solutions Flashcards
what is a solution
a mixture of two or more components that form a single phase which is homogeneous down to the molecular level [when we mix a solid and liquid]
Solvent/the continuous phase:
the dissolving agent / determines the phase of the final solution
Solute/the dispersed phase:
the substance dissolved throughout the solvent
solution characteristics
solute: individual ions / molecules
invisible to naked eye, no scattering of light
e.g. salt water
colloid characteristics
solute: 1nm-1um
invisible to naked eye, scattering of light
e.g. milk
suspension characteristics
solute: >1um
visible to naked eye
scattering/reflection of light
interacts with gravity
e.g. flour in water
solution formulation advantages
Syringeable
Able to access cavities
Homogenous (uniform dosing)
Rapid Absorption (no dissolution step)
Simple to manufacture (e.g. compared to suspensions)
Easy to swallow
solution formulation disadvantages
Solubility may be poor
May be bulky/heavy/difficult to handle
Potential for microbial growth - repeat dosing from same container
Dosing uniformity potentially poor
Unstable - hydrolysis, oxidation, etc
Can have issues with palatability
main methods of expressing concentration
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what is solubility technically
the concentration of a saturated solution
→ therefore when you add solid above the solubility you end up with a suspension
solubility = dependent on solvent and solute
what is supersaturation
- where the concentration is higher than the solubility
- unstable and eventually the excess will precipitate out to form a saturated solution (and a suspension)
a common method to form crystals using supersaturation
- 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
why does solubility matter:
- choose a solvent where you are at a reasonable distance from the solubility
- relevant to what happens when you swallow / inject med
- The drug will be present in biological fluids at some stage – related 2 bioavailability
- A drug must be in solution for it to cross biological membranes, otherwise no therapeutic effect!
- An injected drug must NOT precipitate out on injection e.g. into iv bag
solubility of gases in liquids: what is henrys law
C = kP
c - concentration of dissolved gas
k - constant characteristic for the gas
p - partial pressure
henrys law is C = kP: what is it for, and what does each letter refer to
c - concentration of dissolved gas
k - constant characteristic for the gas
p - partial pressure
for the conc of gas/their solubility in liquids
solubility of liquids in liquids: this is based on what 2 systems
miscible and immiscible
how to check solubility for immiscible systems
- a formulation strategy is to prepare emulsions (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 xtra info e.g. why is it important in pharmacy
- 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 on a molecular level to form a dispersion, otherwise colloid formed.
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
dissolving is entropically favourable: makes it more disordered
what are the 3 factors affecting solubility:
- solid-solid bond strength
- solvent-solvent bond strength
- interaction between solute and solvent
how does strength of solid-solid bonds affect solubility
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)
how does the strength of solute-solute bonds affect solubility
- If solvent-solvent bonds strong, more work required to create cavity e.g. water strong bonds due to H bonds
[However H2O 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 (like dissolves like)
- key 2 the solubility of a system
- Placing molecule into cavity requires solute-solvent contacts to be made → Larger the molecule (or greater area), more contacts required
like dissolves like = solute and solvent with similar polarity are likely to allow dissolution
but also depends on lattice enthalpies
large molecules - less soluble why
larger solubility
why are substituents on drug important for solubility
e.g. ch3, ch2, ph groups = hydrophobic
-nh2, oh, coo = hydrophillic
ionised groups are hydrophillic!!!! e.g. one charge species can solubilise like 20 c atoms
what is dissolution
a rate of how fast or slow drugs can dissolve (to give rapid action or sustained delivery)
dissolution and permeation are key in getting the drug into the blood - they determine bioavailability.
what does the rate of dissolution depend on?
