Emulsions and Creams PDF

**Emulsions and Creams** **[Emulsions]** - Low viscosity resistance of flow disperse systems -- (% w/v) - O/W watery or W/O greasy - External application - Two immiscible phases 1) oil 2) water -- thermodynamically unstable + appropriate amount of emulsifier surfactants to stabilise...

**Emulsions and Creams** **[Emulsions]** - Low viscosity resistance of flow disperse systems -- (% w/v) - O/W watery or W/O greasy - External application - Two immiscible phases 1) oil 2) water -- thermodynamically unstable + appropriate amount of emulsifier surfactants to stabilise (≤ CMC) **What is an emulsion?** - An emulsion is a type of colloid small droplets of particle either liquid/solid - Colloids are macro-heterogeneous systems that are comprised of one substance dispersed in another - They are **[not]** solutions, the dispersed particles do not dissolve, but instead are dispersed or suspended through another substance - The dispersed particles may have at least one dimension in the order of [10^ − 9^]{.math.inline}m to [10^ − 6^]{.math.inline}m (1-1000nm) which is too small to see without a microscope - The dispersed substance is called the dispersed or internal phase, the material it is dispersed in is called the continuous or external phase - Depending on the physical state of the internal and external phases, determines the type of colloid. **Instability of Emulsions** kinetic processes - Once the water and oil have separated out, the substance is no longer an emulsion - 'Emulsion Stability' describes the length of time a mixture remains an emulsion before it separates out - To understand 'emulsion stability' we must first discuss what makes an emulsion stable - **Thermodynamic instability -** [*Δ***A**]{.math.inline} a. [*ΔA*]{.math.inline} is the surface area between two surfaces -- in this case between the oil and water b. To create an emulsion requires a large increase in surface area between the two phases c. Therefore [*ΔA*]{.math.inline} is always positive and large for emulsification or negative and large for separation - **Thermodynamic instability -** [*Δ***A**]{.math.inline} **and** [**γ**~AB~]{.math.inline} a. [*ΔA*]{.math.inline} and [*γ*~AB~]{.math.inline} together represent the forces that need to be overcome to create an emulsion b. To explain, energy is required to overcome the interfacial tension between the phases c. And, once the interfacial tension is overcome, more energy is required to create more surface area between the phases d. Together [*ΔA*]{.math.inline} and [*γ*~AB~]{.math.inline} represent the **[work needed]** (W) to create an emulsion with a certain droplet size, expressed in J \ [*W* = *γ*~AB~ *ΔA*]{.math.display}\ Emulsification -- the result of two competing processes that occur simultaneously 1. Requires energy input to disrupt the bulk liquids and form fine droplets - ↑ the free energy of system 2. Involves the coalescence of droplets - ↓ the interfacial area and minimize the free energy - **Kinetic instability** a. There are 4+1 processes of Kinetic instability: A diagram of a colloidal dispersion Description automatically generated - **Kinetic instability -- Creaming and Sedimentation** a. Creaming and Sedimentation are vertical process and are related: - Creaming: This occurs when the dispersed particles are not as dense as the continuous phase and they tend to rise to the surface to form an upper layer of cream (in o/w emulsion) → creamed emulsion can be restored but is undesirable because 1) the patient may receive an inadequate dose if the emulsion is not agitated sufficiently before use 2) the emulsion is inelegant To reduce creaming -- emulsions with small droplet sizes & thicken the external phase by the addition of viscosity modifiers - Sedimentation: Similar to creaming except for the fact the dispersed phase has a higher density compared to the continuous phase. The particles tend to settle to the bottom of the container under gravity and remain as discreet entities - Sedimentation and creaming occurs due to gravity. A difference in density between the phases will result in the less dense phase migrating above the denser phase. This results in an increase in concentration of the internal phase at the surface (creaming) or bottom (sedimentation) A white background with black text Description automatically generated- dissolve sugar to increase the density of continuous phase ㄴless creaming or sedimentation - V = the velocity of dispersed phase particle i.e. rate of sedimentation and creaming r = the radius of the particle, g = the acceleration due to gravity µ = the viscosity of the continuous phase gums or micelles ↑, viscosity ↑ ρC and ρD = respective densities of the continuous (C) and dispersed phases (D) - What