List of things to know: LECTURE 1 – INTERFACIAL PHENOMENA AND SURFACTANTS

1. Surface tensiona. It is what happens if a liquid or solid is exposed to area.b. The tendency of liquids to reduce their exposed surface to the smallest possible area

i. The molecular interactions in the bulk of a liquid is very different from that on the surface of the same liquid. In the bulk, one molecule interaction equally in all directions with other similar molecules. However, when a molecule is located on the surface of the same liquid, the molecule will only be attracted by other similar molecules in the liquid, but not from above the surface. Thus, a liquid has the tendency to reduce its exposed surface to the smallest possible area. It is defined as the work required to increase the surface area A of a liquid by 1 area unit. Its unit is dynes per cm or mNewton per meter. Therefore, the surface tension is unique to each individual liquid.

c. Surface tension is an effect within the surface layer of a liquid that causes the layer to behave as an elastic sheet.

2. Interfacial tensiona. At interfacial region/boundary/interface between two immiscible liquids or liquid-solidb. If oil and water are putting together. There will be two

phases/layers, with the oil on the top of water. The question is that will the density of the liquids change abruptly or gradually in the interface region.

i. Experimental data showed that B is correct. This region is called interfacial region. In the bulk of water and oil, every molecule will have coherent attraction from similar molecules in all directions. However, in the interfacial region, the water molecules will be attracted by water in one half, and by oil in another half. Thus, the molecules in the interface region behave differently from those in the bulk phase of both water and oil.

c. The density will gradually change3. Surfactant

a. Any substance that when dissolved in water or an aqueous solution reduces its surface tension or the interfacial tension between it and another liquid.

b. Surfactants are usually organic compounds that are amphipathic, meaning they contain both hydrophobic groups (their "tails") and hydrophilic groups (their "heads"). Therefore, they are typically sparingly soluble in both organic solvents and water.

i. C18ii. Saturated

iii. acid4. Requirements for a surfactant

a. See #3bb. A surfactant needs a lipophilic part and a hydrophilic part. When the carbon chain length of the

alcohol is increased, their effect in decreasing the surface tension of water increased dramatically.

i. Sodium will form a oleic acid soap with the oleic acid, and thus further decrease the surface tension.

ii. The longer the chain, the less the surface tension (see graph)

5. Soft soapa. More hydrophilicb. Positive ion is univalent

i. Na+, K+, NH4+

c. All of the soaps (sodium oleate, etc) are fatty acid salts. They are characterized by a long hydrocarbon chain and a carboxylate group at the end.

6. Hard soapa. More lipophilicb. Positive ion is divalent

i. Ca++, Mg++

c. All of the soaps (sodium oleate, etc) are fatty acid salts. They are characterized by a long hydrocarbon chain and a carboxylate group at the end.

7. Anionic surfactants: fatty acids, sulfate (SDS or SLS), sulfonate a. Sodium dodecyl sulfate (SDS or NaDS), also known as sodium lauryl sulfate (SLS), is an ionic

surfactant that is used in household products such as toothpastes, shampoos, shaving foams and bubble baths for its thickening effect and its ability to create a lather. The molecule has a tail of 12 carbon atoms, attached to a sulfate group, giving the molecule the amphiphilic properties required of a detergent.

b. Sodium laureth sulfate, or sodium lauryl ether sulfate (SLES), is a detergent and surfactant found in many personal care products (soaps, shampoos, toothpaste etc.). It is an inexpensive and very effective foamer.

c. Docusate sodium [USP] is anionic surfactant used as a stool softener and is administered orally or rectally; as a tablet disintegrant or as an emulsifier and dispersant in topical preparations. When sold as Colace, it is docusate sodium, or sodium salt of dioctyl sodium sulfosuccinate (DSS).

8. Cationic surfactants: CTAB, benzalkonium chloridea. Benzalkonium chloride (alkyl dimethyl benzyl ammonium chloride) is an organic compound that

is used as an antiseptic and spermicide. This product is a nitrogenous cationic surface-actin agent belonging to the quaternary ammonium group. Benzalkonium chloride is a mixture of alkylbenzyl dimethylammonium chlorides of various alkyl chain lengths. The greatest bactericidal activity is associated with the C12-C14 alkyl derivatives.

b. It is one of the safest synthetic biocides known, and has a long history of efficacious use. Applications are extremely wide ranging, from disinfectant formulations to microbial corrosion inhibition in the oilfield sector. It is deemed safe for human use, and is widely used in eyewashes, hand and face washes, mouthwashes, spermicidal creams, and in various other cleaners, sanitizers, and disinfectants. The mechanism of bactericidal/microbicidal action is thought to be due to disruption of intermolecular interactions. This can cause dissociation of cellular membrane bi-layers, which compromises cellular permeability controls and induces leakage of cellular contents. Other bio-molecular complexes within the bacterial cell can also undergo dissociation

c. Cetyl trimethyl ammonium bromide (CTAB) , also known as hexadecyltrimethylammonium bromide or 1-hexadecanaminium, N,N,N-trimethyl-, bromide is one of the components of the antiseptic cetrimide. It is a cationic surfactant. Its uses include providing a buffer solution for the extraction of DNA.

d. As any surfactant, it forms micelles in aqueous solutions. At 303 K (30 °C) it forms micelles with aggregation number 75-120 (depending on method of determination, usually avg. ~95) and degree of ionization α (fractional charge) 0.2 - 0.1 (from low to high concentration).

