surface 3
3 2.3. Fundamental Properties: The Surface Properties Significance: physical stability Zeta potential: definition: unit charge from infinity to the fixed layer; charge: adsorption or ionization; crystal lattice extension diffuse double layer: fixed layer and mobile diffuse layer Determination: electrophoresis method Crystal Growth NaI + AgNO AgI + Na + NO excess 3 + 3 - NO3 - NO3 - NO3 - Na+ Na+ Na+ Na+ Na+ Na+ Na+ NO3 - NO3 - Na+ NO3 - NO3 - NO3 - Na+ Na+ Na+ Na+ I - I - I - I - Ag Ag + + Ag+ I - I - Ag+ I - I - I - I - Ag Ag + + Ag+ I - I - Ag+ I - I - I - I - I - I - I - negatively charged colloidal particle From “Colloidal Systems” by R. Gary Hollenbeck, Ph.D. I - I - I - I - I - I - I - Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na Na+ + NO - 3 NO - 3 NO - 3 NO - 3 NO - 3 Na+ Particle Surface Stern Layer (fixed layer) Gouy-Chapman Layer Distance from particle surface Bulk Solution Equal concentration of similions and counterions Diffuse Double Layer Na+ Na+ I - I - From “Colloidal Systems” by R. Gary Hollenbeck, Ph.D. I - I - I - I - I - I - I - Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na Na+ + NO - 3 NO - 3 NO - 3 NO - 3 NO - 3 Na+ Particle Surface Distance from particle surface Diffuse Double Layer Na+ Na+ I - I - NO - 3 From “Colloidal Systems” by R. Gary Hollenbeck, Ph.D. Shear plane
From Colloidal Systems"by Shear plane R Gary Hollenbeck,Ph_D. 2.4.Rheological Properties Particle Surface 平o RHEOLOGY Zota Potentlal Surface Potontial rheo-to flow Dynamic potential Ther logos-science To the shear plane To the particle Influenced by the Rheology describes the flow of liquids and the deformation of solids. Ψz=Zeta potential :Ψ=0 Distance from particle surface 2.4.Rheological Properties Five main types: Significance: related to tropical use and stability Rheological type Example Mixding .Flow of materials -Packaging into containers Simple Newtonian Fluid solution -romoval prior to use Plastic Fluid flocculated Suspension. Classification:the Newton Equiv. Yield Value shear rate(velocity gradient) Simple Pseudoplastic Fluid polymer solution shear stress viscosity coefficient (Shear-thinning systems) Dilatant Fluid Suspensions containing a high Measurement:viscometer and empirical data concentration (50%or greater)of (Shear-thickening systems) small,deflocculated particles. thixotropy 4
4 I - I - I - I - I - I - I - Particle Surface Distance from particle surface Shear plane Ψo Ψ=0 Ψz = Zeta potential From “Colloidal Systems” by R. Gary Hollenbeck, Ph.D. To the particle surface To the shear plane Influenced by the iron on the particle surface Influenced by other irons Thermodynamic potential Dynamic potential Zeta Potential Surface Potential 2.4.Rheological Properties RHEOLOGY rheo - to flow logos – science Rheology describes the flow of liquids and the deformation of solids. 2.4.Rheological Properties Significance: related to tropical use and stability - Mixing - Flow of materials - Packaging into containers - removal prior to use Classification: the Newton Equiv. shear rate( velocity gradient) shear stress viscosity coefficient Measurement: viscometer and empirical data Five main types: thixotropy Suspensions containing a high concentration (50% or greater) of small, deflocculated particles. Dilatant Fluid (Shear-thickening systems) Simple Pseudoplastic Fluid polymer solution (Shear-thinning systems) flocculated Suspension, Yield Value Plastic Fluid Simple Newtonian Fluid solution Rheological type Example
3.Solubilized Systems 3.1 Surfactant Solubilization:the process to increase the apparent solubility There are molecules or ions that have both lipophilic and lipophoblc (or hydrophilic)groups in the same molecule. The related manipulations: These substances are caled amphiphiles and atso surface 1.Surfactant micelles (micellar solubilization) active agents due to their ability to lower the surface or intertacial tension of the meaum in which they are dissolved. 2.Cosolvents 3.complexation M● 4.Solid-state changes Nonpolar or lipophilic group: Le.hydrocarbon chain Polar or hydrophilic group 5.Hydrotropic agents 6.Prodrug formation Depending on the nature of the polar groups.amphiphiles can be anionic.cationic.nonionic.or ampholytic. 3.1.1Chemical classification 3.1.2 Physical Classification Type Examples Solubizers Anionic Sodium Laureate (SDS) ge CHa(CH2)++OSO:Na' 09 Cationic CTAB.with antimicrobial activity CHa(CH2)asN"(CHa)3 Br lipophilic hydrophilic Nonionic Polymeric surfactants such as Tween /Span,Pluronic The hydrophilic-lipophilic balance (HLB)is a measure (in an arbitrary scale)of the ratio Leeehin between the polar and non-polar groups (or Amphoteric zones)in the surfactant molety.The higher the HLB the more polar the surfactant. 5
