Sterile products- formulation Flashcards
Types of sterile products
Parenteral products e.g. injections, infusions
Ophthalmic products e.g. eye drops, eye ointments, contact lens solutions
Sterile fluids e.g. water for irrigation, haemodialysis and peritoneal dialysis solutions
Medical devices e.g. artificial heart pumps. dressings
Parenteral preparations definition
Sterile preparations intended for administration by injection, infusion or implantation into the human or animal body
Why are excipients added to parenteral preparations?
To make isotonic with blood/cells
To adjust the pH
To increase the solubility of active drug
To prevent deterioration of the active ingredients
To provide adequate antimicrobial properties
These should not adversely affect the intended medicinal action or, at concentrations used, cause toxicity or undue local irritation
What containers are used for parenteral preparations?
Manufactured in containers made as far as possible from materials that are sufficiently transparent to permit the visual inspection of the contents, except for implants and in other justified and authorised cases
e.g. glass, plastic, coated glass
ampoules, vials, infusion bottles, infusion bags etc.
Types of parenteral drug systems
Aqueous solutions/ suspensions Oily injections/ suspensions Emulsions Colloidal solutions Mixed solvent systems Concentrated solutions Powders for injection Implants
What are the routes on parenteral drug delivery?
Intravenous Intramuscular Subcutaneous Intradermal Intra-arterial Intra-spinal Intra-thecal Intra-cardiac Intra-mammary
Characteristics of the intravenous route
Directly into a prominent vein- rapid response as directly into blood, in theory 100% bioavailability, titrate dose to response
Small volumes- up to 10mL may be given by bolus injection
10-50mL injections should be controlled by a syringe driver as slow push
50mL to 3L or greater should be delivered to a large vein using an infusion pump
What are the five potential problems of inserting a catheter?
Phlebitis Infection Bruising Extravasation Infiltration
Characteristics of the intramuscular route
Small volume injection into a relaxed muscle mass, 2mL into arm, 5mL into buttock
Rate off injection controlled by pain patient suffers
Drug bioavailability controlled by parenteral dosage formulation- suspension having delayed release rates
Must avoid blood vessel, excess volume may damage muscle tissue
Characteristics of the subcutaneous route
Injection of small doses usually (less than 1mL) into loose connective tissue below dermis layer of the skin
Large local response- without large uptake of drug in bloodstream e.g. local anaesthetics
Slower uptake than intramuscular route, but faster than oral route
Insulin pumps
Dosage instructions are entered into the pump’s small computer and the appropriate amount of insulin is then injected into the body in a calculated, controlled manner
What are the five regions of the spine?
Cervical Thoracic Lumbar Sacral Coccyx
The intra-spinal route
Aqueous injection of not more than 29mL into particular areas of the spinal cavity
The solutions should not contain antioxidants or preservatives
Should be single dose preparations with ampoule presented in a clear sterilised overwrap
Adjustment to isotonicity is critical, control of specific gravity of medicament may be important
National Patient Safety Agency (NPSA)- intrathecal injections
Doctor sentenced to 8 months jail for wrong drug into spinal cord
Intra-spinal delivery: future
Colour code delivery equipment and administration sets
Non-compatibility with IV equipment, administration sets and syringes
Factors to consider in the formulation of parenterals
Clinical/economic research Legal requirements Formulation issues Manufacturing issues Quality assurance/quality control
Pre-formulation information
Pharmacopoeias- general monographs, specific product monographs, specific drug monographs
Literature- drug information (stability/uses etc. ), methods of manufacture etc. drug handbooks
Pre-formulation issues
pH adjustment Oxidation Solubilising agents Suspending agents Osmotic activity/isotonicity Preservatives
pH adjustment
Effect on solubility and stability of the active medicament
Ideally products should be pH 7.4 (blood)
Below pH 3- painful injection
Above pH 9- tissue necrosis
IV can accept wider pH range of products as blood buffers the effects
Effects of heat sterilisation must be considered- sterilisation required?
Oxidation
Oxygen- highly reactive species
Container/headspace effects
Hospital vs industry
Purging- use an inert gas to displace oxygen
Container/headsapce
Properties of container material, method of filling, storage conditions
What can be used to prevent oxidation?
Antioxidant- material preferentially oxidised in comparison to the active medicament
Chelating agents (antioxidant synergists)- enhance antioxidant effects
Properties of the antioxidant- high solubility, stable, compatible, non-toxic etc.
Osmotic activity
Osmotic and tonicity- solute concentrations
Colligative properties are properties of solutions that depend on the number of molecules in a given volume of solvent and not on the properties of the molecules
Movement of molecules and effect of water balance (solution concentrations) across cell membranes
Isotonic/hypertonic/hypotonic solutions
A solution is isotonic when it causes a cell to neither lose or gain water
Hypertonic solutions cause the cell to lose water (cell shrinks and becomes crenated, reversible process)
Hypotonic solutions cause the cell to gain water (cell swells and ruptures, irreversible process, cytolysis or osmotic lysis)
Effect of osmotic activity on route of administration
Route of administration important consideration for pre-formulation decisions
Intra-thecal: must be made isotonic
Intravenous: <15mL does not need to be isotonic, >15mL does need to be isotonic
Intramuscular: needs to be isotonic to aid dispersion of drug into surrounding tissue
Subcutaneous: does not need to be isotonic
Definitions of osmolality and osmolarity
Osmolality- concentration of solution expressed as moles of solute particles per kilogram of water
Osmolarity- concentration of solution expressed as moles of solute particles per litre of water
Calculation of osmolarity
mOsmol/L= ((g/L of solute)/(mol weight of solute)) x 1000 x No. of ions
Above about 900 mOsmol/L, should use central vein not peripheral vein
Freezing point depression
W = (0.52-a)/b W = g per 100mL (or %w/v) b= Freezing point depression produced by 1% w/v solution of the adjusting substance a= Freezing point depression of unadjusted substance (multiply 1%w/v for unadjusted substance by concentration of the unadjusted substance as %w/v)
Sterilisation, containers and closures
Sterilisation- autoclaving, dry heat, filtration, radiation and gaseous methods
Containers and closures- glass vs plastic, single dose vs multi dose (preservatives), compatibility issues, novel containers
Manufacturing issues
Overages- 10% of volume
Pharmaceutical excess- to allow for losses during manufacture
Validation- all stages (labelling)
Quality control issues
Sterility testing- test for bacterial endotoxins or pyrogens, uniformity of content (of active ingredient), if powder injection then uniformity of mass also
Particulate contamination- only in specific products, different rules in different countries
Labelling- information on original container e.g. ampoule and outer containers
Overlabelling
Purging
Physical activity as an alternative to adding an antioxidant, no oxygen left as displaced by nitrogen