i. Capric acid, decanoic acid9. Lecithin

a. Is an amphoteric surfactanti. Amphoteric: substance is one that can react as either an acid or base (more generally, the

word describes something made of, or acting like, two components)b. The safest surfactantc. Lecithin is extracted from plant (soy) or eggs. There are very biocompatible. It’s a natural

component of cell membrane. 10. Span

a. A non-ionic surfactantb. More lipophilicc. R-groups will form estersd. The HLB value of span decrease as the Span XX

increasesi. His is because Span 85 has three oleate chains,

and is very lipophilic11. Tween

a. Tween is polyoxyethylene sorbate ester. The polyoxyethylene groups are more hydrophilic, and the R group is more lipophilic. Due to the many polyoxyethylene groups, Tweens are in general more hydrophilic and have larger HLB.

b. Poloxmers are polyoxyethylene/polyoxypropylene block copolymers. c. Used as a solubilizer in cosmetics and cleansers

12. Micelles (structure, properties, applications, factors affecting CMC and size of micelles)a. Structure

i. A (micelle) shows a spherical structure of a micelle formed by an anionic surfactant. The lipophilic tails located in the center, while the anionic group is projected out and in close association with the continuous phase.

ii. B is a polymeric surfactant. Lipophilic region of the polymers was assemblied in center, while regions have high hydrophilicity is in the outsurface.

iii. When the concentration is further increased, other unique structures can be formed such as the cylindrical and lamellar structures.

iv. A micelle is an aggregate of the surfactant molecules dispersed in a liquid colloid.

1. Colloid = a kind of dispersed system with particle size ranging from 1 nm to 0.5 mm. Aggregation number

b. Propertiesi. Solubilization

1. The ability of the micelles to increase the solubility of materials that are normally insoluble or only slight soluble in the dispersion medium.

c. Applicationsi. Cholesterol-bearing pullulan self-aggregates (micelles)

1. CHP is polysaccharide conjugated with cholesteryl groups. It was used to coated liposomes to target liver cells. When the polymer is dispersed into water, and stirred contineously at 45oC overnight. The dispersion can self-assembly into micelles. This system has been tried to incorporated insulin for controlled delivery

of insulin. This kind of macromolecular micelles take time to form, and also take time to dissociate.

ii. Polymer surfactantiii. Counter-ion

d. CMCi. Critical micelle concentration

1. The concentration of surfactant at which micelles form.ii. Micelle aggregation number

1. The number of surfactants that aggregate to form a micelle.a. i.e. number of molecules

iii. CMC of the mixture of two surfactants1. 1/CMC = f1/CMC1 + f1/CMC2 2. (f = mole fraction)

* Micelles are not a solid particles. The individual molecules in the micelles are in dynamic equilibrium with monomers in the bulk and at the interface (b/w monomer and micelle)

* When the micelles are too diluted, they will breake. Factors affecting CMC and micelle size

i. Structure of hydrophobic groupii. Nature of hydrophilic group

iii. Nature of counter ionsiv. Addition of electrolytes to ionic surfactants decreases CMC and increase sizev. Effect of temperature

13. Kraft pointa. The temperature at which the solubility of the surfactant equals the CMC.b. The solubility of surfactant increases rapidly above the kraft

point.14. HLB and HLB calculation for a blend of surfactants

a. Hydrophilic-lipophilic balanceb. The higher the HLB value, the more hydrophilic the surfactant isc. Each surfactant is assigned a valued. An arbitrary scale of values to serve as a measure of surface

active agentsi. RHLB (required HLB) used for emulsions

ii. Emulsion: a suspension of small globules of one liquid in a second liquid with which the first will not mix.

e. HLB calculations (blending of surfactantsi. HLB values are additive

ii. More of the times, a blend of surfactants was chosen to prepare emulsion of the best stability.

iii. Example calculation1. HLB of Tween 80 = 152. HLB of Span 80 = 4.33. We need 2 g of Tween 80 and Span 80 blend having a HLB value of 10.6. How

much Tween 80 and Span 80 are needed?4. Suppose we need X fraction of Tween 80; the fraction of Span 80 will be 1-X5. 15X + 4.3 (1-X) = 10.6; X = (10.6-4.3)/(15-4.3) = 0.596. Fraction of Span 80 = 1- 0.59 = 0.417. Weight of Tween 80 = 2 * 0.59 = 1.18 g8. Weight of Span 80 = 2 * 0.41 = 0.82 g

9.

10. B = Tween 80 = 6.3/10.711. A = Span 80 = 4.4/10.7

15. Applications of surfactantsa. Detergentsb. Emulsifiersc. Paintsd. Adhesivese. Inksf. Alveolig. Wetting

h. Ski Wax i. Snowboard Wax j. Foaming k. Defoaming l. Laxatives

(docusate sodium)

m. Agrochemical formulations

n. Herbicideso. Insecticides

p. Wetting agentsi. A wetting agent is a surfactant that, when dissolved in water,

lowers the advancing contact angle, aids in displacing an air phase at the surface, and replacing it with a liquid phase.

