Stability of Medicines

Pharmaceutical products may be degraded in which three ways? (1)

Chemical degradation (due to effects of moisture, oxygen, light, heat). Physical degradation (specific to dosage form e.g. caking/flocculation of suspensions, phase separation in emulsions)

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Pharmaceutical products may be degraded in which three ways? (2)

Microbial (metabolism of drug molecule or physical spoilage of dosage form, microbial contamination may result in infection

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Describe the extent of acceptable degradation (1)

Degradation results in loss of active drug product in dosage form that are no intended. Most medicines not perfectly stable. 5-10% loss limit over total shelf-life (~ 5 years) acceptable

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Describe the extent of acceptable degradation (2)

Depends on toxicity, effects on physical properties of dosage form and aesthetics

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Describe features of the justification of expiry date and storage conditions (1)

Concept (store product under various conditions, assess instability at end of storage period using specific methods). Disadvantages (takes too long, no idea of storage abuse, wish to start study before final pack/product defined)

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Describe features of the justification of expiry date and storage conditions (2)

Industry/regulatory (have evolved specific protocols of testing that include accelerated/stress testing)

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Describe features of formal stability testing

Generation of data to justify expiry date and storage conditions. Consider conditions, monitor instability, toxicity/efficacy, options if product unstable (modify storage conditions, reformulate) - must get product onto market ASAP

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Describe features of definitive stability testing protocol

Batches of product tested at different temperatures for different storage time periods, test for chemical/physical/microbial degradation

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Describe features of zero order kinetics

Rate of degradation of A is independent of concentration of reactants. Half life and t5% are dependent of initial concentration. t5% = [A]0/20k

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Describe features of first order kinetics

Rate of degradation is directly proportional to the concentration. Half-life and t5% are independent of concentration. t5% = 0.051/k

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Describe features of pseudo zero order reaction

Initially first order but appears as zero order reaction (e.g. poorly soluble drugs, suspensions)

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What is the equation for second order reactions?

-dA/dt = k[A][B]

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Describe features of pseudo first order reactions

Second order reaction appears as first order due to buffer solution being in large amounts (high amounts of H+ ions, fixed pH)

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Describe features of irreversible parallel reactions

First order. Degradation to form two sets of possible products (k1, k2)

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Which factors affect solution stability?

Hydrolysis (e.g. ester - into alcohol and carboxylic acid, chloramphenicol), pH, temperature

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How can the rate of hydrolysis be reduced?

Adjust pH to maximum stability in aqueous solution, dry formulations (no hydrolysis/no water present), changing dielectric constant of solution, storage temperature, coating, choice of packaging

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What does a pH-rate profile show?

The relationship between pH and stability (plot k obs as a function of the proton activity in a double log system)

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What should be considered in a pH-rate profile?

Order of reaction, degradation products, buffer catalysis (HA - H+, A-), pH, ionic strength, solvent (dielectric constant), temperature

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How is a pH-rate profile constructed?

Identify bonds or functional groups that may influence the stability of the molecule (drug), chose buffers to maintain pH at various pH-values. Perform experiments

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Describe features of degradation of species and buffer solution

When the drug is an acid or base, both protonated and unprotonated can be part of the rate expression. pH of buffer concentration can affect the rate constant (graph, y-intercept is the degradation independent of buffer)

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How can you determine if mecillinam can be put into an aqueous IV formulation? (1)

Identify bonds/functional groups with their pKa values and their charges in particular conditions e.g. amine, lactam ring (subject to hydrolysis), carboxylic acid, amidino etc. Plot of pH-rate profile from experiments (acidic/neutral/basic condition)

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How can you determine if mecillinam can be put into an aqueous IV formulation? (2)

Determine rate constants in different conditions. Minimum on pH-rate plot shows most stable area (suitable pH). Able to calculate time for 5% degradation. Conclude if formation is feasible

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Describe features of temperature effects

Reaction rates may double for each 10 K increase in temperature. Relationship between rate of reaction and temperature is given by the Arrhenius equation

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State features of the Arrhenius equation

k = A.e^-Ea/RT (k - rate constant, A - frequency factor/number of molecular collisions per unit time, e - exponential, EA - activation energy/fraction of number of successful collisions, R - ideal gas constant/8.314 JK^-1mol^-1, T - temperature (K))

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How does temperature link to collisions?

