Injections

Question 1

Concepts

Answer 1

• Delivery that bypasses the alimentary canal
• Usually delivers solutions, suspensions or emulsions
• Bypasses the skin, normally a barrier to passive absorption of exogenous chemicals
• First officially recognised in the 1867 BP (1874 addendum) for morphine
• Still commonly used for many medicines, i.e. type I diabetes mellitus, and in particular areas (emergency medicine)
• Products must be sterile

Question 2

Errors:

“Herceptin vials open to infection”

Answer 2

• “Containers used to package the breast cancer drug Herceptin have defects that could cause them to become infected and a risk to patients. The European Medicines [Evaluation] Agency said it had received about 20 complaints from hospitals in the UK, France and Germany about vials that had been broken open”

• From The Independent, No. 6273, 23/November/2006
• Not just the drug, but the totality of the dosage form, inc packaging

Question 3

Errors in compounding parenteral products

Answer 3

• 1990: Johannesburg, South Africa
– Contaminated IV feeds – 15 infant deaths
• 2001: USA
– Contaminated eye drops, recalled by the FDA, containing
Pseudomonas mendocina / Klebsiella pneumoniae
• 1996: Brazil
– Endotoxin contaminated IV medication – 36 infant deaths
• 2004: South Africa
– Enterobacter cloacae - 6 premature babies died
– Found to be caused by dirty hands of the pharmacist who prepared the medicines.
• In 1971: Devonport Hospital, Plymouth,
– 5% Sterile Dextrose Solution, Lot D1192
– Found to be responsible for 5 deaths
– Same batch, some are safe, others are not (autoclave problem)

Question 4

Sites of injection

Answer 4

Bypasses the skin, one of the major body barriers

There are three major types of parenteral injection:

• Subcutaneous
• Intramuscular
• Intravenous

Typically, the gauge of needle used will vary, e.g. 21 (s.q. & i.v) and 20 (i.m.)

Question 5

Intravenous

Answer 5

• Delivers the formulation to a large vein, usually a large
proximal vein
• Rapid response
• 100% bioavailability
• Different volumes can be administered – 10mL (injections) to 500mL (i.e. TPN infusions)
• Usually solutions or emulsions, not conventional
suspensions (purposely manufactured nano suspensions are fine)
– Emulsions
– oil droplets <1µm
– Suspensions or solutions that precipitate are not suitable as they may disrupt blood flow

Question 6

Intravenous can be used to deliver which drugs

Answer 6

• Can be used to deliver drugs that are irritating by other routes
– The injection is diluted once in the vein
• Rate of administration key
– Trained clinicians only
– Too rapid: drug-induced shock can result if the concentration at the receptor is too high

Question 7

Intramuscular

Answer 7

• Into the muscle
– Gluteal (buttocks), vastus lateralis (thigh), deltoid(upper arm / shoulder)
– Poor injection technique can cause muscle damage
• Small volume of injection
– Normally 1 – 3 mL, up to 10 mL in divided doses
• Onset is formulation dependant
– Fast onset (though slower than i.v.)
– Controlled release formulations

Question 8

Subcutaneous

Answer 8

• Injection into s.c. fat
– Arms, legs, abdomen
– Slower onset time than i.v. or i.m.
– Formulation-dependant – slower release from oily
or viscous vehicles (although viscous vehicles are to be avoided if possible)
• Normally a small (1mL) injection volume – limits potential applications

Question 9

Advantages of injections

Answer 9

• Quick (particularly in the case of i.v.) onset and physiological response
– Emergency medicine – Asthma, anaphylaxis, cardiac arrest
• Bioavailability
– Avoids the liver first pass metabolism of the oral route
– Dose required (compare to solid oral doses, for example) and toxicity profile / side effects (+/-)
• Deliver drugs to unresponsive (i.e. unconscious) patients
• Usually not administered by the patient, so good control of dosage and frequency (insulin?)
• Can rapidly achieve local effects
– Local anaesthesia (lidocaine / lignocaine)
• Formulations and the use of infusion can allow a wide range of therapies to be considered:
– Rapid-acting
– Long-acting
– Can be delivered and mediated by exact route (i.v., i.m., etc.) and formulation
• Total parenteral nutrition
– TPN is usually needed only if the patient cannot receive
adequate nutrition via the oral route. Consider alternative enteral supplementation if appropriate.

Question 10

Onset time

Answer 10

• For a wider context, consider the onset times for different formulations of GTN (glyceryl trinitrate)
– Sublingual spray
– Patch
– Ointment
– Tablet
• Each formulation has a different function, and
would find use under particular circumstances,
and this is reflected in their relative onset times

Question 11

Disadvantages of Injections

Answer 11

• Cost
– Compared to other dosage forms, cost is significantly greater
– Requires clean room technology
– regular quality checks and audits
• of the product, and
• the environment
– specialist training on staff
• Administration
– Painful
– Specialist skills needed – the person should have knowledge of formulation types as well (i.e. suspensions)
– Certain types of injection require further specialist training due to potential risks (i.e. epidural, intra-arterial, intra-vitreal)
– Difficult to reverse effects once administered (compare to a transdermal patch, for example) which might cause toxic or allergic issues and which can be removed relatively rapidly by the patient or practitioner.

