Fig. 5.1
Decision tree relating to the oral liquid form
The main choice will be between an oral solution and an oral suspension. For some active substances an emulsion or solubilisate is the appropriate form. However in some cases (e.g. because of an intermediate solubility of the active substance) the pharmacist will have no other option than to dispense an oral solid dosage form and instruct the patient how to manipulate it safely (see Sect. 37.6.2). Proper consideration of the options may prevent formulation mistakes with probably severe consequences. This especially applies to the unreflected use of ‘suspending bases’ for rendering an oral solid into an oral liquid.
If the patient has an enteral feeding tube, specific requirements have to be taken into consideration (see Sects. 5.4.3 and 37.6.3).
An aqueous solution is the first choice because of high dosage accuracy and homogeneity. If an active substance is not sufficiently water-soluble, a solution may be achieved by adjusting the pH, by adding co-solvents or the use of a more soluble salt. A disadvantage of a solution can be the unpleasant taste or insufficient stability.
A suspension is the first choice if the aqueous solubility is low. Also substances with a very unpleasant taste or substances that are not stable in an aqueous solution can better be processed as a suspension. The taste sensation is less prominent and they are less susceptible to degradation when dispersed and not dissolved. However, as a suspension is a disperse system, much attention has to be paid to homogeneity at dosing. This risk has to be considered for potent medicines.
Active substances with intermediate solubility may cause the greatest challenge. When the solubility is too low for a solution but too high for a suspension (because the risk of crystal growth, see Sect. 18.1.6) the best option seems to be to choose a solid dosage form in combination with instructions for the patient how to handle in case of swallowing problems.
For lipophilic liquid active substances an emulsion or solubilisate seems the only option; if a high amount has to be processed, an emulsion is the best choice; if low amounts are present a solubilisate may be an option.
The choice of a dosage form finally has to be taken into account that the dose range must be feasible with appropriate volumes and for ease of calculation concentrations such as 1, 2, 5 or 10 mg/mL will be preferred.
A hydrochlorothiazide oral liquid has to be formulated for children, especially for neonates. Because of the limited solubility of hydrochlorothiazide in water (0.6 mg/mL) and to avoid the presence of organic solvents such medicine may be formulated as a low concentrated solution or a higher concentrated suspension. The concentration should be calculated keeping the amount of fluid for dosing low. The solution has a concentration of 0.5 mg/mL below the limit of solubility (Table 5.1).
Hydrochlorothiazide | 0.05 g |
Citric acid monohydrate | 0.87 g |
Disodium phosphate dodecahydrate | 0.835 g |
Orange essence (local standard) | 0.052 g |
Methyl parahydroxybenzoate | 0.045 g |
Syrup BP (preserved with methyl parahydroxybenzoate 1 mg per g) | 32 g |
Water, purified | 73.88 g |
Total | 107.7 g (= 100 mL) |
5.4.3 Additional Formulation Demands when the Patient is on Enteral Feeding
There are additional requirements for an oral liquid administered via a nasogastric feeding tube:
It must not block the feeding tube
It must not interact with the enteral feeding
It must not interact with the material of the feeding tube
5.4.3.1 No Blocking the Tubes
Enteral feeding tubes can be very narrow, especially those for children. The minimum external diameter is about 1.3 mm, with the internal diameter depending on the wall material: polyvinyl chloride (PVC) being the thinnest, closely followed by polyurethane (PUR), and by silicone that being relatively thick does not leave much room for the internal diameter.
Diameter Feeding Tubes
The external diameter of feeding tubes is expressed using the Charriere (Ch) or French (Fr) unit (1 Ch = 333 μm = 1 Fr). The external diameter of the narrowest tube is Ch 4; the external diameter of the thickest tube is Ch 20, with Ch 8 or 10 being the most used.
The viscosity of the oral liquid has to be low enough to be administered through an enteral feeding tube. If necessary they have to be diluted with water. However, some solutions may precipitate upon dilution, e.g. because they contain co-solvents. Dilution also causes a decrease of the solubility of the active substance. Therefore solutions with co-solvents have to be administered undiluted.
The particles of the active substance in oral suspensions are required not to exceed 180 μm and should therefore not block the tube. Larger particles may be encountered however if ground tablets or the contents of capsules are used. In that case water-soluble fillers (such as lactose) will diminish the risk of blocking.