As T increases, the fraction increases - more successful collisions

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Describe features of the Arrhenius plot

ln k = ln A - Ea/RT, ln k = ln A - Ea/R.1/T. Plot ln k vs 1/T. y-intercept (ln A), gradient (-Ea/R). Easier to do experiments at higher temperatures (larger values for k) - extrapolation to cold temperatures which would have smaller values for k

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Describe features of shelf-life production

Study kinetics of drug degradation at elevated temperatures (takes only short amount of time). Extrapolate to determine rate constant at ambient conditions. If degradation first order: t = 1/k. ln ([A]0/[A])

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How do you calculate the shelf-life?

Assuming 5% decomposition acceptable at end of life: t = 1/k 298 x ln (100/95)

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Describe features of statistics in stability prediction (1)

Distribution of ln k values for a given 1/t obtained during accelerated stability testing. SD of the mean gives an indication of the spread of values in the distribution. Confidence interval of +/- 1 contains 68% of data, +/-2, 95% and +/-3, 99.7%

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Describe features of statistics in stability prediction (1)

Plot of ln k bx t/T. SD gives curved lines around the linear regression time (worst case and best case for stability). 95% confidence interval, one-sided upper confidence limit for mean, taken as acceptable value for shelf life

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Give two examples of isomerisation in solution

Mild acidic conditions induce racemisation of tetracycline to form 4-epi-tetracycline (stereoisomer) - minimal antibacterial effect. Lactose switches between alpha/beta form in solution

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Describe features of polymerisation in solution (1)

Formaldehyde polymerises in aqueous solution to form solid paraformaldehyde. Amino-penicillins (ampicillin) polymerises in aqueous solution. Beta-lactam ring of one molecule is opened by the side chain of another molecule to form a dimer (polymer)

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Describe features of polymerisation in solution (2)

Polymeric ampicillin is highly antigenic and is implicated in allergic reactions to penicillins in humans. Dimerisation is unavoidable with basic side chains

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Describe features of circumvention solvent effects (1)

Solutions should be buffered in order to control the pH within limits at which the drug is most stable. Drugs for IV injection may be formulated using a co-solvent (propylene glycol, alcohol, glycerol)

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Describe features of circumvention solvent effects (2)

Poorly soluble drugs sequestered from solvent by incorporation into surfactant micelles or cyclodextrins

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Describe features of oxidation

Loss of electrons, addition of oxygen, removal of hydrogen. Occurs via action of free radicals (high reactive species possessing one or more unpaired electrons). Radicals generated by action of light energy/heat/trace metals e.g. nifedipine (UV)

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Describe features of auto-oxidation

Reaction of free radicals with drugs/biomolecules leads to formation of peroxyl radicals which initiate auto-oxidation. Propagation reactions (chain). Reaction is terminated by side reactions breaking into chain/inhibitors to destroy peroxyl radicals

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Which drug structures of prone to auto-oxidation

Phenols (paracetamol turns red/steroids). Catechols (L-DOPA). Aldehydes (paraldehyde). Thiols (dimercapol). Thioesters (chlorpromazine)

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Describe features of circumvention of oxidation (1)

Remove initiators (chelation of trace metals with chelating agents, ethylene diamine tetra-acetic acid (EDTA), citric acid, tartaric acid. Exclude O2 (sparge liquids with inert gas/N2 to displace O2)

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Describe features of circumvention of oxidation (2)

Add free-radical scavengers e.g. BHT more readily oxidised than oils - used to stabilise fatty/oily products. Add antioxidants e.g. ascorbic acid - possess lower redox potential than more/readily oxidised

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Describe features of photochemical effects (1)

Energy of photon increases with decreasing wavelength (E = hc/lamba). UV light has high energy which can catalyse reactions. UV light may induce complex reactions (oxidation, ring re-arrangement, polymerisation)

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Describe features of photochemical effects (2)

UV radiation induces polymerisation of chlorpromazine (anoxic conditions) - HCl produced with polymer

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Describe features of circumvention of photochemical effects

Exclude light by - storage in dark or packaging in foil. Filter out light by - storage in amber glass or coating tablets with pigmented polymers

