Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis PDF

Fundamentals of Analytical Chemistry (FAC) Lecture 1 Introduction to Pharmaceutical Analysis 1 Slides originally by: Dr Ute Gerhard Fundamentals of Analytical Chemistry (FAC) I...

Fundamentals of Analytical Chemistry (FAC) Lecture 1 Introduction to Pharmaceutical Analysis 1 Slides originally by: Dr Ute Gerhard Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Aims of this lecture To answer the following questions: ▪ What is pharmaceutical Analysis? ▪ How is it applied to the pharmaceutical process? ▪ Why is it important? 2 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Pharmaceutical analysis techniques Qualitative Quantitative Chemical Electrical Instrumental Volumetric Potentiometry Spectroscopy (Titration) Voltammetry Chromatography Gravimetric (HPLC, mass spectrometry) 3 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis What would you want to know before you take a new medicine? 1. Does it work? 2. Is it safe? 3. How much do I need to take? 4. How often do I take it? 4 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis New medicine production process https://www.youtube.com/watch?v=3Gl0gAcW8rw Identify diseases that will need treatment in the future. Identify which protein (receptor or enzyme) may be involved in the disease. Biochemists/pharmacologists develop tests on receptors, enzymes and cells so that the effect of chemicals (new drugs) can be measured. 5 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis New medicine production process Chemists make new compounds specifically designed to improve their biological properties. For example: To improve solubility in the gut or small intestine (different pH levels). To reduce toxicity. Drug needs to be stable enough to have a chance to work but not so stable that it can’t be broken down and excreted. 6 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Making New Medicines Laboratory Involves testing, formulation, production This Photo by Unknown Author is licensed under CC BY-SA-NC and trials on animals and patients, lots of different scientists involved. Patients It takes about 12 years, costs £ 500 million, that’s £ 114,000 per day. 7 This Photo by Unknown Author is licensed under CC BY Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Research and Development Screen Hit to Lead Lead to Candidate Clinical phases File & Launch Compound Candidate Selection I to III Library Where do you think analysis is needed? 8 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Research and Development Screen Candidate Clinical phases File & Launch Hit to Lead Lead to Compound Selection I to III Candidate Library Selection of ‘Hits’ Structures correct? Spectroscopy Purity of compounds: HPLC, GC or LC- 9 MS Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Research and Development Screen Candidate Clinical phases File & Launch Hit to Lead Lead to Compound Selection I to III Candidate Library Are chemical structures correct?: Spectroscopy Are we making compounds that have good physicochemical properties such as solubility, pKa, LogD Are compounds pure?: HPLC, GC or LC-MS 10 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Research and Development Screen Candidate Clinical phases File & Launch Hit to Lead Lead to Compound Selection I to III Candidate Library Select candidate with the best physicochemical properties: solubility, pKa, logD Determine particle size and crystal structures (these affect how effective the drugs are) Check purity of manufactured drugs: HPLC, GC or LC-MS 11 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Which analytical questions do we ask in Research Have I made the correct compound? Is it pure enough for in vitro and in vivo testing? Physicochemical properties – Aqueous solubility, acidity (pKa), fat solubility (logD) Can I make it clean enough so it could be fit for testing? Predict drug metabolism and pharmacokinetics – Will it stay in the body long enough to be active – Will it get to the part of the body where it needs to act Solid state properties – Particle size – Polymorphism 12 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Research and Development Screen Candidate Clinical phases File & Launch Hit to Lead Lead to Compound Selection I to III Candidate Library What kind of analysis do you think is needed here? 13 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Which questions do we ask in Development If this compound is good enough to be a medicine - how can I make it? – Enough – Reliable – At the quality required – Safely and at a reasonable price Is it pure? – do I know where impurities come from – Are they safe (i.e. not toxic or genotoxic) → Patient safety 14 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Which questions do we ask in Development Can I prevent the formation of impurities? Measure human drug metabolism and pharmacokinetics – Does it stay in the body long enough to be active – Does it get to the part of the body where it needs to act – How is it excreted Which formulation will work best for this compound? Is the compound stable as a drug substance and the formulated product? – Predict shelf life – Understand the mechanism of formation of degradation products 15 Which questions do we need to answer in the Development of a Vaccine https://www.cdc.gov/vaccines/basics/test-approve.html Useful website if you are interested Adapted from: https://www.cdc.gov/vaccines/parents/infographics/journey-of-child- vaccine.