Solution Formulation Flashcards
How can the solubility of a drug be increased?
Use of surfactants to increase aqueous solubility
Use of chemical complexing agents to increase aqueous solubility
Use of physical complexing agents to increase aqueous solubility
Chemical modification to increase aqueous solubility
Use of co-solvents to increase aqueous solubility
Manipulation of pH to increase aqueous solubility
Salt formation to increase aqueous solubility
Discuss how surfactants can be used to increase aqueous solubility.
Include any issues with this process
Also include how surfactants work and then type of formulation they can be used with
Sodium lauryl sulphate (sodium dodecyl sulphate)
CMC= 0.23%
Polysorbate 80 (tween 80) CMC= 0.014%
Siri tan mono-oleate (span 80)
Issues with quantity and toxicity
Surfactant levels below cmc may help ‘wetting’
They can reduce the surface energy of a drug particle
Can be used for suspensions and tablet formulations
How can the use of a chemical complexing agent increase aqueous solubility?
State any issues with this method
Make a ‘complex’ between the drug and another material
Similar idea to a salt, but full ionisation is not achieved for either component
No covalent bonds so not a new drug molecule
It is held together by a range of molecular interactions
Sometimes called a ‘co-crystal’
Issues with stability of the complex
Issues with the release of the active drug
Issues with toxicity/dose of the complexing agent
How can the use of physical complexing agents be used to increase aqueous solubility?
State any issues with this method
Give an example
Cyclodextrins:
Cyclic glucose polymers
Arranged in aqueous solution as a truncated cone
Hydrophobic core provides a reservoir for poorly water-soluble drugs to increase the water solubility
Number of glucose residues: alpha= 6 beta= 7 gamma=8
Cyclodextrins:
Can have 1:1, 1:2 or 2:1 complexes
Can have modifications to basic glucose unit i.e. hydroxyl-beta-
Issues with acceptability/toxicity
Issues with the stability of the complex
Will the drug released from the complexing agent be effective?
Example:
Itraconazole
Solubility in water (neutral pH) = 1ng/ml
Solubility in 40% HP-beta-CD solution (neutral pH) = 10mg/ml
Used in the marketed products
Oral liquid and IV injections
How can chemical modification increase aqueous solubility?
Design in some hydrophilic character
This is now a new drug
Needs to be completely retested or biological activity and toxicity
What are non-aqueous solutions?
Oral formulations:
Oil soluble vitamins or very non-polar drugs
Fixed oils e.g. soybean oil, arachis oil, sesame oil
Volume of oil is important
Taste is important
Intramuscular depot injections:
Long acting
Fixed oils e.g. soybean oil, arachis oil, sesame oil
Volume 2 to 5ml
Enemas:
Fixed oils e.g. arachis
Topical lotions/ paints:
Ethanol’s/IM’s
Solvent volatile
Ear drops:
Olive oil to remove wax
What needs to be considered when selecting a vehicle for drugs:
Toxicity
Quality:
Chemical
Microbiological
Pharmaceutical grade
Flammability:
Ethanol (lotions/paints/collodions)
What are acceptable Ph ranges for oral medications?
PH 3 to 9 for routine dosing
PH 2 to 10 for occasional dosing
What is the acceptable pH range of intravenous drugs?
PH target = 7.4
Small volumes (<5) pH 5 to 9 Large volumes (>5) ph 7 to 8
If the pH is far from 7.4 the drug needs to be administered via the central vein
What is the acceptable pH ranges of other injection routes?
PH target is 7.4; a very limited pH range is acceptable
What is the acceptable pH ranges of ocular preparations?
PH target is 7.4; very limited pH range available
What is the acceptable pH ranges of nebuliser solutions?
PH 6.5 target
PH 6.0 to 7.0 is acceptable
What is the acceptable pH ranges of nasal solutions?
Target pH is 6.8; very limited pH range is acceptable
What does sterility mean?