solubility, surface area (particle size), concentration of drug in solution
types of formulations and their characteristics e.g. whats Diff between oral dosing, ear drops, injections etc
Formulation Type Characteristics
Oral dosing ·Especially for children and the elderly ·Issues with palatability · Usuallynon-sterile ·Wide pH range acceptable
Mouthwashes/gargles ·Usuallynon-sterile ·Wide pH range acceptable
Topical lotions/paints/gels ·Usually non-sterile·Can be non-aqueous
Nasal drops/sprays ·Narrow range of pH acceptable·Usually non-sterile·Requires a device
Ear drops ·Usually non-sterile
Eye drops ·Need to be isotonic·Need to be sterile·Need to be pH-controlled
Nebulisation solutions ·Need to be sterile·Fairly narrow range of pH acceptable
Irrigations ·Need to be sterile·Narrow range of pH acceptable
Injections ·Need to be sterile·Free of pyrogens·Need to be pH-controlled, especially large volumes
why do we manipulate solubility
- You do not want to formulate close to the solubility
- Many drugs have poor solubility so this presents a problem for preparing solutions
formulation issues we would consider for solutions
viscosity, density, ease of use, manufacture
patient acceptability, tonicity, chemical stability, sterility, pH etc
how to manipulate solubility
- temperature: but not rly useful, gen public can only do room temp or fridge
- including cosolvents (liquids that alter the solvent properties of the water e.g. make the drug more soluble
- Manipulation of pH to increase aqueous solubility: ionisable drugs solubility varies 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
go over Henderson hasselback
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Salt formation to increase aqueous solubility
If drug is a weak acid:
react with a base and evaporate off the water to give a solid
salt
R-COOH + NaOH R-COO-Na+ + H2O R-COO-Na+
If the drug is a weak base
react with an acid and evaporate off the water to give a solid
salt
R3-N + HCl R3-NH+Cl- + H2O R3-NH+Cl-
Acceptable cationic salts:
Na+, K+, Ca2+
Acceptable anionic salts:
Cl, HCO3-, SO42-, HSO4-, PO43-, HPO42-, H2PO4-,
- use of surfactants (surface active agents) to increase aqueous solubility:
surfactants are amphiphilic
In water, surfactants at low concentrations will form a layer on the surface of the water, ie at the air-water interface
- In water, surfactants at concentrations will also form high micelles in the bulk of the water
- Above the “Critical Micelle Concentration”
(CMC) micelles are formed
- The centre of the micelle is hydrophic
- hydrophobic drugs can localise there
use of complexing agents to increase aqueous solubility
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xtra about anti-microbial preservatives:
- All medicines should be produced in a “clean” or “sterile” room
- Preservatives are for “in use” protection
- “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
Commonly used preservatives include sorbic acid, methyl paraben and many others
notes on chemical stability
Routes of degradation
Study chemical structure of drug and identify routes of degradation
- oxidation
- photolysis
- hydrolysis
Consider potential catalysts
- pH
- trace elements
- oxygen
- heat
- water
- light
- non-aqueous solvents
chemical stability enhancers
https://www.notion.so/week-8-9-Solutions-13300bb3982d80608033d1527e74baf6?pvs=4#13300bb3982d81108c7cfdd3e193ec51
viscosity notes
https://www.notion.so/week-8-9-Solutions-13300bb3982d80608033d1527e74baf6?pvs=4#13300bb3982d81189bf6d47bfd0d0d06
aesthetic considerations:
color and flavour
Colour
- Difficult issue
- artificial colourants may have some biological effect
- children tend to like brightly-coloured things
- Regulations are complex, variable and changeable
- best to avoid colours if possible
- May act as a warning
Flavour
- Drugs tend to taste bitter
- adults may accept
- children probably won’t accept
- Flavour perception
- sweet, sour, salt, bitter, unami (savoury)
- complicated process
- Flavour masking
- try to compete directly with drug
- formulate to hide it
formulations that do/don’t work with patient acceptability:
Oral solutions
- easy to administer
- dose adjustment easy
- difficult to carry around
Injections
- difficult to self-administer
Eye drops
- relatively easy to administer
- Nasal drops/sprays
