Midterm #2 Flashcards
Dispersed systems: Definition
- When one component is distributed more or less evenly throughout the second component
- Ex: Drug in solvent (or medium)
- Surfactants are often added
- Classified on particle size
Molecular Dispersion
- Ex: solutions
- Usually a molecule
- Diameter of particles <1.0 nm
Colloidal dispersion
- Ex: aerosol preparation
- dispersion of liquid or solid in gas
- inhalation solutions
- Fog (dispersion of liquid)
- Smoke (dispersion of solid)
- Diameter of particles: 1.0 – 500 nm
Coarse dispersion
- Ex: emulsions and suspensions
- Emulsion, oil dispersed in water (L/L)
- Suspension is (S/L)
- Diameter of particles: > 500 nm
- The sizes of dispersions are a range, there might be some overlap
Pharmaceutical significance of dispersions which are not solutions
- Solutions not always possible to formulate
- Insoluable
- Unstable
- Solutions not required
- Aesthetic reasons
- Prolonged effect
- Taste effect
- Targeting effect
Solutions not always possible to formulate
- Drugs that are insoluble
- Solution is not practical
- Can add surfactants to stabalize dispersion system
- Ex: Penicillin
- Not stable in aqueous solutions
- Hydrolysis
Solutions not required: Ointment or lotions vs. solution
- “aesthetic reasons”
- Solution not ideal for topical
- spread out everywhere
- Use emulsion products instead
Solutions not required: Prolonged effect
- Ex: procaine-penicillin
- IM suspension for injection
- 13-24 hours in plasma
Solutions not required: Targeting effect
- Ex: kaolin
- Clay that absorbs toxins
- Antidiarrehal
- Oral suspension
Solutions not required: Taste effect
- Ex: Cod Liver Oil
- coating of cod liver oil in emulsion mask the taste
Interactions in dispersed systems
- In order to understand how drug molecules are dispersed, we must first consider drug-medium interactions.
Interactions in dispersed systems: Two phases
- Ex: liquid-liquid; solid-liquid; gas-liquid
- Phase separation
Examples of Cohesive and Adhesive Forces
- Oil molecules
- van der Waals forces
- cohesive force
- H20 molecules
- Hydrogen bonding
- cohesive force
- Oil/Water
- adhesive force
Cohesive Force Definition
- interactions between like molecules
Adhesive Force definition
- interactions between unlike molecules
interaction between oil/H2O molecules
- little interaction
- no adhesive force
- oil pulls away from H2O and stay with other oil
- contact between oil and water is reduced as much as possible
- Cohesive force >>> adhesive force in this example…leads to no mixing
Cohesive and Adhesive and mixing
- If cohesive > adhesive: no mixing
- If adhesive > cohesive: mixing
- prefer this in pharmaceutical preparations
Interfacial tension: Definition
- owing to phase separation
- tension between any two separated phases
- the force acting at the right angles to a line 1 m in length along the interface
- Maintain the interface and keep the phases separated
- To mix, have to reduce the interfacial tension
Classification of Interphases: Gas/gas
- No interface possible
Classification of Interfaces: Gas/liquid
- Liquid surface, body of water exposed to atmosphere
Classification of Interfaces: Gas/solid
- Solid surface, table top (ex: table and air interface, typically aerosol)
Classification of Interfaces: liquid/liquid
- Liquid-liquid interface, emulsion
Classification of Interfaces: Liquid/solid
- Liquid-solid, suspension
Classification of Interfaces: Solid/solid
- Solid-solid interface
- powder particles in contact
Surface tension: Definition
- special type of interfacial tension
- referring to the tension between gas/solid or gas/liquid
- Water has the highest surface tension compared to any other pure liquids
Surface tensions of pure liquids and interface tensions against water: Trend
- Lower interfacial tension, more hydrophilic, due to molecular structure
Surfactants: Definition and AKA
- AKA: Surface active agents/amphiphiles
- substances that can spontaneously collect at interfaces of solids, liquids or gases
- thus lowering surface tensions or interfacial tensions
Surfactants Characteritic
- two distinct regions in their chemical structure
- hydrophilic and hydrophobic
- amphipathic molecules
Critical Micelle Concentration (CMC)