5 3.Solubilized Systems Solubilization: the process to increase the apparent solubility The related manipulations: 1. Surfactant micelles (micellar solubilization) 2. Cosolvents 3. complexation 4. Solid-state changes 5. Hydrotropic agents 6. Prodrug formation 3.1 Surfactant 3.1.1Chemical classification Amphoteric Polymeric surfactants such as Tween /Span, Pluronic Nonionic CTAB, with antimicrobial activity CH3(CH2)15N+(CH3)3 BrCationic Sodium Laureate (SDS) CH3(CH2)11OSO3-Na+ Anionic Type Examples 3.1.2 Physical Classification
3.1.3 Surfactant:amphiphilic properties 3.1.3 Surfactant:amphiphilic properties As the concentration of the surfactant is Surfactant properties:Aggregation raised in water.the bulk concentration and the number of molecules in the interface are increased. Cn(云时CC5ean6d eG■en At a certain point.both the surface and equibttum wth thn miceles. the bulk phase become saturated and if more amphiphile is added to the system Monomer concentration the molecules aggregate to form micelles. The concentration of surfactant at Surface tension which micelle fomation occurs is called the critical micelle concentration. CMC CMC,and the number of molecules Surfactant Concentration forming each micelle is called the eggregation number. 年中 Different types of aggregates depending on the SA 3.2.Surfactant:solubilization concentration The aggregates or micelles of a surfactant have the ability of increasing the solubility of slghtly soluble substances.The non-polar molecules of the slightly soluble substance locate into the non-polar core of the miceles. Lysroncal or Hos-snaped Concertration 88888888#88# 888中年0布年中 ● C Biametar Surfactant Concentation 古 6
6 3.1.3 Surfactant: amphiphilic properties 3.1.3 Surfactant: amphiphilic properties Different types of aggregates depending on the SA concentration 3.2. Surfactant: solubilization
3.2.Surfactant:solubilization 3.2.Surfactant:solubilization Solubilization (as micelle formation)is a dynamic Micelle core: process.The solubilized substance is in equllibrium hydrocarbon,suitable for the lipophilic material to with the non-solubilized fractien. be incorporated in thus to be dissolved. Solubilization Equilibrium: The solubilization can be considered as a partitioning process between the [Drao] Ks [Drm] aqueous enviroment and the Lumen (free drug) (micellar-bound drug) micellar phase. Taking effect drug depot,sustained release In this way.if the non-solubilized solute is removed from the aqueous enviroment.part of the solubilized molecules will exit from the micelles to re-establish the equilibrium. 3.3 Properties of pharmaceutical solubilized systems 4.1 Suspension 1.Contributions: Why we choose suspension to deliver a drug? .To improve the apparent solubility: advantages and disadvantages:given route anti-neoplastic and anti-HIV agents etc. ·To improve the sta bility of the drug in water How to formulate Formulation consideration 2.Potentially Negative influence on the action of preservatives How to prepare and quality-control? 3.Limitations: lab scale and pilot scale;process validation 4.Safety consideration:chronic toxicity and given route How to evaluate Evaluation:Safety,Stability and Efficiency >
7 3.2. Surfactant: solubilization 3.2. Surfactant: solubilization Micelle core: hydrocarbon, suitable for the lipophilic material to be incorporated in thus to be dissolved. Solubilization Equilibrium: [Draq] Ks [Drm] (free drug) (micellar-bound drug) Taking effect drug depot, sustained release 3.3 Properties of pharmaceutical solubilized systems 1.Contributions: z To improve the apparent solubility: z anti-neoplastic and anti-HIV agents etc. z To improve the stability of the drug in water 2. Potentially Negative influence on the action of preservatives 3. Limitations: 4. Safety consideration: chronic toxicity and given route 4.1 Suspension Why we choose suspension to deliver a drug? advantages and disadvantages; given route How to formulate ? Formulation consideration How to prepare and quality-control? lab scale and pilot scale; process validation How to evaluate ? Evaluation: Safety, Stability and Efficiency
1).Why we choose it? Examples of Pharmaceutical Suspensions: Antacid oral suspensions Advantages Disadvantages Antibacterial oral suspension tthe solubility,thus the volume Problems in the uniformity and dose-accuracy .Dry powders for oral suspension(antibiotic) 个The stability To mask the smell poor physical stability Analgesic oral suspension Easy to take In liquid form and bulky Anthelmentic oral suspension Anticonvulsant oral suspension Sustained-release effect in im.route Antifungal oral suspension Suspension is not allowed for IV.administration. Marketed preparations: ready-to-use dry powders which must be reconstituted before administration 2).Formulation consideration The properties of the drug substance solubility,stabilty,crystal fomm,dose etc. The properties of the yehicle excipient,lab-preparation method.stability.safety The potential interaction between the drug substance and the Meloxican oral suspension for dogs vehicle: inactive excipient 8
