Formulation and requirements of parenteral medicines

• what does parenteral mean?

  outside the GI tract - usually injections/infusions
• Parenteral routes of administration

  1. intravenous = into vein - rapid, small/large volume

  2. intramuscular = into muscle - small vol, relatively rapid, can be MR

  3. subcutaneous = into sub tissue - slower, used for implants

  4. intradermal = between epidermis and dermis - allergy tests

  5. intrathecal = cerebrospinal fluid

  6. epidural = outside dura

  7. intra-articular = into synovial fluid of joint cavity

  8. intra-cardiac = heart muscles - emergencies

  9. intro-arterial = riskier

  10. intraocular = the eye
• advantages

  - immediate response for acute situations

  - drugs with poor bioavailability can be used

  - used with uncooperative patients

  - control of dosage/frequency

  - requirement for localised effect

  - correction of electrolytes

  - TPN
• disadvantages


  - complicated manufacture (aseptic) and expensive

  - skill of administration

  - pain and SEs

  - allergy to formulation

  - difficult to reverse drug effect
• requirements


  1. sterile and free from endotoxins and pyrogens (cause fever)

  2. free from visible particulates - droplets <-3um could block capillaries
• colligative properties


  properties that depend on the concentration of solute particles to solvent particles but not on their identity

  
• vapour pressure depression


  - addition of non-volatile solute to solvent decreases the vapour pressure above liquid

  - no volatile solution to evaporate

  
• boiling point elevation


  dissolution of non-volatile solute in solvent increases the bpt of solution with respect of pure solvent

  
• freezing point depression


  dissolution of non-volatile solute in solvent decreases fpt of solvent

  
• osmotic pressure


  external pressure that must be applied to prevent osmotic movement across a selectively permeable membrane
• osmotic pressure equations

  1. for non-electrolyte solutions = pi = nRT/V = CRT

  2. electrolyte solutions = pi depends on number of particles in solution - pi = iCRT

  3. complete dissociation = i =a + b
• approximate i values


  1. non = 1

  2. 2 ions = 1.8

  3. 3 ions = 2.6

  4. 4 ions = 3.4
• osmolality


  - the concentration of a solution expressed as the total number of solute particles per kilogram

  - normal blood osmolality = 27.5-29.5 mOsm/kg
• parenterals


  - degree of deviation from tonicity due to location/vol/speed of injection

  - isotonic preferred

  - hypotonic adjusted with dextrose or NaCl

  - hypertonic can't be adjusted - into large vein or slow delivery
• intravascular


  - hypo = haemolysis, water intoxication

  - iso = possible increase in extracellular fluid vol and circulatory overload

  - hyper = RBC crenation, low BP, cardiac arrest, hyperglycaemia
• intraspinal

  CSF has small vol and low circulation so MUST be isotonic
• intradermal

  use isotonic to avoid false signs of irritation (for allergies)
• IM+SC

  isotonic preferred - hyper may increase IM drug absorption
• osmolarity method


  1. calculate osmolarity generated by formulation components

  2. determine remaining osmolarity required to make isotonic with body fluids

  3. calculate amount of adjusting substance (e.g. NaCl) required to make up shortfall

  
• freezing point depression method


  - always require Tf of 0.52oC for isotonic solution

  - so work out how many degrees NaCl must contribute

  - 0.9% NaCl = 0.52oC so multiply fraction by 0.9

  
• NaCl equivalents method


  - multiply masses to ENaCl values to get NaCl masses

  - add up total masses to get percentage of NaCl

  
• % of saline?

  0.9%
• fpt for isotonic solution?

  0.52 degrees