does Stokes law tell us? I we have a creaming or sedementing formula what does Stokes law tell us we can do? - Size of internal phase particle is important -- as particle size ↑ rate of sedimentation or creaming ↑. So for **[increased stability]** the **[smaller particle size]** the **[better]**. Hence, any flocculation or coalesces will have an effect on rate of sedimentation or creaming - Rate of creaming and sedimentation is **inversely proportional** to viscosity of the continuous phase. As viscosity ↑, the rate of creaming or sedimentation ↓ - Viscosity is dependent on many things, including for most fluids, temperature - **Kinetic instability -- Coalescence and Flocculation** a. Coalescence and flocculation occur due to collisions of the dispersed phase droplets b. These collisions can result in: - Repulsion, droplets move apart again with no change to the colloidal state - Coalescence, where the droplets join to make a larger droplet, decreasing overall surface area of the colloid 1) the drainage of liquid films of continuous phase from between the oil droplets as they approach one another 2) become distorted 3) ends with the rupture of the film ㄴuse charged surfactants -- less likely to coalesce - Flocculation, where the droplets do not move apart but associate and move together through the colloid, but overall surface area remains the same c. Disproportionation is a process -- often referred to as Ostwald ripening -- that is dependent on the diffusion of disperse phase molecules from smaller to larger droplets through the continuous phase To reach the equilibrium 1) the small droplets dissolve 2) their molecules diffuse through the continuous P 3) redeposit onto larger droplets → overall increase in average droplet size d. It is driven by the phenomenon that smaller droplets have a higher internal pressure than larger droplets. As expressed in the Laplace equation:  e. Where, P is the Laplace pressure (different in pressure between inside and outside), [*γ*]{.math.inline} is the surface tension and r is the droplet radius **Stabilising Methods -- Emulsifiers** - Emulsifiers are surface active ingredients (surfactants) that migrate to the interface between the two phases → maintain the dispersion state of the emulsion for an extended time after the cessation of agitation - They have two effects on the system: a. Lowering the interfacial tension between the phases -- formation of droplets ↑, tendency for coalescence ↓ b. Creating repulsive forces between the internal phases particles to retard the rate of coalescence and flocculation - Creating a physical barrier to coalescence and flocculation by extending into the continuous phase. This stops collision by entanglement of the molecules 1) external (continuous) P -- thickened, viscosity ↑ 2) forms a rheological barrier 3) prevents movement ⇒ the close approach of droplets - Emulsifiers create a repulsive force by: a. Creating a surface charge on the surface of each droplet. This creates an electrostatic charge on the particles and the creation of an electrical double layer 1. Electrostatic repulsions -- o/w emulsion/stabilise by ionic EF 2. Steric repulsive forces -- hydrated polymer chains approach/dominate with non-ionic EF in w/o emulsion **Stabilising Methods -- Zeta potential** stabilised by a charged interfacial film/assessing instability due to flocculation - Crucially, as the particle moves through the continuous phase, the outer portion of the diffuse layer is in flux beyond the slipping plane. Meaning that the whole double layer still has an electric potential that extends into the continuous phase. This is commonly referred to as the Zeta potential - The higher the Zeta potential the more repulsive the particles are to each other -- stabilising the system - As a generalisation a [±]{.math.inline}30 mv is often cited as the threshold of colloidal stability - Above [±]{.math.inline}30 mv and the particles repel each other enough to maintain colloidal stability and below the repulsion is not enough to prevent particle collision - Remember this is only a measure of stability with respect to coalescence and flocculation **"↑ Z potential = ↑ repulsive F = ↑ stabilised system"** **Emulsion Rheology** Emulsion should possess shear thinning rheological characteristics appropriate to its intended use  - [*η*]{.math.inline} = viscosity of emulsion - [*η*~0~]{.math.inline} = viscosity of continuous phase - [*φ*]{.math.inline} = internal (dispersed) phase volume Ex) dermatological cream -- must be thin enough to spread easily onto skin / should rapidly regain structure (thick enough to remain in place on the skin after application) The rheological properties of emulsions are **influenced** by: 1. **Phase volume ratio** 