Chapter 9-11

Question 1

Factors Determining the **Shape of Amphiphile aggregates **

Answer 1

i) Optimum head group area, a₀

a₀ controlled by:

• • repulsive forces: electrostatic or steric repulsion between the surfactant molecules
• • attractive forces: to minimize the contact area between hydrocarbon tails and water

ii) Critical chain length, lc
* lc - length of fully extended tail
iii) Hydrocarbon volume, v

• v - volume of the tail
• # of tails, side groups,

Question 2

Given different possible arrangements with comparable free energy, η_N,entropy will always favor what type of aggregate?

Answer 2

entropy will always favor the smallest aggregate.

Question 3

1. In order for the sphere to be physically possible, **the radius has to be **
2. Equations to determine the shape of a micelle. N? r? V? A? Sphere?
3. N_s for micelle (cone-spherical)? cylinder (cylindrical rods)? Vesicles? planar bilayer?

Answer 3

1. the radius has to be** less** than the Critical length, **r < lc **
2. Equations
   
   • spherical micelle of radius r containing N molecules . Its volume is V = (4/3) πr³ = Nv
   • The surface area is A = 4πr² = Na_o
   • N = 4πr²/a_o
   • r = 3v/a_o
   • Sphere v/(l_ca_o) =< 1/3
3. micelle ​​​N_s =0.33; Cylinder (cylindrical rods) N_s = 0.3-0.5; Vesicles N_s = 0.5-1 bilayer N_s = 1

Question 4

How do we calculate HLB value of a surfactant blend ?

Answer 4

HLBmix = [M1HLB1 +M2HLB2 +M3HLB3 +⋅⋅⋅] / M mix

Example:

1. Calculate the HLB for a 50/50 blend of steareth-2 (HLB = 4.9) and steareth-21 (HLB = 15.5)

HLB_mix = [M₁HLB₁ +M₂HLB₂] / M_mix= [50(4.9) + 50(15.5)] / 100 = 10.2

1. What is the HLB value of a surfactant system composed of 10g Span 60 (HLB = 4.7) and 20g Tween 60 (HLB =14.9)?

HLBmix = [M1HLB1 +M2HLB2 ] / Mmix= [10(4.7) + 20(14.9)] / 30 = 11.5

Question 5

An important property of micelles is their ability to

Answer 5

increase the solubility of sparingly soluble substances in water.

Micellar solubiliza,on is a powerful alterna,ve for dissolving hydrophobic molecules (e.g. drugs, oils) in aqueous environments

Question 6

Bolaform surfactants

Answer 6

• are amphiphiles with two head groups attached on both ends of a single hydrocarbon chain.
• Their unique structural features that can induce the head group interactions on both ends give them packing geometry very similar to others

Question 7

1) Bilayer - Formation
2) Bilayer - Forming Surfactants

Answer 7

1. bilayer formation is a thermodynamically driven process and the self-assembled bilayer is in equilibrium with its monomer.

Bilayer formation requires specific conditions that can ensure
- the increased hydrophobic interaction between surfactant hydrocarbon chains and/or

• the decreased repulsive interaction between **head groups. **
  2. Typical amphiphiles that can form bilayers and emulsions under the usual **conditions of low concentration and at low (or no) concentration of additional counterions. **
• **Most of them have two (or branched) hydrocarbon chains. **This structural characteristic helps them have bulky tail groups, which makes them suitable to fulfill the molecular packing requirement for the formation of a bilayer structure
  1. Bolaform surfactants
• Lamellar liquid crystals are a stacked form of extended bilayer self - assembled unit with one - dimensional symmetry.
• Bicontinuous cubic liquid crystals consist of a regularly curved bilayer unit (the secondary building unit) with clearly defined three - dimensional geometry.
• Amphipiles with narrow heads and long tails tend to form bilayers.

Question 8

Applications of Bilayer Systems

Answer 8

• Delivery systems
• Catalytic reaction such as self-replicating membranes
• Surface recognition of biomolecules
• Nanoscale reactors
• Model system for biological membranes

Question 9

Vesosome -

Answer 9

A large unilamellar vesicle with different sizes of smaller unilamellar vesicles inside.

Question 10

Liposome

Answer 10

which means “ fat body ” in Greek, refers to _vesicles that are composed solely of lipids (both natural and synthetic). _

• Lipids: Are a diverse group of organic compounds.

• **Neutral fats, phospholipids, cholesterol, steroids, waxes are all examples of lipids! **

Question 11

Niosomes

• Paclitaxel drug

Answer 11

are vesicles formed solely by nonionic surfactants.

