Science of Medicines Flashcards
(214 cards)
1
Q
What is the difference between chemical and physical properties?
A
Physical properties are those that can be observed or measured without changing the composition of matter
E.g. melting point, density, solubility, Log P
Chemical properties describes a substance’s potential to undergo chemical change
E.g. flammability, reactivity, acidity
2
Q
Why do we need to understand the physical and chemical properties of a drug?
A
To identify and quantify the molecule
To understand drug action
To understand drug delivery
To assure product quality
3
Q
How do we measure the quality of a medicine?
A
Purity of drug
Purity of excipients
Phase behaviour
Phase characteristics (size, quantity, etc.)
Drug release
Drug absorption
Formulation stability
4
Q
What knowledge is required to understand different drug formulation properties?
A
Emulsion properties – intermolecular interactions, emulsion science
Emulsion stability – thermodynamics (energy favourability, phase separation)
Visual appearance – colloid science (particle size, light scattering)
Feel (e.g. texture, spreadability) – rheology (flow and deformation of matter)
Chemical stability – kinetics (rate of chemical degradation)
Physical stability – thermodynamics, kinetics and emulsion behaviour
Deposition on skin or mucosa – rheology (viscosity affects retention)
Drug release – diffusion principles
Absorption – biological absorption mechanisms (permeability, transport)
5
Q
What is an intermolecular force?
A
An attraction or repulsion between molecules that influences physical properties
6
Q
What are the different types of intermolecular forces?
A
Coulombic/Electrostatic interactions
Hydrogen bonding
Van der Waals forces
* Dipole-dipole interactions
* London dispersion forces
Hydrophobic interactions
7
Q
What are coulombic/electrostatic interactions?
A
The force between between charged particles:
* Like charges (both positive or both negative) repel each other
* Opposite charges attract each other
The closer and more highly charged the particles are, the stronger the interaction
8
Q
How does the strength between ions change when they are in a solid crystal (in the air) compared to a solution (in water)?
A
In a solid crystal (air) forces are stronger due to lack of shielding and close packing
In solution (e.g. water) forces are weaker because water molecules shield charges and allow greater separation between ions (screening)
9
Q
What is the relevance of coulombic/electrostatic interactions to pharmacy?
A
Solubility
* charged drugs will interact favourably with water because of electrostatic interactions between charges and water dipoles
Binding
* electrostatic interactions between charged drugs and oppositely charged sites at the target receptor/enzyme will result in very strong binding
Salt formation for drug formulation
Stability of dosage forms (e.g. emulsions, suspensions)
Absorption
* charged drugs will not easily cross lipidic cell membranes
10
Q
What are Van der Waals interactions?
A
Dipole-dipole:
* Attractive forces between polar molecules due to their permanent dipoles
London Dispersion Forces:
* Attractive forces between temporary dipoles induced by temporary fluctuations in electron distribution within molecules
11
Q
What factors affect Van der Waals interactions?
A
Molecular size
more electrons → stronger temporary dipoles → stronger dispersion forces
Molecular shape
Long, flat or linear molecules have greater surface area for contact, enhancing Van der Waals forces compared to compact, spherical or branched shapes
12
Q
What are hydrogen bonds?
A
A type of strong dipole-dipole interaction between a hydrogen atom (attached to N, O or F) and an electronegative atom
The hydrogen bond donor provides the hydrogen atom involved in the bond
The hydrogen bond acceptor accepts the hydrogen atom in the hydrogen bond + provides lone pairs of electrons to interact with the hydrogen, forming the ‘bond’
13
Q
What are hydrophobic interactions?
A
Tendency of non-polar molecules or regions to aggregate in aqueous environments
14
Q
Why are intermolecular forces relevant to Pharmacy?
A
The efficacy of a drug is determined by how strongly it interacts with the target
The ability of a drug to go across a cell membrane is controlled by the interaction of the drug and the molecules that make up the membrane
Drug formulation relies on the interactions between the drug and the molecules that make the drug carrier (excipients)
During tablet making, flowability and compaction depends on interactions between particles
15
Q
What is potential energy (U)?
A
The stored energy an object has due to its position, condition, or configuration
It represents the energy an object can release or convert into kinetic energy
Units = Joules (J)
E.g.
* An object held at a height has gravitational potential energy
* While a compressed spring stores elastic potential energy
16
Q
What is the relationship between force and potential energy?
A
Force pushes or pulls things toward where they have less potential energy
Force is the negative gradient of potential energy with respect to distance
F = - dU/dr
Where:
* F = force
* U = potential energy
* r = distance
17
Q
What is the relationship between potential energy and intermolecular forces?
A
Intermolecular forces arise from changes in potential energy between molecules as their distance varies:
When molecules are far apart, they have higher potential energy because they aren’t interacting strongly (i.e. haven’t “released” stored energy by coming together)
As they move closer, attractive intermolecular forces pull them together, lowering their potential energy
Analogy: As two magnets move closer, the magnetic force pulls them, and the stored potential energy is released, turning into motion or kinetic energy, lowering the overall energy of the system
When molecules get too close, repulsive forces kick in and the potential energy increases again
Molecules tend to settle at a distance where attraction and repulsion is balances and potential energy is miniised
18
Q
Why is there repulsion when molecules get too close?
A
Because of overlapping orbitals - due to the Pauli exclusion principle, which prevents electrons from occupying the same space
19
Q
How to interpret the potential energy curve
A
The y axis of the curve represents potential energy (U)
* Positive values of potential energy indicate repulsion
* Negative values of potential energy indicate attraction between the particles
The 𝑥 axis represents the distance (r) between two particles
* As we move leftward (←), the particles are getting closer together
* As we move rightward (→), the particles are moving farther apart
20
Q
Describe the potential energy curve.
A
At large distances:
* Curve is flat and near zero
* Molecules are far apart → no significant interaction
As distance decreases:
* Curve slopes downward
* Indicates increasing attraction between molecules
Minimum point (well):
* The lowest point of the curve
* Represents the equilibrium distance where attraction and repulsion are balanced
* Potential energy → stable
At short distance:
* Curve rises very steeply
* Reflects strong repulsion due to electron cloud overlap
* High potential energy → unstable configuration
21
Q
Describe the potential energy curve.
A
The curve starts at a high positive value on the left side, indicating strong repulsive forces when particles are extremely close together (small distance, r). The potential energy is high because the particles cannot occupy the same space.
As the distance between the particles increases (moving to the right on the x-axis), the curve begins to dip down to a negative value, reflecting the decrease in potential energy due to the attractive forces between the particles
As distance continues to increase, the curve reaches its lowest point - the minimum value of potential energy. This point indicates the optimal distance between the two particles, where the attractive and repulsive forces balance each other out. At this equilibrium distance, the system is most stable.
As distance increases further, the potential energy gradually approaches zero, indicating very weak attractive forces.
At large distances, the curve flattens out and approaches zero, which means that there is minimal interaction between the particles.
22
Q
What is the hard sphere potential model?
A
Describes particles as solid spheres which do not interact until they collide, at which point they are repelled
When r > d, U = 0
When r ≤ d, U = ∞
Where:
* U = Potential energy
* r = distance
* d = sum of their radii
When particles are farther apart than their combined radii, they do not interact or exert any force on each other
When particles are at a distance less than or equal to the sum of their radii there is infinite repulsion - i.e. the particles can’t overlap/occupy the same space/pass through each other
23
Q
What is the the Lennard-Jones potential model?
A
It describes particle behaviour as:
At large distances
as distance (r) increases, the attraction between particles decreases, becoming very weak
At short distances
* as distance (r) decreases, the repulsive force becomes dominant, preventing the particles from overlapping
* as particles get closer, potential (U) rises steeply
At intermediate distances:
* there is an optimal separation (r≈σ) where the potential is at its minimum, representing the most stable configuration
* balance between attractive and repulsive forces
24
Q
How is the Lennard-Jones potential more realistic than the hard-sphere potential?
A
It accounts for both repulsion at short distances and attraction at longer distances, unlike the hard-sphere model which only accounts for repulsion
25
What is Gibbs phase rule?
F = C − P + 2
Where:
* F = number of degrees of freedom in the system
* C = number of components
* P = number of phases present
26
What is the number of degrees of freedom (F) ?
