Physical Pharmaceutics and Formulation A Lecture Notes 1822 Notes

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Physical Pharmaceutics and Formulation A - Lecture notes -

1822 notes
Physical Pharmaceutics and Formulation A (University of Sydney)
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PHAR1822 Notes
Pharmaceutical calculations
𝑚 𝑚𝑎𝑠𝑠 (𝑔) Drug/mixture
𝑑 = 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 (𝑔/𝑚𝐿) =
𝑣 𝑣𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿) w/w grams/100g
𝑛 𝑚𝑜𝑙𝑒𝑠 (𝑚𝑜𝑙) w/v grams/100mL
𝑐 = 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝑚𝑜𝑙 𝐿) =
𝑣 𝑣𝑜𝑙𝑢𝑚𝑒 (𝐿) v/v mL/100mL
𝑚 𝑚𝑎𝑠𝑠 (𝑔) v/w mL/100g
𝑛= 𝑛𝑜. 𝑚𝑜𝑙𝑒𝑠 =
𝑀𝑀 𝑚𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑚𝑎𝑠𝑠 (𝑔 𝑚𝑜𝑙)
𝑐! 𝑣! = 𝑐! 𝑣! 𝑢𝑠𝑒 𝑓𝑜𝑟 𝑑𝑖𝑙𝑢𝑡𝑖𝑜𝑛𝑠

-‐ dL = decilitre = 100mL
-‐ If a mixture is made up of water and drug, add x grams of drug, and then (100 – x) mL of water to
make the mixture a total amount of 100mL (or 100g)
o I.e. add water to make the volume up to 100mL
-‐ Dilution ≈ paediatric sample – use C1V1=C2V2
-‐ If working with a liquid drug or solvent other than water (e.g. ethanol) – density formula

Liquids and Solutions
Solution Mixture of two or more components that form a single phase which is homogeneous
down to the molecular level
Phase Part of a system separated by one or more boundaries/interfaces, which can be
separated physically (e.g. filtration, centrifuge)
Dissolution Transfer of molecules or ions from the solid state into solution
Miscibility Combination of two solvents that mix completely to form a homogenous solution

Solubility
-‐ Limit to which a solute can be dissolved in a solvent under a particular set of conditions
-‐ Determined at 20°C
-‐ Based on amount of solvent in mL or grams (“parts”), required to dissolve 1g of drug/excipient
o Soluble – 10-‐30 parts solvent
o Insoluble – >10000 parts solvent
-‐ Water solubility – depends on polarity and functional groups – H-‐bonds and ion-‐dipole bonds
o -‐NH, -‐OH or C=O functional groups will H-‐bond with water
o Ion-‐dipole bonds are even stronger than hydrogen bonds

Salt form of drugs
-‐ Salt form of drugs are more water soluble than neutral form
-‐ They form more, and stronger, hydrogen bonds with water
-‐ However:
o Samples can be hygroscopic (draw in moisture from air)
o Can change pH of solution (important for injection and oral solutions)
o Reactions with packaging (glass and basic solutions)
o Different salts of a drug can work differently
o Salts interact with each other and precipitate out of solution
-‐ Most common salt forms of drugs:
o Acidic drugs – Na+, K+, Ca2+, Zn2+
o Basic drugs – Cl-‐, SO42-‐, PO43-‐

Salting out
-‐ Precipitation of peptides and proteins from solution at high salt concentrations
-‐ At high [salt], water molecules bind to the salt instead of the protein (not enough free water
available) – causes precipitation of protein molecules (less soluble solute)
-‐ Some drugs based on proteins and peptides – must ensure drugs do not precipitate

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-‐ Van der Waals radius – imaginary radius of an atom or molecule
o Physical space the drug/particle takes up
-‐ Hydrodynamic radius – imaginary radius of drug/particle and any bound
subparticles (e.g. water) that travel through the solution with the drug particle
-‐ Brownian motion – random movement of particles suspended in a liquid or gas
o Caused by collisions with molecules of the surrounding medium
o Rate of drug/particle movement through solution is directly related to size

Stokes – Einstein equation
-‐ Rate at which drug diffuses through solution is largely dependent on hydrodynamic radius and
solvent viscosity
!" Change Rate of drug
-‐ 𝐷 =
!!"# diffusion
o D = diffusion coefficient (m2s-‐1) Increase temperature Faster
o K = Boltzmann constant (1.38*10-‐23JK-‐1) Change form water to oil Slower
o T = temperature (K) Change from neutral Slower
o η = solvent viscosity (water: 1.232*10-‐3Pa S) drug to salt form
o r = hydrodynamic radius (metres) Make a nanoparticle Slower
formulation of the drug
Vapour pressure
-‐ Pressure of vapour above liquid when liquid and vapour are at equilibrium
-‐ Amount of vapour about liquid depends on intermolecular forces
o More bonding between molecules – less vapour formed – lower vapour pressure
-‐ Lower vapour pressure – boils at higher temperature
-‐ Higher vapour pressure – boils at lower temperature
-‐ 50/50 mixture of ethanol and water
o Does NOT mean mixture of vapour is also 50/50
o More ethanol molecules in air than water since
ethanol has a higher vapour pressure
-‐ 𝑃!"!#$ = 𝑋! 𝑃! + 𝑋! 𝑃!
o Ptotal = total pressure from all molecules in the gas/vapour phase
o XA = mole fraction of gas A
§ Total of mole fractions (XA + XB) must equal 1
o PA = vapour pressure of gas A
o Raoult’s Law

2 polar molecules 1 polar 1 non-‐polar 2 non-‐polar
H-‐bonding – keeps in liquid phase Repulsion – more molecules in Ideal conditions
gas/vapour phase Hydrophobic forces very weak;
no repulsion
Lower vapour pressure for both Higher VP No effect on partial pressures of
Higher BP Lower BP the gases/vapours

Freezing point depression
-‐ Dissolution of polar solute into a solvent results in drop in the freezing point of the solvent
o Salt + water – lowers freezing point, so water doesn’t freeze as easily
o Blood contains many polar molecules (proteins, salts) – lowers freezing point of blood
-‐ Size of FPD depends on solvent and amount of solute (no. molecules, not no. moles)
-‐ Any solution injected into vein, or eye drops – must have FDP of 0.52°C

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Physical factors affecting solubility

How drugs dissolve
-‐ High concentration of drug in the ‘diffusion layer’ (area close to the drug particle)
o However, drug molecules in solution ⇌ drug molecules back to drug particle
-‐ Only drug molecules at the solid particle surface can dissociate and dissolve
o Drugs dissolve into bulk solution

Factors affecting solubility
-‐ Size of the particles
o Smaller particles have higher SA:V than larger particles
-‐ Dispersibility of the solid particles – e.g. if they stick to each other
-‐ Porosity of the particles
o Holes within structure allows water access to inner parts of the particles
-‐ Crystalline or amorphous or a mixture of both
Amorphous Crystalline
No organised structure Organised structure
Generally more soluble Both polar and non-‐polar bonds are present
(less bonds to break)
Crystal type I Crystal type II

Polymorphism
-‐ Bonds between drug molecules in the solid state must be broken to dissolve
o Amorphous drugs almost always more soluble than crystalline
-‐ However, all systems try to move to the lowest energy state
o Over time, amorphous drugs can become crystalline
o Crystalline drugs can change into another form of crystalline
-‐ Polymorphism – where there exists more than one crystalline state for a drug
o Paracetamol – metastable polymorph II dissolves faster in water and is used for tablets
§ Heating converts into less desirable polymorph I
o Ritonavir – plate-‐like crystal is preferable over needle-‐like crystal
§ Needle-‐like form was very stable (didn’t change form) but less soluble

Solid drug production
-‐ Methods – spray drying, freeze drying, evaporation, precipitation
o Involves removal of solvent
o Produces amorphous material – fast drying – no time to form crystalline bonds
-‐ Solvates and hydrates – solvent trapped in solid drug particles
o Less soluble than anhydrous solid particles
§ Drugs are already bonded to solvent molecules

Chemical Kinetics
-‐ Used to determine:
o How fast a drug is metabolised or excreted
o How long radioisotopes will emit radiation within the body
o Shelf-‐life of drugs based on their rate of degradation
o How long after one drug is administered you have to wait before next drug can be given
o Drug release from controlled or modified release formulations and patches
-‐ For chemical kinetics, only non-‐reversible reactions will be considered


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Rate of reaction

-‐ How fast reactants are consumed or how fast products are formed
-‐ R (rate of reaction) = ∆products ÷ ∆time = −∆reactants ÷ ∆time
-‐ R = [P2] – [P1] / t2 – t1
-‐ Determined by:
o Order of reaction
o Temperature
o Activation energy
o Whether a catalyst is used

Reaction orders
Definition Reaction rate (R) Equation Units of k
Zero-‐ R not affected by conc. of 𝑅 = 𝑘 𝐴 = 𝐴 ! − 𝑘𝑡 Conc. ×
order reactants or products time-‐1
reactions
-‐1
First-‐ R depends on [one 𝑅 = 𝑘[𝐴]! ln
[!]
= −𝑘𝑡 or 𝐴 = [𝐴]! 𝑒 !!" Time
order reactant]1 [!]!
reactions
Second-‐ Type 1: Only one reactant 𝑅 = 𝑘[𝐴]! 1 1 Conc.-‐1 ×
= + 𝑘𝑡
order (A → B) [𝐴] [𝐴]! time-‐1
reactions
Type 2: Two reactants 𝑅 = 𝑘[𝐴][𝐵] 1 [𝐵][𝐴]!
ln = 𝑘𝑡
(A+B → C or A+B → C+D) [𝐵]! − [𝐴]! [𝐴][𝐵]!