Sterility is an absolute concept, something cannot be half sterile
If the target site is sterile, the dosage form should be sterile such as parenterals, oculars and inhalation’s
If the target site is not sterile the dosage form should be micro biologically clean
E.g. orals and topicals
What are anti-microbial preservatives
All medications should be produced in a clean or sterile room
Preservatives are for in use protection
Single use sterile solutions do not require preservatives, for example, small volume injections, single use eye drops and nebuliser solutions
‘Multiple use’ solutions require preservatives, these included bottles of eye drops, nasal solutions, oral solutions, lotions
Preservative efficacy must be established case-by-case
What are five anti-microbials used in oral solutions?
What are their positive aspects and limitations
What strength is required
Sucrose:
Minimum 67% w/v for efficacy
Acts by hypertonicity and viscosity
To maintain preservative activity it should not be diluted
Has a sweet taste
Cariogenic (can cause tooth decay)
Used orally in extemporaneously produced products
Not generally used in proprietary products
Not used for other routes
Sordid acid: CH3CH=CHCH=CHCOOH
Approximately 0.1 to 0.2% w/v
In-ionised form effective
Best in weakly acidic solutions
Benzoic acid/ sodium benzoate C6H5-COOH / C6H5-COONa Approximately 0.1 to 0.2% w/v Unionised form effective Best in weakly acidic solutions Cats are very sensitive to benzoic acid
Parabens X para hydroxy benzoic acid X = methyl, propyl Approximately 0.1 to 0.2% w/v Often used with benzoic acid or sodium benzoate
Chloroform: CHCl3
0.25% v/v for oral use
Used in extemporaneously produced products
What are four anti-microbials used in injections ?
What strength is required
Benzoyl alcohol
Not to be used in neonates especially premature
Approximately 0.1 to 4% w/v
Parabens
Approximately 0.1 to 0.2% w/v
Phenol:
Approximately 0.2 to 0.5% w/v
Sodium bisulphite/ sodium metabisulphate
Approximately 0.1 to 1% w/v
What are seven anti-microbials used in topical preparations ?
What are their positive aspects and limitations
What strength is required
Phenoxyethanol
Approximately 1% w/v
Chlorocresol
Approximately 0.1% w/v
Chlorobutanol
Approximately 0.1% w/v
Parabens
Approximate 0.1 to 0.3% w/v
What is an anti-microbials used in ocular solutions?
What are their positive aspects and limitations
What strength is required
Benzalkonium chloride
Approximately 0.01 w/v
Long chain surfactant
What is the minimum shelf life of marketed products and extemporaneously prepared products
Marketed products: 2 years
Extemporaneously prepared products: 1 week
What is the initial specification for active drug contents?
General specification of 95.0 to 105.0% of stated
What does end of shelf life specification for active drug content mean?
Usually one indicative specified degradate at a maximum specified level e.g. 0.5%
Also specify total degradates allowed e.g. maximum 1.0%
Dependant on pharmacological activity and toxicity
How can drugs be degraded?
Oxidation
Reduction
Hydrolysis
What are catalysts for drug degradation?
PH Oxygen Water Non-aqueous solvents Trace elements Heat Light
How to prevent degradation by acid/base catalysis:
Use a buffer to maintain pH of maximum stability
How to prevent degradation by oxidation:
Use an antioxidant such as:
Ascorbic acid 0.2% w/v
Alpha-tocopherol 0.2% w/v
Sodium metabisulphate 0.1& w/v
Reduce O2 permeation into package e.g. glass not HDPE
Replace air with nitrogen or CO2 in package headspace
How to prevent degradation by trace elements?
Use a chelator to absorb them e.g. EDTA
How to prevent degradation by temperature?
Refrigerate
How to prevent degradation by light?
Use amber glass
Why is toxicity needed?