How many independent/intensive variables (e.g. temperature, pressure, concentration, density, etc.) you can change without changing the number of phases in the system
27
What is the number of components?
How many different substances are in the system
28
What is the difference between intensive and extensive properties?
Intensive properties do not depend on the amount of substance
E.g. temperature, pressure, density
Extensive properties depend on the amount of substance
E.g. mass, volume, internal energy
29
What is the first law of thermodynamics?
The law of the conservation of energy
Energy cannot be created or destroyed, only transferred or converted from one form to another
The internal energy of an isolated system is constant
A totally isolated system (i.e. one that cannot exchange heat or interact mechanically to perform work) cannot experience a change in its internal energy
30
What is internal energy?
The total energy contained within a system - i.e. the sum of all kinetic and potential energy
ΔU = Q + W
Where:
* ΔU = change in internal energy of the system (J)
* Q = heat (added to the system)
* W = work done
If a system releases energy to the surroundings, ∆U is negative
31
What are the properties of internal energy?
An extensive property
* it depends on the total amount of matter in a system
* the more mass or volume a system has, the more internal energy it can store
* molar internal energy (Um) is an intensive property
A state function
* depends only on the current state of the system, not on the path or process by which the system arrived at that state
* depends only on the system’s initial and final states, not on how the system got there (regardless of any intermediate steps)
* ΔU(reaction) = ΔU(products) – ΔU(reactants)
32
What is enthalpy (H)?
The total heat energy of a system that is at constant pressure
Describes the energy change associated with a reaction in an open system at constant pressure
∆H = q (at constant pressure)
∆H is positive when heat is supplied to the system - Endothermic
∆H is negative when heat is released from the system - Exothermic
Extensive property
Needs to be expressed per mole of the limiting reagent (ΔH = q ÷ moles)
State function (Hess's Law)
ΔU(reaction) = ΔU(products) – ΔU(reactants)
33
What is heat capacity (C)?
The amount of energy as heat (dq) that a material or body must absorb for its temperature to increase by (dT)
C = dq/dT
Extensive property - i.e. depends on the amount of material present
34
What is molar heat capacity (Cm)?
The amount of heat energy required to raise the temperature of 1 mole of a substance by 1 degree Celsius (°C) or 1 Kelvin (K)
Intensive property
Cm = c × M
Cm = C/n
35
What is specific heat capacity (c)?
The amount of heat energy required to raise the temperature of 1 kilogram of a substance by 1 degree Celsius (°C) or 1 Kelvin (K)
Intensive property
q = mcΔT
Where:
* q = heat energy (J)
* m = mass of the substance (kg)
* c = specific heat capacity (J/kg/°C)
* ΔT = change in temperature (°C or K)
36
How do you calculate the enthalpy change for a reaction?
1. Calculate the energy change for the reactants, using q = mcΔT
2. Identify the limiting reagent and calculate the number of moles
3. Calculate the enthalpy of reaction per mole (ΔH = q ÷ moles)
37
What is entropy (S)?
A measure of disorder or randomness
The more disordered a system is, the higher its entropy / When a system becomes more disordered or random, the entropy of the system increases
It is the driving force for processes to occur
38
What factors increase entropy?
Thermal energy
Changes of state (solid → liquid → gas)
Expansion of gases
More molecules produced in a reaction
39
What is the second law of thermodynamics?
The entropy of the universe or an isolated system always increases during a spontaneous process or remains constant
ΔS universe/total = ΔS system + ΔS surroundings ≥ 0
40
What happens to the total entropy during reversible and irreversible processes?
Reversible processes:
* System is in equilibrium with surroundings
* The total entropy always remains constant
* ΔS universe = 0
* Very slow
Irreversible processes:
* The total entropy always increases
* ΔS universe > 0
41
What happens to entropy during phase transition?
Melting (solid to liquid) → entropy increases
Vaporisation (liquid to gas) → entropy increases
Condensation (gas to liquid) → entropy decreases
Freezing (liquid to solid) → entropy decreases
42
What happens to entropy during melting?
As a solid melts, its ordered molecular structure breaks down into a less ordered liquid state. This increases the system's entropy
∆S = ∆H fusion ÷ T
Where:
* ∆H fusion = enthalpy of fusion (melting)
* T = melting point
Enthalpy of fusion is always endothermic, so ∆S fusion is always positive
43
What happens to entropy during vaporisation?
When a liquid evaporates into a gas, the molecules move more freely and become much more disordered, resulting in an increase in entropy
∆S = ∆H vaporisation ÷ T
Where:
* ∆H vaporisation = enthalpy of vaporisation
* T = boiling point
Enthalpy of vaporisation is always endothermic, so ∆S vaporisation always positive
44
How does entropy change when a perfect gas expands/contracts?
During gas expansion (Vf > Vi), entropy increases (∆S > 0) because molecular disorder increases with greater volume
During gas contraction (Vf < Vi), entropy decreases (∆S < 0) because molecular disorder decreases with smaller volume
∆S = n R ln (Vf / Vi)
Where:
* Vf = final volume
* Vi = initial volume
* n = number of moles
* R = gas constant (8.314 J/K/mol)
45
How does entropy change with temperature?
Increasing temperature → increases molecular motion → increases randomness → increases entropy
Entropy increases more significantly at lower initial temperatures, because molecules start with less energy, so added thermal energy causes a more substantial increase in motion and disorder
At higher initial temperatures, molecules are already moving energetically, so while the entropy still increases with temperature, the increase is smaller compared to lower temperatures because the system is already in a disordered state
46
What is standard entropy?
The entropy of 1 mole of a substance at standard conditions (298K and 100kpa/1bar/1atm)
State function
∆S°reaction = Σ∆S°products - Σ∆S°reagents
47
What is the third law of thermodynamics?
The entropy of a perfectly crystalline material is zero when temperature is 0K
48
What is Gibbs free energy (G)?
The maximum amount of useful work a system can perform at constant temperature and pressure
G = H - TS
Where:
* G = Gibbs free energy
* H = Enthalpy
* T = Temperature (K)
* S = Entropy
49
Change in Gibbs free energy (∆G)
Describes the spontaneity of a process
∆G = ∆H - T∆S
At constant temperature and pressure, no changes in H are possible, so:
∆G = -T∆S
If ΔG < 0 the process is spontaneous
If ΔG > 0 the process is non-spontaneous
If ΔG = 0 the system is at equilibrium
50
How can the Gibbs free energy equation be represented graphically?
Plot ΔG on the y-axis vs T on the x-axis
ΔG = −ΔST + ΔH
y = mx + c
Y-intercept (c) = ΔH
Gradient (m) = –ΔS
Can calculate the minimum temperature at which a reaction becomes feasible by equating to zero and solving for T:
T = ΔH / ΔS
51
Does a negative ∆G guarantee a reaction/process will occur?
A negative ∆G indicates that it is favourable/can happen but there is still a possibility that the reaction/process will not occur or will occur so slowly that effectively it doesn’t happen
Kinetics also plays an important role (e.g. high activation energy needed)
52
How do changes in enthalpy (ΔH) and entropy (ΔS) determine the spontaneity of a reaction?
When:
* ΔH < 0 (negative) + ΔS > 0 (positive) → Spontaneous at all temperatures (ΔG < 0)
* ΔH > 0 (positive) + ΔS > 0 (positive) → Spontaneous at high temperatures (TΔS is large)
* ΔH < 0 (negative) + ΔS < 0 (negative) → Spontaneous at low temperatures
* ΔH > 0 (positive) + ΔS < 0 (negative) → Non-spontaneous at all temperatures (ΔG > 0)
53
What is Gibbs free energy of formation?
The change in free energy when 1 mole of a compound is formed, under standard conditions from its constituent elements in their standard states
State function
∆G°reaction = Σ∆Gf°products - Σ∆Gf°reagents
54
What is the equilibrium constant (K)?
The ratio of the concentrations (or partial pressures) of products to reactants at equilibrium for a given chemical reaction at a specific temperature
Kc = [C]^c [D]^d / [A]^a [B]^b
Where:
* [C] and [D] = concentration of products
* [A] and [B] = concentration of reactants
* a, b, c and d = the stoichiometric coefficients from the balanced chemical equation
OR
Kp = (PC)^c (PD)^d / (PA)^a (PB)^b
Where:
* PC and PD = partial pressures of the products
* PA and PB = partial pressures of the reactants
* a, b, c and d = the stoichiometric coefficients from the balanced chemical equation
55
What does a high value of K indicate?