Question 12

Formulations for parenteral delivery

Answer 12

• Solutions – oil or water-based
• Suspensions – oil or water-based
• Emulsions

Question 13

Choice of formulation

Answer 13

• Physicochemical properties of the drug – i.e. Solubility, stability in aqueous solution
• Route of administration (i.v., i.m., etc.)
• Amount (volume) to be administered – Again, solubility may be an issue here
• Preferences for formulation type may be based on previous clinical experience and performance

Question 14

Solubility of drug

Answer 14

• Solubility in vehicle (formulation) is usually expressed as good, moderate or low:
– GOOD – can be readily formulated in a suitable vehicle
– MODERATE – reasonable but possibly not sufficient solubility for therapeutic needs
• Can use co-solvents to enhance solubility (must
consider stability, such as recrystillation), or
• Suspensions
– LOW – usually formulated in suspension form

Question 15

Co-solvents / Non-aqueous solvents

Answer 15

• Non-aqueous vehicles: 
– Oils (e.g. corn oil, sesame oil) 
– Irritation 
– Change in viscosity at different temperatures
(minimise viscosity)

• Co-solvents:
– Glycerol, ethanol (high concs. are painful), PEG400
– Aim is to render the active drug soluble and allow it to be delivered while reducing or minimising pain and
discomfort

Question 16

Route of administration

Answer 16

• Influences formulation choice
• For example:
– i.v. formulations must normally be aqueous solutions, due to issues of precipitation and blockage of veins
with components of suspensions, for example
– Parenteral suspensions must be given s.c. or i.m.
– If emulsions have to be used the particle size must be kept as small as possible

Question 17

Volume

Answer 17

• Larger volumes normally given i.v.
• Up to 500mL
• Small volumes may be given by all routes

Question 18

Onset time

Answer 18

• i.v. – immediate pharmacological effects
• s.c. and i.m. are slower than i.v.
• Absorption is faster from aqueous solutions than other formulations when given i.m. or s.c.
• Slower release from suspensions or emulsions can be used for prolonged, controlled release formulations

Question 19

Question: Insulin s.c.

Answer 19

• Fast-acting:
– Aqueous solution of insulin – onset of therapeutic
action in 30 minutes, peaks between 2 and 4 hours and has a duration of action up to 8 hours
• Slow-acting:
– Aqueous suspension of insulin – onset 1 to 2 hours, peak 4 – 12 hours, duration 16 – 35 hours

Question 20

Poorly soluble therapeutic agents

Answer 20

• When a drug is in solution it presents fewer physical and absorption problems
• When in suspension its physical properties
become important, with regard to bioavailability
and subsequent efficacy
– Particle size
– Sedimentation – Caking
– Crystallisation – etc

Question 21

Poorly soluble therapeutic agents

• Solid state properties

Answer 21

– Crystalline structures: repeating ordered structures. Usually therefore have higher melting point than amorphous materials
– Polymorphic materials have the same chemical structure but different physical forms, therefore different melting points and different rates of dissolution, hence effecting bioavailability
– E.g. examples of polymorphism include paracetamol and spironolactone, which have polymorphs that have different properties that are clinically relevant

Question 22

Poorly soluble therapeutic agents

• Particle size

Answer 22

– Affects rate of absorption and dissolution
– Affects stability of the drug in the dosage form
– The rate of dissolution of poorly soluble drugs increases as the surface area increases (i.e. as the particle size decreases) – cf. Noyes-Whitney equation
– So, a smaller particle size may result in a greater rate of dissolution for poorly soluble drugs

Question 23

Poorly soluble therapeutic agents

• For example:

Answer 23

• For example: 
– Suspension of water-insoluble testosterone propionate 
– Particle size range 40 – 100 mm 
– i.m. administration 
– Duration of action 8 days 
– Particle size range 50 – 200 mm 
– i.m. administration 
– Duration of action 12 days 

– Longer duration due to slower rate of dissolution
– Changing the form (from propionate to isobutyrate) and increasing the lipophilicity reduced solubility further, hence dissolution was also reduced further and the duration of action was longer, at 20 days