-‐ For reaction A+B → C+D, R = k [A]x [B]y
-‐ Pseudo-‐first order reactions
o Some reactions that would normally be higher order reactions can be considered pseudo
first-‐order reactions
o E.g. aspirin + water → salicylic acid + acetic acid
§ R = k [aspirin] [water]
§ But in the human body, [water] is essentially constant and so can be removed
from the equation, making R = k [aspirin]
-‐ Example of type 2 second-‐order reaction
o Renaturation of DNA in solution – DNA fragments are heated and denature into single
strands (A and B). As the solution cools, the single strands recombine (renature) to form
double-‐stranded fragments

[A0] Starting concentration of reactant
[A] Concentration of a reactant after time (t)
K Rate constant
t Time


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Activation energy (Ea)

-‐ Activation energy – minimum amount of energy required to initiate a chemical reaction
-‐ Linear relationship between temperature and reaction rate
!!
!
o ln 𝑘 = ln 𝐴 − ! or 𝑘 = 𝐴𝑒 !!"
!"
o T = absolute temperature (K)
o R = gas constant
-‐ Determining activation energy
!! !! ! !
o ln = ( − ! )
! ! ! !

Half-‐life (t1/2)
-‐ Half-‐life of a reaction – time taken for the concentration of the reactant to decrease by half of its
original value
-‐ Only applicable to first and second order reactions
!" ! !.!"#
-‐ Half-‐life equation: 𝑡!/! = =
! !
o I.e. to calculate the half-‐life, only the rate constant is required
o Deriving the equation:
[!]
§ First-‐order reactions: ln = −𝑘𝑡
[!]!
§ Where [A0] is the initial concentration, [A] is half the original concentration
!"
§ Hence, ln = ln 0.5 = −𝑘𝑡
!""

Osmosis
-‐ Reverse osmosis – produce clean drinking water from seawater (using force)
-‐ Osmotic pressure – amount of external pressure applied to a solution to prevent it being diluted by
the entry of solvent via osmosis
o No net movement of water across membrane = solutions are at equal osmotic pressure =
iso-‐osmotic = equilibrium
-‐ Blood cells and serum – osmotic system
o Dissolved components – salts, proteins and drugs contribute to osmotic pressure
o Normal blood serum concentration is 308mOsM (milliosmolar)
-‐ Osmole – total number of dissolved components in a solution
-‐ Hypertonic – concentration of blood serum > of RBC
o Cells pump water out into blood serum
o Shrinks RBC (repairable)
-‐ Hypotonic – concentration in blood serum < of RBC
o System pumps water into the RBC
o Cell expands/bursts (irreparable)
-‐ Any solution for injection into bloodstream or ocular dosage form – must be isotonic – 308mOsM
o Either add NaCl or sugar
-‐ Energy drinks – when you sweat, you lose both water and salts
o Drinks are slightly hyper-‐/hypo-‐tonic – use salts or sugars to rebalance osmotic pressure
-‐ Osmotic pump – for slow drug release
o E.g. so patient doesn’t have to visit doctor too frequently
o Water enters through rigid semipermeable membrane causing contraction of the inner
flexible membrane holding the drug. This pushes the drug into the bloodstream

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Surfaces and Surface Interactions

-‐ Interactions between different particles or phases in a medicine can affect performance and API
o Solid-‐solid interactions – tablets, capsules
o Solid-‐liquid interactions – suspensions
o Liquid-‐liquid interactions – creams, lotions, ointments, emulsions
o Liquid-‐gas interactions – foams
-‐ Surface – any boundary where two or more phases meet and interact with each other
o E.g. water/air boundary, solid/liquid boundary (solid tablet in water), oil/water (oil
droplets in water or water droplets in water
o Shaving cream – air molecules trapped within foam interact with liquid

Surface forces Explanation
Cohesion Intermolecular force between like molecules, helping them to bond and stick together
Adhesion Intermolecular forces between two different types of molecules, particularly particles
or surfaces
Surface tension Property of liquid that causes its surface to appear to be enclosed in elastic skin
Aim to minimise surface area (surface particles attracted to bulk of liquid
Interfacial Occurs when surfaces of two immiscible liquids come into contact, and are not
tension attractive
-‐ E.g. oil and water – pull away from each other, causing interfacial tension
-‐ Water droplets on leaves – bead-‐like shape of water molecules

-‐ Stronger cohesive forces = stronger surface tension
o Water – highest cohesive force and surface tension – due to hydrogen bonds
§ Strong surface tension – stops water from spilling over when glass is full, allows
insects to walk along the surface
-‐ Strong adhesive forces act to reduce surface tension
o E.g. water being drawn up roots in trees
-‐ Wettability and tablets
o Adhesive forces are important in the function of tablets when swallowed
1. Water molecules adhere to the surface of the tablet
2. Water is taken up by the tablet
3. Swelling of tablet causes it to disintegrate, thus releasing the drug

Rheology
Rheology -‐ Study of particle flow and deformation
-‐ Affects drug dissolution, bioavailability, stability of suspensions and emulsions
Viscosity -‐ Solution’s resistance to flow or movement
-‐ ↑ solute, temperature or humidity = ↑ viscosity
Stress η -‐ Force applied to a material that can cause material deformation
Shear stress σ -‐ Component of stress that causes deformation of material by slippage along a plane
parallel to the imposed stress
Shear strain -‐ Degree of deformation
Shear rate γ -‐ Change in shear strain with time, e.g mixing, shaking


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-‐ Closest to stress experiences highest shear rate

-‐ Reference plate – e.g. side of bottle, stomach wall
-‐ Boundary layer – region over which differences in velocity are observed
o Depth of layer depends on viscosity of solution and applied force
§ Large stress = smaller boundary layer
§ Increase viscosity = larger boundary layer
o Thickness of layer affects energy and mass transfer
§ Affects diffusion, and hence how fast a drug dissolves
§ Small boundary layer = diffuses quickly = dissolves quickly
-‐ Eating food can affect viscosity in stomach – affects dissolving of drug

Newtonian flow
-‐ Stress = viscosity × shear rate
o σ = η γ
-‐ Viscosity is independent of shear rate
-‐ Applies to simple liquids and very dilute solutions, e.g. eye drops
-‐ Slope of line = viscosity (for all graphs)

Non-‐Newtonian Explanation and examples
Plastic -‐ ↑ shear rate = ↓ viscosity – “shear thinning”
-‐ E.g. some ointments, flocculated suspension
Pseudo-‐plastic -‐ Viscosity shows Newtonian flow at low shear rates, but decreases above a critical
shear point
-‐ Becomes less viscous the harder you shake it
-‐ E.g. long high MW solutes, polymer strands
Dilatant -‐ ↑ shear rate = ↑ viscosity – “shear thickening”
-‐ E.g. high conc. of small deflocculated particles
-‐ Issues when high speed mixers are used – more viscous with mixing/shaking
Thixotropic -‐ Viscosity decreases at constant temperature and constant shear rate over time
(pseudoplastic or -‐ Returns to original state in a finite time when shear is removed
dilatant) -‐ Fluid is thixotropic if stress is not achieved when shear rate is applied (there is a lag)
-‐ E.g. polysaccharides – need to break many H-‐bonds which takes time

Application to pharmacy
-‐ Suspensions
o Medicine is easily administered by pouring from bottle or pushed through syringe
o Sedimentation is prevented or retarded
o Product has elegant appearance
-‐ Emulsions – pseudo-‐plastic properties
o Creams, lotions and ointments – harder you rub, the easier to apply


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Colloids and suspensions

Colloid -‐ System in which finely divided particles are dispersed within a continuous medium that
1nm – 1µm prevents them from being filtered easily or settled rapidly
Suspension -‐ System in which microscopic (liquid or solid) particles are dispersed throughout a less
1µm – 50µm dense liquid or gas from which they are easily filtered but not easily settled due to
viscosity or intermolecular interactions