The equilibrium lies to the right
Forwards reaction is favoured
High concentration of products
56
What does a low value of K indicate?
The equilibrium lies to the left
Backwards reaction is favoured
Low concentration of products
57
What is the relationship between Gibbs free energy and equilibrium?
∆G° = - RT lnK
Where:
* ΔG° = standard Gibbs free energy change of the reaction
* R = universal gas constant (8.314 J/mol/K)
* T = temperature (K)
* K = equilibrium constant at that temperature
If ΔG° < 0, then K > 1, meaning the products are favoured at equilibrium
If ΔG° > 0, then K < 1, meaning the reactants are favoured at equilibrium
If ΔG° = 0, then K = 1, indicating an equal balance of reactants and products (equilibrium)
Can be used to to predict the equilibrium constant
(K) from tabulated ∆G° values without performing
an experiment
58
How is rate of reaction measured?
Change in concentration
* change in concentration of reactants or products with respect to time
* for reactants: titration, spectroscopy, conductivity
* for products: gas volume, weight
Change in physical properties
* color change
* temp change
Time to completion
Rate laws and kinetics
* initial rate method
* integrated rate laws
59
How do you calculate the instantaneous rate of a reaction?
The instantaneous rate of reaction at any time t is given by the gradient of the curve at that time
Need to draw a tangent to the curve and calculate the gradient
60
What factors affect the rate of a reaction?
Concentration
Temperature
Pressure
Surface area
Catalysts
61
What is a zero-order reaction?
The reaction rate remains constant, irrespective of concentration
Units = conc·t⁻¹
Rate law:
v = k
Integrated rate law:
[A] = [A]₀ - kt
Conc. vs time graph:
Straight line with negative gradient
Rate vs time graph:
Horizontal line (constant)
62
What is a first-order reaction?
The rate is directly proportional to the concentration of one reactant
E.g. SN1, E1, radioactive decay
Units = t⁻¹
Rate law:
v = k[A]
Integrated rate law:
[A]t = [A]₀ e^(-kt)
ln[A] = ln[A]₀ – kt
Conc. vs time graph:
Exponential curve
ln[A] vs time graph:
* Straight line with negative gradient
* Gradient = -k
* y-intercept = ln[A]₀
Rate vs time graph:
Straight line with positive gradient
63
What is a second-order reaction?
The rate is directly proportional to the square of the concentration of one reactant
Units = conc⁻¹·t⁻¹
Rate law:
v = k[A]²
Integrated rate law:
1/[A]t = 1/[A]₀ + kt
Conc. vs time graph:
* Exponential curve
* Steeper than first-order
1/[A]t vs time graph:
* Straight line with positive slope
* Gradient = k
* y-intercept = 1/[A]₀
Rate vs time graph:
Upwards curve
OR
The rate is directly proportional to the product of two reactant concentrations
E.g. SN2, E2, Nucleophilic Addition-Elimination
Units = conc⁻¹·t⁻¹
Rate law:
v = k[A][B]
Integrated rate law:
ln ([A]₀[B]t / [B]₀[A]t) = ([B]₀ - [A]₀)kt
ln ([A]₀[B]t / [B]₀[A]t) vs time graph:
* Straight line with positive slope
* Gradient = k([B]₀ - [A]₀)
64
What is a pseudo first-order reaction?
A reaction that appears first-order because one reactant is in large excess and its concentration remains effectively constant. The rate of reaction depends on the concentration of the limiting reactant
Rate law:
v = k[A][B]
If B is in excess [B] ≫ [A]
v = k'[A]
65
What is a pseudo-zero-order reaction?
The rate of reaction remains constant and independent of the concentration
Generally occurs when there is:
* Saturation of a catalyst
* Saturation of an enzyme
* Constant supply of reactant
66
How do you determine the order of a reaction?
Method of initial rates:
* Measure how the initial rate changes as the concentration of one reactant is varied while others are kept constant
* Use the rate law to solve for the order
Graphical method:
* For a zero-order reaction = the plot of [A] vs. time is linear
* For a first-order reaction = the plot of ln[A] vs. time is linear
* For a second-order reaction = the plot of 1/[A] vs. time is linear
- The gradient of plot of ln(t1/2) vs. ln[A]₀ is 1-n, where n is the order of the reaction
Half-life method:
* If the reaction is zero-order = half life increases with increasing [A]
* If the reaction is first-order = half life is constant, regardless of the concentration
* If the reaction is second-order = half life decreases as [A] increases
67
What are reversible reactions and how are their rates expressed?
When equilibrium is reached, the forward and reverse rates are equal
The equilibrium constant (K) determines the extent of the reaction in either direction
K = [B eq] / [A eq] = kf / kr
The higher the equilibrium constant (K), the further the reaction goes in the forward direction
The overall rate is the sum of the rate of the forward and reverse reactions
kf[A] + kr[B]
68
What are parallel reactions and how are their rates expressed?
A single reactant forms different products via separate pathways
A single reactant undergoes different reaction pathways to form multiple products
A → B and A → C
Rate laws:
* Consumption of A = k1[A] - k2[A] = -(k1+k2)[A]
* Formation of B = k1[A]
* Formation of C = k2[A]
Product distribution depends on rate constants (k1, k2)
69
What are consecutive reactions and how are their rates expressed?
A reaction sequence where the product of one reaction serves as a reactant for another
A → B → C
Rate laws:
* Consumption of A = -k1[A]
* Formation + consumption of B = -k2[B] + k1[A]
* Formation of C = k2[B]
70
What is the function of a catalyst?
A catalyst speeds up a chemical reaction without being consumed in the process, by providing an alternative reaction pathway with a lower activation energy (Ea)
The presence of a catalyst does not alter the equilibrium position, only the rate at which equilibrium is achieved
71
How does temperature affect the rate of reaction?
Rate increases with temperature due to more frequent and energetic molecular collisions
Expressed by the Arrhenius equation
k = Ae^(−Ea/RT)
Where:
* k = rate constant
* A = frequency factor (no. collisions per unit time)
*e^(-Ea/RT) = fraction of the number of successful collisions
* Ea = activation energy (J/mol)
* R = universal gas constant (8.314 J/mol*K)
* T = temperature (K)
As T increases, the exponential term increases ⇒ more successful collisions ⇒ increased rate
72
How can the Arrhenius equation be used to determine activation energy graphically?
ln k = ln A − Ea/RT
Plotting ln k vs. 1/T gives a straight line with
* Gradient = −Ea/R
* y-intercept = ln A
73
How can you predicted the shelf life of a drug that follows first-order kinetics?
Drug degradation is studied at elevated/high temperatures (as it takes a shorter amount of time) and then extrapolated to determine rate constant at ambient conditions (i.e. room temp)
Shelf life (t) = 1/k ln([A]₀/[A])
For %
[A]₀ = 100
[A] = 100 - x%
E.g. for 5% decomposition [A]₀/[A] = 100/95
74
What is an interface?
A boundary between two phases
Can be between:
* a liquid and a solid
* two solids
* two liquids
75
How is an interface created?
An interface exists when the cohesive/attractive forces between molecules within each phase are stronger than the adhesive forces between molecules of the two different phases
This leads to a separation between the phases, forming a distinct boundary
76
What is a surface?
The boundary between two phases where one phase is a gas (generally air)
77
What is surface tension (γ)?
The elastic-like force present at the surface of a liquid
γ = F/L or F/2L
Where:
* γ = surface tension (N/m)
* F = force exerted along the surface (N)
* L = length along which the force acts (m)
78
How does surface tension arise?
Inside a liquid, (bulk) molecules are surrounded by other molecules on all sides.
These molecules all exert attractive forces that are balanced and cancel out.
At the surface, molecules lack neighbouring molecules from above and are therefore pulled more strongly by those within the liquid.