Question 24

Salt Forms

Answer 24

• Not all salt forms have the same solubility
– E.g. compare ibuprofen, ibuprofen sodium and ibuprofen lysine
• Certain counter ions are used to enhance solubility/dissolution, and bioavailability
• Salt form may affect – Stability
• α-styrylcarbinol HCl salt looses up to 12% of chloride after 6 hours
• α -styrylcarbinol Mesylate salt stable for three weeks at 60°C
– Solubility
– Dissolution rate
– Hygroscopicity
– Crystal form / polymorphism
– Mechanical properties (i.e. compression during tabletting)
• For stable salt formation, ionisation must be, in effect, complete – such that a single ionization state is formed.
– Typically, a difference of two pH units between the pKa of the base and the pKa of the acid are usually required to achieve this

Question 25

Salt Selection

Answer 25

• Commonly used salts include:
– For basic drugs - hydrochloride, sulphate, mesylate, maleate, phosphate, salicylate, tartrate, lactate, citrate, succinate, acetate.
• HCl is the most commonly used, found in approximately 43% of basic drugs as the counter ion
– For acidic drugs – K, Na, Li, Ca, Mg, diethanolamine, Zn, choline and Al are common.
• Sodium is the most common, found as the counter ion in approximately 62% of basic drugs
• The choice of counter ion can be important for considering future dosage forms. Eg, taste of oral solution may be affected by salt forms as they may have different
– Solubility
– Acidity
• Materials that are too alkaline might degrade glass during storage

Question 26

Example

• Relationship of solubility with pH and pKa

Answer 26

– Drug is HA
– Total saturated solubility of drug is S
– S0 is the solubility of the undissociated species HA
– S, total solubility (ionised + unionised) is
– S = S0 + [conc. Ionised species]

– Deriving from the Henderson equation:
pH - pKa = log (S - S0 / S0)

Question 27

• What is the pH below which sulfadiazine will

begin to precipitate in an infusion fluid?

Answer 27

• Note that:
– The initial molar concentration of sulfadiazine sodium is 4 x 10-2 moldm-3
– Solubility of sulfadiazine is 3.07 x 10-4 moldm-3
– Sulfadiazine has a pKa of 6.48

pH = 6.48 + log (4.00 x 10-2) - (3.07 x 10-4)/ 3.07 x 10-4

• Therefore pH = 8.60

Question 28

Vehicle (formulation)

Answer 28

• Aqueous 
– Solution 
– Suspension 
– Emulsion
• Non-aqueous 
– Solution 
– Suspension

Question 29

Aqueous solution

Answer 29

• Water for Injection BP – Used for soluble and poorly soluble agents and as the aqueous phase of an emulsion
– Specifications: clear, colourless, within pH range 5 – 7
– Limits for impurities, e.g. metals, ions and oxidisable compounds and undissolved solids (< 10 ppm).
– Sterility - complies with the test for sterility
– Pyrogens – fever-producing compounds (usually from bacteria)
• Thermostable, water soluble and resistant to bactericides,
• Should be removed by the use of the correct process, e.g. distillation
• Sorted in pyrogen-free containers at defined temp

Question 30

Non-aqueous vehicles (formulation systems)

Answer 30

• Used for non-water-soluble therapeutic agents
– Non-aqueous parenteral solutions of water in soluble
therapeutic agents
– Non-aqueous parenteral suspensions of therapeutic agents that are water-soluble
– The internal phase of parenteral emulsions
• Materials;
– Fixed (non-volatile) oil, e.g. sesame seed oil, corn oil, peanut oil
• NOT mineral oils or solid paraffins
– Sesame seed oil favoured choice due to its stability
– Can also used synthetic materials, such as esters:
– Ethyl ethanoate
• Problems:
– Pain
• Irritation upon injections, often due to viscosity effects at different temp
• Viscosity should be reduced to ensure as little pain on application as possible, and to improve ease of administration
– Sensitivity
• i.e. peanut oils and allergies (oil used should be stated on the label)
– Enhancers
• Used to improve solubility of the therapeutic agent, i.e. benzyl benzoate

Question 31

Manufacture

• Regulatory Requirements:

Answer 31

– Buildings and facilities 
– Personnel, training, qualification and monitoring 
– Components and containers / closures 
– Endotoxin control 
– Time limitations 
– Validation of processes 
– Laboratory controls 
– Sterility testing 
– Batch Record Review: Process Control, Documentation

Question 32

Laminar Flow Cabinets

Answer 32

The diagram on the left hand side shows the incorrect placement of objects in the LFC.
Air flow is obstructed by the objects and those objects at the front of the hood are blocked off from the critical stream of air.

The diagram on the right hand side shows the correct placement of objects in a horizontal laminar flow cabinet. None of the objects obstruct the critical flow of air in through the cabinet.

Question 33

isotonicity calculation

Answer 33

W = (0.52 - a)/b

– Where W is the concentration (%w/v) of the adjusting substance to be added
in the final solution – a is the freezing point depression of the unadjusted hypo-osmotic solution
due to all other solutes – b is the freezing point depression produced by 1% w/v of the adjusting
substance

Question 34

henderson equation

Answer 34

pH - pKa = log ((S - So)/So)