Solutions Theory and Formulation Flashcards
Understand concepts of the liquid state, concentration and solubility Be able to describe the way in which this basic understanding relates to the formulation and the patient Be able to predict how some common difficulties found in solution formulation may be overcome
What is a liquid?
A liquid is intermediate between these two states; the molecules can move but the intermolecular interactions result in volume being restricted
How do the molecules interact in a liquid?
Intermolecular interactions
VDW forces (4 types)
* Ion-dipole
* Dipole-dipole (includes H bonding)
* Dipole-induced dipole
* Induced dipole-induced dipole (London forces)
These tend to be quite weak, short range forces but crucially important in determining liquid properties
Polarity measured by “Relative Permittivity”
Dipole-dipole
- Two permanent dipoles attracts
- Important sub-class is H bonding
- Strong bonds and result in high b.p.
- Also results in a ‘structuring’ of water around solutes, resulting in a degree of order in supposedly random systems
- Entropic considerations
Dipole-induced dipole
- Occur when a polar molecule induces a distortion in the electron cloud of a non-polar molecule
- Explains why many non-polar molecules will dissolve in water
- Induced dipole-induced dipole are due to fluctuations in the electron clouds
- Occurs with all molecules and are very weak, but explain why non-polar molecules such as pentane exist as liquids
The phase diagram of water
Look at diagram
The concept of vapour pressure
A proportion of molecules will have enough energy to escape the vapour phase even below the b.p. - that proportion increased with temperature
HIGH kinetic energy = exerts ATMOSPHERIC pressure
LOW kinetic energy = VAPOUR pressure
STRONG bonds = LOW vapour pressure
Vapour pressure at the boil
- HEAT gives molecules in liquid energy
- Increases VAPOUR pressure
- If vapour p = atmospheric p
- BOIL occurs
Solution
A mixture of two or more components that form a single phase which is homogenous down to a molecular level
Solvent
The dissolving agent and determines the phase of the final solution (i.e. the continuous phase)
Solute
The substance which is dissolved throughout the solvent (i.e. the dispersed phase)
Properties of solute in solution
Solute: individual ions / molecules
* Invisible to naked eye
* No scattering of light
Properties of solute in colloid
Solute: 1nm-1micrometre
* Invisible to naked eye
* Scattering of light
e.g. milk
Properties of solute in suspension
Solute: > 1μm
* Visible to naked eye
* Scattering/reflection of light
* Interacts with gravity
e.g. flour in water
Advantages of solution formulations
- Rapid absorption - no dissolution step
- Easy to swallow
- Homogenous (uniform dosing)
- Simple to manufacture
- Syringeable
- Able to access cavities
Disadvantages of solution formulations
- Solubility may be poor
- Potential for microbial growth - repeat dosing from same container
- May be bulky / heavy and difficult to handle
- Can have issues with palatability
- Dosing uniformity potentially poor
- Unstable - hydrolysis, oxidation etc.
Main methods of expressing concentration
Molarity (mol/L or M) is the number of moles of solute in 1L of solution
Molality (𝑏=𝑛_𝑠𝑜𝑙𝑢𝑡𝑒/𝑚_𝑠𝑜𝑙𝑣𝑒𝑛𝑡 ) is the number of moles of solute in 1000g of solvent
Mole fraction (𝑥_𝑖=𝑛_𝑖/𝑛_𝑡𝑜𝑡𝑎𝑙 ) is the number of moles of solute divided by the total number of moles of solute and solvent (often denoted X)
% w/v – g of solute in 100ml solution
% w/w – g of solute in 100g of solution
What is solubility?
Concentration of a saturated solution
Very dependent on the solvent andthe solute
Supersaturation can occur - where conc is higher than solubility
Such systems are unstable and eventually the excess will precipitate out to form a saturated solution
Using supersaturated to generate crystals
- Prepare a solution with the material of interest in a hot solvent and then force the concentration above the solubility by cooling
- At the lower temperature, the solubility decreases so you are now above the saturation concentration
- When the solute is above the saturation level at the lower temperature it has to precipitate out
- May take a while to happen
Solubility of gases in liquids
Described by Henry’s Law
C=kP
C - conc of dissolved gas
K - constant characteristic for the gas
P - partial pressure
Solubility of liquids in liquids
systems described as either completely miscible (e.g. ethanol and water) or immiscible (e.g. oil and water)
For immiscible systems, a formulation strategy is to prepare emulsions
These are liquid in liquid dispersions, whereby stability is maintained by using an emulsifying agent
These are typically SURFACTANTS which have both hydrophilic and hydrophobic sections in the same molecule
Solubility of solids in liquids
Vital for liquid formulations and for solids
Drug must be dissolved to have an effect
Solids can be DISSOLVED to form a solution or DISPERSED to form a dispersion
What happens on a molecular level when a solid dissolves?
