In emergency cases, e.g. cardiac arrest, anaphylactic shock or severe asthma, immediate action is required. Aqueous parenteral solutions administered intravenously are suitable for rapid onset of action.

Prolonged action of parenteral medicines is achieved by a different route of administration and different formulations. In general for example parenteral suspensions have a later onset and prolonged activity compared to parenteral solutions.

With an increasing use of parenterally administered proteins there is an increased risk for hypersensitivity reactions. Proteins of any origin might elicit an immune response. Antibody formation against the protein may induce different results, e.g. no impact on efficacy, decrease of efficacy and neutralisation of the physiological protein. Reduced activity is derived from reduced half-life of the protein molecules in the circulation and rapid clearance by immune cells. Many factors influence the immunogenicity of proteins, including changes in the primary structure (sequence variation and glycosylation), storage conditions and changes in the tertiary structure (denaturation or aggregation) (see Sect. 18.​4.​1.​4), contaminants or impurities arising from the production process, dose and length of treatment, the route of administration, and patient characteristics. Aggregation, which includes formation of dimers and high-order aggregates, may be mediated by pH, ionic strength, concentration, counter-ion composition of the formulation, temperature, sheer stress. Purification and concentration processes such as ultrafiltration, ion-exchange chromatography, lyophilisation, precipitation or ‘salting out’ can induce aggregation (see Sect. 22.​2.​5). Appropriate formulation of a protein product and stabilisation of the active substance is therefore extremely important. In any case the proteinaceous medicine should be stored and handled under optimal conditions. Freeze-dried particles should be completely dissolved, the recommended storage conditions should be adhered to, the preparation should not be shaken and should be not be administered with a peristaltic pump. The route of administration can influence the immunogenicity of the protein. Subcutaneous injection is associated with higher potential of immunogenicity than i.v. administration [8].

Phlebitis is an infection of a blood vessel. Infusion-related phlebitis is characterised by pain, tenderness, erythema, induration, oedema and a local temperature increase. These circumstances may lead to thrombus formation or venous tissue destruction or both.

The incidence and duration of phlebitis seems to be dependent on a variety of factors. Physical-chemical factors such as low pH, hypertonicity, particles and precipitation play a role in the cause. Active substances that are poorly soluble in water may precipitate and can cause acute phlebitis. Active substances with adequate aqueous solubility may tend to cause phlebitis only because of prolonged or chronic administration. Clinical factors involving injection technique (infiltration, extravasation, type of needle, duration of infusion) but also irritating characteristics of the active substance can contribute to the occurrence of phlebitis [9, 10]. Sometimes (septic) phlebitis is caused by bacterial infection (e.g. cause of inappropriate aseptic technique during catheter insertion) and is characterised by inflammation with suppuration of the vein wall. Local responses to the parenteral challenges can be diminished by dilution of the medicine or by central venous instead of peripheral venous administration (see Sect. 13.10.3).

Parenteral administration can be associated with pain at the injection site. The so-called injection fear may be diminished by applying topically anaesthetics prior to injection. Eutectic mixtures of local anaesthetics (e.g. lidocaine/prilocaine cream or a tetracaine gel) have proven to be effective and well-tolerated in the relief of pain associated with intramuscular injections, venepuncture or intravenous injection in adults and children.

Non-physiological osmolality and pH or increased buffer concentrations in formulations can be responsible for pain at the injection site. Therefore some formulations for intramuscular use contain a local anaesthetic. Needle-free injection technologies are alternatives to reduce the intensity of injection pain [11].

Extravasation is the process by which any injection or infusion solution accidentally leaks into the surrounding tissue. The degree of damage due to extravasation depends on the active substance, the concentration, the localisation of the extravasation and the length of time an active substance may develop the damage. According to the type and severity of damage, active substances are categorised as irritants or vesicants [12].