Suspensions
Reasons for -‐ More stable than solutions
use -‐ Dose flexibility
-‐ Easy to swallow
Usage -‐ Oral suspensions, topical preparations (lotions), aerosols, injections
-‐ E.g. paracetamol syrup – solid paracetamol suspended in syrup to mask bitterness
Requirements -‐ Suspensions should not settle rapidly
-‐ Particles should settle on standing, not cake (particles fuse together)
-‐ Easily re-‐dispersed
-‐ Not too viscous (pour from bottle or through needle)
-‐ Acceptable taste, odour, colour
-‐ Optimal pharmacological properties
Suspension -‐ Depends on density and concentration of particles
medium -‐ Product requirements – viscosity, liquid choice, etc.
-‐ Adding suspending agents to increase viscosity
-‐ Addition of flavours, colours and perfumes
Particle size -‐ 1–50µm, but typically 1-‐5µm
-‐ Smaller particle = better suspension (however very fine particles risk caking)
Particle shape -‐ Uniform particles form more stable suspension that asymmetric plate or needle-‐
shaped particles
Agglomeration -‐ Larger particles may stick together prior/post settling – results in rigid cohesion
-‐ If agglomerates are not broken, the suspension properties change
Flocculation -‐ Prevent rigid cohesion by forming loose aggregates
(ideal for -‐ Particles come close together, but don’t stick – type of agglomeration
pharmaceutical -‐ Lattice type structure – resists complete settling, reduces caking, aids redispersion
formulations) -‐ However, tends to settle more rapidly – but easily redispersed
-‐ E.g. negatively charged colloidal particles repel – add cations to neutralise and
allow particles to flocculate and settle out
-‐ Greater size (>1µm) – has surface
o Surface properties must be considered
o Tend to clump together to reduce SA and hence surface energy
-‐ High surface area = high surface free energy

Stoke’s equation – sedimentation of suspensions
-‐ For dilute suspensions containing <2%w/v
-‐ Limitations – assumes:
o Ideal, uniform particle size
o Spherical particles
o Dilute suspension
o No chemical-‐physical attraction between mediums
-‐ Alter properties of particles before altering medium
↑ particle = ↑ sed. rate
o Adjust primary particle size and particle size distribution
↑ particle density = ↑ sed. rate
o Increase separation – reduce agglomeration
↑ viscosity = ↓ sed. rate
o Particle engineering


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Physical stability of suspensions

-‐ Condition in which particles do not aggregate – remain distributed throughout dispersion medium
-‐ Resuspended with moderate agitation
-‐ Small particles = high SFE – stabilise system by reducing surface free energy
o Reduce interfacial tension by adding surfactants
o Intentional regrouping particulates – controlled flocculation/aggregation
-‐ Particles in medium are generally insoluble – become charged
o Selective adsorption of ionic species onto particles (usually –OH)
o Ionisation of groups on particles (e.g. COOH) – influenced by pH

Electric double layer forces
-‐ In solution, surface charge of particle affects distribution of surrounding ions
o Causes increase in concentration of counter-‐ions
o Region over which influence extends – electrical double layer
§ Stern layer – inner region of strongly bound ions
§ Diffuse layer – outer layer of loosely associated ions
-‐ As particle moves through solution, ions move with it
-‐ Slipping plane – boundary (within diffuse layer), beyond which the ions don’t move with particle
-‐ Zeta potential ξ
o Potential difference between that at the slipping plane, verses a point in the bulk fluid
away from the double layer
o Determines stability of a colloidal suspension
§ Large (±) ξ – electrically stable
§ Low ξ – tendency to coagulate or flocculate increased
-‐ Henry equation

↑ ξ = ↑ repulsion (thick diffuse layer, large difference in

charge between the two phases)

DLVO theory
-‐ Electrostatic repulsion and Van der Waals attraction forces between hydrophobic colloids
-‐ Overall energy state of suspension VT = VA + VR
o VA – attractive Van der Waals forces – varies inversely with distance
§ Tend towards aggregation
o VR – repulsive electrostatic forces – varies exponentially with distance
§ Tend towards separation
VR 1o max 2o min
Reduce Decreases Deepens
Increase Increases Reduces

Inter-‐particle distance Forces Particles
Short Attractive dominates (1o min) Agglomerate
Increased (+ sufficient energy input Repulsive dominates (max) Remain in suspension
to separate particles)
-‐ If inter-‐particle distance is increased further, repulsive force effect is reduced, particles tend to be
weakly attracted (2o min.) – flocculated particles (ideal)
o Addition of small amount of energy allows fully dispersed solution to be obtained
-‐ Flocculated particles are trapped in the 2o minimum
-‐ 1o maximum must be sufficient to make the particles stay in the 2o min and not fall into the 1o min
o I.e. barrier between 1o and 2o min

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Particles in water – charge effects

-‐ Shake – energy – dispersed
o Repulsive charges keep particles apart
o Particles gradually fall and compress at base
o Smaller particles fill gaps through sliding
o Low sedimentation volume – cake – increases in size over time
o Difficult to re-‐suspend
-‐ Reduce zeta potential by adding counter ions to reduce repulsive force
o Results in flocculation stability, large sedimentation volume, reduced caking
o However, adding too many counter ions will result in caking

Flocculation control
-‐ Flocculation – desirable in physical stability of formulation
-‐ Deflocculation – good suspension but agglomerates on settling – difficult to re-‐suspend
-‐ Over-‐flocculation – large bulky agglomerates, unsightly, rapid settlement
Particle size control -‐ Stoke’s equation
-‐ Increase particle size = increased settling rate
Use inorganic -‐ Modifies zeta potential
electrolytes -‐ Schultz-‐Hardy rule: ability of electrolyte to flocculate hydrophobic particles is
directly related to valence of counter-‐ions
o Divalent > monovalent
Add surfactants -‐ Make insoluble particles mix with liquid phase
-‐ Ionic – cause flocculation or de-‐flocculation depending on particle charge
o If particle opposite charge to surfactant, neutralisation results in
flocculation
Add polymers -‐ Linear, branched chain molecules form gel-‐like networks within aqueous
E.g. starch, silicates phase and adsorb to the dispersed molecules – increase flocculation

Measurement of suspension behaviour
-‐ F = Vu/Vo
o F = sedimentation volume
o Vu = ultimate volume of the sediment
o Vo = original volume of the suspension
-‐ In flocculate suspensions, flocs tend to fall together – produces distinct boundary between the
sediment and supernatant liquid
-‐ In deflocculated suspensions, no clear boundary formed, supernatant stays turbid for much longer
-‐ Sedimentation volume just gives the qualitative account of flocculation – normally, F < 1

Other additives Purpose
Sweetening agents -‐ Taste (sucrose, glycerol, sorbitol)
-‐ Alter Newtonian properties – affects rheology
-‐ Salt may affect flocculation
Humectants -‐ Substance used to retain moisture
-‐ Used in topical applications
-‐ May influence Newtonian flow
-‐ E.g. glycerol, polyethylene glycol, propylene glycol
Buffers -‐ Chemical stability
-‐ Tonicity
-‐ Physiological compatibility


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Emulsions
-‐ Colloid involving two immiscible liquids
-‐ Particles of one liquid uniformly distributed (dispersed phase) as droplets throughout another
(continuous phase)
o Thermodynamically unstable
-‐ Constituents of emulsions
o Aqueous phase, interface, non-‐aqueous phase
o Emulsifying agents – emulsifiers or emulsion stabilisers
o Preservatives
o Antioxidants
o Homogenisers – reduce particle size, raises viscosity of emulsion
-‐ Phase volume ratio
o Ratio of disperse phase volume to total volume
o Stable range is 30-‐60% of total volume
o If disperse phase >74% of total volume – leads to phase inversion and cracking
-‐ Oil in water emulsion (o/w) (e.g. milk)
o Easier to prepare – oil is relatively easy to disperse in aqueous continuous phase
o Solubility in oil phase
o Topical – washable, more cosmetically acceptable than w/o emulsions
o Oral – feel, aqueous volume and taste masking
o IV injections are o/w
-‐ Water in oil emulsion (w/o)
o Topical – oil base makes emulsion feel greasy, hydrating effect, cleaning effect
o Injectables – generally only depot
-‐ Cohesive force between the molecules of each separate liquid > adhesive force
o Thus, the two immiscible liquids fail to remain mixed
-‐ Identifying emulsion type – measure conductivity, dye tests (phenol red), miscibility test with water

Emulsion formation
-‐ Two competing processes
1. Disruption of the interphase between bulk and immiscible phases
2. Stabilisation of the dispersed phase once formed – emulsifying agents

Interfacial free energy of emulsification
-‐ Cohesive force of the individual phases = interfacial energy/surface tension at the boundary
between the immiscible liquids
-‐ Interfacial phenomena
o W = γΔA
§ W = surface free energy/work
§ γ = surface tension
§ ΔA = increase in surface area
o Cohesive force > adhesive force
o Net inward attraction of molecules into the liquid
o Surface tends to contract
o Results in interfacial or surface tension between the two immiscible phase, contributes to
large interfacial free energy
-‐ Agitation forms temporary emulsion
o ↑ Interfacial tension, ↑ surface area, ↑ surface free energy
o Phases reform when agitation stops because thermodynamically unstable


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Emulsifying agents
-‐ Role of emulsifying agents
o Emulsion formation
o Stability – form a film around the dispersed droplets
o Reduce interfacial tension
-‐ Mix 2 emulsifying agents – more stable interfacial films and good emulsions formed
-‐ Types of emulsifying agents – surface active agents, natural products, finely divided solid particles