- When the concentration of a surfactant is greater than the concentration that can be accommodated by the surface or interface, micelles are formed
- This cut-off concentration is called the critical micelle concentration
- One application of surfactant is to help dissolve hydrophobic drugs in micelles formed by the surfactant
- adding surfactant could increase drug solubility in aqueous solutions
Plot of Surface Tension against Surfactant Concentration
- Surface tension decrease: @ some pt. surface tension does not change
- No room for surfactants to go to interphase
Micelle Solution
- Too hydrophilic, form micelle
- Too hydrophobic, completely dissolve in oil
- can form reverse micelle in oil phase
- trap a water molecule
- Micelle solution is not a true system
- it is a dispersion system
- cannot see with naked eye because transparent
Surfactant Classifications
- By the nature of the polar head
- Nonionic
- H2O insoluable
- H2O soluable
- Anionic
- Cationic
- Zwitterionic
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Nonionic Surfactants
- Most frequently used because
- Stable
- Low Toxicity
- (less toxic than others such as cationic surfactants)
- Compatible with most pharmaceuticals
H20 insoluble (hydrophobic) Surfactants
- Ex: Spans
- fatty acid esters of Sorbitan
- Sorbitan monolaureate (Span 20)
- Sorbitan trioleate (Span 80)
- Have hydrophilic region and a hydrophilic chain
- Example of nonionic surfactant
H20 soluble (hydrophilic) Surfactant
- Example of nonionic surfactant
- Ex: Tweens
- derived from spans by adding polar polyoxyethylene glycol chains to non-esterified hydroxyls
- Polyoxyethylene sorbitan monooleate (Tween 80), also known as polysorbate 80 (USP
Anionic Surfactant
- negatively charged polar head usually contains a carboxylate (soap) and a sulfonate
- Ex: Aerosol OT (bis (2-ethylhexyl) sodium sulfosuccinate)
- not stable at pH < 10 as they are weak acids and unionized fatty acid is formed at this pH
- weakly antibacterial
- laxative and unpleasant soapy taste
- incompatible with high concentration of electrolytes (salting out effect)
- R - C00- Na+, K+, NH4+ - H20 soluble – Soft soaps
- R - C00- Ca2+, Mg2+, A13+ - H20 insoluble – hard soaps
Cationic Surfactant
the positively charged polar head usually contains quaternary ammonium
- [R4 N]+ C1- e.g., alkyl substituted pyridinium chlorides such as benzalkonium chloride in contact lens solutions
- More often used as antibacterial preservatives than surfactants
- Could be used in emulsion skin preparations due to antiinfective properties. The suitable pH range is 4 – 6.
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Mixing Anionic and Cationic Surfactants
Anionic and cationic surfactants are generally incompatible and should not be mixed.
Zwitterionic Surfactants
- the polar head contains both positive and negative charges such as carboxylate (-), phosphate (-), quaternary ammonium (+)
- Ex: natural products such as protein, lecithin, gelatin, and phosphatidylcholine
Hydrophilic Lipophilic Balance (HLB) classification
- arbitrary scale of ratio of hydrophilicity to lipophilicity
- Greater HLB means a greater hydrophollicity
- The HLB value determines how a surfactant is used
- Solubilizing agents work at >CMC
- Detergents trap oil in micelles
Approximate HLB Values for a Number of Surfactants
- Can search for surfactants that have certain HLB values
- Span 85,b Arlacel 85b
- HLB: 1.8
- Span 80b
- HLB: 4.3
Pharmaceutical applications of surfactants
- Promote wetting by reducing the interfacial tension between liquid/solid
- Antibacterial or antimicrobial
- Stabilize colloids and foams
- Stabilize emulsions (will be taught in “Emulsions”)
Surfactants promote wetting
- reducing the interfacial tension between liquid/solid
- wetting of solid (e.g., zinc oxide) by liquid: in the preparation of a suspension, you would wet powders, otherwise powders will float.
- Void at surface of powder than are full of air. Surfactant introduces liquid into the void space
Degree of wetting by surfactants
- The degree of wetting is determined by the contact angle (theta) which is a measure of the solvent’s ability to wet a solid. For example, for contact lenses, you want maximum wetting.