8 1). Why we choose it? Advantages ¾ the solubility, thus the volume ¾ The stability ¾ To mask the smell ¾ Easy to take ¾ Sustained-release effect in im.route Disadvantages ¾ Problems in the uniformity and dose-accuracy ¾ poor physical stability ¾ In liquid form and bulky Suspension is not allowed for IV. administration. Examples of Pharmaceutical Suspensions: z Antacid oral suspensions z Antibacterial oral suspension z Dry powders for oral suspension (antibiotic) z Analgesic oral suspension z Anthelmentic oral suspension z Anticonvulsant oral suspension z Antifungal oral suspension Marketed preparations: - ready-to-use - dry powders which must be reconstituted before administration Meloxican oral suspension for dogs 2).Formulation consideration The properties of the drug substance solubility, stability, crystal form, dose etc. The properties of the vehicle excipient, lab-preparation method, stability, safety The potential interaction between the drug substance and the vehicle: inactive excipient
2).1)The properties of the vehicle I.DLVO Theory: the factors responsible for controlling the aggregation rate Physical Stability:two main problems Vt=Vr+Va I.aggregation and ll.sedimentation ++:very good resistance to aggregation; ↑ -very rapid aggregation Curve Interaction Forces Interaction Implication Energy DLVO theory Brownian Motion A VrVa positive ++ Aggregation Kinetics Crystal Growth With change to Vm,S,P distance Q Vr>mean thermal energy,very stable; (PP): P:the first energy minimum,very tightly bound together density difference between the particle and the continuous phase: r:the particle radius: viscosity 9
9 2).1) The properties of the vehicle Physical Stability: two main problems I. aggregation and II. sedimentation DLVO theory Brownian Motion Aggregation Kinetics Crystal Growth I. DLVO Theory: the factors responsible for controlling the aggregation rate Vt=Vr+Va *++: very good resistance to aggregation; *－－: very rapid aggregation C VrVa positive +*，－* With change to Vm, S, P distance B A Vr>Va positive ++* Interaction Implication Energy Curve Interaction Forces Curve B Describe the interaction energy changes according to the distance between two particles. S : the secondary energy minimum, loose aggregation; Vm : high potential energy barrier, Vm>> mean thermal energy, very stable; P : the first energy minimum, very tightly bound together II. Sedimentation r: particle radius r very small : Brownian Motion is dominant; r increases : Sedimentation dominant. η ρ ρ 9 2( ) 2 1 2 r g V − = (ρ1-ρ2): density difference between the particle and the continuous phase; r: the particle radius; η: viscosity
Sedimentation Prevention Another problem:crystal growth v=2(e-p:)rg The reason: 9n Sensitive to the temperature fluctuation wv: Tem.↑：small particle dissolved↑(higher surface free energy) :add sorbitol etc. Tem.↓：solubility↓，crystallize rRadius:micronization or controlled-crystallization particles growing bigger(suspension coarser) viscosity:add glycerol,polymeric agents etc. Inhibition Method: *not so useful because of the limitations in increasing Gums adsorbed to the crystal surface: the vehicle viscosity Freeze-thaw method; Physical Stability Conclusion 3).How to prepare suspensions Aggregation Sedimentation Two main methods:Dispersion'&Precipitation Dispersion Method: 1.Make finely divided drug powders. Reason: Reason: by micronization or controlled-crystallization the mutual repulsive forces gravity,particle size 2.Dispersion and Homogenization. Solution: Solution: by sonication or colloid mill to increase Zeta potential; adjust these factors Controlled Aggregation. steric hindrance By controlling the zeta potential to produce a very rapid sedimentation resulting in a loose.very easy to be redispersed aggregated suspension 10
10 Sedimentation Prevention V: (ρ1-ρ2)*: add sorbitol etc. r Radius: micronization or controlled-crystallization ηviscosity: add glycerol, polymeric agents etc. *: not so useful because of the limitations in increasing the vehicle viscosity η ρ ρ 9 2( ) 2 1 2 r g V − = Another problem: crystal growth The reason: Sensitive to the temperature fluctuation Tem.↑: small particle dissolved↑(higher surface free energy) Tem.↓: solubility↓, crystallize particles growing bigger (suspension coarser) Inhibition Method: Gums adsorbed to the crystal surface; Freeze- thaw method; Physical Stability Conclusion Aggregation Reason: the mutual repulsive forces Solution: to increase Zeta potential; steric hindrance Sedimentation Reason: gravity, particle size Solution: adjust these factors 3).How to prepare suspensions Two main methods: Dispersion* & Precipitation Dispersion Method: 1.Make finely divided drug powders. by micronization or controlled- crystallization 2. Dispersion and Homogenization. by sonication or colloid mill Controlled Aggregation: By controlling the zeta potential to produce a very rapid sedimentation resulting in a loose, very easy to be redispersed aggregated suspension