Surface active agents – surfactants
-‐ Most effective emulsifying agents
-‐ Polar head: anionic, cationic, non-‐ionic, amphoteric
o Hydrophobic tail of variable length
-‐ Adsorbed at oil-‐water interfaces to form monomolecular films – reduces interfacial tension
-‐ Different uses depending on size of tail to head – Hydrophilic-‐Hydrophobic balance (HLB)
o Low: Antifoaming agents, emulsifying agents (water-‐in-‐oil)
o Medium: Wetting or spreading agents
o High: Detergents, emulsifiers (oil-‐in-‐water), solubilising agents
Anionic Cationic Non-‐ionic
Long chain organic Long chain organic cations Long chain alcohols, polyethers or esters of
anions polyhydric alcohols
pH dependent – pH > 8 pH dependent – pH 3-‐7 Less sensitive to pH
Only used in external Only used in external Vary degree of hydrophilic to phobic groups to
preparations preparations alter solubility – water soluble – stabilises o/w;
oil soluble – stabilises w/o
Not used with cationics Toxicity – antiseptic Low toxicity
Cheap Expensive

Natural products
-‐ Form a multimolecular film around the dispersed droplets of oil in o/w emulsion
o Acts as barrier to coalescence

Finely divided solid particles
-‐ Adsorbed at the interface between two immiscible liquid phases
-‐ Forms film of particles around dispersed globules
o I.e. particulate film is formed that prevents coalescence of the dispersed globules

Emulsifying agents Surfactants Natural Particles
o/w Sodium lauryl sulphate Acacia Veegum
Cetrimide Gelatin Bentonite
w/o Sorbitan esters Cholesterol Bentonite
Polyvalent soaps Wool fat, fatty alcohol Carbon black

Evaluation of emulsion stability
Agitation Increases rate of droplets meeting – thus decreases time-‐scale over which
collisions occur
Centrifugation Rapidly induces creaming or coalescence in potentially unstable systems
Temperature change Alternating between high and low temperatures, e.g. thaw-‐freezing cycles
-‐ Looking for: phase separation, viscosity, electrophoretic properties, particle size and count
-‐ Multiple emulsions – issues with stability due to complexity – likely to coalesce
o E.g. w/o emulsion – delayed action but viscous
o w/o/w – bulk phase is aqueous, but has similar effects


lOMoARcPSD|3031718
Physical stability
-‐ Issues relating to stability – interfacial tension and reduction of Gibbs free energy
-‐ Formulation considerations – density of liquids, particle size, volume density, viscosity
Stability issue Explanation Promoted by
Creaming -‐ Accumulation of droplets at top or -‐ Large dispersed globules
bottom of system (depends on density) -‐ Lower viscosity of continuous
-‐ Gravitational sedimentation phase – large difference in density
-‐ Re-‐dispersion achieved by shaking between the two phases
-‐ Possible breakdown of o/w interphase
Cracking or -‐ Coalescence of dispersed globules -‐ Add emulsifier of opposite type
breaking -‐ Serious type of instability -‐ Decomposition or precipitation of
-‐ Irreversible – re-‐dispersion not easily emulsifying agent
achieved by shaking -‐ Addition of common solvent
-‐ Disruption of the emulsifying system – -‐ Microbial action
film surrounding globules is destroyed -‐ Excess disperse phase
and globules tend to coalesce -‐ Temperature
-‐ Accurate dosage becomes impossible
Flocculation -‐ Globules form loose aggregates -‐ Zeta potential
-‐ Reversible -‐ Concentration of ions
-‐ Possible precursor of creaming -‐ pH of emulsion
coalescence -‐ Surfactants
-‐ Polymer
Phase -‐ Reversal or inversion in the phases -‐ Alteration in phase-‐volume ratio –
inversion -‐ Diverse phase ↔ continuous phase if dispersed phase conc. > 74% of
-‐ E.g. o/w emulsion → w/o emulsion total volume
-‐ Temperature change
-‐ Addition of substance that alters
solubility of emulsifying agent

Using HLB to make emulsions
-‐ HLB – hydrophilic-‐lipophilic balance value
-‐ Low HLB – soluble in oil
-‐ High HLB – soluble in aqueous
-‐ HLB values are additive – based on proportion of each component
-‐ HLB value of Emulgant blend should equal the required HLB of oily phase
1. Calculate total required HLB from oil phase
!!!"#(!)
2. Calculate percentages of emulsifies required using: ×100
!"#(!)!!"#(!)
3. Calculate amount of emulsifiers/emulgants required in formulation
Example: mL HLB required
Oil phase
Liquid parffin 30 12
Wool fat 5 10
Emulgant system 5
Tween80 15
Span80 4.3


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Preservatives in emulsions

-‐ Microorganisms can cause:
o Physical separation of phases
o Discolouration
o Gas formation and unpleasant odours
o Changes in rheological properties
-‐ Incompatibility between preservatives and emulsion ingredients
o Partitioning of preservatives between oil and water
o Must be unionised to penetrate bacterial membrane
o Must not bind to other components of emulsion system
-‐ Adequate concentration to prevent bacterial growth
-‐ Preferably bactericidal than bacteriostatic

Microemulsions/swollen micelles
-‐ Clear colloidal solutions (<100nm), thermodynamically stable
-‐ Dispersion of two liquid phases, stabilised by an interfacial film of surfactant
-‐ Relatively low viscosity
-‐ Form spontaneously with correct component concentrations – don’t need high shear like with
normal emulsions
-‐ Comprises of high concentration of oil/water and surfactant components
-‐ Issues – stable but difficult to make
o Size – requires very low interfacial tension to avoid coalescence
o Often used with co-‐surfactant
o If temperature is low, two phases exist

Liquid formulations – solutions as an oral dosage form
Advantages Disadvantages
Fast-‐acting (compared to tablets; no Solubility – some substances cannot dissolve directly
disintegration or dissolution required) in water
Dosage can easily be altered Subjectivity when measuring doses – dose accuracy –
how well patient can use/read syringe
Uniform – drug is uniformly distributed in liquid Chemical stability/disintegration
(unlike suspensions) -‐ Drugs more reactive in liquid than solid form
-‐ Microbial growth due to moisture
-‐ Important issues to consider
o Stability of active ingredient
§ Potential incompatibility between drug and excipients
o Solubility of AI and excipients
o Bioavailability – may be affected by additives used to enhance solubility
-‐ Amount of drug dissolved ST = D + D-‐ = unionised + ionised form


lOMoARcPSD|3031718
Aqueous solutions: enhancing aqueous solubility

pH adjustment
-‐ Increase ionisation to increase solubility
!! !"
-‐ For a weakly acidic drug: 𝑆! = 𝐷𝐻 +
[! ! ]
+
o Decrease [H ] to increase solubility, i.e. increase pH
!! !"# [! ! ]
-‐ Basic drug: 𝑆! = 𝐷𝑂𝐻 +
!!
-‐ Criteria for buffer selection
o Buffer is used if pH range of drug stability is small
o pH – if drug is neutral, adjusting pH won’t have any affect on ionisation
o Buffer capacity – capacity to resist change in pH
o Toxicity
o Compatibility with drug/excipients – e.g. if they react and precipitate
-‐ Buffer preparation
o Based on HA ↔ H+ + A-‐
1. Choose a weak acid, HA, having pKa ≈ pH at which buffer is to be used
[!! ]
2. Calculate ratio of to obtain desired pH (using Henderson-‐Hasselbach equation)
[!"]
3. Decide on concentration of [HA] and [A-‐] to obtain desired buffer capacity
4. Measure the pH

Co-‐solvency
-‐ Solute is more soluble in a mixture of solvents than in a single solvent alone
-‐ Purpose – solubilise unionised form
-‐ Dielectric constant of solvent – energy to separate two opposite charges in the solvent compared
to a vacuum (1)
o Inclusion of co-‐solvent – decrease dielectric constant
§ Reduces degree of dissociation of drug
§ Increases solubility of unionised drug
-‐ E.g. add organic co-‐solvent – lowers dielectric constant – solution more like organic solvent –
unionised drug solubilises
o ST = ↑D + ↓D-‐
-‐ For aqueous formulations, co-‐solvent must be miscible
-‐ Common co-‐solvents – ethanol, glycerine, propylene glycol, sorbitol, syrup
-‐ Choice limited by – toxicity, compatibility, irritancy, stability, solubility
-‐ E.g. phenobarbital is acidic – ionised in basic solutions
o Higher pH = higher % ionised
o As organic solvent is added, ionised drug is not as soluble – drop
in solubility (middle of curve)

Micellar solubilisation
-‐ Low concentrations – surfactants orientate at surfaces/interfaces
-‐ Critical micelle concentration (CMC) – micelles form
-‐ HLB value ≥15 are useful solubilising agents
-‐ Large excess of surfactant – toxic
-‐ Micellular solubilisation examples – polysorbates for fat-‐soluble vitamins, soaps for phenols
-‐ Optimum [surfactant] determined by max. [drug] which will form a clear solution at a given
concentration of surfactant