Niosomes are the synthetic analog of liposomes in structure, but have generally more penetrating capability and physiochemical stability, less toxicity and improved therapeutic index for entrapped drugs.

Niosome have diameters of 100 nm – 2 μm, and there center is an aqueous cavity enveloped by layers of nonionic surfatant in lamellar phase.

• Paclitaxel Cancer drug: was successfully entrapped in all of the formulations prepared with various nonionic surfactants.

Question 12

Polymersomes

Answer 12

are nanostructures composed of amphiphilic block copolymers that have a size range from 50 nm to 5 μm and encapsulate drugs inside the vesicle membrane.

They are capable of encapsulating hydrophobic and hydrophilic drugs and they can be surface functionalized.

Polymersomes share many similarities with liposomes, but are more stable and less permeable to small water-soluble molecules than liposomes.

Question 13

Reverse micelle

Answer 13

Phase inversion of particle-stabilized emulsions from oil in water to water in oil can be achieved either by
variation of the particle hydrophobicity (transitional) or by variation of the oil/water ratio (catastrophic).

Question 14

Explain micellar solubilization $$$

Answer 14

An important property of micelles is their ability to increase the solubility of sparingly soluble substances in water.

Micellar solubilization is a powerful alternative for dissolving hydrophobic molecules (e.g. drugs, oils) in aqueous environments

Question 15

Micelle formation Kinetically vs thermodinamically. $$

Answer 15

1. thermodynamically driven process is: all about “if”
   
   • spontaneous, well - defined cmc (critical micelle concentration), finite size of self - assembled structures.
   • tells whether or not a process or a reaction can occur
     • applicable to systems in stable or metastable equilibrium
     • sufficient driving force is needed to enforce a favorable transformation,.
   • Many amphiphiles that can form typical micelles usually have an ability to form bilayers, liquid crystals, and emulsions.
2. kinetically driven or dependent on external energy input: All about “how”
   
   • Often does not show a clear-cut cmc, generate not-well-defined, sometimes infinite-size self-assembled structures
   • how fast or slow a process can occur, i.e., determining the rate applicable to systems in transition from nonequilibrium to equilibrium, or between two equilibrium states
     • kinetics of a process is generally about how to overcome the energy barrier to finish the transformation from the starting (reactant) state to the final (product) state.

Question 16

Describe the bilayer formation process. $$$

Answer 16

Bilayer formation is a thermodynamically driven process and the self-assembled bilayer is in **equilibrium with its monomer. **

Bilayer formation requires specific conditions that can ensure the increased hydrophobic interaction between surfactant hydrocarbon chains and/or the decreased repulsive interaction between head groups.

"”formation of bilayers, liquid crystals, and emulsions often involves a complex kinetically driven process, and ends up with much larger self - assembled aggregates than the usual micelles.”” (?)

Question 17

Bilayer self-assembly occurs because the ___________ ________ all point towards the _______________ ________, while the _______________ _______ try to avoid it $$

Answer 17

Bilayer self-assembly occurs because the _hydrophilic heads _all point towards the aqueous phase, while the hydrophobic tails try to avoid it

Question 18

Types of amphiphiles that form bilayers. $$

Answer 18

Most of them have two (or branched) hydrocarbon chains.
This structural characteristicc helps them have bulky tail groups, which makes them suitable to fulfill the molecular packing requirement for the formation of a bilayer structure.

1. Phospholipids
2. Bolaform surfactants

Question 19

Bolaform surfactants

Answer 19

are amphiphiles with two head groups attached on both ends of a single hydrocarbon chain.

Question 20

1) The thickness of the bilayer ranges
2) CMC values for bilayers is much _______ than for spherical micelles. Range?

Answer 20

1) 3 – 5 nm, and is always determined by the dynamic molecular length of monomers.

2) CMC values for bilayers is much lower than for spherical micelles (10 μM to 10 mM) and ranges from **10^-3 to 10^-10 mM. **

Question 21

What determines the unique planar-like structure of a bilayer ? $$$

Answer 21

The molecular geometry of its monomer, is what determines the unique planar-like structure of a bilayer

Question 22

What is the monomer exchange rate with bilayers

Answer 22

The monomer exchange rate with bilayers is on the order of 10⁻³ – 10² second, that is, bilayer dynamics are 2–5 orders of magnitude slower than those of micelles.

Thus, the lifetime of bilayers is much longer than that of micelles. Micelles experience constant formation/breakup on the order of **10⁻³ – 10⁻¹ second. **

Question 23

What is a vesicle?

Answer 23

A vesicle is a metastable suspension of spherical (globular) enclosed bilayers.