Flushing the feeding tube with 20–30 mL of fresh potable water before and after each addition of medicines can prevent clogging. But take care: many patients who are being tube fed require frequent monitoring of the fluid balance. The amount of water used to administer medicines (as an oral liquid and to flush the tube) may be subject to restrictions and should be recorded in that case. Carbonated fluids can exacerbate tube clogging by causing feed to coagulate or protein and amino acids to denaturise. Therefore they should not be used to flush the tube.
5.4.3.2 Incompatibility with Tubes
The relatively short time that the active substance is in contact with the feeding tube may be long enough for adsorption to the tube. When using lipophilic solvents there is also a risk of the leaching of plasticisers from the tube. This depends on the material of the feeding tube.
The use of PVC feeding tubes is limited. PVC is firm but can be uncomfortable for the patient. The plasticisers in PVC dissolve when exposed to gastric juices. As a result, the feeding tube becomes hard and fragile and can therefore be used for a maximum of 10 days [2]. In practice the use is limited to 1 week. Lipophilic medicines easily adsorb to PVC. Lipophilic solvents, such as acetem (see Sect. 23.3.6) when administered through PVC feeding tubes may cause plasticisers (phthalates) to dissolve and the feeding tube to crumble.
Polyurethane (PUR) feeding tubes can remain in the patient up to a maximum of 6–8 weeks. PUR is a rather flexible and inert material that offers more comfort for the patient than PVC. However, the greater flexibility can make the insertion more difficult. Adsorption of active substances rarely occurs.
Silicone feeding tubes are even more flexible than PUR and thus more difficult to insert. These feeding tubes are used when the tube should remain in the patient longer than 4–6 weeks. Silicone is highly resistant to gastric juices. However, silicone feeding tubes are weaker than PVC or PUR tubes [3].
5.4.3.3 Microbiological Quality
Enteral feeding does not contain preservatives because of the large volume being administered. Although tube feeding is used by vulnerable patients, sterility is not necessary. However, the food is often sterilised to get a sufficient shelf life.
If the oral liquid has been prepared from an oral solid using potable water, it has to be added immediately after preparation, thereby causing no larger microbiological load than that of potable water. Oral liquids made from raw materials are preserved in most cases and thus have a low bioburden.
5.4.4 Active Substance Solubility
Aqueous solutions can be formulated if the active substance is soluble in the desired concentration. The solubility may be enhanced by adjustment of the pH, addition of organic solvents (so-called co-solvents) or the use of a better soluble salt or ester. Some active substances only dissolve in lipophilic vehicles, see Sect. 5.4.5.5.
5.4.4.1 Sufficient Solubility
An active substance such as metoprolol tartrate, which is very soluble in water, may be processed in a simple aqueous base (Table 5.2).
Metoprolol tartrate | 0.1 g |
Potassium sorbate | 0.14 g |
Citric acid, anhydrous | 0.07 g |
Water, purified | 99.69 g |
Total | 100.0 g (= 100 mL) |
5.4.4.2 pH
In general salts dissolve well in water but the solubility often depends on the pH (see Sect. 18.1.1). A high pH may not be a good option because an oral solution with a high pH is not tolerated by the gastrointestinal tract and tastes unpleasant. A furosemide oral solution may serve as an example (Table 5.3). The solubility of furosemide in water is less than 0.1 mg/mL but it increases at alkaline conditions. The solubility at pH 8 is more than 100 mg/mL [5]. An oral solution containing 2 mg/mL can be formulated by setting the pH at 6.6–8.0 with trometamol.
Furosemide | 0.2 g |
Methyl parahydroxybenzoate | 0.15 g |
Saccharin sodium | 0.1 g |
Trometamol | 0.1 g |
Water, purified | 99.8 g |
Total | 100.4 g (= 100 mL) |
5.4.4.3 Co-solvents
The solubility in mixtures of water with organic solvents (co-solvents) can be predicted (see Sect. 18.1.3) but is in practice determined by experiment. Information on solubility in water or organic solvents may be available [7–10], but solubility in solvent mixtures is not. It is not correct to make an assumption about solubility based on the solubility in one of the solvents because all components of the mixture influence it.
An example of increasing the solubility by using co-solvents is a phenobarbital oral solution with ethanol and propylene glycol (Table 5.4). The formula is only suitable for use of limited duration in adults. Both solvents make the solution unsuitable for children. Prolonged use can make the amount of propylene glycol also too high for adults.
