Stability of Medicines - PHA 111

PHA 111 Stability of Medicines Dr Stephen Childs Senior Lecturer in Pharmaceutical Chemistry [email protected] de 1 PHA 111: Stability of Medicines  Role of Pharmacist / Learning O...

PHA 111 Stability of Medicines Dr Stephen Childs Senior Lecturer in Pharmaceutical Chemistry [email protected] de 1 PHA 111: Stability of Medicines  Role of Pharmacist / Learning Objective Design of stable medicines – Understanding of causes of instability – Appreciation of stability enhancing methods – Ability to assess long term stability and consider techniques for assessments Maintenance of stability – Storage of medicines – Medicine preparation (extemporaneous dispensing) Advise on medicine use – Suitable storage and use (Medicine Compliance Aids) Judgement on implications – Comprehension of clinical implications of loss of stability de 2 PHA 111: Stability of Medicines  Product Stability Stability: ability to retain the original characteristics during manufacture, transport, storage and use. Three main factors in product stability – Physical stability – Microbial stability – Chemical stability An apparent instability in one area may be due to primary change in another – Chemical or microbial degradation of surfactant may lead to emulsion cracking – Hydrolysis of antimicrobial agent may lead to loss of protection against microbiological spoilage – Adsorption into container may lead to apparent loss of active agent – Hygroscopic properties – powders may liquefy - suppositories may loose structure de 3 PHA 111: Stability of Medicines  Physical Instability Change in bioavailability – Alteration of drug solubility – Loss of active through evaporation Change in medicine form – Separation of liquid phases in emulsions – Settling of solids in suspensions Changes in patient acceptability – Alteration of viscosity – Change in colour, odour or taste – Production of particulate matter de 4 PHA 111: Stability of Medicines  Crystalline Forms Polymorphism – Different crystal structures – One stable form (I), one or more metastable forms (II..) – Form I has highest MP, lowest solubility and dissolution rate Polymorphic form used may affects bioavailability Chloramphenicol palmitate – Use of stable polymorph leads to low blood levels Digoxin – Mechanical stress (grinding) converts powder to amorphous form with higher dissolution rate Conversion occurs more rapidly in suspension – Novobiocin, cortisone acetate de 5 – Crystal growth, slower PHA 111: dissolution Stability of Medicines  Therapeutic Window de 6 PHA 111: Stability of Medicines  Suspensions Two-phase system comprising solid particles dispersed in a liquid Particles < 1 μm termed colloids Particles > 1 μm termed coarse suspensions Instability due to settling 2 gr 2 1   2  Vs  9  Stoke’s Law applies to coarse suspensions Large particles may settle too quickly Small particles settle more slowly but may form a cake Partially soluble drug may change particle size if temperature fluctuates de 7 PHA 111: Stability of Medicines  Emulsions Dispersion of two immiscible liquids, one evenly distributed as fine droplets in the other – May be oil in water or water in oil – Thermodynamically unstable – Requires an emulsifying agent Partial separation of disperse phase – Creaming in o/w emulsions – Water droplet settling in w/o emulsions – Small droplets reduce effect – High viscosity reduces creaming Complete separation of phases – Cracking (oil separated from water) – Irreversible – Breakdown of emulsifying system de 8 PHA 111: Stability of Medicines  Incompatibility Pharmacological – β-blockers and salbutamol -opposite effect “cancel out” https://bnf.nice.org.uk/interaction/ Pharmacokinetic – Tetracyclines and some antacids - metal ion binding (Mg/Ca) reduces absorption Apparent interactions (visual) – Precipitation, colour change, phase separation Physicochemical – Drug-drug interactions – Drug-excipient interactions – Primary amines bound to microcrystalline cellulose – Drug-packaging interactions e.g. Glass –surface may affect pH, light transmission, inorganic radicals? Plastic – phthalate leaching, drug migration? de 9 PHA 111: Stability of Medicines  Drug-Excipient Interaction Reaction between amino acids and sugars. Unfortunately an area of pre-formulation that is often overlooked! E.g. Maillard reaction between chlorpromazine and dextrose CHO HC N-DRUG HC N-DRUG H2C N-DRUG H OH H OH OH O HO H DRUG-NH2 HO H HO H HO H H OH H OH H OH H OH H OH H2O H OH H OH H OH CH2OH CH2OH CH2OH CH2OH Dextrose Amadori Compound de 10 PHA 111: Stability of Medicines  Physicochemical Effects O N Cl N Solvent effect on solubility – e.g. diazepam – poor water solubility – 5 mg/ml injection prepared with 40% propyleneDiazepam glycol, 10% ethanol – mixtures lead to precipitate depending on concentration – 1:10 or 1:20 insoluble – 1:50 or above clear for 24 hr Similar potential problems with other drugs – digoxin: 0.5 mg/2ml; dilute > 1:4 – etoposide: 20 mg/ml injection should be diluted to