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Advanced Pharmaceutics > Drug Solubilisation I > Flashcards

Drug Solubilisation I Flashcards

1
Q

What is a solution?

A

A system in which molecules of a solute (drug/ protein/ crystal etc.) are dissolved in a solvent vehicle.

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2
Q

Stages of solubilisation

A
  1. Solute or drug molecule removed from its crystal
  2. Cavity for the molecule created in the solvent
  3. Solute molecule inserted into this cavity
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3
Q

Factors effecting solubility of drugs in

formulation

A 
1. Nature of solvent/s
• Aqueous
• Organic
2. Size/shape drug molecule
3. Molecular weight
4. Temperature
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4
Q

Nature of solvent

• Polarity

A
  • Like dissolves in like
  • Non-polar drugs in non-polar solvents
  • Polar drugs in polar solvents
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5
Q
  1. Size/shape of drug
A

•In order to be solvated within a given solvent, its
molecules must first be able to be accommodated within
the cavities between the solvent molecules
• Therefore decreasing particle size will increase solubility

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6
Q

Noyes-Witney Equation: The rate of solution of solids

A

dw/dy = k(cs - c) where k = DA/o

dw/dt - rate of dissolution of solid
A – surface area of solid
c – concentration in bulk of medium
cs – saturation solubility of the dissolution layer
k – rate constant of dissolution
D – diffusion coefficient of dissolved solute
σ - thickness of diffusion layer

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7
Q

What would happen if you reduced the particle size (A)?

A

As A↑ then k ↑
resulting in dw/dt ↑

•If dissolution was rate limiting step in bioavailability then change in A (or cs) will result in change in bioavailability

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8
Q

Partition coefficient

A
  • In solution drugs can partition between two immiscible solvents relative to their concentration and affinity for each phase.
  • Partition coefficient (P)– measure of hydrophobicity of molecule

𝑃= Co/Cw

CO – concentration in oily (non-aqueous phase)
CW – concentration in aqueous phase

  • Useful for estimating distribution of drugs within the body
  • Higher value P, the greater the lipid solubility of the solute.
  • Often referred to in log form (logP)
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9
Q

Traditional excipients for drug solubilisation

A
  1. Surfactants
  2. Cosolvents
  3. Microemulsions
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10
Q
  1. Surfactants
A
  • Low molecular weight amphiphilic compounds
  • Hydrophobic regions usually consists of saturated or unsaturated hydrocarbon chains, heterocyclic or aromatic ring systems
  • Classified according to their hydrophilic group
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11
Q

Surfactant micelles

A

In aqueous environments surfactants spontaneously aggregate to form micelles. Type of intermolecular aggregation.

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12
Q

Critical micellar concentration

A

• Concentration above which micelles will be formed in solutions is known as the critical micellar concentration (CMC)

↓ CMC = ↑ micellar stability

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13
Q

• Factors effecting CMC:

A
  • Structure and nature of hydrophobic group
  • Addition of electrolytes
  • Temperature
  • pH
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14
Q

Examples of commonly used surfactants

A
  • Tweens e.g. Tween 80
  • Spans E.g. Span 80
  • Cremophor EL
  • Sodium docecyl sulphate (SDS)
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15
Q

Disadvantages of surfactants

A
  • Possess relatively high CMC values – unstable upon dilution resulting in premature drug loss
  • High excipient/drug ratio - low efficiency
  • High levels needed can cause safety concerns and can lead to unnecessary side effects
  • Oily/viscous solutions cause great patient discomfort upon administration
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16
Q
  1. Cosolvents
A
  • Where drug solubility in one solvent is limited, the presence of two solvents employed
  • Two miscible solvents mixed, one is water and one is a solvent the drug dissolves readily in.
  • E.g. polypropylene glycol, glycerine or ethanol mixed with water.
  • This method not preferred as residual organic solvents remain in formulation may be toxic to patient
17
Q
  1. Microemulsions
A
  • Microemulsions are liquid mixtures of oil, water and surfactants (or cosurfactants)
  • They are usually clear and are thermodynamically stable
  • Microemulsions are essentially swollen micellar systems
  • It is difficult to make clear a distinction between emulsification and solubilisation as there is a very gradual transition from one process to the other
  • At the transition to swollen micelles (also known as microemulsions) occur
  • The microdroplet size formed is usually less than 100 µm.
18
Q

Disadvantages microemulsions

A
  • High excipient:drug ratios
  • Costly
  • Viscous
  • Side effects
  • Low efficiency
  • Relatively low stability
19
Q

Advanced technologies for hydrophobic drug solubilisation

A

• Liposomes

Amphiphilic polymers
• Block copolymer
• Graft polymers
• Star shaped polymers
• Dendrimers

• Cyclodextrins

20
Q

Advantages of nano sized drug delivery systems

A
  • At such a small size, particles have the capability of showing a wide range of unique physical and chemical properties.
  • The exaggerated surface: volume ratio of nanoparticles makes them ideal for functionalization and specialization.
  • Nanoparticles can be fabricated through controlled synthesis enabling their physical properties such as size, shape, composition and other properties, to be tailor made.
  • The surface reactivity of nanoparticles can be modified by using a variety of functional groups giving them ‘intelligent properties’.
  • Nanoparticles injected systemically, can accumulate in the leaky microvasculature of tumour cells due the phenomenon known as the enhanced permeability and retention effect (EPR)
21
Q

What are liposomes?