This imbalance creates a net inward force, causing the surface to contract and behave like a stretched membrane
Molecules at the surface possess a higher free energy (G) than those in the bulk. Any attempt to expand the surface must involve an increase in energy
79
Why does water have a larger surface tension than ethanol?
Surface tension depends on the cohesive forces between the molecules.
Each water molecule can form up to four hydrogen bonds, creating a highly cohesive network.
Ethanol, while also capable of hydrogen bonding, has only one hydroxyl group. The rest of the ethanol molecule consists of a non-polar ethyl group which does not participate in hydrogen bonding. This disrupts cohesion and reduces surface tension.
The small size of water molecules allows for closer packing at the surface, enhancing the cohesive forces. Ethanol's larger molecular size, due to the ethyl group, results in less efficient packing and weaker surface forces.
80
What is interfacial tension?
The force that exists at the boundary between two immiscible liquids (e.g. oil and water)
Arises because molecules in each phase are more attracted to their own kind, creating a "tension" at the boundary where the phases meet
81
What is the difference between surface tension and interfacial tension?
Surface tension is the force per unit length acting at the interface between a liquid and air due to cohesive forces within the liquid
Interfacial tension is the force per unit length at the boundary between two immiscible liquids, caused by the difference in cohesive and adhesive forces between the two liquids.
Interfacial tension values are generally lower than surface tension values
82
What is Antonoff’s Rule?
The interfacial tension between two mutually saturated liquids is approximately equal to the difference in their surface tensions
83
What is surface free energy?
The excess energy at the surface of a material compared to its bulk
The work (w) required to increase the surface by 1 m²
γ = W ÷ ΔA
Where:
* γ = surface free energy (J/m²)
* W = work done to increase the surface area (J)
* ΔA = change in surface area (m²)
84
What is the difference between surface free energy and surface tension?
Surface free energy = energy per unit area
Surface tension = force per unit length
They are numerically equal but not equivalent
85
What is work of adhesion (Wa)?
The work required to separate a liquid/liquid interface to form two separate liquid/air interfaces
i.e. the energy required to separate two different substances at their interface
Wa = γ1 + γ2 − γ1/2
Where:
* Wa = work of adhesion (J/m²)
* γ1 = surface tension of phase 1
* γ2 = surface tension of phase 2
* γ1/2 = interfacial tension between phase 1 and phase 2
It quantifies the strength of the adhesive forces between molecules of two materials - a higher Wa means stronger adhesive interactions
86
What are some applications of work of adhesion (Wa) in pharmacy?
Helps determine the stability of emulsions (low Wa indicates weaker interactions at the oil-water interface, which may lead to phase separation)
Helps optimise the adhesion of coatings
Wa indicates how well a liquid spreads on a solid surface (wetting, drug formulation/delivery)
87
What is work of cohesion (Wc) ?
The energy required to completely separate a liquid into two identical parts, creating two new liquid/air interfaces
Wc = 2γ
Where:
* Wc = work of cohesion (N/m or J/m²)
* γ = surface tension of the liquid (N/m or J/m²)
It quantifies the cohesive forces within a single material
A high Wc means stronger cohesion, which can result in a more stable liquid surface or resistance to spreading
88
How can the work of adhesion (Wa) and work of cohesion (Wc) predict liquid behaviour in emulsions?
Initial spreading coefficient (Sint):
Sint = Wa − Wc
If S > 0, the liquid will spread
If S < 0, the liquid will not spread and will form a lens
89
What factors affect surface tension?
Temperature
Pressure
Time
Solute
90
How does temperature affect surface tension?
As temperature increases, surface tension decreases. This is because increased molecular motion weakens the cohesive forces at the surface of the liquid.
91
How does pressure affect surface tension?
High vapour pressure decreases surface tension, though the effect is less dramatic than that of temperature.
This is particularly important in aerosolised drug delivery, where lower surface tension helps with droplet formation and dispersion
92
How does time affect surface tension?
Surface tension decreases over time until equilibrium is reached, as molecules migrate to the interface and orient themselves to reduce surface energy
This process takes longer in solutions than in pure liquids
93
How does solute affect surface tension?
The surface tension of a solution depends on the nature and concentration of the solute, which can be classified into three types of behaviour:
* Type I solutes
* Type II solutes
* Type III solutes
94
What is Type I solute behaviour and how does it affect surface tension?
Includes simple electrolytes (e.g. NaCl, KCl) and sugars (e.g. glucose)
Are heavily hydrated and exhibit negative adsorption at the surface (stronger solute-solvent interactions than solvent-solvent interactions), leading to a lower concentration at the surface compared to the bulk solution (surface deficit)
∴ effect on surface tension is minimal
95
What is Type II solute behaviour and how does it affect surface tension?
Co-surfactants
Typically unionised organic molecules (e.g. organic acids, alcohols, amines)
Amphiphilic (have both polar and non-polar regions)
Concentration at the surface is greater than in the bulk solution (surface excess) due to positive adsorption
Decrease surface tension by reducing the attractive forces between water molecules
96
What is Type III solute behaviour and how does it affect surface tension?
Surfactants
Typically ionised organic molecules (e.g. potassium or sodium salts of organic acids) or molecules containing a water-soluble polymer as a head group
Amphiphilic (have both polar and non-polar regions)
Concentration at the surface is greater than in the bulk solution (surface excess) due to positive adsorption
As concentration increases, surface tension decreases because more molecules adsorb at the surface and disrupt water’s cohesive forces
This continues until the surface becomes saturated at a critical concentration (CMC)
Beyond this point, surface tension levels off – extra molecules form aggregates (e.g. micelles)
97
What is the critical micelle concentration (CMC)?
The concentration of surfactants in a solution above which micelles start to form
Below the CMC, surfactants exist primarily as individual molecules while above it, they aggregate into micelles
98
How does hydrocarbon chain length of solutes affect surface tension reduction?
Longer hydrocarbon chains lead to a greater reduction in surface tension
This is because they have a stronger tendency to adsorb at the air/water interface to minimise free energy
99
What is Traube’s Law?
For a homologous series adding one –CH₂ group (i.e. one carbon) to the hydrocarbon chain decreases the concentration needed to achieve the same surface tension by a factor of 3
Add 1 carbon → divide concentration by 3
Remove 1 carbon → multiply concentration by 3
100
What is the difference between Type II and Type III molecules/solutes?
Type II:
* Unionised polar head groups (e.g. OH, CO₂H, NH₂)
* Do not aggregate
* Act as co-surfactants
* Are oil soluble
Type III:
* Ionised (e.g. CO₂⁻, SO₄²⁻) or polymeric head groups
* Aggregate into micelles
* Act as surfactants
* Are water soluble
101
What are colligative properties?
Properties of a solution that depend only on the number of solute particles, not their chemical identity:
Vapour pressure lowering
Boiling point elevation
Freezing point depression
Osmotic pressure
102
What is vapour pressure lowering?
When a non-volatile solute is added to a solvent it decreases the vapour pressure of the solution. This is because solute particles occupy surface space, decreasing the number of solvent molecules that can escape into the vapour phase.
103
What is Raoult’s Law?
Psol = Psolv x Xsolv
Where:
* Psol = vapour pressure of solution
* Psolv = vapour pressure of solvent
* Xsolv = mole fraction of the solvent (i.e. moles of solvent ÷ total moles)
Obeyed by ideal solutions, where solute–solvent interactions are equal to solute–solute and solvent–solvent interactions
Positive deviation occurs when solute–solvent interactions are weaker than solvent–solvent interactions (↑ vapour pressure)
Negative deviation occurs when solute–solvent interactions are stronger than solvent–solvent interactions (↓ vapour pressure)
104
How does thermodynamics explain vapour pressure lowering?
ΔH > 0 because breaking intermolecular forces to turn liquid into vapour requires energy
* ΔHsolution ≈ ΔHsolvent (similar intermolecular forces)
ΔS > 0 because molecules in the vapour phase are more disordered than in the liquid
* ΔSsolution < ΔSsolvent (less disorder because fewer solvent molecules are free to escape as solute blocks the surface)
ΔG = ΔH – TΔS
If ΔS is smaller for the solution, ΔG becomes less negative so evaporation is less favourable for the solution than for the pure solvent
105
What is boiling point elevation?