DISSOLUTION
* The crystal lattice has to break to free a molecule, the solvent has to form a hole and then the freed molecule has to go into the hole
* Breaking / making bonds - enthalpy changes
* Mixing of two species - entropy changes
Factors influencing solubility
- Strength of solid-solid bonds
- Strength of solvent-solvent bonds
- Interaction between solute and solvent
- Strength of solid-solid bonds
Stronger bonds will increase the energy needed to break lattice
Bond strength within crystal (or indeed within liquids for liquid drugs) indicated by melting point (or boiling point for liquid)
- Strength of solvent-solvent bonds
- If solvent-solvent bonds strong, more work required to create cavity
- Water has very strong bonds due to hydrogen bonding
- However it is also an excellent solvent for many molecules, while liquids showing low intermolecular bonding (e.g. hydrocarbons) are not necessarily good solvents
- Interaction between solute and solvent
Pivotal to the solubility of many systems
Placing molecule into cavity requires solute-solvent contacts to be made
Larger the molecule (or greater area), more contacts required
We can predict…
- Molecular size
- Substituents on drug are important
- Ionised groups will be hydrophilic
Dissolution
Rate at which rugs dissolve
Factors affecting rate of dissolution
- Solubility
- SA
- Conc
What determines BIOAVAILABILITY
Dissolution and permeation
(Important to get drug into blood)
Formulations of solutions
Oral dosing, mouthwashes, topical lotions, nasal drops / sprays, ear drops, irrigations, injections
What are the formulation issues we need to consider for solutions?
Quality of water required – pure water BP/water for injection BP
Solubility of the drug
pH
Sterility (and anti-microbial preservatives)
Chemical stability (and stability enhancers)
Tonicity
Viscosity and density
Aesthetic considerations
Reproducibility of dosing
Patient acceptability
Ease of use
Ease of manufacture and low cost
Examples of non-aqueous solutions
Oral formulations - oil-soluble vitamins or very non-polar drug, volume of oil important, taste important
Intra-muscular depot injections - long acting, volume 2-5mL
How to manipulate solubility
- Temperature (not useful, 2 options, fridge or room temp.)
- Cosolvents
- Manipulation of pH
- Salt formation
- Surfactants
- Complexing agents
Cosolvents
Liquids that alter the solvent properties of the water
The cosolvent may increase the solubility of the drug but it is quite difficult to predict how.
General principle of like dissolves like applies – addition of cosolvent brings dielectric constant of liquid closer to ideal for drug
Manipulation of pH to increase aqueous solubility
- If drug is ionisable,
its solubility may vary with pH - If the drug is a weak acid (R-COOH)
dissolve in a basic solution - If the drug is a weak base (R3N)
dissolve in an acidic solution - May wish to use buffering agents
Ranges of pH
- Narrow range of pH acceptable for ocular, nasal and some injection formulations
- Wider range of pH for oral preparations
- May need a buffer to maintain pH
- citrate, phosphate, acetate, bicarbonate, gluconate, lactate, tartrate
- effect of buffer on solubility and stability of drug
- effect of buffer on taste
BUT: - absorption mainly occurs in the unionised form
- varying pH may affect stability of drug
- varying pH may affect action of other components
Salt formation to increase aqueous solubility
If the drug is a weak acid, react with a base and evaporate off the water to give it a solid salt
If the drug is a weak base, react with an acid and evaporate off the water to give a solid salt
Acceptable cationic salts: Na+, K+, Ca2+
Acceptable anionic salts: Cl-, HCO3-, SO42-, HSO4-, PO43-, HPO42-, H2PO4-,
maleate, tartrate, citrate, lactate, succinate, mesylate
About 50% of drugs in solid dosage forms given as salts
Use of surfactants to increase aqueous solubility
A surfactant (surface-active agent) is amphiphilic
In water, surfactants at low concentrations will form a layer on the surface of the water, ie at the air-water interface
The centre of the micelle is hydrophic - hydrophobic drugs can localise there
Use of complexing agents to increase aqueous solubility
Cyclodextrins
cyclic glucose polymers
arranged in aqueous solution as a truncated cone
hydrophobic core provides a reservoir for poorly
water-soluble drugs, ie increases water solubility
Anti-microbial preservatives
- “Single use” sterile solutions do not require preservatives
- small volume injections, single use eye drops, nebuliser solutions
- “Multiple use” solutions require preservatives
- eye drops, nasal solutions, oral solutions, lotions etc
e.g. sorbic acid, methyl paraben
Chemical stability - routes of degradation
Oxidation, photolysis, hydrolysis
Potential catalysts for degradation
pH, oxygen, water, non-aqueous solvents, trace elements, heat, light
Chemical stability enhancers
- Choose stability enhancer / reformulation / packaging to match the degradation route
- Acid / base catalysis - use a buffer to maintain pH of maximum stability
- Oxidation - use an anti-oxidant, (ascorbic acid), reduce O2 permeation into package, replace air with nitrogen
- Trace elements - use a chelator
- Temp - fridge
- Light - use amber glass
Viscosity
- Oral and parenteral solutions should be of LOW viscosity, easily poured, pain free
- Increasing viscosity for eye drops - promotes retention on surface of eye, babies’ oral liquids, reduces chance of dribble
- Increase viscosity by adding polymeric material - methycellulose
Aesthetic considerations - colour
Colour - artificial colourants may have biological effect, children like brightly coloured things
Regulations are complex, variable and changeable, best to avoid colours
May act as a warning
Aesthetic considerations - flavour
Drugs tend to taste bitter, which adults may accept but children won’t
Flavour perception - sweet, sour, salt, butter, unami, complicated process
Flavour masking - try to compete directly with drug, formulate to hide it
Patient acceptability
Oral solutions - easy to administer, dose adjustment, difficult to carry
Injections - difficult to self administer
Eye drops - relatively easy to administer
Nasal drops / sprays - A/A