The presence of visible foreign particles, which cannot be metabolised, must be avoided in injection solutions (see Sect. 32.​12). However, the release of particulate matter (such as rubber chips, chemical fibres, glass fragments) is an intrinsic element of the production process. They originate from the formulation, processing equipment, primary package or the preparation process prior to use. Particles larger than 8 μm are generally trapped in the capillaries of the lungs, causing (thrombo) phlebitis and embolism. Smaller particles can be trapped in the liver, spleen and spinal cord [13]. Foreign body granulomas may result from intramuscular or subcutaneous injection of products containing foreign particles.

The parenteral route is used for the administration of ‘small’ molecules as well as for ‘large’ molecules (proteins, monoclonal antibodies, vaccines, immunoglobulins).

Solubility can be improved by chemical modifications (change of pH, use of buffer, derivatisation, complexation, salt formation) and other techniques (use of excipients such as surfactants, solubilisers, cyclodextrines and phospholipids).

Water for injection is the preferred vehicle for the preparation of parenteral solutions (injections and infusions). When the active substance is poorly or not soluble in water, co-solvents or non-aqueous vehicles can be employed, or dosage forms such as liposomes or microspheres can be used.

Solubility and stability of the active substances are to be considered when evaluating the optimal pH of parenteral solutions. Moreover the pH of the solution has an impact on the infusion tolerance, which is also depending on the volume and rate of administration and the buffer capacity of the formulation. To prevent possible adverse effects the pH should preferably be in the physiological range. The pH of the blood varies between 7.35 and 7.45 and has a large buffer capacity and, theoretically, a deviant pH of an intravenous injection will be corrected fast. The mixing, and thus the neutralisation process, however takes rather long as blood flows are laminar. Fast infusion will disturb this laminar flow and with irritating solutions might be preferred above slow infusion. This effect is confirmed in animal tests [20]. Intravenous injections have a higher chance of causing phlebitis in smaller vessels than in larger vessels where the blood flows faster. If the injection remains for too long at the place of injection such as with subcutaneous and intramuscular administration there is more chance of irritation than with intravenous administration.

If a larger volume is given intravenously, the tolerated pH range is 3–11 [1]. The more the pH of the formulation approximates to the lower and upper limit of this pH range the higher is the probability of discomfort and irritation at the injection site. Non-toxic acids and bases are used to set the pH of parenterals. Lactic, maleic and hydrochloric acid and sodium hydroxide are used most often. They have some buffering capacity in the acid area. Whether the resulting solution has sufficient buffering capacity depends on the pK_a of the used base or acid and the pH of the solution (see Sect. 18.​1.​1).

Buffers, mostly phosphate buffer solution, are included in the formulations to ensure the pH of the solution being maintained throughout the shelf life of the product. The buffer prevents pH changes caused by degradation products or leaching of ions from glass containers (see Sect. 24.​2.​1). Buffers may increase the hydrolysis rate of the active substances (see Sect. 22.​2.​1) and may decrease solubility (Sect. 18.​1.​1). High buffer capacity should be avoided in order to minimise irritation and pain at the injection site and disturbance of the physiological pH.

As a measure of the tonicity of blood one can calculate with the osmotic value because active substances and additives cannot pass the membrane of the erythrocyte (see Sect. 18.​5.​2). The osmotic value of blood is around 290 mOsm/kg. Some parenteral fluids however contain substances that can pass the membrane fast: ethanol, glycerol, urea. Hyperosmotic solutions of these substances may cause haemolysis; so they are hypotonic. The iso-osmotic concentration of ethanol is for example 1.39 % m/m. Ethanol 5 % v/v infusion fluid is therefore hyperosmotic but appears to be practically isotonic.

Parenteral products with osmotic values differing from the physiological value may cause phlebitis and irritation. This is especially applicable when the injection remains relatively long at the site of injection such as after subcutaneous, intramuscular, epidural and intrathecal administration. There is a higher chance of phlebitis in small vessels after intravenous administration. However, it is not known which limits should be considered to prevent phlebitis and irritation. According to some sources [22] the osmolarity of an intravenous injection should not be higher than 500 mOsm/kg. For subcutaneous and intramuscular administration the range is smaller.