When a non-volatile solute is added to a solvent the boiling point increases. This is because the presence of solute particles reduces the solvent’s vapour pressure, requiring more heat to reach the boiling point.
Below the boiling point, the liquid phase is thermodynamically favoured
Above the boiling point, the vapour phase is favoured
Adding a non-volatile solute lowers the free energy of the liquid, making it less likely to vaporise so a higher temperature is needed to boil
ΔG = 0 ⇒ ΔH = TΔS
the heat required to vaporise the liquid (ΔH) is directly related to the increase in disorder (ΔS)
∆Ssolution < ∆Ssolvent ⇒ Tsolution > Tsolvent
106
What is freezing point depression?
When a non-volatile solute is added to a solvent the freezing point decreases. This is because solute particles disrupt the formation of the solid phase, making it harder for the solvent to freeze
ΔG = 0 ⇒ ΔH = TΔS
∆Ssolution > ∆Ssolvent ⇒ Tsolution < Tsolvent
107
What is osmotic pressure (π) ?
The pressure required to prevent the flow of water across a semipermeable membrane from a region of lower solute concentration into a region of higher solute concentration
A pure solvent has no osmotic pressure because there are no solute particles present to create a concentration difference across a membrane
π = MRT
Where:
* M = molar concentration of the solute
* R = gas constant (8.314 J/K/mol)
* T = temperature (K)
108
What is adsorption?
The accumulation of molecules at an interface
109
What are the two main types of adsorption?
Physical adsorption:
* Involves weak van der Waals forces
* Reversible
* Occurs at low temperatures
Chemical adsorption (chemisorption):
* Involves the formation of chemical bonds
* Usually irreversible
* Occurs at higher temperatures
110
How is adsorption measured?
1) Prepare a series of solutions of known concentrations
2) Add a fixed amount of adsorbent to each
3) Allow equilibrium to be reached
4) Measure the final concentration of the solute
5) Use the difference between initial and final concentrations to calculate the amount adsorbed
6) Plot the adsorption isotherm
111
What is the Langmuir isotherm?
Assumes monolayer adsorption
Can be saturated - curve will level off
x/m = abc/1+bc
Where:
* x = amount of solute adsorbed
* m = mass of adsorbent
* c = concentration of solution at equilibrium
* b = a constant related to enthalpy of adsorption
* a = a constant related to the surface area of the
solid
Tells you how adsorption varies with solute concentration
Can be rearranged to linear form y = mx + c
Where:
* Gradient = 1/a
* y-intercept = 1/ab
a = maximum adsorption capacity (when all sites are filled)
b = adsorption affinity (how strongly the adsorbate binds to the surface)
112
What is the Freundlich isotherm?
Takes into consideration the formation of
multilayers
Adsorption increases with concentration + does not level off
x/m = ac^(1/n)
Where:
* x = the amount of solute adsorbed
* m = mass of adsorbent
* c = concentration of solution at equilibrium
* a and n are constants
Can be rearranged to linear form
log (x/m) = log a + (1/n) log c
(plot log (x/m) vs log c)
Where:
* Gradient = 1/n
* y-intercept = log a
smaller 1/n means stronger adsorption
113
What factor affect adsorption?
Solubility
pH
Nature of adsorbent
Temperature
114
How does solubility affect adsorption?
Lundelius’s Rule:
Extent of adsorption (α) = 1 ÷ Solubility
High solubility reduces adsorption, as the solute prefers to remain dissolved in the bulk rather than attach to the surface
Can be resolved by increasing hydrocarbon chain length
Low solubility increases adsorption, as solute has less affinity for the solvent and is more likely to adsorb onto the surface
115
How does pH affect adsorption?
pH can change ionisation states
Unionised = better adsorption
Ionised =. reduced adsorption
Can affect surface charge and therefore electrostatic interactions
116
How does the nature of the adsorbent affect adsorption?
Surface area
* higher surface area = more sites for adsorption
* more finely divided/more porous = greater adsorptive capacity
Chemical nature
* compatibility between the adsorbent and adsorbate enhances binding (e.g. polarity, functional groups, charge)
117
How does temperature affect adsorption?
Adsorption decreases with increasing temperature because it is exothermic and driven by weak van der Waals forces
118
What are the applications of adsorption in pharmacy?
Drug Analysis
* Used in chromatographic techniques to separate and identify drugs based on how well they adsorb to stationary phases
* Purity testing, drug identification and quantification
Drug Formulation
* Activated charcoal and other adsorbents are used in formulations to improve stability or modify drug release
* Adsorption onto excipients can improve solubility, taste-masking or protection from degradation
Drug Interactions
* Unintended adsorption of drugs onto other substances (e.g. antacids, kaolin, activated charcoal) can reduce bioavailability
* Tetracycline adsorbs to calcium-containing antacids, reducing its absorption
Drug Packaging
* Packaging materials may adsorb moisture + oxygen, protecting sensitive formulations
119
What are the phases of oral drug absorption?
Disintegration → Dissolution → Diffusion/Permeation
120
What factors affect oral bioavailability?
Drug dissolution rate
Solubility
Intestinal permeability
Pre-systemic metabolism
121
What are the stages of dissolution?
1) Solid drug is exposed to a dissolution medium
2) Interfacial reaction
* Liberation of solute molecules from the solid surface/phase into the surrounding liquid phase
* Instantaneous
3) Solvation
Detached solute molecules become surrounded and stabilised by solvent molecules, forming a homogenous mixture
4) Formation of the boundary layer (h)
A thin layer, saturated with the solute, forms around the dissolving particle
5) Diffusion through the boundary layer
* Solute molecules diffuse from the saturated boundary layer (high concentration) into the bulk solution (lower concentration)
* This is the rate-limiting step in dissolution
* Governed by Fick’s first law of diffusion
122
What is Fick’s first law of diffusion?
Describes the rate of diffusion of solute molecules across a concentration gradient
States that flux (J) is proportional to the concentration gradient
J = −D d𝜑/dx
Where:
* J = diffusion flux
* D = diffusion coefficient
* d𝜑 = change in solute concentration
* dx = change in position
* d𝜑/dx = concentration gradient of the solute
* The negative sign shows diffusion moves from high to low concentration
123
What is diffusive flux (J) ?
The rate of movement of solute molecules from a high to a low concentration
124
What factors control diffusive flux (J) ?
Larger/higher concentration gradient → greater flux (J)
Flux is directly proportional to diffusion coefficient (D)
Increasing temperature → increased brownian motion → increases D ∴ greater flux (J)
Increasing viscosity (𝜂 ) → decreases D ∴ lower flux (J)
Increased solute size → decreases D ∴ lower flux (J)
125
What is the Stokes-Einstein equation?
D = kB T / 6 π η r
OR
D = RT / 6 π η r N
Where:
* D = diffusion coefficient
* kB = Boltzmann constant
* T = absolute temperature
* η = viscosity of medium
* r = radius of solute particle
* R = Universal gas constant (8.314 J/K/mol)
* N = Avogadro’s constant (6.022× 10^23)
D increases with temperature/energy but decreases with solute size and viscosity
126
What is the Noyes-Whitney equation?
dm/dt = DAΔC / h OR dm/dt = kAΔC
Where:
* dm/dt = dissolution rate
* A = surface area of drug particle
* ΔC = (Cs − C) = difference in solute concentration at the surface vs in bulk solution
* h = thickness of boundary layer
* D = diffusion coefficient
* k = D/h = dissolution rate constant
127
What are sink conditions?
Sink conditions occur when the concentration of drug in the bulk solution (C) is kept very low (typically < 10% of Cs)
Ensures a constant concentration gradient (Cs – C ≈ Cs)
Promotes maximum and consistent dissolution rate
128
What is the Intrinsic Dissolution Rate (IDR)?
The dissolution rate independent of factors such as boundary layer thickness, etc.
Reflects intrinsic properties of the drug
IDR = kCs
129
How is the Intrinsic Dissolution Rate (IDR) measured?
Drug to be assessed is compacted into a non-disintegrating disc
The disc is mounted onto a holder so that only one face is exposed to the dissolution medium
Conditions (e.g. stirring, temperature, medium) are kept constant
The rate of drug release is recorded over time
The gradient of the dissolution line divided by surface area (A) gives the IDR
130
What factors affect the rate of drug dissolution?