Chemical modification
-‐ Synthesise more water-‐soluble chemical derivative of drug
o Add hydrophilic group to drug structure without affecting receptor binding properties
o Add salts
-‐ Nanoparticles (<100nm) – smaller particle = greater solubility

lOMoARcPSD|3031718
Complexation
-‐ Drug + inclusion compounds = complex
-‐ Complex will be more water soluble
-‐ Inclusion compounds – cyclodextrins
o 3 types – α-‐, β-‐, γ-‐CD consist of 6, 7, 8 glucose units respectively
o The molecules in solutions form a structure with internal diameters 0.5, 0.6, 0.8nm
o Drug can fit inside complex cavity to solubilise (based on size – α is too small)
-‐ Usually form 1:1 complex with drug molecule via hydrophobic (–CH2 groups) interior cavity
-‐ Cyclodextrins used to enhance:
o Solubility
o Bioavailability – to be absorbed into body
o Chemical stability – drug molecule is inside compound – protected
o Taste-‐masking
-‐ Drawback – β-‐CD has nephrotoxicity; chemical derivatives can reduce toxicity but also changes
other properties
-‐ Complex equilibrium
o For a given drug D and a complexing agent C, xD + yC ↔ DxCy
o Total solubility, ST = [D] + [DC] = free drug (unionised/uncomplexed) + complex drug
!"#$
o 𝐾𝑠 =
!!! !
§ log 𝐷𝑥𝐶𝑦 = log 𝑘𝑠 + 𝑥 log 𝐷 + 𝑦 log 𝐶
§ Hold [D] constant and change [C] (or vice versa) to measure [DxCy]
§ Plot log[DxCy] vs. log[C] gives line with slope = y, intercept = ks
§ Plot log[DxCy] vs. log[D] gives line with slope = x, intercept = ks

-‐ Limitations of complexes
o Complex must be able to dissociate back into free drug when inside body: DC → D + C
o Complex needs to be absorbable

Additives Purpose
Preservatives -‐ Used if probability of microbial contamination (for multiple-‐use medicines)
-‐ Effective against broad spectrum of microbes
Viscosity -‐ Enhance palatability for patients or pouring properties (e.g. dose adjustment)
Density -‐ For spinal anaesthetics to avoid rise/fall in cerebrospinal fluid
Tonicity -‐ Avoid pain/irritation
Colour -‐ Product identification
-‐ Aesthetic appearance and masking (e.g. colour of safe degradation products)
-‐ Use natural products or synthetic dyes
Flavours -‐ Sweet, sour, salty, bitter
Sweeteners -‐ Sucrose, polyhydric alcohols, artificial sweeteners
Stability -‐ Chemical and physical degradation – visual inspection, spectrophotometry
-‐ Taste and odour – subjective assessment

Manufacturing
1. Dissolution of active ingredients and additives in water to form clear, homogenous solution
2. Filtration to remove particulates/solids
-‐ Raw materials must meet microbial content specifications
-‐ Purified water requirements – use UV sterilisation, filtration

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Non-‐aqueous solution formulations

Fixed (non-‐volatile) oils Castor, olive, maize, sesame oils
Drugs in oils often used for depot (slow-‐release) therapy
Alcohols E.g. salicylic acid lotion for external application
Polyhydric alcohols Propylene glycol, polyethylene glycol, glycerol – used as co-‐solvents w/water
Ethyl ether Used in collodions, not for internal use

Liquid preparations
Oral use External use – membranes
Mixture -‐ Eye drops
-‐ Usually aqueous -‐ Ear drops (antibiotics, antiseptics, wax softeners)
-‐ Solution or suspension -‐ Mouthwashes and gargles
-‐ Dose given in 5mL spoon
Elixirs External use – skin
-‐ Solution of a potent or nauseous drug -‐ Lotions (apply to skin without friction)
-‐ Usually with alcohol -‐ Liniments (massage into skin)
-‐ Dose given in 5mL spoon -‐ Paints – drugs dissolved in organic solvents, applied
Linctuses with small brush
-‐ Viscous preparation for cough relief -‐ Collodions – form tough, flexible film after solvent
-‐ High concentration of sucrose evaporates; castor oil used as plasticiser to make film
-‐ E.g. codeine Linctus flexible

Intermediate products
Peppermint and anise water Carminative properties (relieve flatulence)
Chloroform water Preservative
Tinctures Alcoholic extracts of drugs
Spirits Alcoholic solutions of volatile materials used for flavouring

Protein liquid formulations
-‐ Proteins – generally injectables
o E.g. insulin, human growth hormone
-‐ Surface active – tends towards surface of container
o Proteins: slight; small molecules: none (except surfactants)
o Difficult to get correct amount of drug when pouring/injecting – inaccurate dosing
-‐ Solutions – clear, faster onset, shorter time to peak and duration
-‐ Suspensions – cloudy, slower onset, longer time to peak and duration

Key objectives in formulation
-‐ Stable Excipient Purpose
-‐ Bioavailable (issue due to high MW) Zinc Stabiliser
-‐ Deliverable M-‐cresol Preservative, stabiliser
-‐ Achieve by optimising delivery (route of Phenol, m ethylparaben Preservative
administration) and formulation Phosphate, a cetate Buffer
Glycerol Tonicity
Protein instability – common degradation reactions
Oxidation Proteins containing AA’s: Tyr, Trp, Cys, His, Met or disulphide bonds
Deamidation Amid group turns into carboxylic acid
Gln → Glu; Asn→ aspartic acid
Aggregation Causes precipitation
Consequences -‐ Less effective – lose potency and bioactivity
-‐ Side effects/toxicity
-‐ May become immunogenic – treated as foreign protein, cause immune response


lOMoARcPSD|3031718
Insulin
-‐ Regular and rapid-‐acting soluble insulin
o Solubility enhanced by acidic pH 3-‐5 (insulin pI = 5.3)
o Asn-‐21A undergoes deamidation – chemically unstable
o Stability enhanced by preservatives – Zn2+, phenol, m-‐cresol
-‐ Intermediate/long-‐acting insulin
o Use solids – precipitates, crystals
o Suspension: solid → dissolution into hexamer → monomer → absorption
-‐ Chemical stability
o Deamidation – low and neutral pH due to Asn
o Aggregation – molecular aggregates formed due to covalent bonds
-‐ Physical instability
o Store in fridge – in freezer, ice crystals can damage proteins, preventing re-‐suspension

rhDNase (recombinant human deoxyribonuclease)
-‐ Degradation pathways:
API rhDNase
o Deamidation – alkaline pH
Tonicity NaCl
o Aggregation – acidic pH
Stabiliser CaCl2
-‐ Formulation – 2.5mL nebule
-‐ Delivery – nebulisation pH 6.3
o Localised treatment – direct delivery to airways Storage 2-‐8°C
o Disadvantages – long time to deliver dose

Aerosols
-‐ Dispersion of particles (liquid droplets, powder) in a gas (air, oxygen)
-‐ Aerodynamic diameter – determines whether or not drug enters lungs
o Diameter of a unit-‐density sphere with same sedimentation velocity as particle of interest
-‐ Fine particle mass/dose/fraction (%)
o Amount that is <5μm (considered “fine particle”)

Purpose of use
-‐ Rapid onset and direct delivery to lungs – localised action
-‐ Drug targeting – dose required is relatively low as no metabolism encountered, not diluted
o Low dose = less side effects

Human airways – dichotomous branching
-‐ Upper airways – oropharynx, larynx
-‐ Conducting airways: trachea (generation 0) → bronchi (gen. 1) → bronchioli
o Are ciliated – muco-‐ciliary clearance – drugs deposited here will be cleared by cilia
-‐ Target aerosols wherever it is needed
o For systemic delivery – deeper the better

In vivo characterisation
-‐ Deposition – measure using gamma scintigraphy (Tc-‐99m radiolabel)
-‐ Throughout the lungs: absorption
-‐ Ciliated airways – muco-‐cilliary clearance
-‐ Alveoli – (non-‐ciliated) – macrophage consumes solid particles


lOMoARcPSD|3031718
Deposition of aerosols

Inertial impaction ∝ D2Q -‐ ↑ Particle diameter = more likely to hit back of
mouth and be deposited there
D = particle diameter -‐ ↓ Particle diameter = less inertia = more likely to
Q = flow rate of aerosol continue further down airway path
Gravitational ∝ D2t -‐ Stoke’s equation
sedimentation -‐ ↑ Time = ↑ chance of going down airway due to
<3μm t = time gravitational pull
o Hold breath for a few seconds to increase
sedimentation
Diffusion (Brownian ∝ 𝑡/𝐷 -‐ Move around slowly instead of going down
motion) <1μm directly, due to random motion
Electrostatic ! !! -‐ q = attraction force
∝
attraction !
Interception -‐ Drug particle (usually elongated particles) get
caught and deposit on airway walls
-‐ Avoid deposition in oral pharynx – not site of action
-‐ Want deposition in alveoli
o Small particles deposited by diffusion
-‐ Impaction and sedimentation are used if deposition required in airway