Phenobarbital | 0.4 g |
Bitter-orange-epicarp and mesocarp tincture | 1 mL |
Ethanol (96 %) | 20 mL |
Propylene glycol | 10 mL |
Saccharin sodium | 0.1 g |
Sorbitol, liquid (crystallising) | 60 mL |
Orange essence (local standard) | 1 mL |
Water, purified | 98.9 g |
Total | 100.4 g (= 100 mL) |
5.4.4.4 Better Soluble Salt or Ester
Several salts or derivatives (e.g. esters) of active substances are more soluble in water than the parent substance (see also Sect. 18.1). Well-known examples are the sodium salts of the phosphate esters of prednisolone and dexamethasone (Table 5.5).
Dexamethasone sodium phosphate | 0.143 g |
Bananas essence (local standard) | 0.1 g |
Disodium edetate | 0.1 g |
Disodium phosphate docecahydrate | 1.9 g |
Methyl parahydroxybenzoate | 0.15 g |
Sodium dihydrogen phosphate dihydrate | 0.21 g |
Sorbitol, liquid (crystallising) | 25.8 mL |
Water, purified | 78.4 g |
Total | 106.8 g (= 100 mL) |
5.4.4.5 Low Solubility: Suspension
As said (Sect. 5.4.2) an active substance that does not dissolve sufficiently to be administered as an aqueous solution can be processed in a suspension. But the solubility of the active substance should be sufficiently low, taking into account the desired concentration of the active substance in the suspension. Too high a percentage of dissolved active substance can lead to crystal growth of the suspended particles. Large particles settle faster, which can cause insufficient physical stability of the suspension and a lower dissolution rate.
Ideally, for a stable suspension, the solubility of the suspended substance should be not higher than 0.1 mg/mL and the proportion of the dissolved substance should be not higher than 0.1 % of the total amount of the oral liquid. If this is not quite to be achieved, extra attention to the particle size of the active substance should be paid. Crystal growth will more likely occur with very small particles or a high spread in the particle size. This is called Ostwald ripening (see Sect. 18.4.2.3).
For the indications epilepsy, diuresis, increased intracranial pressure and glaucoma with children an oral liquid dosage form with acetazolamide 5 mg/mL was required. The aqueous solubility of acetazolamide is 0.1–1 mg/mL, pKa is 7.2 and the stability is optimal at pH 4. To obtain a solution with the concentration 5 mg/mL the pH has to be fixed at 8 but that caused a 20 % degradation of acetazolamide within 2 weeks. For an oral suspension the solubility is relatively high; for about 2–20 % of the substance would be dissolved, giving quite some cause for crystal growth. A solid dosage form would be a better option but the physicians definitely wanted to be able to adjust the dose immediately. An oral suspension was designed (see Table 5.6). However, a concentration of 10 mg/mL was used to decrease the relative percentage of dissolved acetazolamide and thus risk for crystal growth. During storage the dissolution rate appeared to decrease which may be a sign of crystal growth. Therefore, the shelf life has been limited to 3 months.
Acetazolamide | 1 g |
Aluminium magnesium silicate | 0.89 g |
Carmellose sodium M | 0.89 g |
Citric acid monohydrate | 0.37 g |
Methyl parahydroxybenzoate | 0.07 g |
Raspberry essence (local standard) | 0.3 g |
Sodium citrate | 4.7 g |
Syrup BP (preserved with methyl parahydroxybenzoate 1 mg per g) | 33.3 g |
Water, purified | 72.5 g |
Total | 109 g (= 100 mL) |
This phenomenon of crystal growth is a very realistic risk in practice if active substances, whether as raw material or as crushed tablets, are processed in a universal ‘suspension base’ without noticing that the actual solubility is too high for a suspension. These bases are often not clear and therefore, it cannot be controlled whether the active substance dissolves or not. If the crushed tablets are processed, the control of an eventual dissolution is impossible anyway because of the insoluble excipients.
5.4.5 Vehicles
The most commonly used vehicle is water, for solutions as well as suspensions, emulsions and solubilisates. If a solution is required, co-solvents may be added (see Sect. 5.4.4) such as ethanol, glycerol 85 % and propylene glycol. Their toxic and adverse effects should be fully considered. They are miscible with water and often have an antimicrobial effect as well. Lipophilic active substances may be brought into solution by a lipophilic solvent such as acetem. Another way of processing lipophilic solvents is to convert them into an emulsion.
5.4.5.1 Water
Usually purified water (Aqua purificata) is used. Because of the chemical and microbiological quality it is preferred over potable water (see Sect. 20.3.1) although the taste of potable water may be better due to presence of ions. Water is a good growth medium for micro-organisms, so aqueous oral liquids generally have to be preserved, see Sect. 5.4.9.