Surface area
* Exposes more drug to solvent = faster dissolution (Noyes-Whitney equation)
Temperature
* ↑ Temperature = ↑ solubility and diffusion = faster dissolution
* Endothermic process
Solubility
* Greater solubility = higher Cs = greater concentration gradient = faster dissolution
Nature of dissolution medium
* ‘Like dissolves like’
* Hydrophilic substances dissolve in aqueous fluid
* Lipophilic substances dissolve in oil or organic solvents
pH
* Ideal pH ≈ pKa (optimal ionisation ~50%)
* Acidic drugs: ionised when pH > pKa → more soluble
* Basic drugs: ionised when pH < pKa → more soluble
* Ionised form dissolves faster but may not permeate membranes
* Unionised form crosses membranes but may precipitate if solubility is low
Volume of dissolution medium
* A large volume helps maintain sink conditions (C ≪ Cs), supporting continuous dissolution
Boundary layer thickness
* Thinner boundary layer = faster diffusion
Presence of ions (e.g. Cl-)
* Can lead to common ion effect = decreased solubility
* Concentration in the boundary layer will decrease = slower dissolution
Complex formation
* Soluble complexes can enhance dissolution
* Insoluble complexes can retard dissolution
131
How can you improve drug dissolution?
Reduce particle size
* Increases surface area (per Noyes–Whitney equation)
Addition of disintegrants
* Promotes breakup of tablets into smaller particles
* Increases surface area and exposure to the dissolution medium
Increase porosity
* Enhances solvent penetration into drug particles
Addition of surfactants
* Lowers surface tension between drug and solvent
* Improves wetting and dispersion
Co-solvents (e.g. ethanol, propylene glycol)
* Improves drug solubility and therefore dissolution rate
Molecular modifications
* Introduction of a hydrophilic groups (e.g. -OH) improves aqueous solubility
* Esterification reduces aqueous solubility
Salt formation
* Greater solubility
Crystalline structures
* Amorphous forms or unstable polymorphs dissolve faster due to weaker intermolecular forces
132
What is an acid?
Arrhenius = H⁺ or H₃O⁺ producer
Brønsted-Lowry = proton (H⁺) donor
Lewis = electron pair acceptor
133
What is a base?
Arrhenius = OH⁻ producer
Brønsted-Lowry = proton (H⁺) acceptor
Lewis = electron pair donor
134
What is pKa?
pKa = − log Ka = log (1/ Ka)
Where
Ka = [H⁺] [A-] / [HA]
Lower the pKa = stronger the acid (more dissociation)
Higher pKa = stronger base (as the conjugate acid is weaker)
135
What is pKb?
pKb = -log Kb
Lower the pKb = stronger the base (more dissociation)
136
What is the relationship between pKa and pKb?
pKa + pKb = 14
137
What is the formula for pH?
pH = -log[H⁺]
138
What is the Henderson-Hasselbalch equation?
For acids:
pH = pKa + log [A⁻]/[HA]
For bases:
pH = pKa + log [B]/[BH⁺]
Indicates degree of ionisation:
* For acids: ionised when pH > pKa
* For bases: ionised when pH < pKa
139
What is a buffer?
A solution that resists pH changes when small amounts of acid or base are added
Work by neutralising the added acid or base to maintain a stable pH
Common components
* Weak acid + its conjugate base
* Weak base + its conjugate acid
E.g. Phosphate buffer
140
What are surfactants?
Amphiphilic molecules that lower the surface tension between two substances
141
What are micelles?
Spherical aggregates formed by (~ 50-100) surfactant molecules where the hydrophobic tails are tucked inside and the hydrophilic heads face outward toward the aqueous environment
142
What are the different classes of surfactants?
Ionic surfactants
Non-ionic surfactants
Zwitterionic surfactants
143
What are ionic surfactants?
Surfactants that carry an ionic charge
Can be anionic (-) or cationic (+)
Examples:
* Sodium dodecyl sulfate (SDS)
* Sodium lauryl sulfate (SLS)
* Cetyltrimethylammonium bromide (CTAB)
144
What are non-ionic surfactants?
Surfactants that do not carry an ionic charge
Typically composed of hydrophilic groups
Examples:
* Polysorbates (Tweens)
* Sorbitan esters (Spans)
145
What are zwitterionic surfactants?
Surfactants that contain both positive and negative charges, but in such a way that the overall molecule is neutral
Examples:
* Lecithin
* Dodecyl sulfobetaine
146
What is the Critical Packing Parameter (CPP)?
Predicts the shape of structures formed by surfactants in solution
CPP = V / (a × lc)
Where:
* CPP = critical packing parameter
* V = volume of the hydrophobic tail
* a = area of hydrophilic head group
* lc = length of the hydrophobic tail
When:
* CPP < 1/3 → spherical micelles
* 1/3 < CPP < 1/2 → cylindrical micelles
* CPP ≈ 1 → bilayers or lamellar phases
147
What evidence is there of micelle formation?
Osmotic Pressure
* Increases linearly with surfactant concentration below the CMC
* But levels off above the CMC as monomers form micelles and no longer contribute to osmotic pressure
Molar Conductivity
* Decreases in conductivity at the CMC because micelles are less mobile than monomers
Light Scattering
* Increases significantly above the CMC due to the formation of larger micellar aggregates that scatter light more effectively
Drug Solubilisation
* Poorly soluble drugs become more soluble above the CMC as they are incorporated into the hydrophobic core of micelles
Surface Tension
* Decreases sharply with increasing surfactant concentration up to the CMC
* Then plateaus as additional surfactant forms micelles instead of accumulating at the surface
148
Describe the thermodynamics of micelle formation
Micelle formation is energetically favourable (ΔG < 0)
This is because hydrocarbon chains are shielded in the core of the micelle (hydrophobic effect), allowing water molecules to regain freedom of motion ( loss of the cage structure) so entropy increases (ΔS > 0) and free energy decreases (ΔG = ΔH – TΔS)
149
What stops micelles from growing and growing?
As micelles grow, surfactant head groups are brought into close proximity, leading to electrostatic or steric repulsion
Further growth would require bending the micelle into a shape that traps water inside the hydrophobic core, which is entropically unfavourable
150
What factors oppose micelle formation?
High CMC + large aggregation number → larger micelle size → less favourable (due to increased repulsion + trapping of water inside hydrophobic core)
151
What factors affect micelle formation?
Hydrophobic chain length
Altering hydrophilic head group region
Temperature
Addition of electrolytes
Nature of counter ion
pH
152
How does altering hydrophobic chain length affect micelle formation?
Increasing the hydrophobic chain length
Promotes micelle formation
* By strengthening the hydrophobic effect, making aggregation more thermodynamically favourable
Decreases CMC
* For ionic surfactants CMC decreases by a factor of 2 for each additional C in the chain
* For non ionic surfactants CMC decreases by a factor of 10 for every additional 2C in the chain
Larger hydrophobic volume → larger aggregation number → larger micelle size
153
What affect does altering size of hydrophilic head group have on micelle formation?
For ionic surfactants not much effect
For nonionic surfactants:
Increasing size of hydrophilic head group → increases CMC → decreases micelle size (because aggregation number decreases)
154
What affect does temperature have on micelle formation?
For ionic surfactants
* Relatively little effect
* Increasing temperature → increases brownian motion → decreases water structure (weaker hydrophobic effect) → increase in CMC + slight reduction in micelle size
For nonionic surfactants
* Larger effect
* Increasing temperature → desolvation of hydrophilic head groups → enhances hydrophobic interactions → decreases CMC + increase in micelle size
155
What affect does addition of electrolytes have on micelle formation?
For ionic surfactants:
* Addition of extra counter ions → reduces charge on surfactant head group (screening) → reduces repulsion between surfactant molecules → CMC decreases + micelle size increases
* Can also drive a sphere-to-rod transition, by
decreasing the surface head group area, increasing CPP
For nonionic surfactants:
* Have minimal effects
* Can indirectly influence water structure, slightly affecting CMC
156
What affect does the nature of the counter ion have on micelle formation?