As is the case for the pH level and buffer capacity, adjustment of osmotic value to physiological conditions is advisable. Sodium chloride or glucose are mostly used to adjust tonicity of parenterals. Sometimes deviating medical requirements are to be met. For example, hyperbaric solutions of local anaesthetics are used in spinal anaesthesia (see Sect. 13.2.4). Hyperbaricity in comparison to the cerebrospinal fluid is achieved by a high glucose concentration (7.5 %) which is also a hyperosmolar.

Baricity and dose of the local anaesthetic along with the patient position determine the anaesthetic block height.

Parenteral formulations should not be more viscous than water because as the viscosity of the formulation increases, the ease of administration decreases and the likelihood of pain caused by injection increases. Polymers that modify viscosity of the formulation are more frequently used in parenteral suspensions than in parenteral solutions. By addition of hydrophilic or lipophilic polymers parenteral suspensions are stabilised.

Typical excipients used in parenteral suspensions include surfactants that are used to stabilise emulsions and suspensions as wetting agents (polysorbate 80, poloxamer), as micelle makers for the preparation of solubilisations and to influence the flocculation and deflocculation behaviour of a dispersed system (carmellose sodium, polyvidone). Parenterally used surfactants in high concentrations are toxic and may cause venous irritation and occasional thrombophlebitis. However, these high concentrations are not necessary to formulate stable parenteral suspensions.

Only a limited number of emulsifiers are commonly regarded as safe to use in emulsions for parenteral administration. Most important are lecithin, poloxamer and macrogolglycerol ricinoleate (Cremophor EL®). This latter excipient is linked to anaphylactic reactions and temporary haematological disorders.

Antioxidants are used to reduce or inhibit the oxidation of active substances or excipients. Active substances in parenterals which may undergo oxidative degradation are e.g. phenothiazines, catecholamines, polyene antifungal agents, steroids, morphine. Antioxidants either prevent the formation of free radicals (i.e. butylated hydroxyanisole, butylated hydroxytoluene) or have a lower redox potential than the active substance to be protected (i.e. sodium metabisulfite, sodium formaldehydesulfoxylate). Edetate increases the activity of antioxidants by chelating polyvalent cations, which may generate free radicals or be involved in electron transfer reactions (see also Sects. 23.​10 and 22.​2.​2.​2). Another strategy to diminish oxidation is to remove oxygen by flushing the injection solution with nitrogen prior to closure (see Sect. 13.7.4).

Single dose vials should be used as much as possible to avoid microbial contamination entering the vial as in the case of multidose vials. However, for economic reasons parenteral solutions are still packaged in multidose vials and preservatives are incorporated in them. According to the Ph.Eur. multidose vials must contain a preservative. However, the single dose may not exceed 15 mL. Parenteral solutions which contain high concentrations of co-solvents such as propylene glycol or glycerol, or oil-based products, mostly do not require the addition of preservatives, although it has been established that micro-organisms may survive in non-aqueous solutions [24]. The activity of preservatives can be affected by the pH, the concentration, the presence of binding or complexing excipients, and incompatibility reactions with proteins and rubber as container closure material. Commonly used preservatives and typical concentrations used are: benzyl alcohol (1.0 %), chlorobutanol (0.5 %), phenol (0.5 %), and metacresol (0.1 %). Some preservatives, such as the parabens, cause irritation or adverse reactions and are hardly used anymore in parenterals. If a formulation is intended for paediatric administration, restrictions for certain preservatives must be considered. European Medicines Agency (EMA) recommended that parenteral solutions containing benzyl alcohol should not be used in pre-term and full-term neonates, due to neurotoxicity, cardiovascular failure, intraventricular haemorrhage, gasping respirations and metabolic acidosis (‘gasping syndrome’). Due to the risk of fatal toxic reactions arising from exposure to benzyl alcohol in excess of 90 mg/kg/day, this preservative should also not be used in children up to 3 years old [25].