- complete wetting: theta = 0°
- incomplete wetting: 0° < theta < 90°
- poor wetting: 90° < theta < 180°
- no wetting: 180 degree angle
what are other methods that could be used to increase wetting of powders?
- Ex: ethanol, because high affinity to hydrophobic powder
Antibacterial or antimicrobial property of surfactants
- Cationic surfactants such as benzalkonium chloride.
Surfactant Stabilize colloids and foams
- E.g., aerosol OT stabilizes foams when used in air-aerosol preparation. (Aerosol is a dispersion system with solid or liquid dispersed in air)
- Ex: Nasal spray; dip tube into the bottom of the bottle, liquid and vapor phase, also a propellant added in both liquid and vapor phase, When open valve, liquid is dispersed
- Foam: liquid that contains air, stabilize by increase concentration at liquid and air interface
Surfactant and Emulsions
- Stabilize emulsions
Emulsion: Definition
- at least two immiscible liquid phases, one of which is dispersed as globules (100 - 10,000 nm) in the other liquid phase
- If globules are small (10 – 100 nm), the emulsion is defined as a colloidal emulsion or microemulsio
Examples of pharmaceutical emulsions
- ointments, creams, lotions, liniments, vitamin E drop
- Most of pharmaceutical emulsions are with droplets > 500 nm
Components of Emulsions
- internal phase–dispersed, discontinuous, droplets, “the solute.”
- external phase–dispersing medium, continuous, “the solvent.”
- emulsifying agents–prevent droplets from contact or coalescing
- emulsions are dynamically unstable
Types of Emulsions
- Oil in Water (o/w) - oil as the droplets
- Water in Oil (w/o) - water as the droplets
Pharmaceuticl Significance: o/w emulsions
- water washable
- convenient method of administering water insoluble liquids/solids
- masks bad taste of oil-soluble drugs
- increase absorption of oil-soluble drugs
- increase stability of drugs which are easily hydrolyzed
Pharmaceutical use of o/w emulsion
- oral, parenteral (e.g., IM injection), and external (e.g., o/w emulsions are common for creams and lotions) use
- Ex: preparation of liquid paraffin, intralipid for total parenteral nutrition (for the delivery of oils and lipids)
- Ex: o/w emulsions as delivery vehicles for hydrophobic drugs.
Pharmaceutical Significance w/o emulsions
- convenient when administering water soluble liquids/solids
- increase efficacy of percutaneously applied drugs
- enables elegance and aesthetic appeal
Pharmaceutical Uses w/o emulsions
- used almost exclusively for external applications
- will remain on the skin longer and drugs in ointments take a longer time to be absorbed
- Such onintments are usually very moisturizing, and thus good for dry skin
- Note that both ointments and creams can be o/w or w/o
Theory of Emulsification and emulsifying agents
- ∆F = W = gammaSL • ∆A
- ∆F: surface free energy increase or the work done (W) to make an emulsion resulting in increase of surface area by 1m2.
- ∆A: increase in total surface area of droplets. ∆A = Atotal droplets – Ainterface
- GammaSL: Interfacial tension
- the lesser work done (W), the more stable the emulsion.
- spontaneous tendency for the droplets in an emulsion to coalesce so that ΔA is decreased and the emulsion reaches a more stable state.
- all emulsions are thermodynamically unstable systems
Emulsifying agents (E.A.s) act by
- gamma SL
- preventing droplets from coalescing - physical barrier
- surface charges cause repulsion between droplets
- Not all E.A. are surface active agents
Surface active agents (surfactants): what they do
- reduce interfacial tension, e.g. potassium laureate, Tweens
- form monomolecular layer around the dispersed droplets (physical barrier)
- may also cause surface charge if ionic surfactants are used
Surface Active Agents: Anionics
- e.g., K+, Na+, NH4+ salts of lauric acid and oleic acid
- Soluble in water
- form o/w emulsions
- Disagreeable taste and irritating to GIT (for external use only).