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Describe features of solid state reactions in solution

Major source of solvent-residual moisture/solvent from wet granulation. Moisture sorption into/onto excipients (starch/lactose), moisture in capsule shell may migrate, a solvate or hydrate loses lattice solvent with time/temp fluctutuations

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Describe features of particulate factors (1)

Physical form - differences in intrinsic vibration, particle size/SA, crystal morphology. Presence of functional groups - different on crystal faces, different reactivities with functional groups

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Describe features of particulate factors (2)

Defects/concentration - solid state reaction usually initiates at high energy sites (hot spots) e.g. surfaces, impurities, defects

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What are the other factors which affect solid state stability?

Temperature, relative humidity (measure of the amount of water vapour in the atmosphere/use hygrometer), packaging, light (wavelength/intensity), oxygen

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Describe features of excipient factors

Acting as surface catalysts. Altering pH of moisture layer. Undergoing direct chemical reactions with drug (powder mixing/packaging). Drug:excipient, physical contact of reactive species

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Give examples of formulation incompatibilities

Primary amine (mono/disaccharides), ester (basic components), alcohol (oxygen), phenol (metals) etc.

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Describe methods of stabilisation (1)

Reaction occurs in solution state in solid dosage forms - reaction rate is proportional to amount of dissolved drug. Amount of dissolved drug = volume of available solvent x saturated solubility of drug

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Describe methods of stabilisation (2)

Altering properties of solid drug - increase m.p., choose non-hygroscopic form (crystal/salt form), reducing solubility by choosing a less soluble salt, micellar/cyclodextrin inclusion

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Describe methods of stabilisation (3)

Minimise level of moisture in formulation - choice of excipients, co-solvents, manufacturing conditions, storage conditions, packaging

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Describe methods of stabilisation (4)

Changing the micro-environment around the drug particles in the formulation - adjust pH using acid/base/buffer salts. Incorporating chelating agents to inactivate trace metal ions, displace oxygen with nitrogen or argon, incorporating antioxidants

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Describe methods of stabilisation (5)

Physically separate reacting species - minimise contact among interacting drugs/excipients and water. Techniques include - coating with polymers or micro-encapsulation (e.g. HPMC)

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Describe features of physical degradation

Kinetics not understood, implications can be serious as those for chemical degradation. Affects appearance of dosage form, uniformity and bioavailability. Types of degradation specific for different dosage forms

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Describe features of physical degradation of solutions

Solutions of drugs with low aqueous solubility - precipitation/crystal growth over storage - affects bioavailability of drug (e.g. insulin). Injection of precipitated drug is painful. Packaging and storage conditions need to be taken into account

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Describe features of physical degradation of suspensions

Colloidal suspensions of poorly soluble drug particles. Stability arises through optimisation of formulation excipients - wetting agents (surfactants), suspending agents (hydrocolloids), flocculating agents (salts)

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Describe features of wetting agents

Surfactants decrease interfacial tension between hydrophobic surfaces of drug particles and aqueous phase. Without (adequate) surfactant, re-dispersion of drug particles upon shaking would result in particles coated with air - floating on the surface

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Give examples of wetting agents

Sodium alkyl sulphate (anionic), alkyltrimethylammonium bromide (cationic), alkyl polyoxyethylene ether (non-ionic)

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Describe features of suspending agents

Hydrocolloid suspending agents e.g. polysaccharides, MC, sodium alginate, ****** sedimentation. Help to ensure uniformity of dose upon re-dispersion

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What is caking?

Irreversible aggregation of drug particles during storage of sedimented suspension - caking is prevented by flocculation of drug particles

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Describe features of flocculated suspensions

De-flocculated suspensions sediment slowly - low sediment height (prone to caking). Flocculated suspensions sediment quickly - high sediment height

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Describe features of zeta potential (1)

Measure of charge on the surface of the particle (depends on concentration of electrolytes). Flocculation depends on zeta potential. Measured by detection of movement of drug particles in induced electric field (electrophoresis)

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Describe features of zeta potential (2)

Only stern layer moves with particles (due to presence of counter ion in stern layer). Measure diffuse layer and stern layer to get zeta potential

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Describe features of the DVLO theory (1)