For a cationic surfactant:
* CMC decreases and micelle size increases as Cl- < Br- < I-
For an anionic surfactant
* CMC decreases and micelle size increases as Na+ < K+ < Cs+
Ionic surfactants with organic counter ions (e.g. maleates) have lower CMCs and higher aggregation numbers than with inorganic counter ions
157
What effect does pH have on micelle formation?
For ionic surfactants:
* pH affects ionisation of the surfactant head group
* Unionised at low pH for anionic surfactants
* Unionised at high pH for cationic surfactants
* If surfactant becomes unionised → repulsion decreases → micelle size increases (can lead to phase separation) and CMC decreases
For nonionic surfactants:
* Little or no effect
158
How does the nature of a solubilisate/solute affect its location in a micelle?
Non-polar solute
* Localises in the hydrophobic core
* E.g. octane
Semi-polar solute
* Depends on the size and hydrophobicity
* Small + more hydrophobic (e.g. octanol) → core
* Large and/or more polar (e.g. octanediol) → mantle or core–mantle interface
Polar solute
* In mantle region for nonionic micelles
* Adsorbed on the surface for ionic micelles
159
What factors affect solubilisation?
Nature of surfactant
Nature of solubilisate/solute
Temperature
Additives
160
How does drug solubility affect bioavailability?
Poorly soluble drugs → slow dissolution → diffusion-rate limited bioavailability
Highly aqueous-soluble drugs → rapid dissolution → permeability-limited bioavailability
161
Why is the stomach not a favourable environment for drug absorption?
Low pH → causes ionisation of basic drugs ∴ poor permeability
Enzymes + acidity can cause degradation of drugs
Small surface area compared to the intestine
Thick mucus layer reduces drug contact with epithelium
Short residence time due to gastric emptying
162
What is the difference between paracellular transport and transcellular transport?
Paracellular transport:
* Through gaps ‘tight junctions’ in between cells
* Passive diffusion
Transcellular transport:
* Through cells
* Can be via passive diffusion, carrier mediated transport or transcytosis
163
What properties favour transcellular drug transport?
Lipophilic (Log P > 0 OR ~1–3)
Low-to-moderate polarity
Small (molecular weight < 500 Da)
Unionised at intestinal pH
164
What properties favour paracellular drug transport?
Small (molecular weight < 270 Da)
Hydrophilic
Ionised
Low lipophilicity (log P < 0)
165
What is the pH partition hypothesis?
Used to predict route of absorption
Only the unionised form of a drug can readily cross biological membranes
Acids are unionised at low pH + bases are unionised at high pH
Therefore the pH partition hypothesis predicts that:
* Acidic drugs are absorbed in the stomach
* Lowest pKa (acid) for rapid absorption is ~3
* Basic drugs are absorbed in the intestine
* Highest pKa (base) for rapid absorption is ~7/8
166
How do you calculate the degree of ionisation of a drug?
For acids:
pH = pKa + log [ionised (A-) ÷ unionised (HA)]
For Bases:
pH = pKa + log [unionised (B) ÷ ionised (BH+)]
For acids:
* If the pH is 2 units below the pKa of a molecule, the molecule is totally unionised
* If the pH is 2 units above the pKa of a molecule, the molecule is totally ionised
* If pKa approx 2.5 = strong acid
* If pKa 2.5-8 = weak acid
* If pKa > 8 = very weak acid
For bases:
* If the pH is 2 units above the pKa of a molecule, the molecule is totally unionised
* If the pH is 2 units below the pKa of a molecule, the molecule is totally ionised
* Low pKa = weak base
* High pKa = strong base
167
What is Log P?
A measure of the lipophilicity of a molecule
LogP = log(conc. in organic phase/octanol ÷ conc.in aqueous phase)
LogP > 0 (lipophilic)
LogP < 0 (hydrophilic)
LogP ~ 0 (neutral species)
A LogP between 0 and 3 is best placed to cross the membrane
168
What is the relationship between rate of absorption and LogP?
A LogP between 0 and 3 is best placed to cross the membrane
Low log P values (usually ≤ 0)
* slow rate of absorption
* molecule prefers to reside in aqueous (lumen) phase
Intermediate log P values
* absorption rate is maximal
* optimum balance between molecule entering membrane and leaving
High log P values
* slow rate of absorption
* molecule prefers to reside in membrane + does not want to partition back out into the aqueous (blood) phase
169
What are the limitations of the pH partition hypothesis?
GI tract is not a closed system → equilibrium is rarely achieved
At high log P, absorption is better than predicted (e.g. via fat absorption pathways)
At low log P, absorption is better than predicted (may occur via paracellular route if MW < 270 Da)
Dissolution may be rate limiting
pH requirements for dissolution are opposite to that required for absorption
Ion pairing - charged drugs may form absorbable complexes (e.g. quaternary ammonium compounds (ionised at all pH) are absorbed by interacting with negatively charged bile salts)
Gastric emptying
Surface area
First-pass metabolism
Efflux transporters (e.g. P-glycoprotein)
170
What is the Biopharmaceutics Classification System (BCS)?
A system which categorises drug molecules into one of four classes, based on their intestinal permeability and aqueous solubility
Used to predict oral drug absorption and guide formulation strategies
171
What defines ‘highly soluble’ and ‘highly permeable’ in the BCS system?
‘Highly soluble’ = the highest strength solid oral dosage is soluble in ≤250 mL aqueous media over the pH 1 – 7.5
‘Highly permeable’ = intestinal absorption ≥90% OR fraction absorbed is ≥ 85% dose compared to IV dose
172
What characterises BCS Class I drugs?
High Solubility + High Permeability
Dissolve rapidly in gastric/intestinal fluids
Readily absorbed across the intestinal membrane via passive diffusion
Minimal bioavailability/bioequivalence issues
Absorption is not limited by dissolution or GI residence time
173
What characterises BCS Class II drugs?
Poor Solubility + High Permeability
Poor solubility and/or slow dissolution are the rate-limiting steps for oral absorption
174
How can absorption of BCS Class II drugs be improved?
Salt formation
Particle size reduction
* increases surface area to enhance dissolution rate
Metastable forms
* crystalline forms with higher solubility
Solid dispersions
* disperses drug in a hydrophilic matrix to improve dissolution
Micelles/emulsions
Precipitation inhibitors
pH adjustment
* optimises ionisation for solubility at GI pH
Co-solvents
175
What characterises BCS Class III drugs?
High Solubility + Low Permeability
Permeation is the rate-limiting step for oral absorption
176
How can absorption of BCS Class III drugs be improved?
Prodrugs
* modify drug structure to increase lipophilicity
* carrier-mediated transport
Permeation enhancers
* temporarily loosen tight junctions or fluidise membranes
Metabolic inhibitors
* block enzymes that degrade the drug
Motility modifiers
* slow down intestinal transit to increase absorption time
Efflux inhibitors
* inhibit P-glycoprotein and other pumps that expel the drug
177
What characterises BCS Class IV drugs?
Low Solubility + Low Permeability
Pose tremendous challenges to formulation development
Require multifaceted formulation approaches:
* solubility-enhancing methods
* permeability-enhancing methods
* Nanotechnology (e.g., nanoparticles, nanosuspensions) - improve dissolution and cellular uptake
* Complexes
* Co-crystals
178
What is an emulsion?
A ‘pseudo/meta-stable’ dispersion of at least two immiscible liquids one of which is dispersed throughout the other in the form of fine droplets stabilised by the presence of an emulsifying agent/emulsifier
179
How are emulsions formed?
Providing mechanical energy to disperse one phase into small droplets in the other (mixing under high-shear)
Addition of surfactants to reduce interfacial tension + stabilise droplets
180
What are the two types of emulsions?
Oil in water (o/w) emulsions
Water in oil (w/o) emulsions
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Describe the thermodynamics of emulsion formation
Emulsion formation is thermodynamically unfavourable (ΔG > 0)
Gibs free energy, ΔG = 𝛾ΔA – TΔS
𝛾ΔA is the most dominant term as emulsification increases the surface area between oil and water → ΔG is positive
Emulsions are kinetically stabilised - need energy input (mixing) + stabilisers to remain dispersed
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What is the Hydrophile-Lipophile Balance (HLB) system?