- Not stable at pH < 10
- divalent salts (Ca2+, Mg2+) are water insoluble and form w/o emulsions
When to determine whether on O/W or W/O emulsion will result
- hydrophilic SAAs (with higher HLB values e.g., HLB 9-12) result in O/W emulsions
- hydrophobic SAAs (with low HLB values e.g., HLB 3-6) result in W/O emulsions
- type of emulsion is a function of the relative solubility of the SAA, and the phase in which it is more soluble being the continuous phase
- rule of Bancroft
- explained by the coalescence kinetics of the two liquid phases when they are shaken in the presence of an emulsifying agent
- coalescence rate of oil globules or the coalescence rate of water globules
- depending on which rate is greater
Cationics SAA
- e.g., cethyltrimethylammonium bromide.
- A quaternary ammonium compound
- e.g., [R4N+]Br-
- generally weak emulsifiers
- used together with auxiliary emulsifying agents
- such as cetostearyl alcohol, fatty acids and fatty esters that can thicken emulsions (by increasing viscosity
- not very strong
- usually combined with other emulsifying agents
- do not mix with anions
- optimal pH range 4 – 6
Nonionic SAA
- e.g. Tweens, Myrjs (polyoxylethylene stearates
- often used in combination
- e.g. Tween 80 + Span 80
- stable to pH changes and electrolytes.
- most commonly used and compatible to most drugs
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Natural SAA
- Can form o/w or w/o emulsions
- Stable over a wide pH range
- Physical barrier
- O/W: acacia, gelatin (protein), and lecithin
- W/O: cholesterol and lanolin
hydrophilic colloids
- Acacia and gelatin
- multimolecular layers around the dispersed droplets of oil in o/w emulsion
- don’t lower surface tension much
Finely divided particles
- form a film of particles
- Physical barrier
- e.g. zinc oxide, graphite, and magnesium hydroxide
- powder wetted preferentially by water form o/w emulsions
- powders wetted preferentially by oil form w/o emulsions
- W/O: Calamine liniment (Calamine is a mixture of ZnO with 0.5% Fe2O3)
- O/W: Magnesia Magma • Mineral oil
To be effective, emulsifying agents must
have some solubility in both phases (cannot be exclusively soluble in one phase).
Type of emulsifying agents
- Surfactants
- Finely divided solid particles
- Hydrophilic colloids
- Auxiliary emulsifying agents
Methods for determining the type of unknown emulsions
- use water soluble dyes
- Ex: amaranth, a water soluble dye gives color to o/w emulsions, but not to w/o emulsions
- Oil soluble dyes would be used for w/o emulsions;
- dilute with the appropriate solvent
- water is added to w/o emulsions, it will not be mixed
- Oil mixes well
- measure conductance (based on the electrical conductivity of aqueous solutions)
- If the current is passed, it is o/w and if is not passed, it is w/o.
How to choose emulisifying agents
* hydrophilic emulsifying agent, if o/w
- hydrophobic emulsifying agent, if w/o
- often used in combination
- e.g. Na lauryl S04 + Stearyl alcohol in Hydrophilic ointment USP –caution incompatibility
- note instability of agents at various pH’s
- choose a nontoxic compound. Tweens and spans are not toxic.
- take care of taste
- take care of odor
- should be chemically stable.
Physical Stability of Emulsions
- important for maintenance of elegance, odor, color
- Physical instability caused by:
- movement of droplets increasing– creaming for O/W emulsions
- movement of droplets decreasing – sedimentation for W/O emulsion
- movements of droplets are reversible and can be reversed by shaking
Stokes Law
v=(d2(ps-po)g/18no =terminal velocity (cm/sec)
- d: diameter of droplet
- ps and po: densities of dispersed phase and dispersing medium, respectively
- g: gravitational force
- no: viscosity of dispersing medium
- To decrease V
- decrease d, make ps=po
- increase viscosity
- Hard to decrease d, so usually increase viscosity
Cracking of Emulsions
- aggregation and coalescence of droplets to form separate phases – cracking
- This process is irreversible.