1. Examples: displacement of air from the matrix of cotton pads and bandages so that medicinal solutions can be absorbed for application. Displacement of air from sulfur, charcoal, and other powders for the purpose of dispersing these drugs in liquid vehicles.

ii. Wetting agents can lower the contact angle.iii. Wetting agents should have an HLB value of 6-9. iv. When a drop of water is placed on a clean glass surface, the

drop will spread spontaneously and no contact angle exists. However, to spread water on greasy, dirty glass, wetting agents are needed.

q. Detergentsi. Surfactants used for the removal of dirt.

ii. Initial wetting of the dirt and of the surface to be cleaned;iii. Deflocculation and suspension;iv. Emulsification or solubilization of dirt;v. Foaming of the agent for entrainment and washing away.

vi. MAO: the hydrocarbon tails of the detergent anion dissolve in the grease. The grease gradually breaks up and becomes pincushioned by the detergent anions. Then, small bits of grease are held in the colloidal suspension by the detergent.

r. Foaming and anti-foaming agentsi. Any solutions containing surfactants produce stable foams when mixed intimately with

air. A foam is a relatively stable structure consisting of air pockets enclosed within thin films of liquid; the gas-in-liquid dispersion is being stabilized by a foaming agent.

ii. Agents that can disrupt/break foams are anti-foaming agents.s. Decrease surface tension

i. Surfactants reduce the surface tension of water by adsorbing at the air-water interface. They also reduce the interfacial tension between oil and water by adsorbing at the liquid-liquid interface.

B= 15

A = 4.3

10.6

6.3

10.7

4.4

0.970.960.770.790.560.45Cosθ

31.939.248.350.863.472.8 (dynes/cm)

Mineral oil

Benzyl alcohol

Ethylene glycol

Diiodo-methane

GlycerinWaterLiquid

0.970.960.770.790.560.45Cosθ

31.939.248.350.863.472.8 (dynes/cm)

Mineral oil

Benzyl alcohol

Ethylene glycol

Diiodo-methane

GlycerinWaterLiquid

ii.

1. Many surfactants can also assemble in the bulk solution into aggregates that are known as micelles.

2. The concentration at which surfactants begin to form micelles is known as the critical micelle concentration or CMC.

a. When micelles form in water, their tails form a core that is like an oil droplet, and their (ionic) heads form an outer shell that maintains favorable contact with water.

b. When surfactants assemble in oil, the aggregate is referred to as a reverse micelle. In a reverse micelle, the heads are in the core and the tails maintain favorable contact with oil.

iii. Thermodynamics of the surfactant systems are of great importance, theoretical and practical, because surfactant systems represent a systems between ordered and disordered state of matter-surfactant solutions may contain ordered phase (micelles) and disordered phase (free surfactant mollecules and/or ions in the solution).

t. How much the surface tension will be decreasei. When surfactant is added to water, it will decrease the surface tension.

ii. When surfactants are added into water, they will preferentially absorbed on the surface of the water. In the end, a highly compacted surfactant monolayer will be formed. After reaches this point, the extra surfactants added into the water will try to dissolve into the bulk phase of the water. At a certain concentration, the surface tension of the liquid won’t decrease anymore. The extra surfactants then rearrange to form the so called micelles.

1. surface tension will not decrease to zero.u. Effect of surfactant on the properties of a liquid

i. Osmotic pressure increases and reaches constantii. Detergency ability increases sharply

iii. Light scattering becomes significant1. Light scattering is a measurement of the presence of

particles.iv. Surface tension decreases and reaches a constant (critical

micelle concentration)1. Surfactants need to form micelles to have detergency

activity because any dirts have to be solubilized into the micelles.

v. ↑ surfactant [], ↓ surface tensionvi. ↑ surfactant [], ↑ light scattering

16. Critical surface tensiona. Zisman et al found that when the cosine of contant

angle is plotted against the surface tension of a series of liquid of a certain surface, a straight line

was obtained. The surface tension value where the line crosses with the cosine value of 1 is called the critical surface tension. Any liquid having a surface tension of lower than the CST value can spread easily on the surface.

b. For every surface, there will be a critical surface tension.

LECTURE 2 - EMULSION

17. Emulsionsa. An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid

phases, one of which is dispersed as globules in the other liquid phase, stabilized by the presence of an emulsifying agent.

i. A’. Two immisicble liquids, not emulsified; B’. An emulsion of Phase B dispersed in Phase A; C’. The unstable emulsion progressively separates; D’. The (purple) surfactant positions itself on the interfaces between Phase A and Phase B, stabilizing the emulsion

1. butter, margarine, salad dressingii. emulsions are unstable because creating small droplets will create large surface area.

Since the surface has the tendency to decrease due to surface tension, emulsions are unstable.

b. Applications of emulsionsi. o/w (oil in water) is convenient for oral dosing

1. o/w makes it easier to consume2. can ↑ the solubility of drugs with low aqueous solubility

ii. to cover unpleasant tasteiii. to increase oral absorptioniv. I.V. o/w, if oral o/w not possible (RES uptake)v. External use (topical cream)

c. Types of emulsionsi. Oil-in-water (o/w)

ii. Water-in-oil (w/o)iii. Oil-in-water-in-oil (o/w/o)iv. Water-in-oil-in-water (w/o/w)

d. Determination of o/w or w/oi. Water soluble dye (e.g., methylene blue)

ii. Dilution of emulsionsiii. Conduction of current

** Oil dose not mean that it has to be the conventional oil. Any liquid that is not miscible with water will be just OK. Double emulsion is rarely used. It might be good to increase the stability of a certain chemical. However, the chemical has to diffuse through several layers to be released, making the drug not biologically available.

18. Thermodynamically unstable?a. Cholesterol-bearing pullulan self-aggregates are the only thermodynamically stable because they

can form on their ownb. Microemulsions are thermodynamically stable

19. Theory of emulsificationa. Change from A to B will significantly increase of the surface area of phase.

i. e.g., if 1 cm3 of mineral oil is dispersed into globules having diameter of 0.01 mm in 1 cm3 of water, how much will be the surface area increased.

b. The surface area will become 600 m2 (greater than a basketball court); the surface free energy will increase by 8 calories. Therefore, emulsions are thermodynamically unstable, and the droplets have the tendency to coalesce.

c. Emulsifying agents are needed to decrease the surface tension and to stabilize the droplets.

d. Emulsifying agents can prevent coalescence or at least reduce its rate to negligible. It will form a film around the dispersed globules. The strength of an emulsifying agent lies in its ability to form a firm film.

