chemical modification and effect of pH Flashcards
how can the solubility of a drug be manipulated?
by adding solubilising groups to the structure
-the three main aspects that are considered are:the type of group added,whether the reaction is reversible or irreversible, the chemical route of introduction/methods of introduction
what can the addition of polar groups do to solubility?
-can enhance the solubility of the parent compound in water
what are the highly polar functional groups?
-alcohol
-amine
-amide
-carboxylic acid
-sulphonic acid
-phosphorous oxyacid
what are the less polar functional groups?
-ethers
-aldehydes
-ketones
-esters
how does a reaction being reversible or irreversible affect solubility?
-a reversible link can be used to change the solubility temporarily they use the ability of endogenous enzymes of chainGph to break the bond with new functional groups and release the drug
what less reactive bonds being bound to the skeleton of the parent compound are likely to be irreversibly attached?
-C-C
-C-O
-C-N
what groups are likely to be metabolised in-vivo?
groups that are linked by ester, amide,phosphate and sulphate groups
how does the chemical route of introduction/method of introduction affect solubility?
-water solubilising groups can be introduced at any stage in the synthesis or post synthesis and consideration often needs to be given to the protection of groups already present in the molecule
what is the solubility product?
AB⇌A+ + B-
-a sparingly soluble salt in water will establish an equilibrium between solid and liberated ions when present above its solubility value
what is the equilibrium constant defined as for the law of mass action?
K= [A+][B-]/[AB]
if for a sparingly soluble salt the conc of solid in a saturated solution can be considered constant,what is the equation rewritten as?
Ksp==[A+][B-]
what is a partition coefficient?
-it measures the way a compound distributes itself between an organic (lipid phase and an aqueous phase)
-the activity of a drug can often be correlated with partition coefficient and this can be used as a predictive tool
what is used to work out the partition coefficient?
-the log value in which the ratio of the concentration of unionised compounds at equilibrium between the organic and aqueous phases is looked at
formula for partition coefficient…
logP=log10[unionised compound]octanol/[unionised compound]water
what does it mean if log be is a value between -1 and 1?
-it is a polar compound
-it has good aqueous solubility
-it has poor lipid solubility
-it has poor absorption and distribution
what does it mean if log p is a value between 2 and 4?
-a compound of intermediate polarity
-there is a good balance between aqueous and lipid solubility
-there is good absorption and distribution
what does it mean if log p is a value between 4 and 6?
-it is a non-polar compound
-there is poor aqueous solubility
-there is good lipid solubility
-there is an accumulation in lipid-rich environments
-there is slow excretion
what is the most common method for determining logP?
-shake flask method
-the candidate drug is shaken between octane and water layers and an aliquot is taken and analysed
what is the value of the partition coefficient affected by?
-temp
-pH
-nature of the solvent
what are examples of phenomena affected by logP?
-Drug absorption into cells (partitioning between blood or other body fluid and the cell membrane)
-Drug or preservatives absorption into plastic containers or partitioning of plasticisers between the container and the formulation.
-Partitioning of the preservatives between the two phases of an emulsion
-Partitioning of an antibiotic drug into bacterial cells
-Only tetracycline derivatives with high log P value can cross the BBB and are effective in the treatment of meningitis
-Lipophilic penicillins are neurotoxic as they can cross the BBB
-Activity of local anaesthetics is proportional to their log P as the effect is seen when a sufficient concentration of drug on the nervous cell membrane is obtained
what is the BCS?
-the biopharmaceutics classification system
-solubility and permeability are used to compile the BCS
what is the main goal of the BCS?
-improve the efficiency of drug development by recommending methods to enhance drug performance based on their classificatio according to solubility and permeability data
what is a class I drug according to the BCS?
-a drug that has high permeability and high solubility
what is a class II drug according to the BCS?
-a drug that has a high permeability and low solubility