2. **The nature of the continuous phase** 3. **Droplet size distributions** A variety of products ranging from mobile liquids to stuructued fluids and thick semisolids can be **formulated** by altering: 1. **The dispersed phase volume** 2. **The nature/concentration of the emulsifiers** ↓ Internal phase volume emulsion -- The consistency of the emulsion is similar to that of the continuous phase ⇒ W/O emulsions are generally thicker than O/W emulsions the consistency of o/w increased by **the addition of EF** such as gums, clays, polymers and other thickening agents which **impart plastic or pseudo-plastic flow properties** (accompanied by **thixotropy**) **AT REST --** high viscosity **inhibits** the movement of droplets/maintaining phisically **stable** emulsion **DURING USE** -- higher **shear rates** appliednon-aqueous* oil -- lungs (not for orally use) *continuous phase* - *May be **colloidal** (e.g. magnesium hydroxide often in colloidal range) or often a bit **coarser** (therefore gravity will have large impact)* - *Why have suspensions?* - *Difficulty in swallowing solid dosage formulations* - *Stability of drugs e.g. hydrolysis of drugs in solution* → more stable than in solution - *Taste-masking -- unpleasant tastes may be less noticeable in suspention than in solution (e.g. paracetamol)* - *High surface area* - *Main problems:* - ***[Sedimentation]*** → massive one ! \* Particle size reduction → stick tgt → sedimentation - ***[Caking]*** a. Caking **cannot be eliminated** by reduction in particle size, or by increasing the viscosity of the continuous phase -- these **delay** sedimentation and caking, but **do not prevent** it b. To prevent caking, we need to consider **flocculating agents** - ***[Flocculation]*** → re-control flocculation (tends to be a good thing, whereas caking is a bad thing) a. **Flocculating agents** act to **minimise the extent of caking** in a suspension b. Ideally, we want a **partially deflocculated** system - ***[Particle growth]** (dissolution and recrystallisation)* ***Types of Suspension*** - *Classified according to:* - *Dispersion medium: aqueous or oily* - *Formulation: flocculated or deflocculated* - *Stability of the drug:* a. *Ready to use Suspensions (stable drugs)* b. *Reconstituted powder (non-stable drugs)* - *Uses* a. b. *Oral* c. *Parenteral (injections)* d. *Topical preparations* e. *Ocular eye drops (hydrocortisone and neomycin)* f. *X-ray contrast media* ***Formulation of Suspentions -- Main stages*** - ***[Size reduction]*** difficult -- requires loads of energy *(coarse suspension \> 1*μ*m)* - *Large particles, if greater than about 5 μm diameter, will:* a. *Impart gritty texture to the product and settle quickly* b. *Cause irritation if injected or instilled into the eyes* c. *Block hypodermic needle (over 25μm) diameter particularly if acicular in shape rathe rthan isodiametric* - *Use a particular particle size range to control the rate of release of drug and the bioavailability* - *It is advantageous to use a suspended drug of **narrow size range*** a. *Polydispersed drug particle size may give very small crystals (\< 1μm) -- will exhibit a greater solubility thatn the larger ones.* b. *Thus, the small crystals will become even smaller while the larger particles will increase in size* - ***[Wetting]** (contact angle* hydrophilic -- low contact angle*, adsorption* particles got mixed *of surfactants)* - If the drug is water-insoluble, may add a wetting agent amphiphilic (both hydrophobic/hydrophilic) which breaks the interfacial tension energy barrier which prevents the liquid spreading around the solid, ensuring the solid particles disperse easily throughout the liquid ㄴIncreased wetting of hydrophobic drug particles → decrease in surface tension - Without a wetting agent, particles tend to cling to the container - ***[Controlled flocculation]*** no? sink & form a cake *(electrolyte -- valency, concentration) balance between attractive and repulsive forces* - ***[Examples of flocculating agents include:]*** a. *Electrolytes (sodium acetate, phosphate, citrate)* b. *Surfactants (ionic or non-ionic)* c. *Polymers (starch, alginates, cellulose deriivatives)* d. *Carbomers or silicates* - ***[Thicken product]*** - *If we increase viscosity (η) of the liquid phase, the rate of sedimentation is reduced* - ***[Examples of viscosity enhancing agents include:]*** a. ***Polysaccharides** (acacia, alginates, tragacanth, starch, xanthum gums)* hydrates polymers → increase viscosity b. ***Celluloses** (methylcellulose, hydeoxyethylcellulose, sodium carboxymethylcellulose)* c. ***Hydrated** **silicates** (bentonite, magnesium, aluminium silicate)* d. ***Carbomers** and **silicon** **dioxide** (aerosil)* - *We need to take care when using