D12. Stability: physical processes Flashcards
why is stability important?
Stability is an essential factor in the safety, efficacy and quality of a medicine- requires chemical and physical stability
what 3 different states are drugs and excipients found in?
crystalline solid, liquid/solution, gas
equilibrium between phases is dependent on?
temperature and pressure
medicines are at atmospheric pressure with the exception of what?
aerosols
Describe a metered dose inhaler
In head space, gases liquefied in a closed container in equilibria
with gas phase (high vapour pressure)
ONE NOTE
Describe solid- liquid transition
Atoms in solid state oscillate in fixed positions-> increase in temperature -> disrupt ordered nature of lattice
most drugs and excipients with high melting points are stable at what temp?
room temp
Describe liquid-solid transition
Freezing water in a liquid medicine creates crystals of ice that interfere with physical stability of suspensions and emulsions
Describe solid- gas transition
-Iodine can sublime directly to gas (high vapour pressure-more later)
-Freeze drying
-Drug frozen in water-> dried by a sublimation process (reduction pressure/temperature)
Describe liquid to gas transition
Cytotoxics: High vapour pressure (for example carmustine) and if spilt can volatilise to a gas (hazard when working with cytotoxics)
what is evaporation?
Change of liquid into a vapour at a temperature below the boiling point
What is sublimation?
Change of solid into a vapour at a temperature below the triple point in the phase diagram (direct transition from solid to gas)
what is vapour pressure?
Pressure exerted by the vapour at equilibrium is the vapour pressure (constant temperature). The condensed phase (liquid/solid) placed in closed container.
Describe evaporation
Evaporation takes place at the surface of a liquid, where molecules with highest kinetic energy escape
Describe the equilibrium in a closed container?
Equilibrium between evaporation & condensation in closed container at constant temperature
why is the vapour pressure of solids much lower than liquids?
due to stronger inter-molecular forces in solids. In solids, evaporation is more common than sublimation
how can evaporation occur with pharmaceutical liquids?
Pharmaceutical liquids (suspensions, emulsions, solutions)- aqueous vehiclecan evaporate if the lid left off on the bottle. The non-volatile drugs/ low vapour pressures do not escape which can increase concentration of drug in suspension/ solution
Describe gas adsorption
water vapour in the atmosphere can adsorb onto drugs and excipients and form a thin water layer. This could cause chemical degradation (hydrolysis) and also impact the flow and cohesive properties of drug particles
Describe physical adsorption process (no chemical bonds)
-Mono/multi-layers on the surface
-Adsorption-desorption reversible
-Capillary condensation into pores on the surface of the material
What is gas adsorption dependent on?
-Dependant on temperature, pressure & amount of water vapour in the atmosphere (humidity)
-Decreases with increase in temperature
-Increases with increases in water vapour at constant temp
what is a hygroscopic solid?
describes a solid that adsorbs water
what is a hygroscopic solid dependent on?
Dependant on the surface area and surface energy of the drug particle (greater the polar component more water absorbed )
what is equilibrium (or Thermodynamic) Solubility?
the concentration of drug in a saturated solution when excess solid is present, and solution and solid are at equilibrium
ONE NOTE
what is supersaturation/nucleation?
solid drug ppt out
what can happen to a drug in solution if not stored as labelled i.e at lower temperatures ?
Potential for ppt of drugs but concentration remains the same
solubility of solute (drug) decreases with what change in temperature?
decreases in temperature
what is a crystalline structure?
a solid in which the constituent molecules are packed in a regularly ordered, repeating pattern extending in all three spatial dimensions; held together by non-covalent interactions
what is a amorphous structure?
Materials with no apparent crystalline form, i.e. no long range order
surface amorphous content are induced by?
processing e.g milling/micronising)
Describe the physical form of a drug?
-Most drugs (organic molecules) are crystalline and designed to be inherently stable by medicinal chemists
-High melting points so that they are stable at room temperature and during processing
-The most stable polymorph/hydrate is used
Describe the stability of amorphous materials
Amorphous materials generally less stable (physical and chemical stability) than corresponding crystalline form.
Describe the chemical stability of amorphous materials
Water lowers the glass transition temperature (Tg) -> material more plastic-> increases the molecular mobility and ↑ chemical reactivity (more prone to chemical degradation than corresponding crystalline form)
Describe the physical stability of amorphous materials
amorphous phases can crystallise with exposure to moisture
what is polymorphism?