20. Emulsifying agents (surfactants, hydrocolloids, particles)a. Surface active agents (monomolecular film)

i. Rule of Bancroft: The type of the emulsion is a function of the relative solubility of the surfactant, the phase in which it is more soluble being the continuous phase.

ii. a surfactant with a HLB value of 8-16 helps the formation of o/w emulsioniii. a surfactant with a HLB value of 3-8 aids the formation of w/o emulsion. iv. It is necessary to have a predominantly

hydrophilic emulsifier in the aqueous phase and a hydrophobic agent in the oil phase to form a

complex film at the interface. SCS – chol lead to a complex film, and thus excellent emulsion. Oleyl alcohol does not pack well. So the emulsion is unstable.

b. Hydrophilic colloids (multimolecular film)i. Colloid = a kind of dispersed system with particle size

ranging from 1 nm to 0.5 nmii. Hydrated lyophilic colloids (hydrocolloids)

1. providing a protective sheath around the droplets 2. imparting a charge to the dispersed droplets (so

that they repel each other) 3. swelling to increase the viscosity of the

system (so that droplets are less likely to merge) iii. Classification of hydrocolloids

1. vegetable derivatives, e.g., acacia, tragacanth, agar, pectin, lecithin a. Acacia is a carbohydrate gum soluble in water and form O/W emulsions.

Emulsion prepared with acacia is stable over a wide range of pH.b. Lecithin is natural, from eggs or plants. A mixture of lipids, mainly PC,

PI, PE, PS, and phsophatidic acid. 2. animal derivatives, e.g., gelatin, lanolin, cholesterol

a. Gelatin is a protein. It has been used for many years as an emulsifying agent.

Type A: derived from acid treated precursors, having a IE of 7-9. it acts best at pH 3.

Type B: IE = 5, best at pH 8. This affects the stability a lot.b. Choleseterol is a major component of wool alcohols. It is cholesterol that

gives wool fat its capacity to absorb water and form a w/o emulsion.3. Semi-synthetic agents, e.g., methylcellulose, carboxymethylcellulose 4. Synthetic agents, e.g., carbomers (PEG and acrylic acid)

c. Finely divided solid particles (Particulate film)

21. Physical stability of emulsionsa. Creamingb. Creaming is the upward movement of dispersed droplets of emulsion relative to the continuous

phase (due to the density difference between two phases)i. Reversible. Need to be shaken well prior to use. It does not look good. Also, if not

uniformally distributed, required amount of the active ingradient might not be achieved. ii. Can stabilize emollient by ↓ particle size.

c. Stoke’s law: dx/dt = d2 (ri-re)g/18hi. dx/dt = rate of setting

ii. D = diameter of particlesiii. r = density of particles and mediumiv. g = gravitational constantv. h = viscosity of medium

d. Breaking, coalescence, aggregationi. Breaking is the destroying of the film surrounding the particles.

1. breaking is irreversibleii. Coalescence is the process by which emulsified particles merge with each to form large

particles.iii. Aggregation: dispersed particles come together but do not fuse. iv. The major fact preventing coalescence is the mechanical strength of the interfacial film.

e. Phase inversioni. An emulsion is said to invert when it changes from an o/w to w/o or vice versa.

f. Addition of electrolytei. Addition of CaCl2 into o/w emulsion formed by sodium stearate can be inverted to w/o.

g. Changing the phase:volume ratioi. Changing from a soft soap into a hard soap, a hydrophilic surfactant into lipophilic

surfactant. h. Preservation of emulsions

i. Growth of microorganisms in emulsionsii. Preservatives should be in aqueous phase.

iii. Preservatives should be in unionized state to penetrate the bacteria (Henderson-Hasselbach Equation)

iv. Preservatives must not bind to other components of the emulsion** Bacteria have been shown to degrade non-ionic and anionic surfactants, glycerin, and vegetable gums. This will damage the emulsion.

22. Methods of emulsion preparationa. Continental or dry gum method (4:2:1 method)

i. The continental method is used to prepare the initial or primary emulsion from oil, water, and a hydrocolloid or "gum" type emulsifier (usually acacia). The primary emulsion, or emulsion nucleus, is formed from 4 parts oil, 2 parts water, and 1 part emulsifier. The 4 parts oil and 1 part emulsifier represent their total amounts for the final emulsion.

ii. In a mortar, the 1 part gum (e.g., acacia) is levigated with the 4 parts oil until the powder is thoroughly wetted; then the 2 parts water are added all at once, and the mixture is vigorously and continually triturated until the primary emulsion formed is creamy white.

iii. Additional water or aqueous solutions may be incorporated after the primary emulsion is formed. Solid substances (e.g., active ingredients, preservatives, color, flavors) are generally dissolved and added as a solution to the primary emulsion. Oil soluble substance, in small amounts, may be incorporated directly into the primary emulsion. Any substance which might reduce the physical stability of the emulsion, such as alcohol (which may precipitate the gum) should be added as near to the end of the process as possible to avoid breaking the emulsion. When all agents have been incorporated, the

Cod liver oil 50 mLAcacia 12.5 gSyrup 10 mLFlavor oil 0.4 mLPurified water, qs ad 100 mL

emulsion should be transferred to a calibrated vessel, brought to final volume with water, then homogenized or blended to ensure uniform distribution of ingredients.

