Formulation & Requirements of Parenteral Medicines

What does parenteral mean?

Located outside the alimentary canal

What are the 3 main routes of parenteral drug administration?

• Intravenous

• Intramuscular

• Subcutaneous

What are some other routes of parenteral drug administration?

• Intradermal

• Intrathecal (into CSF)

• Epidural (outside the dura)

• Intraarticular (into synovial fluid of joint cavity)

• Intracardiac (into heart muscles)

• Intraarterial

• Intraocular

What are the advantages of parenteral formulations?

• Immediate physiological response (IV route) for acute medical situations, e.g., cardiac arrest, anaphylactic shock, asthma

• Drugs which have poor bioavailability or are rapidly degraded within GI tract (e.g., gentamicin; insulin and other proteins)

• Unconscious/uncooperative patients, patients with nausea/vomiting

• Control of dosage and frequency of administration by trained medical staff (an exception being self-administration of insulin)

• Requirement for localized effect

• Correction of electrolytes (using infusion solutions)

• Range of drug release profiles

• Total parenteral nutrition (TPN)

What are the disadvantages of parenteral formulations?

• More complicated manufacturing process (aseptic technique); cost

• Skill of administration: dosage form administered by correct route

• Pain on administration, possible side-effects from rapid C_p elevation

• Allergy to the formulation (rapid, intense reaction)

• Difficult to reverse the effects of drugs that have been administered parenterally

What are the general requirements for parenterals?

• Sterile – parenterals bypass normal body defences, so contamination can cause infection.

• Essentially free from pyrogens/endotoxins – can cause fever and shock.

• Free from harmful particulates – especially for IV preparations:

  • Must be free from visible particles.

  • There are limits on the number/size of subvisible particles.

  • Suspensions cannot be given IV.

  • IV emulsions must have droplets < ~3 µm.

How does drug solubility affect parenteral formulation?

• Good solubility → solution

• Moderate solubility → solution + co-solvents or suspension

• Low solubility → suspension

• Suspensions have a risk of recrystallisation.

How does the route of administration affect parenteral formulation?

• IV → aqueous solutions or emulsions (<3 µm droplets); must not precipitate in blood

• SC/IM → aqueous/oil-based suspensions, oil-based solutions or aqueous solutions

How does volume affect parenteral formulation?

• Large-volume → usually IV infusion (100–1000 mL or more)

• Small-volume → can be used by all routes, but oil-based and suspension formulations have restrictions.

How does desired onset/duration affect parenteral formulation?

• Aqueous insulin solution → onset ~30 min; duration up to 8 h

• Aqueous insulin suspension → onset 1–2 h; duration 16–35 h

• Suspensions can therefore provide a longer-lasting effect.

What are common co-solvents used in parenteral formulations?

Glycerol, ethanol and propylene glycol.
Parenteral use can cause greater toxicity, especially IV > IM = SC.

What surfactants are used in parenteral formulations?

Non-ionic surfactants, e.g. Tween series (especially for biologicals) and poloxamers.

What buffers are used in parenteral formulations, and why?

Acetate, citrate or phosphate salts to maintain the correct pH.

When are preservatives required in parenteral formulations? Give examples.

Required in multiple-dose parenterals.
Examples: benzoic acid

What are antioxidants in parenteral formulations?

Antioxidants are substances added to a formulation to prevent or slow oxidation of the drug or other ingredients.

• For example: ascorbic acid, α-tocopherol, sodium metabisulphite, sodium bisulphite, citric acid and EDTA.

What are tonicity agents used in parenteral formulations? Give examples.

Used to adjust tonicity

Examples: sodium chloride and dextrose.

What are colligative properties?

Properties of solutions that depend on the ratio of solute particles to solvent particles, not the identity of the solute.

What are the four main colligative properties?

• Vapour pressure lowering

• Boiling point elevation

• Freezing point depression

• Osmotic pressure

What happens to the “particles” of a non-electrolyte vs an electrolyte in solution?

Non-electrolytes form molecules; electrolytes form ions and/or molecules depending on their dissociation.

What happens to the activity of the solvent when solute is added?

The activity of the solvent decreases.

What is vapour pressure depression?

Adding a non-volatile solute to a solvent reduces the vapour pressure above the liquid.

What effect does dissolving a non-volatile solute have on the boiling point?

It increases the boiling point compared with the pure solvent.

What is the boiling point elevation equation?

ΔTb = Kb m

What is Kb?

The boiling point elevation (ebullioscopic) constant; it is characteristic of each solvent and independent of the solute.

What is the boiling point elevation equation for a mixture of solutes?

ΔTb = Kb(ma + mb + mc + ...)

What effect does dissolving a non-volatile solute have on the freezing point?

It decreases the freezing point compared with the pure solvent.

What is the freezing point depression equation?

ΔTf = Kf m

What is Kf?

