Lec 7- Aseptics

Question 1

Pharmaceutics

Answer 1

Question 2

Drug stability and incompatibility summary

Answer 2

• Instability
• Incompatibility
• Shelf life

Question 3

Drug stability and incompatibility

Instability

Answer 3

• The product is modified due to storage conditions (e.g. time, light, temperature, sorption). An unsuitable product is formed
• Degradation-
• Irreversible chemical reactions (oxidation, hydrolysis-degradation in presence of water, photolysis, trace metal catalysis)
• Result in different chemical entities
• May be inactive or toxic (treatment failure)
• May be slowed but not stopped-

Question 4

Drug stability and incompatibility

Incompatibility- Physicochemical

Answer 4

• Concentration-dependent precipitation or insolubility
• Calcium and phosphate precipitate very quickly
  
  • If you put calcium in at the start and phosphate in at the end, the calcium ions have a chance to complex with other materials
• Preventable or reversible
• Acid-base reaction
• If changes are visible- termed, physical (visual) incompatibility
• The new product is unsuitable for the administration because
  
  • ‘Active’ drug has been modified e.g. increase in toxicity or
  • Physical changes have occurred e.g. change in solubility

Question 5

Drug stability and incompatibility

Shelf life

Answer 5

• Restrictions applied by drug instability or incompatibility
• Accelerated stability testing
• Sterility issues e.g. L-glutamine
• Usually much shorter once diluted for administered
• Colour changes may indicate degradation to coloured decomposition products e.g. browning reaction with lysine or basic amino acids. NOTE: Add just before administration (Same with glutamine)
• Time is taken to reduce the concentration of the drug to reduce by 10%

Question 6

Factors affecting incompatibility

Summary

Answer 6

• Saturation or solibility limits
• pH
• Drug-drug co-precipitation
• Choice of diluent or infusion fluids
• Temperature effects
• Concentration effects
• Sorption phenomena
• Leaching of plasticiers
• Photodegradation
• Salting out

Question 7

Factors affecting incompatibility in infusions

Answer 7

• Saturation or solubility limits- drug will remain in solution as long as it’s concentration is below saturation solubility
  
  • For syringe drivers this may be affected time and temperature
  • Precipitation may not occur immediately
  • Co-solvents sometimes used (e.g. etoposide)
  • Calcium and phosphate ions; preparation care

Question 8

Factors affecting incompatibility in infusion

pH

Answer 8

• Some drugs (weak acids) are formulated at high pH to achieve solubility
• If pH is reduced by addition of a less alkaline solution, precipitation may result
• Extremes of pH may affect the degradation rate of some drugs, buffers may be included in the formulation improve stability. Check the likely impact of changes in pH on stability if mixing drugs
• E.g. Ciprofloxacin- basic drug soluble at acidic pH; Infusion contain lactic acid

Question 9

Factors affecting incompatibility in infusions

Drug-drug co-precipitation

Answer 9

• Usually by mixing organic anions with cations (herapin and aminoglycosides e.g. gentamicin)
• May depend on the concentration of the solution
• Never mix in an infusion
• Flush the infusion line between administration with NaCl 0.9% if given via line

Question 10

Sorption phenomena

Answer 10

• Patient given TPN, came in with nothing wrong with eyes
• Patient got night blindness
• This was because vitamin A adsorbed onto the tubing of the delivery system causing night blindness

Question 11

pH of sc injections

Answer 11

Question 12

Factors affecting incompatibility in infusions

Choosing correct diluent and infusion fluid

Answer 12

• Drugs which are relatively unstable in aqueous solution may have degradation accelerated depending on diluent and pH
• E.g. Erythromycin should be reconsituted in water, administration in NaCl 0.9% (not glucose 0.5% which has an acid pH)
• Ringers Lactate/Hartsman’s solution
  
  • Should be used with care

Question 13

Temperature effects

Answer 13

• Each 10 degree temperature rise can increase rate of reaction 2-5x
• Increased rate of hydrolysis of beta-lactam anti-biotics at elevated temperatures
• Cold can also affect some molecules (ampicillin)
• Higher temperatures can evaporate solvents or concentrate the drug solution

Question 14

Concentration effects

Answer 14

• Increases in drug concentration may increase the rate of degradation
• May be more significant in syringe drivers where higher drug concentrations are usually present (central line administration)

Question 15

Solubility- temperature

Answer 15

• Temperature will have an effect on the solubility of the drug dependent upon weather the dissolution reaction is an endo or exothermic reaction
• If exothermic and we increase the temperature we slow down the reaction and decrease solubility (rate of dissolution)

Question 16

Leaching of plasticisers

Answer 16

*

Question 17

Factors affecting incompatibility

Salting out

Answer 17

• If you have an organic and inorganic salt
• Inorganic salt dissociates faster due to higher polarity
• If you have an organic salt in solution and add lots of inorganic salt- the inorganic salt will take the water and precipitate out the organic salt

Question 18

Consequences of precipitation

Answer 18

• If there is precipitate within the tubing, this can block the tubing which can affect the rate of the fluid and so drug entering the patient
• Leading to poor efficacy of the treatment
• Inactivate drug- therapeutic failure
• Damage capillaries- phlebitis
• May lead to an embolism (coronary or pulmonary)
• Calcium phosphate emboli related deaths reported
• May cause site reaction in subcutaneous infusion

Question 19

Examples of incompatibility with syringe driver

Answer 19

• Greater concentrations of drug in solution
• Pumps may administer over prolonged periods of time increasing contact time
• Y site administration may be helpful to avoid incompatibilities
• Temperature of syringe drivers may vary (implantable 37’C, next to body under bedcloths (30-32’C)