A

• Liposomes are closed spherical vesicles consisting of an aqueous core surrounded by one or more concentrically arranged bilayer membranes.
• Membranes can be composed of natural or
synthetic lipid molecules
• Usually phospholipids are used to formulate liposomes, however a range of other polar lipids can be used.

22
Q

Liposomal structure

A
  • Liposome vesicles are composed of unilamellar or multilamellar lipid bilayers which have alternative aqueous layers sandwiched between the bilayers
  • Upon aggregation multilayered liposomes are formed however, these are easily converted to unilamellar entities by sonication
23
Q

Liposome Formation

A
  • To prepare liposomes energy has to be added to the system (forming lamellar and not micellar structures)
  • Driving force is interaction of aqueous regions and segregation of lipid regions from aqueous phase.
24
Q

Liposome formation dependant on:

A
  • Temperature
  • Lipid concentration
  • Electrostatic interactions of polar lipids with solvent and solute molecules
25
Q

Lipid morphology

A

• Shape of lipid is dependant on molecular shape of
constituent amphiphiles
• Shape expressed as its critical packing parameter (p)

p= v/ao lc
v – molecular volume of hydrophobic part of polar lipid
ao – surface area per molecule at hydrocarbon-water interface
lc – length of hydrocarbon region

26
Q

Lipid

Critical packing parameter

Shape

Structure formed

A
  • Single chain lipids with large head group areas e.g.. SDS
  • p < 1/3
  • Cone
  • Spherical micelles
  • Single chain lipids with small head group areas e.g. cetyltrimethylammonium bromide
  • 1/3 < p < 1/2
  • Truncated cone
  • Cylindrical micelles
  • Double chain lipids with large head groups e.g. phosphatidylcholine
  • ½ < p < 1
  • Truncated cone
  • Bilayer vesicles
  • Double chain lipids with small head groups
    e. g. phosphatidylethanolamine
  • p ~ 1
  • Cylinder
  • Planar vesicles
  • Double chain lipids with small head groups and unsaturated chain tails e.g. dioleoyl phosphtidyl ethanolamine
  • p > 1
  • Inverted truncated cone
  • Inverted micelles
27
Q

Commonly used lipids

A
  • Phospholipids e.g. phosphatidylcholines (Lecithin)
  • derived from both natural and synthetic sources
  • Commonly extracted from soya beans or egg yolks
  • Principle phospholipids used due to their relatively low costs, neutral charge and inert nature
  • As with surfactants the lipid head group determines the surface charge of the liposome
28
Q

Lipid tails

A
  • Determine the characteristics of the liposome system

* Carbon chain length and degree of unsaturation influences the transition temperature of the lipid

29
Q

Cholesterol

A
  • Commonly incorporated into lipid bilayer with hydroxyl group nearest to aqueous region and long steroid tail next to phospholipids
  • Influences freedom of movement of phospholipids
  • At high concentrations reduces bilayer permeability (hence reducing drug loss)
  • Has been shown to increase stability of liposomes in vivo
30
Q

Liposomes in drug delivery

A

•Hydrophilic or hydrophobic drugs can become
encapsulated inside the aqueous or lipid phase of
the liposomes respectively
• Liposomes can protect drug from degradation
• Change the biodistribution of drug by promoting passive targeting (EPR effect) or active targeting via
further surface functionalisation
•Drug release rate can be controlled via modification
of bilayer composition

31
Q

A few examples of liposome products

available

A

Doxil
Doxorubicin
80-100nm Pegylated distearoyl phosphotidyl ethanolamine, hydrogenated soy phosphatidyl choline and cholesterol
Advanced ovarian cancer, advanced breast cancer, AIDs related Kaposi’s sarcoma

DaunoXome
Daunorubicin
45nm Distearoyl phosphatidylcholine and cholesterol
Kaposi sarcoma

Mayocet
Doxorubicin 150-190nm
Egg phosphatidylcholine and cholesterol
First line treatment of metastatic breast cancer

Depocyt
Cytarabine
Multivesicle liposomes 3-30µm
Intrathecal treatment of lymphomatous

Advanced Pharmaceutics (5 decks)

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