these -- if a suspension is very viscous, then it may have poor pourability* -- DON'T make it too thick ⇒ patients need to shake before administration - *Also although sedimentation is **delayed**, it is not **stopped**... so we need to consider using flocculating agents too in same cases* A white background with black text Description automatically generated - - **Will the sedimentation V go up if we:** a. Increase the radius of the particles b. Increase the density of the solid c. Decrease the density of the liquid d. Decrease the viscosity of the liquid - **or down if we:** a. increase the density of the liquid b. increase the viscosity of the liquid c. take the suspension to the moon HAHAHA no gravity ***\ *** ***Formulation of Suspensions -- Flocculated System*** - *In practice, avoid aggregation* try to control flocculation (loosely assemble)*/caking and adhesion of particle to vessel surfaces* - *Produce a **[flocculated]** system* a) add some polymer chains, b) manipulate zeta potential → close but not touching & hold tgt (small particles 서로 붙는 게 the worst -- Van der Waals force) - *A **[floc]*** sink *is a loose assembly of particles / Ideal suspension is partially (not fully) flocculated* - *A fully flocculated system:* - *Clear supernatant* clear solution → SHAKE the bottle when administer → floc break down & get the drug - *Large sediment volume* - *Rapid sedimentation* - *Easily redispersed* ***Flocculated Suspension*** where the particles exist as loose aggregates a. ***Clear** supernatant (no indiidual particles left)* b. ***Large sediment** **volume** -- bulky flocs (loose aggregates of particles)* c. *Loose clusters easily redispersed on **SHAKING*** d. *Reform and sediment* settle down ***rapidly** (**Stokes' law**)* → leads to liquid entrapment in the sediment, which tends to be fairly easy to redisperse - **Therefore, in pharmaceutics, flocculated suspensions are better than deflocculated ones** ***Deflocculated Suspension*** where the particles remain as separate units - *Fully deflocculated:* - ***Cloudy*** & uniform *supernatant (individual particles present)* - ***Small sediment volume** (cake formation)* - ***Slow** sedimentation (**small** particles -- **gravity** acts and pushes particles to bottom but some too small and **[remain suspended]**)* depends on the particle size, but generally slow → prevents liquid entrapment in the sediment, which becomes **[compact]** (**caked**) -- very hard to redisperse - *Difficult to redisperse (strong Van der Waals forces between closely packed particles)* A close-up of a yellow paper Description automatically generated - *Because of **[cake]*** smash the bottle or not break down *formation -- deflocculated systems are **no good** for pharmaceuticla suspensions* ***[\ ]*** ***[Flocculated vs. Deflocculated]*** ***Flocculated system*** ***Deflocculated system*** -------------------------------------------- ------------------------------------------------------------- *Loose aggregates of particles* *Particles exist as discrete units* *Large volume of final sediment (loose)* *Small volume of final sediment (compact)* *Rapid sediment rate* *Slow sediment rate* *Suspension clears quickly* *Susmpension remains cloudy for a prolonged period of time* *Entrapment of liquid within the sediment* *Liquid entrapment in the sediment is prevented* *Easy to redisperse sediment* *Difficult to redisperse sediment* ***[Partial flocculation]*** +-----------------------+-----------------------+-----------------------+ | | ***Advantages*** | ***Disadvantages*** | +=======================+=======================+=======================+ | ***Deflocculated | 1. *Slow | 1. *When settling | | systems*** | sedimentation | does occur, the | | | rate* | sediment is | | | | compact* | | | 2. *Enabling a | | | | uniform dose to | 2. *Difficult to | | | be taken from the | redisperse* | | | container* | | +-----------------------+-----------------------+-----------------------+ | ***Flocculated | 1. *Loose sediments | 1. *The | | systems*** | which are easily | sedimentation | | | redispersed* | rate is fast* | | | | | | | | 2. *A risk of an | | | | inaccurate | | | | dosage* | | | | | | | | 3. *The product | | | | would look | | | | inelegant* | +-----------------------+-----------------------+-----------------------+ - *A compromise is reached in which suspension is **[partially flocculated]** and **[viscosity is controlled]** so that the sedimentation rate is at **[a minimum]*** ***Electrical properties*** - *Most particles carry a surface charge -- due to ionisation* get -ve charged → **(put +ve electrolytes → bring them tgt)** repel each other → deflocculated system → sedimentation & cake *or adsorption* - *Charge influences distribution of