The freezing point depression (cryoscopic) constant; it is characteristic of each solvent and independent of the solute.

What is the freezing point depression equation for a mixture of solutes?

ΔTf = Kf(ma + mb + mc + ...)

What is the ethylene glycol example for preventing freezing at −20°C?

ΔTf = Kf m → 20 = 1.86 × m → m = 10.75 mol kg⁻¹.
Mass EG = 666.67 g per kg water → 40% w/w solution.

What is osmosis?

The spontaneous movement of solvent through a semi-permeable membrane from the lower concentration solution to the higher concentration solution.

What is osmotic pressure?

The external pressure required to prevent solvent movement via osmosis.

What is the osmotic pressure equation for a non-electrolyte?

π = cRT
where c = concentration, R = gas constant and T = absolute temperature (K).

What is the osmotic pressure equation for an electrolyte?

π = i c R T

What is the van’t Hoff factor (i)?

It accounts for the total number of particles/ions produced when an electrolyte dissociates.

What is the van’t Hoff factor for complete dissociation of MaXb?

i = a + b, because the number of ions equals the number of ionic species.

Why is i often less than a + b in practice?

Many salts do not completely dissociate.

What are the approximate practical values of i?

• Non-electrolyte → i = 1

• 2 ions → i = 1.8

• 3 ions → i = 2.6

• 4 ions → i = 3.4

What is the van’t Hoff factor for a drug salt that dissociates into 2 ions?

Approximately 1.8, e.g. drug salts such as mono-hydrochlorides.

What is an osmole?

The amount of solute that provides one Avogadro’s number of particles.

What is osmolality?

The number of osmoles per kg of solvent (water).

What is osmolarity?

The number of osmoles per litre of solution.

What are the relationships between molarity/molality and osmolarity/osmolality?

Non-electrolytes: osmolarity = molarity; osmolality = molality.
Electrolytes: osmolarity = i × molarity; osmolality = i × molality.

Why is osmolarity more practical than osmolality?

It refers to volume, which is more practical for pharmaceutical preparations.

How different are osmolarity and osmolality in dilute solutions?

Usually only 1–2% different. The difference becomes more significant in concentrated solutions.

What happens to the difference between osmolarity and osmolality in concentrated solutions?

It becomes more significant; e.g. 5% dextrose has a 3.5% error and 25% dextrose has a 25% error.

What is the normal osmolality of blood?

275–295 mOsm/kg, often around 286 ± 4 mOsm/kg.

What mainly determines blood osmolality?

Serum electrolytes, which contribute most of the blood’s osmolality

Approximately how much do NaCl and glucose contribute to blood osmolality?

NaCl ≈ 275 mOsm/kg; glucose ≈ 10 mOsm/kg.

What are the three terms describing solutions relative to intracellular osmolality?

• Isosmotic: πsolution = πintracellular

• Hyper-osmotic: πsolution > πintracellular

• Hypo-osmotic: πsolution < πintracellular

What is isosmoticity?

Two solutions separated by a perfect semi-permeable membrane with no net solvent movement are isosmotic.

What is isotonicity?

Two solutions separated by a biological membrane that remain in osmotic equilibrium are isotonic with respect to that membrane.

Why are isosmoticity and isotonicity not necessarily the same?

Biological membranes are not perfect semi-permeable membranes and may allow some solutes to diffuse through.

What substances can diffuse through RBC membranes?

Ammonium chloride, boric acid, alcohol and urea, as well as water.

What is the key difference between osmoticity and tonicity?

Osmoticity is a property of a solution independent of a membrane. Tonicity depends on a particular biological membrane.

Why does isosmotic not necessarily mean isotonic?

An isosmotic solution is only isotonic if the cells are impermeable to the solute but permeable to the solvent.

What can happen if a solution is hypo-osmotic or hyper-osmotic?

Hypo-osmotic solutions can cause haemolysis; hyper-osmotic solutions can cause cell crenation.

Why must new isosmotic drug solutions be tested?

They must be tested for isotonicity and haemolytic activity.

Which isosmotic solutions can still cause haemolysis?

Ammonium chloride, urea, glycerine and propylene glycol.

What determines the route, volume and formulation used for parenteral drug delivery?

The condition being treated and the drug’s properties; the route determines the volume and type of formulation.

Why are excipients used in parenteral formulations?

To aid drug solubility and stability, maintain pH, prevent contamination and ensure isotonicity.

What are the key points about colligative properties?

They depend on the ratio of solvent to solute, are independent of solute identity, and depend on the number of particles (van’t Hoff factor).

What is the key equation for osmotic pressure?

π = i c R T

What are the key clinical points about osmotic effects?

Normal blood osmolality ≈ 285 mOsm/kg. Hyper-osmotic solutions cause cell crenation; hypo-osmotic solutions cause haemolysis. Incorrect osmoticity calculations can be fatal.