Please enable JavaScript.
Coggle requires JavaScript to display documents.
chemical stability (hydrolysis: ((reacts with H20 (nucelophile) attacking…
chemical stability
hydrolysis:
- reacts with H20 (nucelophile) attacking electron deficient atom
- most common drug decomposition process
- happens in aqueous sol. (injections, eye drops, liquid solution)
- ph and acid/base easy to occur at pH>8 (basic therefore more OH-)
- to counteract: buffer, refrigeration
- can be catalysed by metal ions
- thermally dependant (increase temp increase the reaction of hydrolysis) increase temp by 10 degrees will have a 2-4 fold
- environmental humidity??
nucleophile: negative charge, have lone pair of electrons. increases at higher pH because of OH- contributing to negative charge
-
funcitonal groups
carboxylic derivatives: amides, ester, carbamates, imide,lactam, lactone, thiol ester, thioamides
carbonyl group is very polar due to electronegative oxygen atom
ways oxygen pulls electrons from carbon and makes it more electron deficient:
- inductive effect: oxygen pull electrons from carbon via sigma bond
- resonance: move electrons to oxygen via pi-bond
when electrons move from carbon to oxygen via via sigma + pi-bonds, this polarises the carbon oxygen bond and makes carbon more electron deficient (more positive, therefore looks for electrons from different species such as H2O)- highly attractive to neucleophiles
-
types
acidic: 1. resonance protonates carbonyl group and gives full positive charge (good electrophile, attract poor nucleophile)
basic: conversion of poor nucleophile to strong by adding OH-, proton shift & leaving group
reactivity: depends on delocalisation of leaving group and size of orbital in comparison with carbon (oxygen is bigger)-> less efficient overlapand
increase:
- esters (cyclic, thiol) are more successful to hydrolysis than amides
- small ring will experience huge strain and have a tendency to open making them more reactive
- if side groups are electronegative they will pull electrons away from carbon and therefore easy for poor nucleophile to attack
decrease:
- more bulky & bigger side groups block access to nucleophile (steric hinderance)
- increasing drug lipophicility
- amide: nitrogen is more electronegative than Oxygen therefore will be better delocalisation and is also similar to size of carbon. This will lead to them being less reactive & more stable
-
drug absorption
small intestine:
duodenum- different enzymes from the stomach, liver, gall bladder and the pancreas mix DRUG ABSORPTION
jejunum- inner surface is filled with villi (aid transportation of drug into bloodstream). it increases SA and absorb nutrients and H2O
ileum- absorbs VitB12 and other water-soluble vitamins, bile salts & nutrients that were not absorbed in the jejunum
- large SA
- 'leaky' tissue- more permeable for ions low TEER than stomach
- contain many active transport proteins (vitamins, amino acids, peptides, monosaccharides, nucleosides, drugs with structural similarities)
- has very good blood supply (on a full stomach flow increases by 30%), sympathetic vasoconstriction reduce blood flow, exercise reduce midazolam (anaesthesia)
- well supplied to lymphatic vessel which allows for additional absorption of fatty acid & lipophilic substances
- contents of the small intestine are well mixed and uniformly distributed across membrane into bloodstream
paracellular, transcellular, passive diffusion
rule of 5: no more than 5 H bond donors, no more than 10 H bond acceptors, molecular weight under 500, partition coefficient less than 5, polar SA less 120
carrier-mediated transport: facilitated diffusion, active transport, non-linear graph because not enough binding sites available, peptide transporters, naturally occurring molecule transporters
eflux: specific, pump toxins, P-glycoprotein multi-drug resistant pumps drug back to lumen which decreases absorption (verapamil inhibits)first pass effect: happens in liver, metabolism of drug before enters the systemic circulation (drugs: morphine- oral dosage is higher) main factors: enzyme activity, GI motility,plasma protein & blood cell binding
- cause drug-drug interaction when plasma level is high
degradation of drugs: cytochrome family
gastric emptying rate: quicker drug gets into GI tract quicker the rate of absorption
degrading the rate cause stomach irritation slow absorption rate
How? high fat meal, cold beverages (stomach is warming up fluid) -> delays drug being present in plasma
how to increase: stressful emotional state, some drugs, hyperthyroidism. gastric pH reduced from food, fatty meals before will increase bile flow (form micelles which solubilise fatty acid) which increase solubility of drug and absorption
capsules
hard gelatine (contain different physiochemical drugs) contain: glycerol, water & gelatin
soft (contain liquid/semi-solid), 6 times more glycerol (plasticiser that increases the flexability)
allow poorly soluble/ slowly dissolving drugs to be delivered in a solution (enhance bioavailability)
disadvantage: more expensive than tablets, sensitive to humidity, vegetarians may not want to take it
purpose of some important ingredients:
- preservatives: stop microbial growth during manufacturing
- colorants & opacifying: protect from light and give a pleasant look
- enteric coats: release contents in small intestine and protect stomach
why gelatin?
- non-toxic
- digestible protein
- edible, tasteless, odourless
- forms strong thin films
- stable at room temperature (25 oC) and dissolves at body temperature (37 oC)
- inert
- inexpensive
advantages: more stable, hide unpleasant tase & odors, less need for extra excipients, rapid release, controlled release, easier to swallow
disadvantages: not suitable for very soluble ingredients because it will irritate stomach, cannot be used for efflorescent (contains water and when exposed to air loses this water) and deliquescent (absorbs water from air)materials
-
oxidation
- auto-oxidation, oxygen is present
- most common type
- affects solution rather than solid where drug is exposed to environment
- result: bad smell, taste, little drug loss but still rejected, more toxic products
- temp, light control by refrigeration, proper packaging
- more likely to affect drug with many C=C bonds
- metal ions can catalyse radical formation: to remove them we can add chelating agents
initiation: drug become radical, propagation: drug radical react with diradical oxygen (looking for 1 electron) then cycle will go on to create different drug radical, termination: radicals reacting together and neutralising each other (products are non-reactive)
functional groups:
phenols at basic conditions (result in many products)-> quinone
alcohols (not tertiary)-> aldehyde-> ketone-> carboxylic
aldehyde->carboxylic
aniline (different products because of their ring structure)-> N-oxides
aliphatic amine-> N-oxide-> alkenes-> carbonyl compound
ether-> peroxide-> carbonyl
thioethers-> suffixed
fats& oils be oxidised but prevent other things from oxidising
steroids-> different carbonyl
- reversible electron loss
- no oxygen present
- happens from high temp and in ph> 6 (basic conditions)
- prevented by reduced antioxidants, which reduce oxidised product to initial
funcitonal groups:
catecholamines-> quinone-> melanin rich degradant to avoid: formulate at pH 3 and add salt (increase stability & protonate nitrogen and make less reactive)
prevention types:
- chelating agents:convert metal ions into insoluble solids,form several bonds to a single metal ion
- reduced antioxidant (more susceptible to oxidation first than the drug)
- primary antioxidant (interfering with propagation, resulting in antioxidant radical that is more stable)
for water soluble drugs: use thiol based antioxidant
for oil-based drugs: phenols
electron donating drugs can stabilise radicals
tablets
advantages:
- oral dosing (convenient, elegant, safe, accurate dosing and good compliance)
- physical and chemical stability is an advantage (when compared with liquid dose forms)
- cost of production is relatively cheap and has a consistent quality
disadvantages:
- poorly soluble drugs have poor bioavailability (proportion of drug that enters the body and have an active effect)
- potentially cause irritation as it starts to dissolve in the mouth
-