Important for protecting cells
Discuss osmosis in an open system:
Individual solvent molecules diffuse across the semi-permeable membrane
The level of liquid is the same on both sides
Vapour pressure (and chemical potential) of the solvent is reduced in a solution
Solvent will move across the semi-permeable membrane to equalise its chemical potential, i.e. from pure solvent into the solution
The level of liquid is then higher on the solution side
Applying pressure to the solution will reverse this movement of solvent molecules
The amount of pressure required to return the system to its original state is the osmotic pressure of the solution
In an open system, the changes in volume either side of the membrane is not too important
Describe osmosis in a closed system
In a closed system the changes in volume either side of the membrane are very important, as the membrane will move
Applying pressure to the solution would reverse this movement of solvent molecules
The amount of pressure required to return the system to its original state is the osmotic pressure of the solution
What is osmotic pressure?
Related to the number of molecules (or ions) in solution
Colligative property
Need a way of expressing the osmotic effect of materials
Concept of osmolarity and osmolality
1 osmole = avogados number of osmotically active items
Osmolarity = the number of osmotically active items in 1 litre of solution
Osmolality = the number of osmotically active items associated with 1kg of solvent
What is 1 osmole?
Avogadro number of osmotically active items
What is osmolarity?
The number of osmotically active items in one litre of solution
What is osmolality?
The number of osmotically active items associated with 1kg of solvent
What is the osmotic pressure of 1 osmolar aqueous solution?
22.4 atmospheres at 0 degrees
What is the freezing point of 1 osmolar aqueous solution?
-1.86 degrees
What is the boiling point of 1 osmolar of aqueous solution?
100.52 degrees
What are iso-osmotic solutions?
Two solutions are iso-osmotic when there is no net movement of solvent between them
Irrespective of the actual osmotic pressure of the solutions or of the composition of the solutions of the membrane
What are iso-tonic solutions?
The term iso-tonic is used when referring to biological systems
Two solutions are iso-tonic when there is no net movement of solvent (water) between them
- across a biological membrane e.g. rbc, cornea
- matching the osmotic pressure of the biological system
In a biological system, there is some limited solute movement across the membranes e.g. NaCl
This is allowed for in calculations
Should specify the membrane e.g. RBC
Why are iso-tonic solutions important?
They maintain integrity of plasma components after injection of a formulation
Reduce pain after application of a formulation
Is an iso-tonic solution good?
Yes, Keeps red blood cells at a medium size
Is a hyper-tonic solution good?
No, it shrinks red blood cells
Is a hypo-tonic solution good for red blood cells?
No, it makes them swell and burst
What is the osmolarity of plasma?
325 mOsmolar
What is the osmolal of plasma?
291 mOsmolal
What is the osmolal of 0.9% w/v NaCl aqueous solution?
313 mOsmolal
What is the osmolarity of a 0.9% w/v NaCl aqueous solution?
308 mOsmolar
What is the aim of adjusting tonicity?
Aims to produce a formulation with the same osmolarity/osmolality as plasma components
What is the method to adjusting tonicity concentration?
Assume effects of all components are addictive
Add up all components of osmolarity mode
Subtract 325 mOsmolar
Calculate quantity of NaCL/dextrose required
How to adjust tonicity using freezing point depression method?
All colligative properties work from the same basis
Use fpd as a surrogate marker for osmotic pressure
Assume effects of all components are addictive
What is the freezing point of water
0 degree
What is the freezing point of tears and plasma?
- 0.52 degrees
What is the freezing point depression of plasma a/tears compared to water?
0.52 degrees
What is the freezing point of 0.9% w/v NaCl aqueous solution?
- 0.52 degrees
What is the freezing point depression of 0.9% w/v NaCl aqueous solution compared to water?
0.52 degrees
What is the freezing point of 1% w/v NaCl aqueous solution?
- 0.58 degrees
What is the method of adjusting tonicity using the freezing point depression method?
Calculate or measure the fpd due to all components
Substrate from a fpd of 0.52 degrees
Calculate the quantity of NaCl/ dextrose required
Why is the sodium chloride equivalent method used to adjust tonicity?
