Matt Roberts Flashcards
How do you analyse a drugs solubility?
UV spectroscopy - chromophore 190-290nm
What is intrinsic solubility?
The solubility of unionised drug
At what temperatures do they test the intrinsic solubility of drugs?
4oC - densest point of water
37oC - body temperature
What is the phase solubility of a drug?
The ratio of the drug:solvent
What does it mean when the data of a drug deviates in a phase solubility diagram?
Sign of impurities
How do you work out intrinsic solubility from a phase solubility diagram?
Extrapolate back to zero - only approx
How do you determine the pka of a base?
pka = pH + log (Cs - Co / Co)
How do you determine the pka of an acid?
pka = pH + log (Co / Cs - Co)
How can you improve the solubility of a drug?
Adjusting the pH
Salt formation of the drug
Put drug in non-aq solvent - liquid formulation
What are the disadvantages of strong acids/bases when forming a salt?
Form very soluble salts - but hygroscopic - absorb water which leads to instability
What is the diffusive layer of a salt?
A saturated solution surrounding the crystal - pH micro-environment
What is the purpose of the diffusive layer?
It acts as a buffering agent against the surrounding pH - protects the drug
Do salts change the pharmacological action of a drug?
No they only change the physical properties
List three pharmaceutical solvents? And typically what are these co-solvents limits?
Glycerol <10%
What is paracetamol’s shelf-life at pH9?
4 months
List some dosage form which use oils?
Emulsions
Topical formulations
Intra muscular injections
Liquid filled oral preparations - cod liver oil tablets - mask the taste
What liquid is used when determining log P of a drug? Why?
Octanol - mimics biological absorption in the GIT
What are solvents called that are less polar than octanol?
Hyperdiscriminating - blood brain barrier BBB
What are solvents called that are more polar than octanol?
Hypodiscriminating - buccal
What is dissolution rate?
The rate at which a solid drug releases into a solution
How can you test the dissolution rate of a drug?
Basket method - drug placed in a basket as it floats
Paddle method - drug placed at the bottom of the container as it sinks
What are the units of intrinsic dissolution rate?
mg min-1 cm-2
What is the common ion effect? Example.
Addition of a common ion reduces solubility - water molecules removed as solvent as competition from other ions for hydration
e.g. H2O vs H20 + 1.2%w/v NaCl
Name three methods to determine melting points of drugs?
Capillary method
Hot stage microscopy HSM
Differential scanning calorimetry DSC
What is a polymorph?
A solid material with two or more different molecular arrangements (patterns) that give a distinct crystal species
How can polymorphs be identified?
X-ray powder diffraction
Solid state nuclear magnetic resonance
IR or Raman spectroscopy
What is the difference between a pseudopolymorph and a polymorph?
In pseudopolymorphism the different crystal types are as a result of hydration or solvation
What methods can be used to determine particle size and shape?
Nanophox - photon cross-correlation spectroscopy PCCS
Sieving analysis - range and distribution
How can you measure powder flow?
Angle of repose
Carr’s consolidation index
What features improve particle flow?
Increased particle size
uniform particle density and shape (spherical)
What stability assays are used to assess a drug?
UV analysis
Chromatography
Thin layer chromatography TLC
High performance liquid chromatography HPLC
Define shelf-life?
Period of time that a product retains acceptable chemical, physical and microbiological stability
Define expiry date?
Given on the product packaging to indicate the end of the shelf-life
Define instability?
A change in the physicochemical properties of a pharmaceutical product
What happens to the drug when it is unstable?
Reduced efficacy - API less effective
Increased toxicity - API reacts to form a product which has undesirable effects
How long will a stable drug last?
2-5 years
How long will an extremely stable drug last?
More than 5 years
How long will a moderately stable drug last?
Roughly 2 years
How long will an unstable drug last?
Less than 1 year
What are the two most common interactions which cause instability?
Drug - excipient interaction
Packaging interaction
Give two examples of drug - excipient interaction?
Mg2+ ions and Fosinopril
Lactose and Fluoxetine
How can temperature affect drug stability?
Greater free energy so more rapid reactions - becomes unstable quicker than normal
How can light affect drug stability?
Photolysis which puts in initial energy for degradation
e.g. photolytic oxidation
How can water affect drug stability?
Can cause the drug to hydrolyse
How can you prevent hydrolysis of a drug? (5)
Exclude water from the formulation
Remove metal ions - catalyse reactions like hydrolysis
Add a chelating agent - traps metal ion so unable to catalyse the hydrolysis of the drug
Buffer at pHmin - pH at which the drug is most stable
Store at low temperature - increases hydrolysis rate
Protect from light - UV radiation enough to initiate photolytic reactions
How can oxidation affect drug stability?
Change bonding within molecule
Possible increase in MW
Change in colour
How can you prevent oxidation? (4)
Remove oxygen from the formulation
Protect from light - photolytic oxidation is common
Remove metal ions - oxidation catalysed by metal ions
Add antioxidants - oxidised easier than drug so drug unaffected
Name the three types of antioxidants?
Sulphur containing antioxidants - sodium bisulphite
Free radical scavengers - ascorbic acid
Fat soluble antioxidants - butylated hydroxytoluene
How long will an extremely stable drug last?
More than 5 years
How long will a moderately stable drug last?
Roughly 2 years
How long will an unstable drug last?
Less than 1 year
What are the two most common interactions which cause instability?
Drug - excipient interaction
Packaging interaction
Give two examples of drug - excipient interaction?
Mg2+ ions and Fosinopril
Lactose and Fluoxetine
How can temperature affect drug stability?
Greater free energy so more rapid reactions - becomes unstable quicker than normal
How can light affect drug stability?
Photolysis which puts in initial energy for degradation
e.g. photolytic oxidation
How can water affect drug stability?
Can cause the drug to hydrolyse
How can you prevent hydrolysis of a drug?
Exclude water from the formulation
Remove metal ions - catalyse reactions like hydrolysis
Add a chelating agent - traps metal ion so unable to catalyse the hydrolysis of the drug
Buffer at pHmin - pH at which the drug is most stable
Store at low temperature - increases hydrolysis rate
Protect from light - UV radiation enough to initiate photolytic reactions
How can oxidation affect drug stability?
Change bonding within molecule
Possible increase in MW
Change in colour
How can you prevent oxidation? (4)
Remove oxygen from the formulation
Protect from light - photolytic oxidation is common
Remove metal ions - oxidation catalysed by metal ions
Add antioxidants - oxidised easier than drug so drug unaffected
Name the three types of antioxidants?
Sulphur containing antioxidants - sodium bisulphite
Free radical scavengers - ascorbic acid
Fat soluble antioxidants - butylated hydroxytoluene
What is refrigerator temp?
2-8oC
What is freezer temp?
-20oC
What temp should a drug be kept at when it says keep ‘cool’?
8-15oC
What is room temp?
15-30oC
Name three drug substance stability tests?
Stress testing - identify likely degradation products
Accelerated testing - early estimate on retest date
Long term testing - establishes retest period and storage conditions
Name two drug product stability tests?
Accelerated tests - early indication of shelf-life
Long term tests - establish shelf-life and storage conditions
Define retest date?
The date on which the material should be examined to ensure it still complies with its quality specification
Define expiry date?
The last date on which the product can be expected to comply with its quality specifications (if stored correctly)