Generation of aerosols
-‐ Metered dose inhaler (MDI)
o Formulation types – solution or suspension
§ Solution – co-‐solvent (ethanol) usually used
§ Suspension – suspending agent (e.g. surfactant); co-‐solvent helps dissolve
surfactant in propellant
o Propellant BP <0; ethanol BP = 70
§ Evaporation will be slower as ethanol raises the BP
§ Particles may not be inhalable – fine particle fraction can be altered due to
presence of ethanol
o High density – deposits/settles – need constant shaking
o Density too low – creaming, particles all at the top – also need constant shaking
o ↓ Actuator orifice diameter = ↑ diameter of propellant particles = ↓ fine particle fraction
§ Particles exit faster, so duration is decreased
-‐ Spacers (add-‐on device)
o Avoid timing/coordination issues
o Slow down speed of aerosol coming from inhaler – less drug impacts back of mouth, more
gets into lungs – less medication required for effective dose to reach lungs
-‐ Nebulisers – air jet, ultrasonic
o Air jet nebulisers
§ Compressed gas expands, creating vacuum which draws liquid up to the gas
§ Particles are dispersed – aerosol generated
§ Large particles hit baffle and return down to the bowl. Only small particles can
avoid baffle impaction, and are released
§ Particle size is reduced if airflow is increased
o Ultrasonic nebuliser
§ Liquid sits on ultrasonic crystal which is connected to electricity
§ Vibration at ultrasonic frequency turns liquid into spray and is released
§ Particle size decreases as frequency increases
§ Issues – ↑ frequency = ↑ energy = ↑ heat – need to consider thermal stability


lOMoARcPSD|3031718
Parenteral delivery
-‐ Drug delivery through injection or infusion directly into tissues, tissue spaces and vessels
o Avoids alimentary canal (intestines) – does not include ear, eye, skin, inhalation
-‐ Infusion – continuous injection, e.g. IV drip
-‐ Therapeutic action is more predictable than that of oral drug administration
-‐ Can provide sustained drug release (e.g. oily substance in IM injections)

Reasons for use
-‐ Local drug delivery and effect needed – minimise side effects, lower conc. drug needed
-‐ Rapid therapeutic action of drug – e.g. emergency
-‐ Ensure delivery of accurate and adequate dose – no interaction with food, GI tract – more reliable
-‐ Condition of patient does not allow for other routes – e.g. patient unconscious
-‐ Drug cannot be absorbed, or can be degraded by digestive system
-‐ Provide rapid correction of fluid
-‐ To test new drugs – bioavailability more reliable

Routes of administration
-‐ Closest to skin surface to furthest: intradermal, subcutaneous, intravenous, intramuscular

Intravenous (IV)
-‐ Immediate pharmacologic effect
o E.g. in emergency; blood transfusions
-‐ Continuous administration (infusion)
-‐ Can use large volumes of fluid – up to 500mL at once
-‐ Mostly aqueous solution
o Suspension particles and oily solutions – cause emboli
-‐ Precautions
o Thrombosis, embolism, phlebitis, infiltration, extravasation
o Injection of contaminants
o Uncontrolled administration – e.g. forget to turn IV drip off

Intramuscular (IM): muscle tissue
-‐ Slow action than IV but longer lasting
-‐ Aqueous and oily solution, suspension, emulsion
-‐ Volume 2-‐4mL
-‐ Precautions – entering blood vessel (suspension particles), striking peripheral nerves
-‐ Angle of needle should be close to 90° to reach muscle

Subcutaneous (SC): injection into loose fatty tissue below skin
-‐ Local drug delivery – for drug that cannot be administrated orally
-‐ Absorption is slow and less predictable
-‐ Self-‐administration is possible
-‐ Not used for aqueous or oily suspensions
-‐ Volume <1mL
-‐ Precaution – infection and allergic response at injection

Intra-‐dermal (intra-‐cutaneous): injection into the dermis
-‐ Absorption is slow and unpredictable
-‐ Vaccines or diagnostic tests
-‐ Volume <0.1mL
-‐ Precautions – infection and allergic response at injection


lOMoARcPSD|3031718
Intra-‐arterial: injection or infusion into an artery

-‐ Immediate and local delivery and effect – target particular organ
o Whereas IV – drug carried to lungs
-‐ Used for diagnostic purposes (e.g. radiopaque substance)
-‐ Used for organ-‐specific chemotherapy
-‐ Precautions
o Extremely hazardous route – drugs will not be filtered or diluted by lung
o Drug must not contain contaminants – high risk of infection and emboli
o Risk of damage to arterial wall and haemorrhage

Intra-‐cardiac: directly into cardiac muscle or valve
-‐ Emergency treatment only (e.g. cardiac arrest)
-‐ Not recommended if better route is available
-‐ Precautions – risk of damage by the trauma of injection, haemorrhage, arrhythmia

Intra-‐spinal
-‐ Used for access into or around spinal cord
-‐ Volume <20mL
-‐ Should only be attempted if other routes are not applicable
-‐ Precautions
o Risk of permanent and serious neurological injury
o Risk of inflammatory response
o Must not contain any contaminants, neutral pH, and isotonic
-‐ Epidural space – injection of anti-‐inflammatory medicine or infusion of local anaesthetics
-‐ Subarachnoid space – withdraw cerebrospinal fluid or delivery of antibiotics

Intra-‐ventricular: injection or infusion directly into lateral ventricles of the brain
-‐ Treatment of infections or cancers involving the membranes and cerebrospinal fluid
-‐ Provides a larger cerebrospinal fluid than intra-‐spinal route – minimises risk of host reaction

Intra-‐articular: directly into synovial fluid or joint cavity
-‐ Treatment of pain and inflammation
-‐ Precaution – risk of infection due to low blood circulation

Ophthalmic injection
-‐ Treatment of infections and retinal diseases; anaesthesia of eyeball; pupillary dilation
-‐ Injection <0.2mL
-‐ Precaution – risk of damage to optic nerves, retinal detachment, necrosis, cataracts, haemorrhage
-‐ 4 routes – intra-‐cameral, intra-‐vitreous, intra-‐ocular, sub-‐conjunctival

Choice of route of administration as a function of a drug’s characteristics
-‐ IV and IA – drug should be completely soluble
o Avoid suspensions with fine particles
o Drug in non-‐aqueous vehicle are mostly administrated via IM and SC
-‐ Parenteral routes other than IV – limited max. volume of medication (usually <10mL)

Parenteral routes vs. Oral administration
Advantages Disadvantages
Rapid onset Administration often difficult/painful -‐ invasive
Local drug delivery Drugs are usually more expensive
Absorbed dosage and action more predictable Side effects usually more severe –
hypersensitivity reaction
Can be given to unconscious and nauseated patients Risk of infection


lOMoARcPSD|3031718
High to low Reason

Safety Oral > SC > IM > IV Damage tissues/vessels
Patient convenience Oral > SC > IM > IV
Cost of drug IV > IM > SC > Oral Parenteral needs sterilisation
Predictability of action High/reliable – IV > IM > SC > Oral – Oral interacts with enzymes/food
low/variable
Onset of action Immediate – IV > IM > SC > Oral – delayed
Patient compliance IV > IM > SC > Oral Professional administration
Interactions with food Risk – Oral > IV = IM = SC – no risk
Volume of drug Oral = IV > IM > SC
Availability of IM > Oral > SC > IV
sustained release

Devices for parenteral administration
Needle -‐ Made from stainless steel
-‐ Tips are angular with different bevel form
o Standard bevel – easier penetration, harder to control positioning
o True short bevel – easier control
Catheter or cannula -‐ Tube made from flexible plastic, e.g. PVC
-‐ Eliminate need for repeated punctures; prevents damage by needle
-‐ Allows for continual infusion
-‐ Risk – infections
Syringe -‐ Mostly plastic and are disposable
Implantable devices -‐ Provide long-‐term access, e.g. chemotherapy
-‐ Risk of morbidity – fracture of catheters, infection, irritation, emboli
Implantable pump -‐ Installed under the skin to administer a steady, adjustable dose of drugs
-‐ Mostly used for insulin or chemotherapy drug administrations
-‐ Advantages:
o Delivery of an accurate and continuous dose of drug
o Avoid need of repetitive injection
o Localised delivery
-‐ Disadvantages – pumps clogging, infection, high price

Hazards and complications
Sepsis
-‐ Presence of pathogenic microorganisms or their toxins in blood or tissues
-‐ May be localised, systemic and/or metastatic
-‐ Contamination of product (prior or during use), delivery system, or entry point of injection

Thrombosis
-‐ Formation of blood clot in a vein or artery – more dangerous in artery
-‐ Caused by:
o Trauma in vessel wall – injury at injection site, low pH, hypotonic, immune response, toxic
o Changes in blood flow – big needle in a small vessel, drug insolubility, particulate matter
o Changes in blood composition – pH, osmotic property (both hypo-‐ or hypertonic)

Phlebitis
-‐ Inflammation of vein
-‐ More common in IV infusion – needle remains in same vein for several days
-‐ May cause thrombosis
-‐ Causes – blood vessel injury, low pH, hypotonic solution, particulate matter

Bleeding – caused by damage/rupture of blood vessel

lOMoARcPSD|3031718
Particulate matters (>7μm)

-‐ E.g. glass and rubber
-‐ Large quantities can cause phlebitis or inflammation in tissue

Physico-‐chemical properties of injection
pH:
-‐ Ideally physiological pH, but some drugs are stable only in acidic or basic conditions
-‐ Extreme pHs may cause pain, inflammation, thrombosis
-‐ Volume and rate of injections with extreme pHs must be controlled
Osmotic pressure:
-‐ Hypertonic – cell shrinks; hypotonic – cell bursts
-‐ Although isotonic injections or infusions are preferred, many products are hypertonic
o Isotonic solution requires large amount of water – difficult administration
-‐ Hypertonic solution – use small volumes, inject slowly
-‐ Solution for intra-‐spinal or intra-‐ventricular injections should be isotonic