A basic structure of biological membranes is a bilayer of various **lipids with embedded proteins. **

Question 24

Applications of Bilayer Systems

-

Answer 24

• Delivery systems
• Catalytic reaction such as self-replicating membranes
• Surface recognition of biomolecules
• Nanoscale reactors
• Model system for biological membranes

Question 25

1) Vesicles packing geometry,

2) size and thickness $$

3) Vessicles are classified base on:
4) Vessicles classification groups (3)

Answer 25

1) Vesicles have a packing geometry slightly less than 1 for the outer layer and slightly more than 1 for the inner layer.
2) The size of vesicles can range from 20 nm – 50 μm in diameter, but the thickness of each single layer is limited to **3 – 5 nm. **

**3) Vessicles are classified base on: **their size - and - geometry (lipidic bilayers)

4) SUV: small unilamellar Vesicle
LUV: large unilamellar Vesicle >100nm
MLV: multilamellar Vesicle 100-1000 nm

Question 26

Vesicles are usually classified in three groups based on:

• their size
• geometry (lipidic bilayers)

Answer 26

1. SUV: small unilamellar Vesicle
2. LUV: large unilamellar Vesicle >100nm
3. MLV: multilamellar Vesicle 100-1000 nm

Question 27

Vesosome

Answer 27

• A large unilamellar vesicle with different sizes of smaller unilamellar vesicles inside.

Question 28

1) Liposome $$
2) Lipid
3) What type of molecules can form liposomes? &&

Answer 28

1) which means “ fat body ” in Greek, refers to vesicles that are composed solely of lipids (both natural and synthetic).
2) Lipid is a catch-all term for carbon-containing compounds that are found in organisms and are largely nonpolar and hydrophobic—meaning that they do not dissolve readily in water. Lipids do dissolve, however, in liquids consisting of nonpolar organic compounds.
3) Neutral fats, phospholipids, cholesterol, steroids, glycerolipids

Question 29

Polymersomes $$

1) What are they made of?
2) What are they used for?
3) Stability compared with liposomes.

Answer 29

are nanostructures composed of amphiphilic block copolymers that have a size range from 50 nm to 5 μm and encapsulate drugs inside the vesicle membrane.

They are capable of encapsulating hydrophobic and hydrophilic drugs and they can be surface functionalized.

Polymersomes share many similarities with liposomes, but are more stable and less permeable to small water-soluble molecules than liposomes.

Question 30

What is the main drawback of TDDS (Transdermal drug delivery system )?

Answer 30

The main drawback of TDDS is it encounters the barrier properties of the Stratum Corneum i.e. only the lipophilic drugs having molecular weight < 500 Da can pass through it .

Question 31

Ethosomes

Answer 31

• are the ethanolic phospholipid vesicles which are used mainly for transdermal delivery of drugs.
• Ethosomes are phospholipid-based elastic- nanovesicles containing a high content of ethanol (20–45%)
• Ethanol is known as an efficient permeation enhancer and has been added in the vesicular systems to prepare elastic nanovesicles.
• Ethanol can interact with the polar head group region of the lipid molecules, resulting in the reduction of the melting point of the stratum corneum lipid, thereby increasing lipid fluidity and cell membrane permeability.

Question 32

Transfersomes

Answer 32

Transfersomes® are a form of elastic or deformable vesicle, which were first introduced in the early 1990s.

Elasticity is generated by incorporation of an edge activator in the lipid bilayer structure.

By addition of at least one bilayer softening component (such as a biocompatible surfactant or an amphiphile drug) lipid bilayer flexibility and permeability are greatly increased.

Question 33

Phytosomes

Answer 33

Phytosome is a complex of a natural active ingredient and a phospholipid.

Question 34

Differences between Lyposomes and phytosomes

Answer 34

1. In liposomes no chemical bond is formed and the phosphatidylcholine molecules surround the water soluble substance.
2. In a liposome, the material is simply emulsified.
3. In phytosomes the phosphatidylcholine and the plant components actually form a 1:1 or a 2:1 molecular complex depending on the substance(s) complexes, involving chemical bonds.
4. This difference results in better absorption of phytosomes than liposomes showing better bioavailability.

Question 35

Lyposomes VS. phytosomes

Answer 35

1. In liposomes, the ingredients are dissolved in the central part of the cavity, with limited possibility of molecular interaction between the surrounding lipid and a hydrophilic substance.
2. In a Phytosome® the ingredient is dispersed into lecithin, a dietary surfactant and can be compared to an integral part of the lipid membrane.

Question 36

Cubosomes

Answer 36

Cubosomes are nanoparticles but instead of the solid particles, cubosomes are self- assembled liquid crystalline particles of certain surfactant with proper ratio of water with a microstructure that provides unique properties of practical interest.