Based on the fpd method
NaCl equivalent = the amount of NaCl which has the same osmotic effect as 1g of the drug
NaCl equivalents are additive
Explain the method of adjusting tonicity using the sodium chloride equivalent method:
Calculate the NaCl equivalent due to all components
Subtract from a total NaCl requirement of 0.9% w/v
Calculate the quantity of NaCl/ dextrose required
Which formulations should have a low viscosity?
Oral and parenteral solutions
So that they can be easily poured and pain free
Which formulations should be more viscous?
Eye drops:
Promotes retention on the surface of the eye
Babies oral liquids:
Reduces chances of dribble
How is viscosity increased?
Can be increased by adding a polymeric material such as
Methylcellulose
Polyvinylalcohol
Hydroxypropy;methylcellulose (hypromellose)
What preparations must density be considered with?
Intra-thecal injections such as spinal anaesthesia e.g. epidurals
How can injection density be altered?
Using dextrose
This will determine how it will mix with cerebrospinal-spinal fluid
What does isobaric mean?
Density is the same as CSF, will mix homogeneously
What does hypobaric mean?
Lower density than CSF, will rise
What does hyperbaric mean?
Higher density than CSF, will sink
What aesthetic aspects are considered?
Colour:
Difficult issue
Colourants may have a biological effect
Children tend to like brightly coloured things
Regulations are complex, variable and changeable, best to avoid colours if possible
Examples of colours: Amaranth (red) Tartrazine (yellow) FD+C Blue 2 (blue) Iron oxides (red,yellow) Titanium dioxide (white)
Flavour:
Drugs tend to taste bitter
Adults may accept but children probably wont
Flavour perception: sweet, sour, salt, bitter, savoury
Uncomplicated process
Flavour masking: trying to compete directly with the drug
Preference:
Children prefer sweet and fruity flavours
Adults prefer sharper tastes
Flavour syrups:
Syrup BP plus flavour extract e.g. orange syrup, wild cherry syrup
Used at 10-20% v/v/ in extemporaneous preparation
Solutions and syrups only, not suspensions
Concentrated flavours: Hydroalcoholic extracts e.g. concentrated cinnamon water Clear to cloudy white Best in suspensions Must be diluted 1 in 40 for use
Sweeteners:
Syrup BP, sucrose, fructose, sorbitol, chloroform, aspartame
Problems with dental caries and diabetics
What colour will amaranth turn a liquid
Red
What colour will tartazine turn a liquid
Yellow
What colour will iron oxides turn a liquid
Red and yellow
What colour will titanium dioxide turn a liquid
White
What flavourings should only be used in solutions and syrups and not suspensions?
Flavoured syrups
Syrup BP plus flavour extract e.g. orange syrup or wild cherry syrup
What flavouring works best in suspensions?
Concentrated flavours e.g. hydroalcholic extracts such as cinnamon water
Why are solutions not a suitable formation?
Layering is possible so must be shaken well
What is the usual oral dosing?
5ml
What are the pros and cons of oral solutions?
Easy to administer
Dose adjustment is easy
Difficult to carry around
What are the pros and cons of injections?
Difficult to send administer
Issues with needles and glass
What are the pros and cons of eye drops
Relatively easy to administer
Convenient to carry around
What considerations should be taken in regards to manufacture and cost?
Manufacture:
Easy process
Bulky
Need pharmaceutical-grade water
Cost:
Excipients are cheap
The drug can potentially be expensive
Define solubility
The concentration of a solute in a saturated solution at a certain temperature
Define dissolution
The transfer of drug molecules or ions from its solid phase to the surrounding medium
What is the key difference between solubility and dissolution?
Key difference: Solubility is an intrinsic material property that can only be altered by chemical modification of the molecule while Dissolution is an extrinsic material property that can be modified by various physical and chemical properties such as particle size reduction and solubilisation enhancing strategies
What is a saturated solution?
A kind in which the solute is in equilibrium with the solid phase
What is a solution?