iv. Preparation1. ingredients: 2. Accurately weigh or measure each ingredient3. Place cod liver oil in dry mortar4. Add acacia and give it a very quick mix5. Add 25 mL of water and immediately triturate

to form the thick, white, homogenous primary emulsion6. Add the flavor and mix7. Add syrup and mix8. Add sufficient water to total 100 mL9.

b. English of wet gum methodi. In this method, the proportions of oil, water, and emulsifier are the same (4:2:1), but the

order and techniques of mixing are different. The 1 part gum is triturated with 2 parts water to form a mucilage; then the 4 parts oil is added slowly, in portions, while triturating. After all the oil is added, the mixture is triturated for several minutes to form the primary emulsion. Then other ingredients may be added as in the continental method. Generally speaking, the English method is more difficult to perform successfully, especially with more viscous oils, but may result in a more stable emulsion.

c. Bottle or Forbes bottle methodi. This method may be used to prepare emulsions of volatile oils, or oleaginous substances

of very low viscosities. This method is a variation of the dry gum method. One part powdered acacia (or other gum) is placed in a dry bottle and four parts oil are added. The bottle is capped and thoroughly shaken. To this, the required volume of water is added all at once, and the mixture is shaken thoroughly until the primary emulsion forms. It is important to minimize the initial amount of time the gum and oil are mixed. The gum will tend to imbibe (absorb) the oil, and will become more waterproof.

d. Auxiliary methodi. An emulsion prepared by other methods can also usually be improved by passing it

through a hand homogenizer, which forces the emulsion through a very small orifice, reducing the dispersed droplet size to about 5 microns or less.

e. In situ soap methodi. In situ soap method is also called nascent soap methods. Nascent means beginning to

exist or to develop. The emulsifier is formed as the emulsions are made. * Calcium soaps: w/o emulsions contain oils such as oleic acid, in combination with lime water (calcium hydroxide solution, USP). Prepared by mixing equal volumes of oil and lime water.

f. Nascent soapi. Oil phase: olive oil/oleic acid; olive oil may be replaced by other oils, but oleic acid must

be addedii. Lime water: Ca(OH)2 should be freshly prepared.

iii. Equal volume of oil and lime wateriv. The emulsion formed is w/o or o/w?v. Method of preparation:

1. Bottle method:2. Mortar method: when the formulation contains solid insoluble such as zinc oxide

and calamine. vi.

g. Two tailsi. More lipophilic, less hydrophilic

ii. w/oiii. HLB < 8

h. One taili. Less lipophilic, more hydrophilic

ii. o/wiii. HLB > 8

23. Primary or initial emulsion24. Incorporation of drugs in emulsions

a. Addition of drug during emulsion formationb. Addition of drugs to a preformed emulsion

i. Addition of oleaginous materials into a w/o emulsionii. Addition of oleaginous materials to an o/w emulsion

1. occasionally, a small amount of oily material is added if sufficient emulsifier was used in the original formation

2.iii. Addition of water soluble materials to a w/o emulsioniv. Addition of water soluble materials to an o/w emulsion

25. Microemulsiona. Microemulsions are thermodynamically stable, optically transparent, isotropic mixtures of a

biophasic oil-water system stabilized with surfactantsMicroemulsion Emulsion

Stability Thermodynamically KineticallyTransparent Yes NoSize 0-200 nm Mainly 0.1-10 mmFormation Spontaneous NoType o/w, w/o, bicontinuous o/w, w/o, w/o/w, o/w/o

b. Unique emulsion or swelled micelles.c. Thermodynamically stable--- formed spontaneously. Surfactants and co-surfactants make the

surface tension to zero.d. Transparency is due to its smaller size, which cannot reflex visible light. e. o/w microemulsions can ↑ the solubility of compounds with low solubilityf. Pharmaceutical applications of microemulsions

i. Increase bioavailability of drugs poorly soluble in waterii. Topical drug delivery systems

LECTURE 3 - POLYMERS

26. PLGA microparticles27. Rheology/viscosity28. Colloids29. Ointment bases (examples, properties)

a. Hydrocarbon – very lipophilic and oily. Therefore it is very difficult to get water or other aqueous solutions inside it.

i. A.k.a. Oleaginous bases because they are oily. It has emollient effect when applied on skin to make skin softer. When applied on skin, it can prevent to evaporation of water, it has occlusion effect. This is important because as we will discuss later that increase water container in the stratum corneum can enhance the diffusion of certain drugs through the sc layer.

ii. Emollient effect: hydrates skin due to sweat accumulation

iii. Occlusive dressing1. occlusive – will not evaporate from the skin2. non-occlusive – will evaporate from the skin

iv. Difficult to wash-off/removev. Small amount of water can be incorporated into it

with difficulty and can be protective to water labile drugs such as tetracycline and bacitracin.

vi. Is greasy and can stain clothing. vii. Types of hydrocarbon bases

1. Petrolatum, USPa. Yellow petrolatum/petrolatum jelly

Vaseline (Chesebrough-Ponds/Unilever) (vahser-elaion) Melts at 38-60oC

1. Mineral oila. Liquid petrolatumb. Is a mixture of refined liquid saturated

hydrocarbons obtained from petroleumc. Levigating agent for oily basesd. An excipient in topical formulations where its

emollient properties are exploited as an ingredient in ointment bases.

