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PHAY4 > Solutions Theory and Formulation > Flashcards

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

1
Q

What is a liquid?

A

A liquid is intermediate between these two states; the molecules can move but the intermolecular interactions result in volume being restricted

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2
Q

How do the molecules interact in a liquid?

A

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”

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3
Q

Dipole-dipole

A
  • 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
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4
Q

Dipole-induced dipole

A
  • 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
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5
Q

The phase diagram of water

A

Look at diagram

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6
Q

The concept of vapour pressure

A

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

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7
Q

Vapour pressure at the boil

A
  • HEAT gives molecules in liquid energy
  • Increases VAPOUR pressure
  • If vapour p = atmospheric p
  • BOIL occurs
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8
Q

Solution

A

A mixture of two or more components that form a single phase which is homogenous down to a molecular level

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9
Q

Solvent

A

The dissolving agent and determines the phase of the final solution (i.e. the continuous phase)

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10
Q

Solute

A

The substance which is dissolved throughout the solvent (i.e. the dispersed phase)

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11
Q

Properties of solute in solution

A

Solute: individual ions / molecules
* Invisible to naked eye
* No scattering of light

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12
Q

Properties of solute in colloid

A

Solute: 1nm-1micrometre
* Invisible to naked eye
* Scattering of light
e.g. milk

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13
Q

Properties of solute in suspension

A

Solute: > 1μm
* Visible to naked eye
* Scattering/reflection of light
* Interacts with gravity
e.g. flour in water

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14
Q

Advantages of solution formulations

A
  • Rapid absorption - no dissolution step
  • Easy to swallow
  • Homogenous (uniform dosing)
  • Simple to manufacture
  • Syringeable
  • Able to access cavities
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15
Q

Disadvantages of solution formulations

A
  • 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.
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16
Q

Main methods of expressing concentration

A

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

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17
Q

What is solubility?

A

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

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18
Q

Using supersaturated to generate crystals

A
  • 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
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19
Q

Solubility of gases in liquids

A

Described by Henry’s Law
C=kP
C - conc of dissolved gas
K - constant characteristic for the gas
P - partial pressure

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20
Q

Solubility of liquids in liquids

A

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

21
Q

Solubility of solids in liquids

A

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

22
Q

What happens on a molecular level when a solid dissolves?

A

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

23
Q

Factors influencing solubility

A
  1. Strength of solid-solid bonds
  2. Strength of solvent-solvent bonds
  3. Interaction between solute and solvent
24
Q
  1. Strength of solid-solid bonds
A

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)

25
2. 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
26
3. 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
27
We can predict...
1. Molecular size 2. Substituents on drug are important 3. Ionised groups will be hydrophilic
28
Dissolution
Rate at which rugs dissolve
29
Factors affecting rate of dissolution
1. Solubility 2. SA 3. Conc
30
What determines BIOAVAILABILITY
Dissolution and permeation (Important to get drug into blood)
31
Formulations of solutions
Oral dosing, mouthwashes, topical lotions, nasal drops / sprays, ear drops, irrigations, injections
32
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
33
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
34
How to manipulate solubility
1. Temperature (not useful, 2 options, fridge or room temp.) 2. Cosolvents 3. Manipulation of pH 4. Salt formation 5. Surfactants 6. Complexing agents
35
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
36
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
37
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
38
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
39
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
40
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
41
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
42
Chemical stability - routes of degradation
Oxidation, photolysis, hydrolysis
43
Potential catalysts for degradation
pH, oxygen, water, non-aqueous solvents, trace elements, heat, light
44
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
45
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
46
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
47
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
48
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

PHAY4 (18 decks)

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