A mono-molecular dispersion of drugs in a liquid
Each drug molecule is separate from all other drug molecules
Each drug molecule behaves independently
Optically clear (transparent)
No lumps or visible particles
Where are solutions used medically?
Oral dosing: Especially in children and the elderly Issues with palatability Usually non sterile Wide pH range acceptable
Mouthwashes/gargles:
Usually non sterile
Wide pH rashness acceptable
Topical solutions/paints
Usually non sterile
Can be non aqueous
Nasal drops:
Ideally should be isotonic
Narrow range of pH acceptable
Usually non-sterile
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
Irrigation:
Needs to be sterile
Narrow range of pH acceptable
Injections:
Need to be sterile
Large volumes need to be isotonic
Need to be pH controlled, especially large volumes
What are some formulation issues:
Solubility of the drug
Vehicle acceptability
PH
Sterility and anti-microbial preservatives
Chemical stability and stability enhancers
Tonicity
Viscosity and density
Aesthetic considerations
Reproducibility of dosing
Ease of use
Ease of manufacture and low cost
What is the main solvent used in most pharmaceutical solutions?
Water
Can be:
Purified water BP
Water for irrigation BP
Water for injection BP
Should desired drug concentration be close to the equilibrium solubility?
Desired drug concentrations should not be close to its equilibrium solubility
A small reduction in temperate will cause precipitation
So there will be a non-uniformity of dosing
What co-solvents can be used to increase aqueous solubility?
Ethanol CH3CH2OH
Industrial methylated spirits (IMS) (do not ingest)
Glycerin (glycerol) HOCH2CH(OH)CH2OH
Propylene glycol CH£CH(OH)CH2OH
Polyethylene glycol
What are the pros and cons of using co-solvents to increase aqueous solubility?
Limits on quantity
Acceptability issue with ethanol
Will change rheology of the product
Will effect the taste
How can the pH be manipulated to increase aqueous solubility?
If the drug is ionisable, it solubility may vary with the pH
Use the Henderson- hasselbalch equation to predict pH of maximum solubility
Essentially adding/subtracting H+ to/from a drug
How can pH be manipulated to increase aqueous solubility?
What should be added to what?
If the drug is a weak acid, dissolve it in a basic solution
If the drug is a weak base, dissolve it in an acidic solution
What are the pros and cons of manipulating the pH to increase aqueous solubility?
Narrow range of pH acceptable for ocular, nasal and some injection formulations
Wider ranges of pH for oral preparations
May need a buffer to maintain the pH such as citrate, phosphate, acetate, bicarbonate, gluconate, lactate or tartrate
Effect of buffer on stability and solubility of drug
Effect of buffer on taste
Absorption occurs only in the un-ionised form
Varying pH may affect stability of the drug
Varying pH mat affect action of other components
How is salt formation used to increase aqueous solubility?
Similar idea to the manipulation of the pH
If the drug is a weak acid:
React with a base and evaporate off the water to give a solid salt
Then dissolve the solid salt in water to give a solution with pH>7
If the drug is a weak base:
React with an acid and evaporate off the water to give a sold
Dissolve the solid salt in water to give a solution with pH<7
What are acceptable cationic salts that can be used for salt formation;
Na+
K+
Ca2+
What are acceptable anionic salts that can be used for salt formation;
Cl-
HCO3-
SO4-
HPO4 2-
H2PO4 -
Maleate, tartrate, citrate, lactate, succinate, mesylate
What is a surfactant and how do they behave in water?
Is amphiphilic i.e. it has a hydrophobic tail and a hydrophilic head
In water, surfactants at low concentrations will form a layer on the surface of the water
In water, surfactants at high concentrations will also form micelles in the bulk of the water
Above the critical Micelle concentration (CMC) micelles are formed
The centre of the micelle is hydrophic, so hydrophobic drugs can localise there
Solubility of a drug will sharply increase at the CMC
Need to get the drug out of the micelle for absorption