Due to their toxicity preservatives are not allowed in injections for epidural, intrathecal, intracisternal or intraocular use [26].

Proteinaceous active substances are usually formulated in an elaborated excipient system prior to the freeze-drying procedure. Bulking agents, such as mannitol or glycine, are used to increase the bulk volume and provide a suitable matrix in which a small quantity of protein is dispersed [27]. Further details regarding use of cryoprotective excipients are described in Sect. 22.​2.​5.

Injection fluids are packaged in ampoules, vials or bottles (container size ≤ 100 mL), syringes, and cartridges manufactured from glass or plastic. The containers must be transparent to allow visual inspection of the content. Light sensitive active substances should be preferably protected by light-tight secondary packaging; amber glass is an option as well but it hinders checking for clarity.

Containers for injections are discussed in Sects. 24.​2.​1 (glass quality), 24.​2.​4 (rubber), 24.​3 (closures), 24.​4.​14 (ampoules) and 24.​4.​17 (syringes). Although glass is a preferred material, care should be taken to avoid possible incompatibilities. In particular, for instance, adsorption and aggregation of proteins touching glass surfaces, release of glass particles in solutions with pH > 7 and specific ions or both, release of aluminium from class I glass, etcetera. Class I glass is generally to be preferred but its suitability is not a matter of course and has to be tested. Rubber closures need attention as well because of release of rubber particles during autoclaving,

Because of the high price, type II glass is to be considered, and when tested might be found to be appropriate. Labelling of parenterals is discussed in Sect. 37.​3.​2. For injections usually both the total amount of active substance and the concentration should be indicated.

Details of chemical and physical degradation reactions of medicines (including proteins), and stability investigation are given in Chap. 22.

Injection solutions containing ‘small’ molecules may degrade by hydrolysis, oxidation and epimerisation reactions. The reaction rate determines whether sterilisation by heat can take place or not. Injection fluids that tolerate autoclaving usually have a shelf life of several years at room temperature. Active substances that are not stable in solution are usually prepared as powder – commonly by freeze drying the solution – and have to be reconstituted immediately before administration by the caregiver or the patient. Physical instability regards mainly suspensions (resuspendability) and protein solutions (precipitation and aggregation). Incompatibilities (precipitation) have to be checked for when solutions of poor water-soluble substances in co-solvents are diluted or when parenteral solutions are combined.

Protein products are especially prone to changes of the tertiary and quaternary structure of the molecules and thereby loss of activity. Degradation is induced by heat and shear stress. Rigorous shaking and administration by peristaltic pumps should be avoided.

See Sect. 22.​6.​1 for a general discussion of shelf life. As long as the container of injection fluids remains closed, the storage temperature and shelf life are determined by the rate of the degradation reaction. Most parenterals can be stored at room temperature, exceptions are vaccines and protein medicines. Parenterals that are not sterilised in the final container are to be stored in the fridge or freezer with regard to maintaining their sterility. Storage temperature and in-use stability after first opening of ampoules and bottles are also determined by the chance of microbiological contamination.

The shelf life of reconstituted parenterals prepared in the hospital pharmacy is to be determined by the responsible pharmacist (see Sect. 22.​6). When licensed injection fluids are reconstituted and prepared for individual patients the shelf life is determined by evaluation of the physico-chemical stability and risk of microbiological contamination. Shelf life depends from a microbiological viewpoint on the risks associated with aseptic preparation and the results of validation studies performed under the pharmacy’s specified aseptic preparation conditions (see Sect. 31.​3.​6).

In-use stability of preserved injection fluids in multiple dose vials is limited to a maximum of 28 days. Typical examples are multidose vials of insulin preserved with methyl hydroxyl benzoate and multidose vials of low molecular heparin preserved with benzyl alcohol.

Parenteral solutions are to be tested for absence of visible and non-visible particles and sterility as specified in the Ph. Eur. Furthermore, freedom from pyrogens or endotoxins and the uniformity of dosage units and content are stipulated (see Sect. 32.​8). Suspensions should be easily resuspendable to ensure precise dosing and uniformity of the dose during administration. Parenteral emulsions should be homogeneous.