2. White petrolatum, USPa. Decolored petrolatum,b. White petroleum jelly/white vaseline

3. Yellow ointment, USPa. Yellow wax (5%, w/w), petrolatum (95%)

4. White ointment, USPa. White wax/white petrolatum

viii.b. Absorption bases – oily systems that are w/o emulsions or can become w/o emulsion upon the

absorption of water or other aqueous solutions. Thus, it is possible to get some o/w emulsions.i. Those that permit the incorporation of aqueous solution resulting in he formation of w/o

emulsions 1. hydrophilic petrolatum, USP2. Aquaphor: A gentle healing ointment to help heal dry, cracked skin

a. Aquaphor is a variation of hydrophilic petrolatum and has the capacity to absorb up to 3 times of its weight in water.

** Hydrophilic petrolatum prepared by melting SA with wax in a steam bath, adding the chol with stirring until dissolved, add petrolatum, allow cooling.

ii. Those that are w/o emulsion1. Hydrous lanolin: w/o emulsion containing 25% of water2. lanolin USP: Anhydrous, contains < 0.25% of water, absorbs twice its weight in

water, also called wool wax, wool fat, or wool grease, a greasy yellow substance from wool-bearing animals, acts as a skin ointment, water-proofing wax, and raw material (such as in shoe polish).

a. Lanolin alcohol is a crude mixture of steroidal and triterpene alcohols, including not less than 30% of chol and 10-14 % of isocholesterol. The portion of water that can be added into petrolatum is increased 3-fold by the addition of 5% of lanoline alcohol. Ceresin is a white wax. Panthenol is the alcohol analog of pantothenic acid (Vitamin B3) and has equivalent

biological activity. Bisabolol has a weak sweet floral aroma and is used in various fragrances. It has also been used for hundreds of years in cosmetics because of its perceived skin healing properties. Bisabolol is known to have anti-irritant, anti-inflammatory and anti-microbial properties. Glycerin is a humectant to promote the retention of moisture.

iii. Properties of absorption bases1. Absorption bases (anhydrous)

a. Emollientb. Occlusivec. Absorbs waterd. Greasy

2. W/O emulsiona. Emollient b. Occlusivec. Contains water, absorbs additional waterd. Greasy

c. Water-removable bases – mainly o/w emulsions. This system is not messy and greasy. They are easy to apply and easily removable, and thus preferred by customers.

i. Water-washable bases, O/W emulsionii. Hydrophilic ointment, USP

iii. Vanishing cream: o/w emulsion contains la large % of water and humectant. An excess of stearic acid in the formula helps to form a thin film when the water evaporates.

iv. Dermovan: a hypoallergenic, greaseless emulsionv. Unibase: non-greasy emulsion base has pH close to that of skin

vi. Properties of water-removable bases1. Water-washable, easier to remove2. Non/less greasy3. Can be diluted with water4. Non/less occlusive5. Better cosmetic appearance6. Better compliance

d. Water-soluble bases – prepared from water soluble polymers such as PEG. They are water removable and not greasy. However, these kinds of systems do not have any occlusion activity.

i. Glyceryl monstearate1. polyhydric alcohol esters (widely used)2. wildly used in cosmetic and ointment bases

ii. Cellulose derivatives1. Methylcellulose2. Cellulose3. Hydroxyethyl cellulose

iii. Carbopol/carbomer1. synthetic high MW polymers of acrylic acid cross-linked with either allysucrose

or allyl ethers of pentaerythritol.iv. Examples

1. PEG ointment, NFa. PEG 3350 400 g, PEG 400 600 gb. Polyethylene glycol 200, 300, 400 (4-8oC), 600 (20- 25oC), 1000,

1450, 3350, 4000, 6000, 8000 and 20000c. Only a small amount of liquid (<5%) can be incorporatedd. If 6-25% of liquid is to be incorporated, 50 g of the 400 g of PEG 3350

may be replaced with stearyl alcohol2. Examples

a. ZOVIRAX®, (acyclovir), GSK, Ointment 5%b. BACTROBAN® SmithKline Beecham Mupirocin Topical Antibiotic

(Each g of ointment contains: mupirocin 20 mg (2%) in a bland water-soluble ointment base consisting of PEG 400 and PEG 3 350 (PEG ointment, USP).

v. Indications And Clinical Uses: 1. For the topical treatment of the following when caused by sensitive strains of

staphylococcus and streptococcus species: impetigo, superficially infected dermatosis, lesions which are moist and weeping.

vi. Properties of water-soluble bases1. Water soluble and washable2. Non-greasy3. Non/less occlusive4. Lipid free5. Synthetic base

a. Relatively inertb. Does not support mold growthc. Little hydrolysis, stabled. May dehydrate skin and hinder percutaneous absorption.

vii. Properties chart (KNOW!!)viii.

ix.

e. selection of the appropriate basei. Desired release rate of drug substance

ii. Desirability for topical or percutaneous absorptioniii. Desirability of occlusioniv. Stability of drug in ointmentv. Effect of drug on ointment base

vi. Desire for easy removable f. Ointments

i. Ointments are semi-solid preparations intended for external use. They are easily spread.1. Typically used as:

a. Emollients to make skin more pliableb. Protective barriers c. Vehicles in which to incorporate medication

2. Ointment itself alone can have some beneficial effects, such as being an emollients to make skin more pliable and to form a protective barrier. More importantly, we are interested in using ointment as a vehicle to carry medicinal chemicals.

g. Preparation of ointmentsi. Incorporation: components are mixed until a uniform preparation is attained.

1. Incorporation of solid: 2. Incorporation of liquid:

ii. Fusion: All or some components are combined by being melted together and cooled with constant stirring until congealed.