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fparents%2Finfographics%2Fjourney -of-child-vaccine-text.html Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Obtaining a Marketing Authorisation Product license Massive document – Submitted to regulatory authorities all over the world FDA (Food and Drug Administration, USA) EMA (European Medicines Agency, Europe) Contains all the clinical evidence that the drug works and is safe Describes the manufacturing process Describes all studies supporting the quality of the drug and the shelf life 17 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Manufacture Authorisation Required by all pharmaceutical manufacturers Ensures that only authorized manufacturers manufacture all licensed products Competent authorities regularly inspect the activities of the manufacturers and annually collect samples of marketed medicines for assessment of quality Products should be manufactured by implementing a system of Quality Assurance (QA) incorporating Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP) and Quality Control (QC) 18 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Pharmacopoeias Contains the standards (Monographs) for finished pharmaceutical products and for raw materials used. European Pharmacopoeia (Ph.Eur.), United States Pharmacopoeia (USP) and British Pharmacopoeia (BP). They describe: - purity requirements for raw materials (standards) - methods for control of raw materials - requirements for pharmaceutical formulations (dosage forms) - requirements for finished preparations (e.g., vaccines) 19 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Pharmacopoeias 20 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis 21 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis 22 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Which questions do we ask of a marketed product Manufacturing o Quality: Is each batch fit for human consumption? o Continuity of supply Patent protection o Are other companies infringing our patents? Customer complaints o Quality: If a patient had an adverse effect or is concerned about the quality or effectiveness of a drug Counterfeiting o Criminal activities: Are our products copied? Containing no active ingredient Containing harmful substitutes Again: Patient safety related issues 23 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Counterfeiting – key facts Spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines are medicines that are deliberately and fraudulently mislabelled with respect to identity and/or source. Use of SFFC medicines can result in treatment failure or even death. Public confidence in health systems may be eroded following use and/or detection of SFFC medicines. Both branded and generic products are subject to counterfeiting. All kinds of medicines have been counterfeited, from medicines for the treatment of life-threatening conditions to inexpensive generic versions of painkillers and antihistamines. 24 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Counterfeiting – key facts http://www.who.int/mediacentre/factsheets/fs275/en/ SFFC medicines may include products o with the correct ingredients o with the wrong ingredients o without active ingredients o with insufficient or too much active ingredient o with fake packaging https://www.youtube.com/watch?v=6RNrRnD37ik 25 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Counterfeit Drug Examples 26 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Counterfeit Drug Examples Avastin (for cancer treatment); USA, 2012. o Affected 19 medical practices in the USA. o The drug lacked active ingredient Alli (weight-loss medicines); USA, 2010. o Smuggled into the USA. o Contained undeclared active ingredients with possible serious health risks to the consumer 27 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis What are we looking for? Packaging and appearance often gives a fake drug away, for example: Missing LOT code Expiration date had day, month and year. Drugs only have month and year Misspellings Pill not of the right colour, or no markings Capsule contains a powder, not small pellets as in the authentic drug 28 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis What are we looking for? 29 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis But what is inside? FDA first warned consumers about the counterfeit product on Jan. 18, 2010, based on preliminary laboratory tests that revealed the counterfeit version contained sibutramine and not orlistat Check with which Analysis techniques? 30 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Does it matter? Sibutramine Orlistat Centrally-acting anti-obesity Drug designed to treat drug obesity Reduces appetite Cardiovascular events were Prevents the absorption reported in 11.4% of patients compared to 10% of patients of fats using a placebo Known for unpleasant Associated with an increased risk in strokes gastrointestinal side Withdrawn from the market in effects 2010 Available as prescription Int J Obes Relat Metab Disord. 1998 Aug;22 Suppl 1:S18-28; discussion S29 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPat ientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm191650 drug (Roche) or OTC (GSK).htm www.abbott.co.uk/news/Sibutramine_release_210110.pdf 31 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis Analytical techniques used to tackle Counterfeiting Visual inspection/microscopy of packaging and tablets Chemical analysis o Identify presence or absence of active pharmaceutical ingredients MS, NMR, IR o Identify excipients in formulation MS, NMR, IR Elemental mapping of tablet surfaces Physical Analysis o Particle size 32 Fundamentals of Analytical Chemistry (FAC) Introduction to Pharmaceutical Analysis 33