In practice the pharmacist may dispense special injections. This section briefly describes their formulation and biopharmaceutic characteristics, but not their way of preparation and quality requirements.

Infusions are sterile solutions or emulsions that are administered intravenously, subcutaneously or intrathecally/epidurally. Infusions are used as:

Shifts of the physiological pH may require administration of acid or base containing infusions. Metabolic acidosis is treated by infusion of sodium bicarbonate containing infusion solutions. Metabolic alkalosis is treated with hydrochloric acid containing infusion solutions.

Sodium chloride 0.9 % solution and 5 % glucose solutions are most suitable to be used as vehicle solutions for parenterally administered injections or infusions.

Blood volume expanders can be crystalloid or colloidal. The most often used crystalloid solutions are 0.9 % sodium chloride solution, 5 % glucose solutions and their combinations, e.g. 0.45 % sodium chloride/2.5 % glucose solution. In addition infusion solutions containing multiple electrolytes such as Ringer’s solution or Lactated Ringer’s are administered. These solutions contain also potassium, magnesium, calcium, and phosphate [34].

Blood volume expanders used to compensate loss of plasma are formulated as electrolyte solutions with macromolecular substances such as gelatine, polygeline, hydroxyethyl starch (HES), and albumin. Hydroxyethyl starch is similar to albumin but cheaper. However there are restrictions in its use. European Medicine Agency (EMA) has decided that HES solutions should not be used in critically ill adult patients, including patients with sepsis or burn injuries and excess bleeding particularly in patients undergoing open heart surgery in association with cardiopulmonary bypass, because an increased risk of mortality and renal injury requiring renal replacement therapy [35].

Osmotic diuretics are rapidly filtered in the glomerulus and not reabsorbed in the tubules. As a result of the osmotic gradients thereby achieved in the renal tubules, the reabsorption of water is inhibited, and urine excretion increased (see also Sect. 13.6.3).

Parenteral nutrition solutions are discussed separately in Sect. 13.9.

Large volume infusions should have a physiological pH, e.g. pH 7.4 and little or no buffer capacity. In general infusions with pH 5–9 are tolerated by peripheral veins.

The pH values of commonly used infusion solutions vary between 4 and 8 depending on the type of formulation. A lower pH is acceptable if solutions are not buffered. The pH of 5 % glucose solutions amounts from 4.0 to 5.0. This is necessary to prevent degradation of glucose (see Sect. 13.6.4). Infusion fluids that are used to correct the pH of the blood have a deviant pH value (e.g. pH 8.0 for sodium hydrogen carbonate infusion).

See Sect. 18.​5 about osmosis and tonicity.

Infusion solutions have to be isotonic with blood because of the large volume administered. Typically used isotonic infusion solutions are 0.9 % NaCl solution and 5 % glucose solution.

Hyperosmotic mannitol 20 % infusion is used as osmotic diuretic. Hypotonic solutions such as 0.65 % sodium chloride are used in elderly patients to keep the salt load low, or in children to prevent dehydration.

Infusion fluids for neonates are often hyperosmotic, having no choice since only small volumes can be administered.

According to some recommendations [36] if osmolarity of the infusion is higher than 500 mOsmol/l, administration should occur via a central venous catheter that is inserted in a vessel with high blood flow such as the vena subclavia, proximal axillary vein or superior vena cava.

In addition to what has been said about the stability of injections (Sect. 13.5.12) some specific comments can be given regarding infusions. In practice most concern is about the chemical and physical (precipitation!) stability of active substances when mixing injections with the infusion vehicle. As a consequence of incompatibilities some active substances are only compatible with 0.9 % NaCl vehicle (e.g. furosemide-Na injection concentrate) and others are only compatible with 5 % glucose solution. As the mixtures often have to be kept after mixing also the chemical stability is an issue as well as minimising the chance of microbiological contamination by proper aseptic handling and administration.