1. High melting temperature bases such as beewax, paraffin, stearyl alcohol, and high Mw PEG.

iii. Ointments having emulsion bases usually involve melting and emulsification steps. h. Requirements for ointments Microbial content: do not need to be sterile, but must meet the FDA

requirement of the test for absence of bacteria such as S. areus and P. aeruginosa for dermatological products.

i. Minimum fill:ii. Packaging, storage, labeling: (label should include the type of base used)

iii. Additional standards: viscosity, in vitro release30. Levigating agents

a. For the incorporation of basesb. A spatula with a long, broad blade should be usedc. Insoluble substances should be powdered finely in a mortar and mixed with an equal amount of

base until a smooth mixture is obtained. The rest of the base is added in increment.d. Levigation of powders into small portion of base is facilitated by the use of levigating agents.e. Levigating agents:

i. Mineral oil for oily bases or bases where oil are the external phaseii. Glycerin for bases where water is the external phase.

iii. Levigating agent should be equal in volume to the solid material. f. When liquid is added into an ointment, care must be taken to consider the capacity of the

ointment in accepting the liquid. When it is necessary to add an aqueous preparation to a hydrophobic base, the solution should be added into minimal amount of the hydrophilic base first. The mixture should be then added into the hydrophobic base.

31. Creams/vanishing and colda. Cream

i. Semisolid preparations containing one or more medicinal agents dissolved in either an o/w or w/o emulsion or in another type of water-washable base.

ii. Typically of low viscosity, two phase system (w/o or o/w)iii. Appears “creamy white” due to the scattering of light.iv. Traditionally, it is the w/o cold creamv. Currently and most commonly, it is the o/w emulsion.

vi. As drug delivery systems1. Good patient acceptance2. Water evaporation concentrates drug on skin

surface3. Must avoid drug crystallization4. Can add co-solvents such as propylene glycol

b. Vanishing cream:i. o/w with high % of water and stearic acid.

c. Cold cream: i. (an emulsion for softening and cleansing the skin): w/o, white wax, spermaceti, almond

oil, sodium borate.ii. w/o emulsion frequently using a borax-beewax combination as the emulsifying agent and

mineral oil or vegetable oil as the oily phase. A protective film remains on the skin following the evaporation of the water. The slow evaporation of water gives the skin a cooling effect.

iii. To prepare, melt white wax, spermaceti, and almond oil together, adding host aqueous solution of sodium borate, and stir until the mixture is cool.

iv. A formula1. Water, 34.6%, Borax, 1, methylparaben, 0.25, Light mineral oil, 50%, synthetic

beewax, 13, Glyceryl monostearate, 1, propylparaben, 0.15.32. Borax-beewax33. Gels/jellies

a. Jellies are water soluble bases prepared from natural gums such as tragcanth, pectin, alginates, boroglycerin, or from synthetic derivatives of natural substances such as methylcellulose and NaCMC.

b. Gels: semisolids consisting of dispersions of small or large molecules in an aqueous liquid vehicle rendered jelly-like through the addition of a gelling agent.

c. Single-phase gel:d. Carbomers: high Mw water soluble polymers of acrylic acid cross-linked with allyl ethers of

sucrose or pentaerythritol.

e. Two-phase system: magma/milk of magnesia/magnesia magma, a gelatinous precipate of magnesium hydroxide

34. Skin anatomya. Epidermis

i. 0.8 to 0.006 mm. ii. stratum corneum:

10 mm when dry, horny layer (10-20% moisture)

b. Dermisi. 3-5 mm

ii. a matrix of connective tissues woven fibrous proteins

iii. Nerves, blood vessels (< 0.2 mm deep), lymphatics c. Subcutaneous tissue

i. mechanical cushion, thermal barrier, energy storaged. Appendages

i. Sweat glandsii. hair follicles

iii. Sebaceous glandsiv. Nails

e. *note on topical drug delivery: Topical drug delivery includes dosing of drugs to the skin and other surfaces, such as eye, ear, nasal, rectal, and oral mucosal. Dermatology topical delivery is only dealing with skin. Skin is one of the largest organ of human body. It can protect the host against many different kind of external assaults, and is itself prone to many different damages. It is also a large immune system to combat microbial assaults by initiating immune responses. It is easily accessible, and could be a convenient route for drug delivery.

f. Functions of the skini. Mechanical function

1. mainly from the dermis and s.c. tissues

2. epidermis (minor) ii. Protective function

1. Microbiological barrier2. Chemical barrier3. Radiation barrier4. Heat barrier/temperature

regulation5. Immune response

iii.35. Five main target regions/sites in dermatology

a. Surface treatmenti. Camouflage, protective layer, insect repellent, antimicrobial/antifungal, Sunscreen

b. Stratum corneumi. Emollient, keratosis

c. Skin appendage

i. Acne, antibiotics, depilatory, antiperspirant, vaccined. Viable epidermis/dermis

i. antiinflammation, anesthetics, antihistamine, antipruritice. Systemic treatment

i. transdermal36. Acne

a. Acne vulgaris is a disorder of the pilosebaceous units.b. A plug of the pilosebaceous duct and follicle opening. c. Drugs have to get into the hair follicles and pilosabaceous unitsd. Acne is a disorder of the pilosebaceous units, mainly in face, hest, and back. The lesions usually

start as open or closed comedones, and evolves into inflammatory papules and pustules that can evolve into nodules and cysts. The definitions of all this terms are rather confusing. Please refer to the above website if you would like to get more information.

e. Acne is common in young people in the age of 12-24. In fact, over 85% of all people in the age of 12-24 are affected. It does occur in adults too.