Zeta potential affects colloidal stability of drug particles. Surface/zeta potential govern electrostatic forces acting on drug particles/double layers interfere

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Describe features of the DVLO theory (2)

Electrostatic repulsion between like charges (maximum when touching/decreases to zero outside double layer). Attractive energy used to indication van der Waals changing with particle distance

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Describe features of the DVLO theory (3)

Van der Waals - result of forced between molecules (additive effect - one molecule of first colloid has van der Waals attraction to each molecule in the second colloid)

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Describe features of the DVLO theory (4)

Primary maximum (colliding particles aggregate closer, energy of collision > repulsive energy). Secondary maximum (particles attracted with weak forces, reversible flocculation). Primary maximum (particles strongly bound via van der Waals forces)

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Which part of the graph in the DVLO theory is the most suitable for colloids in formulations?

Secondary minimum

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Describe feature of caking of suspensions (1)

At near zero zeta potential, flocculated suspension is formed, which has loosely packed sediment - no caking

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Describe feature of caking of suspensions (2)

High positive/negative zeta potential - particles pack more tightly in low volume sediment, gravity provides sufficient energy for irreversible aggregation - caking

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Describe other suspension stability issues

Temperature fluctuation during storage - leads to crystal formation (in amorphous particles) or crystal growth (Ostwald ripening) - can affect bioavailability. Solubility of non-ionic surfactants is also affected - particle aggregation (caking)

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What are the two main types of emulsions?

o/w vehicles for oil soluble drugs e.g. lotions, creams. w/o vehicles for i.m. depot of water soluble drugs

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What is creaming?

Separation of droplets of different sizes, uniformity may be re-obtained by adequate shaking

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How can creaming be prevented?

Can be prevented by using more efficient surfactant (smaller droplet size) or increase viscosity by addition of hydrocolloid (MC for o/w emulsions or white paraffin for w/o emulsions)

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Describe features of cracking of emulsions

Flocculation of emulsion droplets is the first step towards coalescence and phase separation (breaking/cracking).

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How can cracking to prevented?

By maintaining high charge density around droplets (ionic surfactants)

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How can steroid stabilisation be used to prevent cracking of emulsions? (1)

Non-ionic surfactants with polymeric head groups are usually used to sterically stabilise o/w emulsions as close approach of oil droplets cause thermodynamically unfavourable crowding of polymer chains

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How can steroid stabilisation be used to prevent cracking of emulsions? (2)

For w/o emulsions, surfactants with long HC chains prevent coalescence

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Which physical changes in tablets over time can affect bioavailability?

Hardness, friability, disintegration, dissolution - due to absorption of moisture, relaxation after compression, crystal polymorphism, changes in binder strength (cases for re-formulation)

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What are the sources of microbial contaminants?

Water (pseudomonas), air (penicillin), raw materials (salmonella), personnel (enteric bacteria) - microbial contamination can result in drug recalls e.g. contamination of E.coli (impact on patients)

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What are the consequences of contamination? (1)

Some microbial contamination may cause no spoilage/drug degradation or harm to patient at all. Parenteral/ophthalmic use - presence of extraneous organisms are dangerous (require sterilisation). Pyrogens present without viable organisms

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What are the consequences of contamination? (2)

Physical effects including cracking of emulsions, signs of general spoilage, production of gas and odours. Also causes chemical degradation of dosage forms without overt signs of spoilage

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Which drugs are susceptible to microbial contamination?

Salicylates, paracetamol, atropine, chloramphenicol, hydrocortisone

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How can microbial contamination be controlled?

Aseptic manufacturing techniques, UV treatment of raw materials, disinfection/sterilisation of equipment, sterilisation of final product, addition of chemical preservatives to prevent growth of microbes e.g. chlorhexidine (impact patients)

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What are the standards for microbial content?

Tolerance of some 'bioburden' is acceptable. Regular testing for total counts of bacteria is necessary. Specific classes of organisms need to be excluded form certain dosage forms. Staphylococcus spp./topical preparations, enteric bacteria/oral doses

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What are the three ways pharmaceutical products can be degraded?

Chemical (light, heat, moisture, oxygen), physical (caking, flocculation, phase separation of emulsion), microbial (metabolism of drug, physical spoilage of dosage form - can result in and infection)

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Stability of Medicines

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