Cubosomes consist of honeycombed (cavernous) structures separating two internal aqueous channels and a large interfacial area.

Question 37

Liposome vs Nanoemulsion vs Lipid nanoparticle

Answer 37

1. Liposome: lipid bilayer enclosing an aqueous core
2. Nanoemulsion: lipid monolayer enclosing a liquid-lipid core
3. Lipid nanoparticle: lipid monolayer enclosing a solid-lipid core

Question 38

Polymersomes

Answer 38

1. Polymersomes are nanostructures composed of amphiphilic block copolymers that have a size range from 50 nm to 5 μm and encapsulate drugs inside the vesicle membrane.
2. They are capable of encapsulating hydrophobic and hydrophilic drugs and they can be surface functionalized.
3. Polymersomes share many similarities with liposomes, but are **more stable and less permeable to small water-soluble molecules than liposomes. **

Question 39

Reverse micelles

Answer 39

Phase inversion of particle-stabilized emulsions from oil in water to water in oil can be achieved either by
variation of the particle hydrophobicity (transitional) or by variation of the oil/water ratio (catastrophic).

Question 40

Application of a liposome

Answer 40

LN (liposomal nanomedicines can be used to deliver cancer cell-killing drugs into tumours

Question 41

Emulsion

Answer 41

Emulsion – is a mixture of two or more liquids that are normally immiscible.

In an emulsion, one liquid (the dispersed phase) is dispersed in the other (the continuous phase)

Question 42

Emulsifying Agents

Answer 42

Emulsifying Agents are the substances added to an emulsion to prevent the coalescence of the globules of the dispersed phase.

These agents have both a hydrophilic and a lipophilic part in their chemical structure. (i.e. amphiphiles)

All emulsifying agents concentrate at and are adsorbed onto the oil:water interface to provide a protective barrier around the dispersed droplets.

In addition to this protective barrier, emulsifiers **stabilize the emulsion by reducing the interfacial tension of the system. **

Question 43

Classification of emulsions

Answer 43

1. Based on dispersed phase:
   
   • Oil in Water (O/W): Oil droplets dispersed in water
   • Water in Oil (W/O): Water droplets dispersed in oil
2. Based on size of liquid droplets:
   
   • 0.2 – 50 mm Macroemulsions (Kinetically Stable)
   • 5-200 nm Microemulsions (Thermodynamically Stable)

Question 44

Common Emulsifying Agents

Answer 44

1. Surfactants:
   
   • ​Anionic: sodium stearate, potassium laurate
   • Nonionic: polyglycol, fatty acid esters, lecithin.
   • Cationic: Quaternary ammonium salts
2. Solids: Finely divided solids with amphiphilic properties such as soot, ** silica, and clay. **
3. For microemulsion only surfactantas are know to be active as emulsifier.
4. For macroemulsion, a greater variety of components such as surfactants, polymers, and colloidal particles (or nanoparticle) can be active as emulsifiers.

Question 45

Bancroft’s rule for emulstions states:

Answer 45

​ “The phase in which an emulsifier is more soluble constitutes the continuous phase.”

1. In Oil in Water emulsions – use emulsifying agents that are more soluble in water than in oil (High HLB surfactants).
2. In Water in Oil emulsions – use emulsifying agents that are more soluble in oil than in water (Low HLB surfactants).

Question 46

What affects the type of emulsion?

Answer 46

1. the ratio of the oil to water(non-polar to polar)phase;
2. •the chemical properties and the concentration of the emulsification agent;
3. the temperature; the presence of **additives; **
4. for solid particles as the stabilizing agents (Pickeringemulsions) the wetting conditions (contact angles of the oil and water phases on the solid)

Question 47

Many synthetic and herbal drugs possess the problem of poor oral bioavailability, and the reason are: $$

Answer 47

• their very low water solubility
• poor permeation through the biological membrane.
• Poorly soluble drugs have suffered from low bioavailability and inefficacy in therapy due to their low dissolution profile in biological fluid.
• Without a proper level of drug concentration in the gastrointestinal (GI) fluid, the drugs cannot be effectively transported by the epithelia of the GI tract, resulting in **low systemic absorption. **
• Several plant actives in spite having potent in vitro pharmacological activities have failed to demonstrate similar in vivo response.

Question 48

although most bioactive molecules of plants are biologically polar or water-soluble, they are difficult to pass through the lipid-rich biological membrane and be absorbed by human, the reasons of which include: $$

Answer 48

1) large molecular weight,

**2) low lipid solubility **

The interaction had been atributed to formation of hydrogen bond and/or hydrophobic interaction between the two molecules.