Drug incompatibilities
-‐ Adverse side effects – inflammation, thrombosis, precipitation (causing emboli)
-‐ May result in loss of drug activity and effectiveness

Hypersensitivity
-‐ May occur with almost any drug due to previous exposure to the agents
-‐ Immediate or delayed reaction
-‐ Can cause local or systemic symptoms – itching, skin lesion, nausea, vomiting, shock

Over-‐dosage
-‐ High risk in IV infusion
-‐ Fluid overload can cause heart failure and pulmonary oedema
-‐ Parenteral drugs cannot be easily neutralised

Air Emboli
-‐ Air in blood vessels
-‐ Measures to reduce risk of air emboli:
o Purge all air bubbles from syringe or IV line
o Discontinue the infusion before the tubing is empty
o Permit infusing tubing to drop below the level of the infusion site
o Make sure all attachments fit tightly
o Extremity receiving infusion should not be elevated above the heart

Infiltration and extravasation
-‐ Infiltration – injection of substance into surrounding tissue
-‐ Extravasation – leakage of substance from blood vessel into surrounding tissue

Formulation
Physical forms of injection (or infusion)
Injection -‐ Liquid preparations that are drug solutions
-‐ Add dry solid with suitable vehicle (solvent)
Injectable emulsion -‐ Liquid preparation of drug dispersed in a suitable emulsion medium
Injectable suspension -‐ Liquid preparation of solid fine particles suspended in suitable liquid
-‐ Dry solid


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Emulsion
-‐ Mixture of ≥ 2 immiscible liquids in which one is dispended in the other as microscopic droplets
-‐ Very difficult to prepare emulsion injection
-‐ w/o emulsions – prolonged drug release (IM injection)
-‐ o/w emulsion – safe IV injection of oily materials

Suspension
-‐ Dispersion of insoluble solid particles which are surrounded by liquid
-‐ Difficult to prepare suspension injection
-‐ Principally used for IM and SC (rarely) injections
o Risk of thrombosis and emboli for other routes
-‐ Can be either oil or water based

Dried forms
-‐ Dry form (powder) can be dissolved in a vehicle (solution) or suspended in a vehicle (suspension)
-‐ Used when drug stability in liquid form is a problem
-‐ Methods of preparation
o Powder filling – filling sterile powder into individual containers under aseptic conditions
o Freeze drying – sublime water from frozen state to form powder directly in container
1. Dissolve drug and sterilise solution
2. Place sterile solution into individual sterile containers
3. Freeze solution
4. Drying: apply a vacuum and heating to sublime the water

Additives Purpose Examples
Antimicrobial Inhibits m icrobial c ontamination Benzyl alcohol, phenol
Buffer Prevents changes in pH Phosphates (pH 7.2),
-‐ pH changes due to degradation reactions, interaction with carbonate (6.4)
container, absorption of gases
Antioxidant Protects against oxidative degradation of drug Ascorbic acid,
-‐ Antioxidants have lower oxidation potential than drug and bisulphites
so are preferentially oxidised
Chelating agent Removes free toxic metal ions by forming compounds EDTA
Tonicity Adjusts osmotic pressure of injection to isotonic solution
Surfactant In suspension – prevent crystal growth Lecithin
In emulsion – inhibit agglomeration of microscopic droplets

Volume of injection dependent on:
-‐ Physico-‐chemical properties of injection – solubility of drug, pH, osmotic properties
-‐ Route of administration
-‐ Convenience of administration
o IV infusions are not worth setting up if <250mL

Vehicles
-‐ Adequate viscosity
-‐ Inert and non-‐toxic
-‐ Maintain solubility of drug
-‐ Chemically and physically stable
o No interference with active agents, additives or container
-‐ Drugs in water vehicles have faster onset of action than in oily vehicles
-‐ Oily vehicles give a depot effect – can release drug for longer time, ideal for steroid drugs


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Aqueous vehicles
-‐ Ideal – well tolerated by body
-‐ Administration by any route
-‐ Limitations – require partial/total replacement by oily vehicle, e.g. co-‐solvent
o Chemical degradation of certain drugs in water – hydrolysis, oxidation
o Poorly water soluble/insoluble drugs
Water for injection -‐ Fresh water purified by distillation or reverse osmosis
-‐ Pyrogen free – pyrogen causes erythema at injection site, pain, ↑ temp.
-‐ Store in tight containers outside of microbial growth temperatures
-‐ Does not need to be sterile
Sterile water for -‐ Used as solvent for already sterilised drugs
injection -‐ Can contain anti-‐microbial agents
Bacteriostatic water -‐ Water for injection + suitable anti-‐microbial agents
for injection -‐ Volume use <5mL – toxic effect of anti-‐microbial agents
-‐ Should not be used in neonates
Sodium chloride -‐ Sterile and isotonic solution of NaCl in water
injection (normal -‐ Used to flush catheter or IV line
saline) -‐ Used as solvent for already sterilised and packaged medications (powders)
Ringer’s injection -‐ Sterile solution of NaCl, KCl, CaCl2 in water – similar [salt] to body fluids
-‐ IV: vehicle for infusion of other drugs
-‐ IV: replenish electrolyte or increase plasma volume
Lactated ringer’s -‐ Ringer’s solution with sodium lactate
-‐ IV: replenish electrolyte or as a systemic alkaliser

Non-‐aqueous vehicles (mainly oil-‐based)
-‐ Fixed vegetable oils (corn, sesame), propylene, glycol, alcohol, glycerine
-‐ Used when aqueous vehicle cannot be used
-‐ Mostly for IM injections
-‐ Limitations:
o Not suitable for IV, IA, Intra-‐spinal
o Too viscous in cold weather to administer
o Causes pain at injection site
o Delivery devices become oily – difficult to clean
-‐ Requirements of fixed vegetable oils
o Stable and clear during refrigeration
o No mineral oils (e.g. paraffin)
o Free from rancidity (decomposition of lipids by hydrolysis/oxidation)

Drug release
Factor How it affects drug release
Diffusion and -‐ In aqueous solution/suspension – drug diffuses/dissolves into tissue fluid or
dissolution bloodstream
-‐ Higher drug dissolution/diffusion = higher drug release
Partition -‐ Drug molecule partitions into water phase (tissue fluid) – K = Cw ÷ Co
coefficient of -‐ Partitioning of drug from tissue fluid into lipid cell membrane – K = Co ÷ Cw
drug -‐ Drug with low P.C. – remains in tissue fluid
-‐ Drug with higher P.C. – passes into membrane – higher rate of absorption
Physiological -‐ Blood and lymph circulation, choice of muscle, movement of patient
factors -‐ Greater blood flow around injection site = higher drug absorption
Route of -‐ Rapid release – IV, intra-‐spinal
administration -‐ Slow release – IM, subcutaneous
Particle size -‐ Large particle size = slower drug solubility = slower absorption


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Effects of physical form of drug on release (fastest to slowest)
Aqueous solution

Aqueous
suspension

Oil-‐based
solution

o/w emulsion

w/o emulsion

Oily suspension
(only for IM –
depot)

Role of lung in drug distribution
-‐ Drugs administered by IM, IV and SC first pass through lung via venous/lymphatic transport
-‐ If drug is partitioned into lung tissue, lung capillary beds:
o Filter the drug
o Act as drug reservoir – gradual release (depot effect)
o Portion of drug may be cleared by exhalation

Packaging
Labelling requirements
-‐ Product name
-‐ Liquid product – % of drug or amount of drug in specified volume
-‐ Dry product – amount of drug and volume of liquid to be added to prepare solution or suspension
-‐ Route of administration
-‐ Storage instructions
-‐ Expiration date
-‐ Name and quantity of all added substances
-‐ Name of manufacturer/distributor
-‐ Identifying lot number
-‐ Whether for human or animal use
-‐ Sufficient area of container should be free from labels to permit inspection of the contents

Container ideal properties
-‐ Does not affect the drug
-‐ No changes during sterilisation
-‐ Protective from light if necessary
-‐ For parenteral products, should be transparent – easy to examine the contents
o E.g. check if precipitation has occurred
-‐ Economical


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Containers Use Purpose

Ampoules Single -‐ Made from neutral or soda glass
-‐ Sealed by heat-‐fusion to exclude micro-‐organisms
-‐ Advantages
o Bought in sterile sealed unit
o Filled and sealed in one operation
o Easily leak-‐tested
-‐ Risks – splinters on opening; inject glass particles into patient
Cartridges Single -‐ Cylindrical glass tubes sealed by rubber at each end – insert into syringe
Pre-‐packed Single -‐ No danger of glass splinters
syringe -‐ Easy to use
Vials Multiple -‐ Rubber capped – allows multiple withdrawal
-‐ Easy addition of solvent
-‐ Not prone to glass contamination
-‐ Disadvantages
o Risk of particle contamination from rubber closure
o Less reliable seal
o Higher risk of bacterial contamination
o Does not offer cost and simplicity of ampoules

Single-‐dose containers Multiple-‐dose
Completely airtight (no bacterial contamination) Allow variation in dose
Essential for drugs that need to be packed in In-‐drawing of air may lead to bacterial
nitrogen atmosphere contamination
No solvent loss Possible particle contamination
Difficult to manipulate

To minimise adsorption of substances of an injection into plastic containers and rubber closures, soak the
container or closure in a solution containing the substances that are liable to be absorbed.