ions in medium* - *Surface is **[negatively]** charged* achieved by the ionisation of water (H2O ↔ H+ + OH-) - *Cations in solution = **counterions*** - *Anions in solution = **co-ions***  A diagram of a chemical reaction Description automatically generated ***Zeta potential and stability of suspensions*** - *Most particles dispersed in water have **charge** -- either surface ionisation (depend on pH) or specific adsorption* - *Sets up **electrical double layer*** - *Magnitude of charge determined by **[microelectrophoresis]** (*movement *measures mobility of* charged *particle under applied elecric field)* - *Velocity of migration can be measured and zeta potential calculated* - As a generalisation a [±]{.math.inline}30 mv is often cited as the threshold of colloidal stability - Above [±]{.math.inline}30 mv and the particles repel each other enough to maintain colloidal stability and below the repulsion is not enough to prevent particle collision - *Changes in zeta potential on addition fo surfactants and electrolytes can be used to predict stability* - *Example -- bismuth subnitrate controls flocculation (Physicochemical Principles of Pharmacy)* ***Microelectrophoresis*** Microelectrophoresis - an overview \| ScienceDirect Topics **Modification of Zeta potential**  ***Formulation of Suspensions -- Flocculating Agents*** - ***[Surfactant]** (HLB 7-9) -- wetting / decrease interfacial tension between solid and liquid, displace adsorbed air* - *Adding a surfactant can neutralise the surface charge of a particle, and hence reduce repulsion between them* - *Use lowest concentration to produce wetting e.g. 0.1% w/v Polysorbates (tweens) or Sorbitan esters (spans). Considerations:* a. *Type* b. *Concentration* c. *Affinity for surface* d. *Molecular orientation* e. *Compatability* - *Surfactants sometimes used as flocculating agents -- e.g. kaolin & cationic surfactant* - *May get steric repulsion due to interaction fo projecting segments of adsorbed surfactant and associated water of hydration -- prevents particles from sticking together and may induce flocculation* - ***[Electrolyte]*** - *An increase in electrolytes (ounter anions) will:* a. *Increase the Debye--Hückel parametres (K)* b. *Decrease the thickness of the electrical double layer (1/k)* c. *Decrease Zeta potential i.e. reduces charge* d. *Increase the depth of the econdary minimum* e. *Mono or divalent -- less toxic e.g. sod phosphate, sod citrate* *⇒ Leading to... [FLOCCULATION]* - *For stability, the repulsive forces must be dominant* - ***Two** mechanisms that affect dispersion stabiltiy:* a. ***Steric repulsion** -- polymers adsorbing onto the particle and preventing the particle surfaces coming into close contact -- at those distances Van der Waals forces are too weak* b. ***Electrostatic or charge stabilization** -- this is the effect on particle interaction due to the addition of electrolytes* - ***Surfactant causing flocculation*** - *e.g. kaolin (slight -ve charge in water) and cationic surfacant (+ve head of surfactant adsorbs to -ve sites on particle)* - *Chain-chain interactions occur* - ***The Schultz-Hardy rule:*** - *Ability of an electrolyte to flocculate particles depends on the valency of ions* - *Trivalent \> divalent \> monovalent* - ***Polymers** -- e.g. starch or alginate* - *Chemical groups in the polymers interact with the surfaces of the particles* - *The free end of the polymers attaches to another particle. This gives **interparticle bridging**, leading to **flocculation*** - *If there are no other particles to interact with, the free end of the polymers coats the particle. This leads to restabilisation and a **deflocculated system*** - *So we need to **carefully control** the polymer concentration* A diagram of a bridging model Description automatically generated ***Quality Control*** - *Physical appearance* - *Particle size analysis* - *Ease of redispersal* - *F (sedimentaition volume ratio) =* [*V*/*V*~0~]{.math.inline} *where* [*V*]{.math.inline} *= final settled volume of sediment and* [*V*~0~]{.math.inline} *= total volume of suspension* - *Zeta potential* - ***[Rheology]** -- particles should remain suspended during storage. Higher shear rate conditions such as shaking and pouring require particles to be mobile* - *Ideally, a suspension will have the properties of:* 1. ***Redispersibility** (dispersed on gentle shaking)* 2. ***Homogenity** (constant particle sizes)* 3. ***Pourability** (easy to pour)* - *A flocculated system's structure breaks down on shaking, and reforms on standing (i.e. the viscosity of the system changes)* - *Shear rate thinning ro **[thixotropy]*** stay thick, but changes into liquid when shaking *(time dependant reversible loss of structure) are desirable qualities*