Water has a low viscosity and high surface tension, which causes an uneven ‘flow’ when dosing the oral liquid from bottles and dosage devices. Thickening agents, especially cellulose derivatives, may be added to improve this.
5.4.5.2 Ethanol
Ethanol is used as co-solvent in a concentration up to 20 % in oral solutions. If present in a concentration of at least 15 %, it also serves as a preservative.
In babies ethanol can lead to convulsions. According to the WHO [14] ethanol has to be avoided in oral preparations for children less than 6 years. Chronic exposure to ethanol (>1 week), even in small doses, is in principle contraindicated in children aged less than 6 years and should be limited to 2 weeks in children aged over 6 years, if a positive risk-benefit balance is not demonstrated.
The influence of ethanol on the responsiveness can especially be a problem for all ages. Pharmacy preparations should be labelled with a warning indication as it is directed for licensed products. Guidelines concerning the content of ethanol and how to deal with in high-risk groups (e.g. patients with liver diseases, alcoholism etc.) and in the handling of machinery are given by the EMA [15].
Children, especially under the age of 6 years, are more vulnerable to the effects of ethanol.
Adverse effects on the central nervous system are already evident at blood ethanol concentrations of 10 mg/100 mL in children. Higher peak ethanol blood concentrations are also observed in children than in adults for a similar intake [15].
5.4.5.3 Propylene Glycol
Propylene glycol is used as co-solvent in a concentration up to 20 %. It has preservative properties when used in concentrations of 15 % or higher. The taste is unpleasant. The acceptable daily intake (ADI) of propylene glycol is 25 mg/kg bodyweight per day without mentioning any age group [16]. Because of the limited hepatic and renal function in preterm and term neonates the application of medicines containing propylene glycol may lead to accumulation and serious adverse effects. Data in chronic use for children are not available and reports about the tolerance in patients of different ages are usually based on IV application. A daily IV dose of about 34 mg/kg bodyweight is reported to be tolerated in neonates in short time use [17]. As long as there are no data available for oral use the amount tolerated in IV application may be an indication for oral consumption as well.
5.4.5.4 Glycerol 85 %
Glycerol 85 % is used as co-solvent, preservative, sweetening agent and viscosity-increasing agent in a concentration up to 60 %. Its sweetening power is about 0.5 times that of sucrose. It functions as a preservative at a concentration higher than 30 %. The osmotic effect of high concentrated glycerol has to be considered in paediatric use and in patients with enteral feeding tubes because of gastrointestinal adverse effects (diarrhoea).
5.4.5.5 Lipophilic Solvents
Lipophilic solvents may be used for dissolution of lipophilic active substances. This option is less desirable because most lipophilic solvents do not taste very well and may render the preparation (or the labels) a bit messy at use. But for formulating an oral solution when toxic organic solvents such as ethanol or propylene glycol are not suitable, such as in paediatric use, the use of a lipophilic solvent such as acetem (see Sect. 23.3.6) may provide a useful preparation. Acetem is allowed in food, also for babies, and there is no restriction on the daily intake. The taste of acetem is unpleasant; therefore saccharin and peppermint oil are added as flavouring agents. A phenobarbital oral solution may serve as an example (Table 5.7).
Phenobarbital | 0.4 g |
Peppermint oil | 0.04 g |
Saccharin | 0.05 g |
Acetem (Myvacet 9–08)a (local standard) | 98.4 g |
Total | 98.9 g (= 100 mL) |
Lipophilic solutions contain less excipients. By the lack of water there is no grow of micro-organisms and no decomposition reactions occur. Preservatives, antioxidants and buffers are thereby not necessary.
Lipophilic solvents can be brought into an emulsion, see Sect. 5.4.7.
5.4.6 Suspending Agents
As is explained in Sect. 18.4.2 the following conditions are favourable for the formulation of an oral suspension:
Primary particles, no agglomerates or lumps
Right particle size (not too large but not too small either)
Vehicle with increased viscosity and increased density
Intermediate between a flocculated and deflocculated sediment (in order to enable safe dosing through easy resuspendability and a not too fast settling)
The achievement of the right particle size is discussed in Sects. 29.2 and 29.3. The primary particle size of substances processed in suspensions is generally < 180 μm. Wetting agents may be necessary to break up agglomerates, mainly through making hydrophilic (hydrophilising).
To increase the density of water sugar syrup can be added. An increase of the viscosity can also be achieved by the addition of viscosity enhancing substances. The character of the sediment may be influenced by electrolytes or surfactants.