Sterilisation
-‐ Destruction/removal of living organisms and their spores from pharmaceutical preparation
-‐ Product is either sterilised or not – no degree of sterilisation
Method How Advantages/disadvantages
Steam Autoclave, using steam -‐ Easy to control
under pressure -‐ Unsuitable for heat and moisture sensitive materials, oil-‐
based products
-‐ Heat + steam – denatures proteins on bacterial surfaces
Dry heat Oven -‐ Higher temperature and longer exposure than steam
sterilisation
-‐ Used for moisture-‐sensitive products
Filtration Physical removal by sieving -‐ Used for heat-‐sensitive solutions
or adsorption mechanisms -‐ Not invasive – doesn’t damage solution
-‐ Removes particles AND microorganisms
-‐ Aseptic sterilisation
-‐ Risk of adsorption of drug onto filter
-‐ Takes long time – only for sterilising small quantities
-‐ Cannot sterilise container
Radiation Gamma ray exposure to -‐ Suitable for parenteral devices or containers
by ionising destroy DNA of cells -‐ Expensive – need highly specialised equipment
-‐ Possible radiation of products and container
Gas Exposure to ethylene oxide Toxic gas – used to sterilise packaging only


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Removing pyrogen
-‐ Pyrogens – thermo-‐stable, water-‐soluble (cannot distil water), unaffected by common anti-‐
microbial agents
o Cannot be removed by sterilisation
-‐ Pyrogen-‐free water – prepared by distillation
o Oxidise volatile pyrogens by permanganates

Sources of contamination during manufacturing
Source Precautions
Air Cleanroom or laminar hood – airflow to filter out particles which may contain
microbes on them
Breath Use mask, avoid sneezing, talking
Skin Wear gloves
Hands and forearms washed with detergent
Hair and clothing Wear sterile gown and covered shoes
Tie hair up, wear cotton cap
Working surfaces Disinfected

Auricular (ear) delivery
Purpose of auricular delivery
-‐ Unlikely to use systemic treatments for or via the ear
-‐ Local treatments – topical administration for:
o Infections
§ Break in skin can lead to infection (naturally acidic skin is barrier to infection)
§ Excessive moisture and shampoos in ear can alter skin’s protective properties
§ Infection of middle ear (otitis media) or outer ear (otitis externa)
§ Analgesics/local anaesthetic, antibiotics, anti-‐inflammatories
o Build up of ear wax (cerumen)
§ Primary component is keratin (from dead skin cells) – not sloughed away from
rubbing and contacting surfaces like the skin on rest of the body

Application of auricular dosage forms
1. Clean and dry ear, lie with affected ear pointing up
2. Patients with minimal swelling of canal – drop solutions directly into canal
3. If swelling narrows canal – saturate sponge wick or ribbon gauze with drop and insert into ear
-‐ Liquid formulations are preferred
-‐ Container can be warmed to reduce viscosity of solution
-‐ Ear ointments are less common – can obstruct canal
-‐ Must be sterile (not necessarily isotonic)
-‐ Usually contain water, glycerol, propylene glycol, diluted ethanol as solvent
o Ethanol evaporates quickly – don’t want water/liquid left in the ear


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Skin delivery
-‐ Rectal and vaginal – generally not liquid or semi-‐solid
-‐ Skin – topmost layer is the “stratum corneum”
o Underneath – epidermis (dead) then dermis (living)
Functions of skin -‐ Mechanical – holds important body parts inside/together
-‐ Microbiological barrier – stops infection
-‐ Chemical barrier
-‐ Radiation barrier – absorbs UV
-‐ Heat barrier and temperature regulation
-‐ Electrical barrier – high dry skin resistance and impedance
-‐ pH and water regulation
-‐ Mechanical shock – defence against blows, shocks (blisters, calluses)
Routes of drug -‐ Transappendageal – drug follows path of least resistance down sweat ducts
transport through and hair follicles
skin -‐ Transcellular – through skin cells – lipophilic
-‐ Intercellular – travels via spaces between skin cells – hydrophilic
Purpose -‐ Systemic delivery (transdermal)
o Nicotine patches – slow release
o Some vaccinations, e.g. smallpox
-‐ Localised delivery (dermal)
o Antiperspirants, sunscreen, psoriasis, eczema, infections
o Acne – caused by pustules formed from dead WBC fighting bacteria –
increased sebum production and inflammation
Principles -‐ Skin condition and site
governing drug o Intact, healthy skin is a tough barrier; diseases can alter skin condition
permeation o Thicker skin is more difficult to enter – elderly have thinner skin
-‐ Skin hydration and blood flow
o Higher blood flow = less time in the skin
o Increased hydration = increased permeability
-‐ Diffusion coefficient – how fast API diffuses through skin
-‐ Partition coefficient and solubility
-‐ Drug concentration – higher conc. = larger conc. gradient = faster diffusion
-‐ pH and pKa
o Ionisation affects diffusion
o Stratum corneum highly resistant to pH alterations (tolerates pH3-‐9)
Properties of -‐ Stable – temperature variations, doesn’t separate into components
effective dosage -‐ High safety range – variable dosage
form -‐ Easy application – rheology properties
-‐ Non-‐irritating – suitable for many skin types, e.g. sensitive
-‐ Aseptic – antiseptics to prevent bacterial, fungal growth during storage
-‐ Does NOT need to be isotonic, or one particular formulation (cream, lotion)


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Nasal delivery
-‐ Nasal delivery – drugs absorbed in nose, not lung delivery via the nose
-‐ Turbinates – high SA:V ratio – where absorption occurs for nasal drugs
Function of nose -‐ Contains cilia – beats together to clear mucus
-‐ Defends against infections, toxins and allergens
-‐ Gets cleared into GI tract
-‐ Mucus clearance half-‐life = 15 minutes
Benefits of nasal -‐ Avoids hepatic first-‐pass metabolism
delivery o Normally conc. of drug absorbed from GI system is much lower as it is
filtered and metabolised before entering systemic circulation
-‐ Avoids blood-‐brain barrier – direct connection to brain
o Delivers hydrophilic drugs that can’t pass BBB
-‐ Localised and systemic drug delivery
-‐ New way to deliver vaccines
Factors affecting -‐ Nasal metabolism by P450 enzymes in mucus
delivery -‐ Mucus is a hydrophilic physical barrier
-‐ Mucus cleared rapidly (~15 minutes) – drugs have short time to be absorbed
-‐ Illness can provide inflammation/congestion
o E.g. blocked nose – mucus, inflammation reduces SA for absorption
Types of dosage -‐ Most commonly MAD – mucosal atomisation device
forms o Provides fine spray of droplets
o 30-‐50μm particle size – trapped in nasal cavity, not enter lungs
o Issues – incorrect usage (how far up nose), inaccurate dosing
-‐ Nasal inserts – accurate dose, easy use, sustained/controlled release

Ocular delivery
Factors affecting -‐ Rapid dilution in tear fluid – need fast action
delivery -‐ Rapid solution drainage
o Gravity, induced lachrymation, blinking reflex, normal tear turnover
o Typical corneal time <2 min – little chance to be absorbed
-‐ Absorption of drug into surrounding tissues reduces conc. available for eyeball
-‐ Low corneal permeability
o Cornea is lipophilic – poor drug absorption, needs delivery vehicle to
penetrate
-‐ Vitreous chamber – mostly water, but 1-‐4% collagen makes it very viscous –
difficult for the drug to move through
Properties of -‐ Isotonic
effective dosage -‐ Sterile
form -‐ Good corneal penetration
-‐ Simplicity of use
-‐ Prolonged contact time – gels, increase viscosity
-‐ Non-‐irritating (prevent invoking of lachrymation or blinking)
-‐ Variable dosage
-‐ Fast acting -‐ tears
Typical APIs -‐ Glaucoma – adrenaline, physotigimine
-‐ Surgery – anaesthetics, e.g. cocaine hydrochloride
-‐ Pupillary dilution – homatropine hydrobromide
-‐ Infection (outside eye) – antibiotics
-‐ Dry eyes – artificial tears containing hydrophilic polymers which improve tear
film strength
-‐ Conjunctivitis – affects outside of eyes – don’t need corneal penetration


Physical Pharmaceutics and Formulation A Lecture Notes 1822 Notes

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Physical Pharmaceutics and Formulation A - Lecture notes -

Physical Pharmaceutics and Formulation A (University of Sydney)

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Physical factors affecting solubility

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Rate of reaction

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Activation energy (Ea)

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Surfaces and Surface Interactions

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-­‐ Closest to stress experiences highest shear rate

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Colloids and suspensions

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Physical stability of suspensions

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Particles in water – charge effects

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Preservatives in emulsions

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Aqueous solutions: enhancing aqueous solubility

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Non-­‐aqueous solution formulations

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Deposition of aerosols

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Intra-­‐arterial: injection or infusion into an artery

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High to low Reason

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Particulate matters (>7μm)

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Containers Use Purpose

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-‐ Closest to stress experiences highest shear rate

Non-‐aqueous solution formulations

Intra-‐arterial: injection or infusion into an artery