When two crystals have the same chemical composition but different molecular packing they are polymorphs
what is polymorphism?
When two crystals have the same chemical composition but different molecular packing they are polymorphs
Describe polymorphs
-Polymorphs have different physical & chemical properties
-Melting point, density, solubility, bioavailability, processing properties
-The more stable the polymorph the lower the solubility
What is a metastable polymorph
-A metastable polymorph is a form of a substance that is stable under certain conditions but is not the most energetically favorable, and may eventually transform into a more stable form.
-A metastable form can convert to more stable form in both solid and liquids (tablets and suspensions)
Describe a meta stable polymorph
it has a high solubility so is therefore absorbed in the GIT. It has a high drug plasma concentration.
Describe what can happen to a meta stable polymorph during storage?
-it can convert to the most stable polymorph which has a low solubility
-It will be absorbed in GIT with a lower drug plasma concentration= potential for reduced pharmacological effect. Therefore solution is to start with the most stable polymorph and no changes on storage
what are hydrates?
-polymorphs with the presence of water molecules as an integral part of crystal structure
-these in turn influence: solubility, stability, dissolution rate, bioavailability
Describe packaging
-protection of the medicine during transportation, storage and use
-it can be made of glass (not permeable), plastics and rubber
why are plastics and rubbers commonly used (semi permeable barrier) as packaging?
-can be permeable to oxygen, water vapour, carbon dioxide
-components of the medicine can also permeate through the packaging e.g parabens/antibacterials, flavorants, water vapour and oils
-Permeation through plastic barrier depends on area, thickness of the barrier, time, differences in partial vapour pressure across the barrier
-Occurs by diffusion
Permeation is described by what?
Fick’s first law (rate of diffusion)
what is fick’s first law?
dm/ dt = -DA (dC/ dx)
where:
dm= mass of substance diffusing in time dt across aea A under the influence of a concentration gradient dC/ dx
-(minus sign denotes the diffusion taking place from an area of high concentration to a low concentration), D is the diffusion coefficient of the permeant
ONE NOTE
What is total water vapour ingress?
total process of water moving into packaging from all separate components, for example, lid, bottle, outer protective pouch (leakage through microscopic cracks and pinholes)
Describe water vapour loss
-IV solutions in flexible plastic packaging- shelf life of the medicine is limited
-Can be controlled with foil overwrap
What are OTHER packaging problems? (leachables and adsorbtion)
-Problems can arise from leachables, discolouration, absorption or adsorption from the medicine (either solid or solution). These are all dependent on temperature, humidity and storage time.
-higher temperatures and humidity increase the likelihood
Leachables definition from FDA?
-”Organic and inorganic chemical species that can be released from the surfaces of components used in storage of drug products (medicine) under conditions of normal use”.
what influences the accumulation of leachables in a medicine (solution)?
-Initial amt of leachable in the container
-Solubility limit of the leachable in solution
-Partitioning of the leachable between the container and the solution
-Migration of the leachable from the container into solution
Describe the packaging problem of adsorption (drug/ excipient) from solution to container surface
Adsorption of solute (drug/excipient) to surface (packaging/container) occurs when chemical groups present that allow interaction
what factors affect the extent of adsorption?
-Solute concentration
-pH –extent of ionisation – unionised more likely to be adsorbed
-Temperature-exothermic -> lower temp more adsorbed
-Surface area
what are the types of glass container materials?
-Type I (borosilicate)- chemically resistant and low leachables, primarily used for parenteral medicines
-Types II and III (soda lime)- Type II suitable for buffered solutions, Type III used only for dry medicines (tablets/powders)
ONE NOTE
Compare the compatibility of plastic container materials
ONE NOTE
Describe PVC plastic container material
PVC –high potential for leachables, permeation and adsorption of insulin and other proteins, vitamin A and warfarin adsorbed (drugs present as additives)
compare the compatibility of rubber container materials
ONE NOTE
medicine product can be protected by what three material?
glass (not permeable), plastics and rubber (semi permeable barrier)
what are plastics and rubbers semi permeable to?
oxygen, water vapour, carbon dioxide and medicine components by diffusion (ficks first law)
What are leachables and what is the issue with them in medicines?
Leachables are chemicals that migrate from the materials of a medicine container or packaging into the drug product. This can cause toxicity, drug instability, degradation, reduced efficacy, changes in taste and odour
what is the main problem with solution medicines
adsorbtion
