Physical Science Revision Question Exam Style

1. You are a part of a team of - partition coefficient/P is a measure of the disscientists working in the tribution of a compound between 2 immiscible area of lead optimisation. phases, typically between octanol and water a) Define, including a - P = conc in lipid or organic phase / conc in suitable equation, the aqueous phase term 'partition coefficient' [3 marks] 2. You are a part of a team of - the partition coefficient is a crucial in drug develscientists working in the opment as it predict's a drug's ability to cross the area of lead optimisation. membrane b) Using your answer - a higher coefficient means better absorption, above, explain why the while a lower one suggests poor permeability partition coefficient is a - log P is important as it determines whether critical physicochemical the drug is too hydrophobic/hydrophilic and what property: ( 8 marks) extent is crosses the biological membrane - the partition coefficient is crucial for a drug's bioavailability in the body - it affects how well the drug is absorbed + distributed, impacting its effectiveness - log P also influences ADME = influences how drug moves in the body, how it spreads in different tissues etc. - logP affects drug metabolism by influencing cell membrane permeability Lipophilic drugs with high logP values may stay longer in the body as they could be reabsorbed in the kidneys instead of being efficiently excreted in urine 3. You are a part of a team of - as unionised (pH of the stomach is 1-2), more scientists working in the likely compound is lipophilic area of lead optimisation. - more likely absorbed in the stomach c) The compound in question is a weak acid (pKa =3.1). Given this information, where is the compound more likely to 1/6 be absorbed in the GI tract and why? 4. For weakly acidic drugs - majority is UNIONISED in gastric fluid (pH 1-2) (pKa = 3.0) - majority is IONISED in intestinal fluid (pH 7-8) - therefore more likely to be absorbed in the stomach 5. For weakly basic drugs (pKa = 5.0): - majority is PROTONATED in gastric fluid (pH 1-2) - majority is DE-PROTONATED in intestinal fluid (pH 7-8) - therefore more likely to be absorbed in the small intestine 6. Deprotonated mean? -proton removed from molecule - formation of ion 7. What is Log D? - distrubution coefficient - ionised molecule at a certain pH 8. The thalidomide disaster contributed to the introduction of the regulatory affairs department. (i) Explain what it meant by the thalidomide disaster [6 marks] - the thalidomide diaster refers to a tragic event in the late 1950s and early 1960s - used for pregnant women for treating morning sickness, caused severe birth defects in thousands of babies worldwide - led to malformation in babies - it was marketed as a replacement for barbiturate + much safer for morning sickness - the drug led to babies being born with limb deformities - little/no regulation at that time - regulation changed - MA 1968 - importance of regulation + oversight in the pharmaceutical industry to ensure the safety + efficacy of drugs before they reach the market - FDA refused to sell thalidomide in USA = they held back + not marketed 9. 2/6 What is the yellow card system? [2 marks] 10. d) Another compound being studied is shown below. It has suboptimal water solubility Draw the analogues of this which would offer increased water solubility + explain the reasoning behind each: - mechanism of reporting adverse drug reactions (ADR) - in UK, go to the MHRA = anyone can report, generally healthcare professional suboptimal = bad undesired water solubility - add polar functional groups - e.g. COOH = easily ionisable/more polar - can add nitrogen - remove ring = reduce carbon atoms, reduce molecular weight, increase water solubility 11. What is the 'The Orange - provides guidance on interpretation of Good Guide'? [2 marks] Manufacturing Practice (GMP) for medicinal products for human + veterinary use - the Orange Guide covers various aspects of pharmaceutical manufacturing, distribution + quality control to ensure compliance with regulatory standards - GMP requirements 12. (a) You are working in a formulation team at a large pharmaceutical company. You have been provided with a new compound which requires formulating. This drug is to be administered orally but must have a rapid onset of action. This drug has a log P of 4.3 and is known for hydrolysis in water within 24 hours. - rapid onset of action = works quickly - hydrolysis in water = don't want drug break down - due to it being dissolved in water = doesn't break immediately - hydrolysis in water within 24 hours = slow breakdown I would choose sublingual tablets : - pass directly through the membrane - higher Log P helps - rapid onset of action - no problem of hydrolysis - disintegrate quickly in mouth for rapid absorption Describe upon a suitable Buccal tablets = released slower, not rapid onset 3/6 formulation in this case, of action explaining how you ar- solution = problem as hydrolysis in water not good rived at this choice. Also, chewable tablets = fraction swallow via GI (slow), explain why you have dis- se under tongue (absorbed direct) counted other formula- ointment = too slow to be released tions as part of your answer [8 marks] 13. (a) You are working in a formulation team at a large pharmaceutical company. You have been provided with a new compound which requires formulating. This drug is to be administered orally but must have a rapid onset of action. This drug has a log P of 4.3 and is known for hydrolysis in water within 24 hours. - sublingual tablets are designed to be placed under the tongue, where the drug can dissolve + be absorbed directly into the bloodstream - bypassing the digestive system + leading to a faster onset of action - this route of administration can be advantageous for drugs that need quck absorption + onset of action Why sublingual tablets be suitable? 14. (a) You are working in a formulation team at a large pharmaceutical company. You have been provided with a new compound which requires formulating. This drug is to be administered orally but must have a rapid onset of action. This drug has a log P of 4.3 and is known for hydrolysis in water within 24 hours. - they are designed to be placed between the cheek + gum for absorption - while buccal tablets can provide rapid drug absorption, they are not as quick in onset as sublingual tablets 4/6 Why are buccal tablets not suitable? 15. Hydrolysis in water / sol- - hydrolysis in water = water splitting / breaking uble? down molecule - soluble = molecule dissolved + intact not broken down 16. Some examples of oral dosage forms: - powder reconstitution - solution - suspension - tablet - sublingual tablet - buccal tablet - emulsion - chewable tablets 17. Does tablets and cap- they are designed to be stable sules cause hydrolysis in - generally do not undergo hydrolysis when exwater? posed to water 18. Does oral powder hydrol- - yes, oral powders can undergo hydrolysis in ysis in water? water 19. Why tablet/capsule not suitable for this? - drug may take longer to dissolve + be absorbed through the GI system - they may not provide the rapid absorption needed for immediate action 20. c) Following early clinical trials, it becomes evident that the drug being investigated does not show the expected level of efficacy due to extensive first-pass metabolism. i) Explain what is meant by first-pass metabolism - refers to the metabolism via hepatic portal vein to the liver before it reaches systemic circulation - this process can significantly reduce the amount of active drug available to produce the therapeutic effect, leading to decreased efficacy - additionally, metabolites generated during first-pass metabolism can sometimes be more toxic than the original drug compound, increasing 5/6 + how they can affect the risk of adverse effects + toxicity drug efficacy and toxicity - drug can be converted into reactive metabolite, which is toxic - efficacy can change structure of drug make it less/more potent - if a drug's metabolites are more potent / exhibit excessive therapeutic effects compared to the original drug, it can lead to increased toxicity = causing adverse effects beyond the intended therapeutic range 21. What is a prodrug? - is an inactive compound that undergoes metabolic conversion in the body to form the active drug - can increase/decrease efficacy 22. ii) How would this information change your choice of formulation in part a) above? What would be a more suitable formulation be in this case? Explain your reasoning [3 marks] I would keep my answer same = sublingual tablet formulation - sublingual tablets = not dissolving it orally - as this routes allow direct entry into the bloodstream, bypassing the liver + enhancing bioavailability 6/6