Inversion of Emulsions
- Brought about by
- electrolytes
- ex:sodium stearate + CaC12 ® Ca stearate (lipophilic) make o/w go to w/o
- change in phase-volume ratio
- add water to w/o to get o/w
- best to make emulsions such that the dispersed phase (droplets) is not greater than 50% v/v
- electrolytes
Changing Temperature of Emulsions
- w/o at high temperature, but o/w at low temperature
- due to temperature-dependent changes in aqueous solubility of emulsifying agents
- Surfactants are associated with water (hydration)
- Dehydration will occur at high temperature and thus surfactants become less water soluble
- caution should be taken when a long-term storage of emulsions in a refrigerator is needed
Chemical Stability of Emulsions
hydrolysis; oxidation, etc.
Microbial stability of Emulsions
- add preservatives
- Ex: parabens – especially acacia containing emulsion
Emulsions Beyond Use Date
- In general, emulsions for internal use have 14 day beyond-use date
- External use products: 1 month beyond-use date
An example of emulsion
- Clobetasol propionate, a synthetic corticosteroid, for topical dermatologic use.
- Clobetasol ointment (w/o): each gram of the 0.05% ointment contains clobetasol propionate 0.5 mg in a base of propylene glycol, sorbitan sesquioleate, and white petrolatum (this is an oil base)
- Clobetasol cream is o/w emulsion with a water base
Wet gum (English) method of making emulsion
- oil added to water
- make mucilage by triturating 2 parts of water with one part of gum (e.g., acacia)
- add 4 parts of oil (and oil miscible ingredients) gradually in increments with trituration to form the primary emulsion
- then add water gradually to volume with trituration
- add ingredients miscible with external phase (water) before making up to volume
Example of a preparation of an emulsion by Dry gum (Continental) method
- the oil:water:acacia ratio (4:2:1) is the same as wet gum
- order of mixing acacia and oil is different for preparation of a primary emulsion
- dissolve or mix any necessary ingredients in oil
- mix 1 part of E.A. (acacia) with 4 parts of oil
- add 2 parts of water all at once while triturating rapidly until the primary emulsion is complete
- add external phase (water) and other water miscible ingredients gradually to volume while triturating
Suspensions: Definitions
Suspensions are liquid preparations that consist of solid particles dispersed throughout a liquid phase in which the particles are not soluble.
Oral Suspensions
- e.g., aluminum suspension as antacid, Tylenol suspension
- have already been prepared (ready-to-use), usually for stable drugs. A manufactured oral suspension should be used if available
- Oral suspensions for unstable drugs, e.g., penicillin are often available as dry powders and need to be reconstituted before use by adding vehicle
Topical suspensions
- application to the skin for a local effect
- which have already been prepared (ready-to-use), usually for stable drugs. A manufactured topical suspension should be used if available.
- Topical suspensions for unstable drugs are available as dry powders and need to be reconstituted before use. Some physicians like to create their own unique suspensions for patients with particular skin conditions
Sterile suspensions for injection
e.g., IM suspensions for penicillin.
Pharmaceutical significance of suspensions
- Easy use for patients (very sick patients, children and infants) unable to swallow solid dosage forms such as whole tablets or capsules.
- Making insoluble drugs palatable, e.g., pediatric suspensions with flavorings to mask disagreeable taste.
- Because bioavailability of drugs in a suspension is comparable to that in a solution, suspensions are often used as experimental formulations in new drug development.
- For aesthetic appeal, e.g., dermatological pastes.
- For prolonged therapeutic effect, e.g., IM suspensions of penicillin and insulin.
- For stability reason of certain drugs. Some drugs may be more stable when present as a solid, e.g., penicillin.
- Suspensions are much easier to prepare and use than solid dosage forms.
Formulation consideration and desired properties of suspensions
- Solid articles in suspensions should settle slowly (a physical stability issue)
- Suspensions should be easily resuspended by shaking:
- Chemical stability: For example, drug hydrolysis in water.
- Microbiological stability: Antimicrobial preservatives can be added if necessary.
- Physical changes:
- Wetting
Suspensions should be easily resuspended by shaking
- Solid particles in suspensions should not form a hard “cake” on the bottom of the bottle upon standing.
- Suspensions should not be too viscous so that redispersion is difficult.