f. P. acne hydrolyzes triglyceride to release fatty acids, which induce inflammatory responsesg. Comedone

i. Comedo (plural comedones)—A comedo is a sebaceous follicle plugged with sebum, dead cells from inside the sebaceous follicle, tiny hairs, and sometimes bacteria. When a comedo is open, it is commonly called a blackhead because the surface of the plug in the follicle has a blackish appearance. A closed comedo is commonly called a whitehead; its appearance is that of a skin-colored or slightly inflamed "bump" in the skin. The whitehead differs in color from the blackhead because the opening of the plugged sebaceous follicle to the skin’s surface is closed or very narrow, in contrast to the distended follicular opening of the blackhead

h. Pustulei. A dome-shaped, fragile lesion containing pus that typically consists of a mixture of white

blood cells, dead skin cells, and bacteria. A pustule that forms over a sebaceous follicle usually has a hair in the center. Acne pustules that heal without progressing to cystic form usually leave no scars. This photo shows pustules, papules and comedones on the face of an acne patient:

i. Papulei. A papule is defined as a small (5 millimeters or less), solid lesion slightly elevated above

the surface of the skin. A group of very small papules and microcomedones may be almost invisible but have a "sandpaper" feel to the touch. A papule is caused by localized cellular reaction to the process of acne. This photo shows papules and comedones on the face of an acne patient

j. Etiologyi. Increased sebum production

1. Androgens regulate sebum production. Testosterone converted to DHT, which induces sebaceous glands to increase in size and activity, resulting in increased amount of sebum.

ii. Abnormal clumping of epithelial horny cells in the pilosebaceous unit1. Horny cells usually sloughed off from epithelial lining of the pilosebaceous duct. 2. Retention hyperkeratosis (increased adherence and production of follicular

epithelial cells)iii. Presence of Propionibacterium acnes

1. P. acnes lipases break triglyceride to fatty acids, which are irritating, cause comedones, and result in inflammation.

iv. Assessment of acne severityGrade Qualitative description Quantitative description

I Comedonal acne Comedones only, < 10 on face, none on trunk, no scars, non-inflammatory lesion

II Papular 10-25 papules, mild scarring, inflammatory lessoin (< 5 mm)

III Pustule 25 pustules, moderate scarringIV Pustulocytic acne Nodules or cysts, extensive scarring,

inflammatory lessions . 5 mm. Cytic acne Extensive nodule/cysts

*self treatment with OTC agents is only okay for grade I

k. approaches to treatmenti. Increased sebum production

1. Testosterone converted to DHT, which induces sebaceous glands size and activity.

2. treatment goal: decrease the amount of sebum producedii. Abnormal clumping of epithelial horny cells in the pilosebaceous unit

1. Retenion hyperkeratosis2. treatment goal: Unblocking the sebaceous ducts

iii. Presence of Propionibacterium acnes1. P. acnes lipases break triglyceride to fatty acids, which are irritating, causing

comedones.2. Treatment goal: kill the bacteria

l. OTC acne productsi. Benzoyl peroxide

1. 2.5% to 10%2. Most effective OTC3. Kill P. acnes and irritant to increase epithelial cell turnover rate. 4. gel, cream, or lotion

ii. Salicylic acid1. 0.5-2%, irritant keratolytic agent, lotion, creams

iii. Sulfur, 3-8% combined with resorcinol 2%, or resorcinol monacetate 3%.1. keratolytic and antibacteria, color/odor

iv. Resorcinol1. 1-4%, keratolytic when combined with sulfur

m. Prescription acne productsi. Tretinoin (retin-A):

1. increase the turnover rate of nonadhering horny cells in follicles.2. Cream, gel, topical solution3. More effective agent for acne (very effective4. Increase hair growth

ii. Others1. Adapalene (Differin), Tazarotene gel and cream (Tazorac), antibiotics

(tetracyline, erythromycin, clindamycin, etc)iii. Isotretinoin (Accutane)

1. For severe racalcitrant nodulocytic acnes2. Decrease sebum and keratinization3. Reduce population of P. acnes4. Birth defect

iv.v.

37. Contact dermatitisa. Inflammation of the skinb. Irritant contact dermatitis

i. Caused by direct contact with the irritantii. Absolute primary irritants: acids, alkalis, industrial chemicals,

iii. Relative primary irritants: soaps, detergent, benzoyl peroxide, etc)c. Allergic contact dermatitis:

i. The result of direct contact with a contact allergen, such as poison ivy and nickel. Allergic contact dermatitis is considered a T-cell mediated delayed-response immune

reaction, because elicitation of an allergic reaction typically takes 48 to 72 hours to occur after reexposure to the same allergen.

ii. Etiology1. Hapten contacts skin epidermis2. Hapten complexes with protein3. Hapten-protein enters lymphatic systems4. Generation of specific Th1 CD4+ and CD8+ T cells.5. Re-exposure6. Dermatitis responses7. Urushiol from poison ivy, poison oak, and sumac.

a. Urushiol oil is presented in the roots, stems, leaves, and fruit. Burning plants can cause droplets of the oil carried by smoke to enter the respiratory system. Can even remain in toilet seat!

* Hapten = small molecules that are only antigenic when combined with a carrier protein.

iii. treatment1. Severe eruptions: systemic corticosteriods2. Less severe eruptions:

a. Relieve itching Local anesthetics (benzocaine) Antihistamines (oral or topical, mainly sedative effect) Topical hydrocortisone

b. Treatment Topical hydrocortisone.

For information about the transdermal drug delivery section, please see previous exams. You do not need to remember the equations for Log P and log S calculations. Do not need to remember the polymeric composition of different transdermal patches. Peneration enhancers (DMSO, water, Azone. Do not need to remember the types of transdermal device the transdermal patches mentioned.