Assigns a numeric value (0–20) to surfactants to indicate their relative affinity for water or oil
HLB 0-6:
* lipophilic (oil-soluble)
* typically used for w/o emulsions
HLB 7-9:
* intermediate surfactants
HLB 10-20:
* hydrophilic (water-soluble)
* typically used for o/w emulsions
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How is the HLB system used to select a suitable surfactant for emulsion stability?
Choose surfactant(s) with an HLB matching the required emulsion type
For o/w emulsions, use surfactants with HLB 8–18
For w/o emulsions, use surfactants with HLB 3–6
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How do you calculate the HLB of a surfactant mixture?
HLBmix = HLBa x + HLBb(1-X)
Where:
* HLBa = HLB of surfactant A
* X = weight fraction of A
* HLBb = HLB of surfactant B
* 1-X = weight fraction of B
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What is the Schulman & Cockbain model?
Describes how surfactants stabilise emulsions by forming a monolayer at the oil–water interface, reducing interfacial tension
The orientation and packing of the surfactant at the interface determines emulsion stability
They found surfactant + cosurfactant mixtures often provide better stability than single surfactants
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What is a surface pressure isotherm?
A plot of surface pressure (π) vs area per molecule
Shows how molecular packing at the interface changes during compression
Used to classify monolayer behaviour into:
* Gaseous
* Liquid-expanded
* Vapour-expanded
* Condensed
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What is the condensed phase?
Surface pressure is very low at large area per molecule due to little/no contact between the
molecules
Surface pressure stays low as the area per molecule decreases until there is a sudden sharp rise due to close packing of molecules
L shape plot
Larger molecules will skew the plot to the right
Form unstable emulsions as molecules are so closely packed that they are not able to take up the curvature required to cover droplet
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What type of molecules exhibit a condensed phase isotherm?
large hydrophobic tail
small hydrophilic head group
e.g. cholesterol, dodecanol, co-surfactants
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What is the gaseous phase?
Surface pressure is low at large area per molecule
Gradual increase in surface pressure with compression
C shape plot
Do not form emulsions as molecules are too far apart to cover whole droplet surface - can be addressed by using a cosurfactant to fill in gaps
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What type of molecules exhibit a gaseous phase isotherm?
Steroids
Dibasic esters
Ionic surfactants (e.g. SDS)
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What is the vapour-expanded phase?
At large area per molecule, the film behaves like a gaseous film
As the area per molecule decreases, starts to behave like a condensed film
Seen in molecules with bulky side chains or a kink in the hydrophobic tail (e.g. oleyl alcohol)
Do not form emulsions as close packing is prohibited by bulky side chains → too far apart to cover whole droplet surface
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What is the liquid-expanded phase?
At large area per molecule, the film behaves like a gaseous film
As the area per molecule decreases, starts to behave like a condensed film
Very similar to vapour expanded but condensation occurs at smaller areas per molecule
Transition often occurs as a result of temperature changes or when using mixtures of surfactants
Form good emulsions as molecules pack more closely but remain fluid
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How can the Schulman and Cockbain model be used to form a stable emulsion?
Surfactants (or mixtures) that exhibit liquid expanded films produce the most stable emulsions because they offer a balance between molecular mobility and interfacial packing
Mixtures of surfactants that individually form gaseous and condensed films (e.g. ionic surfactants with co-surfactants) can combine to form a uniform, well-packed monolayer and therefore a more stable emulsion
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What types of repulsive forces stabilise emulsions formed by different surfactants?
Ionic surfactants stabilise emulsions via electrostatic (Coulombic) repulsion
Nonionic surfactants stabilise emulsions via:
* Osmotic/solvation repulsion = polymer overlap creates a concentrated polymer solution → induces osmotic gradient → water influx → droplet separation
* Entropic/steric repulsion = overlapping chains lose freedom of motion → loss in entropy → thermodynamically unfavourable → droplets repel
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How can the DLVO theory be used to select a suitable surfactant for emulsion stability?
Ionic surfactants are more efficient at stabilising emulsions than nonionic surfactants due to strong electrostatic repulsion
Non-Ionic surfactants generate weaker repulsive forces and therefore may need to be supplemented by other stabilising agents (e.g. co-surfactants, polymers)
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With reference to the DLVO theory what is the effect of increasing surfactant concentration on emulsion stability?
Increasing surfactant concentration → increases the thickness of the electrical double layer → enhances electrostatic repulsion between droplets → raises the energy barrier to coalescence → improves emulsion stability
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With reference to the DLVO theory, what is the effect of adding electrolytes on emulsion stability?
Addition of electrolytes → neutralise or reduce charge → compress the electrical double layer → reduce repulsion → decrease Vmax (maximum repulsive energy) → emulsion destabilisation
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What are the different forms emulsion instability?
Phase inversion
Creaming
Flocculation
Coalescence
Ostwald ripening
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What is phase inversion?
When an o/w emulsion switches to a w/o emulsion or vice versa
Triggered by:
* Temperature shifts
* Addition of ions
* Change in pH
Charge on emulsion droplet is reduced → emulsion droplets come together → once droplets are in contact → interfacial surfactant film re-aligns forming water-in-oil droplets
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What is creaming?
The upward (or downward) movement of dispersed droplets under gravity due to density differences between phases
Reversible
Solutions:
* Reducing droplet size
* Increasing viscosity
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What is flocculation?
The aggregation of droplets into clusters without merging
Caused by weak attractive forces (e.g. van der Waals)
Reversible — droplets remain distinct
Can lead to creaming or coalescence if not controlled
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What is coalescence?
The merging of droplets into larger ones
Irreversible
Causes:
* Emulsifier concentration (inadequate surfactant coverage)
* Change in pH
* Salts
* Phase-volume ratio
* Temperature shifts
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What is Ostwald ripening?
Smaller droplets dissolve and redeposit onto larger ones
Irreversible
Slow/gradual
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What are the different types of semisolid topical formulations?
Ointments
Pastes
Gels
Creams
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What are the differences between the two types of creams?
o/w creams:
* Continuous phase = water
* Dispersed phase = oil
* Lighter, non-greasy texture
* Non-occlusive, washable
* Conduct electricity
w/o creams:
* Continuous phase = oil
* Dispersed phase = water
* Thicker, greasy texture
* Occlusive, water-resistant
* Do not conduct electricity
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Describe the phase structure of o/w creams
Dispersed oil phase
* oil droplets dispersed throughout the water phase
* stabilised by surfactants which form an interfacial layer to prevent coalescence
Crystalline gel phase
* multilayered arrangement of surfactants and fixed water
* protect against coalescence of droplets by retarding their movement
* major contributor to cream viscosity and stability
Crystalline hydrated phase
* ordered structures made up of hydrated surfactant molecules
* affects the consistency and texture of the cream
Bulk water phase
* continuous (aqueous) phase in which the dispersed oil droplets and structured gel phases exist
* contributes to spreadability and hydrating properties
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How are creams typically made?
Heat the oily phase (with emulsifier) and aqueous phase separately to ~60–80°C
Add aqueous phase to oil phase with continuous stirring or homogenisation and cool gradually to avoid separation
Drug incorporation:
Fusion method - melted together with cream ingredients
Trituration - heat-labile or insoluble drugs are added as a fine powder in small increments with a flexible spatula
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What are polymers?
Large molecules composed of repeating structural units
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What are the differences between polymers and small molecules?
State of matter
* Polymers can never be in the gas state
Dissolution:
* Polymers tend to swell and dissolve slowly, sometimes forming gels
* Small molecules dissolve quickly
Solution properties
* Polymer solutions have higher viscosity compared to solutions of low molecular weight substances of the same concentration
Mechanical properties
* Polymers are able to show elasticity and reversible
deformation
* Small molecules are generally more brittle and rigid
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What is polydispersity?
A measure of how broad the molecular weight
distribution is
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What is meant by degree of polymerisation?
The number of repeating monomer units in a polymer chain
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What is a homopolymer?
A polymer made from only one type of monomer
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What are copolymers and the different types?
Polymers made from two or more different monomers
Statistical/random copolymers
* Monomers are randomly distributed along the chain
Alternating copolymers
* Monomers alternate in a regular pattern.
Block copolymers
* Comprised of long blocks of one monomer followed by blocks of another
Graft copolymers
* Side chains of one monomer are grafted onto a backbone of another
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