- Suspensions are thermodynamically unstable, and therefore one aspect of physical stability of suspensions is concerned with keeping the particles uniformly distributed throughout the dispersion.
- two major physical stability considerations: 1) how to control sedimentation; 2) how to prevent particles from caking?
Sedimentation Rate of Suspension Manipulation
- Particle size (d) should be small enough
- achieved through choice of drug form and proper compounding equipments/techniques
- Particle size should not be too small (easy to cake) or too large (easy to settle).
- ps and po should be equal (ideally)
- the density of the vehicle can be increased by adding sucrose, glycerin, sorbitol or other soluble or water-miscible additives
- Glycerin has a density of 1.25, Syrup NF has a density of 1.313, and Sorbitol 70% has a density of 1.285.
- The viscosity (ηo) of the liquid may be increased to decrease the sedimentation rate (v) by adding a viscosity agent (e.g., structure vehicles).
Structured vehicles
- aqueous solutions of polymers
- pseudoplastic or plastic property, that is, the viscosity of the liquid can be decreased upon shaking, but the suspensions can maintain a high viscosity on standing, which is desired for pharmaceutical suspensions
- A dilatent fluid will increase its viscosity upon shaking (e.g., a cornstarch/water mixture). Such dilatent fluids should never be used in pharmaceutical suspensions.
- Polymers used as structured vehicles include sodium carboxymethylcellulose, acacia, tragacanth, and bentonite. Note some of such polymers are anionic, and thus not compatible with charged drugs.
Physical Changes of Suspensions
- Solid particles must remain unchanged in size and form. Crystal growth can lead to changes in particle size. Polymorphic, amorphous-to-crystalline, and degree of hydration of drugs can also change the form and size of particles.
- There should be no physical changes in other suspension ingredients (i.e., sugar crystallization). Crystallization should be prevented.
Wetting Suspensions
- If the liquid vehicle (e.g., glycerin) is one with a low surface tension, this is usually not a problem; the liquid can easily wet the solid.
- In most situations, water constitutes all or part of the dispersing vehicle. Since water has a high surface tension and does not easily wet many solids, especially hydrophobic drugs, we need to consider the following
- If the powders are hydrophilic, they will be wet easily by water or any other polar solvents. In this case, no special additives are necessary. Two common examples of such powders are ZnO and Calamine.
- If the powders are hydrophobic, either a water-miscible liquid with a low surface tension or a wetting agent must be added. Such water-miscible liquids include glycerin, alcohol, propylene glycol, or polyethylene glycol. The wetting agent can be a surfactant such as sodium stearate, sodium lauryl sulfate, docusate sodium, and Tween 80. Note that all additives must be approved for internal use if suspensions are to be used internally
Control of flocculation in suspensions
- prevent formation of a compact “hard” cake of particles that is difficult to redisperse
Attractive forces between particles in suspensions
- Van der Waals interactions or induced dipole-induced dipole interactions
- Dipole-dipole interactions
- Molecular bridging provided by including surfactants or polymers in suspensions
- Adsorption of surfactants and/or polymers onto surface of particles in suspensions causes molecular interactions between surfaces bearing adsorbed surfactants and/or polymers, with the relatively long carbon chains in surfactants or polymers.
Repulsive forces between particles in suspensions
- Electrical repulsion between particles carrying the same charges.
- Adsorption of ions present in suspensions onto surface of particles. The sources of ions can be impurities, ionic surfactants, and electrolytes.
- Ionization of molecules situated on the surface of particles, depending on pH and pKa values of the molecules.
Flocculated suspensions
- formation of light, fluffy groups of particles held together by attractive forces which are predominant
- present as large flocs and form loose scaffold-like structure.
- These particles settle rapidly because they form the large flocs, but do not cake, and can always be resuspened with gentle shaking as particles do not bond tightly to each other.
- clear supernatant boundary
Deflocculated suspensions
- repulsive forces between particles are predominate
- Particles repel and present as discrete, separate entities.
- Particles in deflocculated suspension settle very slowly as each particle settles separately and the size of particle is small, but ultimately form dense sediment (cake) which is difficult to resuspend.
No clear boundary after precipitation