Often substances are used that combine different favourable properties such as increasing viscosity, decreasing surface tension, hydrophilising the particles of the active substance etcetera. It depends on the properties of the active substance and the other components of the suspension, how a substance influences the character of the sediment (see Sect. 18.4.2).
This subsection describes three groups of substances rated by their main quality: wetting agents (including hydrophilic excipients and surfactants), thickening agents and flocculating agents. Their effect on the stability of a suspension has to be determined carefully and in combination. They may interact and turn a positive effect of the other substance into a negative effect. As an example cellulose derivatives may increase viscosity and wettability but decrease resuspendability. The effect of particle size, settling rate, resuspendability of the sediment and dissolution rate may be tested by applying the tests of the British Pharmacopoeia, as described in the general monograph Unlicensed Medicines [19].
5.4.6.1 Wetting Agents (Hydrophilic Excipients)
Substances with high surface energy are sometimes difficult to wet (see Sect. 18.3.2) which makes them difficult to disperse: they float on the liquid or form lumps. Such a substance should be mixed with a hydrophilic substance before dispersion. Appropriate hydrophilic substances are: thickening agents, sugar syrup, or silicon dioxide. The addition of a surfactant, for example polysorbate or polyvidone, to the aqueous phase can improve wetting as well.
The phenytoin in Table 5.8 is a poorly wettable substance. Therefore it is mixed with colloidal anhydrous silica and subsequently triturated with sugar syrup.
Phenytoin | 1.5 g |
Aluminium magnesium silicate | 1 g |
Carmellose sodium M | 1 g |
Citric acid monohydrate | 0.05 g |
Methyl parahydroxybenzoate | 0.09 g |
Raspberry essence (local standard) | 2 dr |
Silica, colloidal anhydrous, compressed | 0.25 g |
Sodium citrate | 4.7 g |
Syrup BP (preserved with methyl parahydroxybenzoate 1 mg per g) | 30 g |
Water, purified | ad 107.5 g (= 100 mL) |
5.4.6.2 Wetting Agents (Surfactants)
Wetting of the active substance can be improved by the addition of a small amount of surfactant to the aqueous phase. A surfactant reduces the surface tension between the water and the solid. A surfactant will also play a role in the character of the sediment. An example is polysorbate 80 that is processed in a griseofulvin suspension 25 mg/mL (Table 5.9). The disadvantage of surfactants in general (particularly polysorbate) is the unpleasant taste.
Griseofulvin | 2.5 g |
Aluminium magnesium silicate | 0.88 g |
Carmellose sodium M | 0.88 g |
Citric acid monohydrate | 0.066 g |
Methyl parahydroxybenzoate | 0.066 g |
Polysorbate 80 | 1 g |
Saccharin sodium | 0.2 g |
Syrup BP (preserved with methyl parahydroxybenzoate 1 mg per g) | 30.5 g |
Water, purified | 69.9 g |
Total | 106 g (= 100 mL) |
Polyvidone K30 is used for wetting in a clioquinol suspension 100 mg/mL (Table 5.10). The addition K30 refers to the chain length and the extent to which it influences the viscosity in water. This substance has many uses including thickening agent, wetting agent and improving dispersion.
Clioquinol | 10 g |
Carmellose sodium M | 0.5 g |
Citric acid monohydrate (crystalline) | 0.1 g |
Methyl parahydroxybenzoate | 0.07 g |
Polyvidone K30 | 2.5 g |
Saccharin sodium | 0.05 g |
Syrup BP (preserved with methyl parahydroxybenzoate 1 mg per g) | 30 g |
Water, purified | 63.8 g |
Total | 107 g (= 100 mL) |
5.4.6.3 Thickening Agents
Increasing the viscosity of water by the addition of thickening agents reduces the settling rate of particles (see Sect. 18.4.2). For thickening agents reference is made to Sect. 23.7 regarding their chemical composition, general use and their way of processing. In Table 5.11 the most commonly used thickening agents in oral liquids are listed. Apart from being used for decreasing the settling rate in suspensions, they may also be used for shielding the taste buds from an unpleasant taste and for improving the flow of the oral liquid from the bottle or the dosing device.
Table 5.11
Thickening Agents in Oral Liquids
Thickening agent | Concentration (%) | Comment |
|---|---|---|
Carmellose sodium (middle viscous) | 0.5–1 | Incompatible with cations |
Carrageenan | 0.1–0.75 | Needs cations (e.g. calcium, potassium, etc.) for gelling [23] |
Aluminium magnesium silicate | 0.5–2 | Provides electrolytes as well (for flocculation) |
Hydroxyl ethylcellulose (HEC) 300–560 mPa.s | 1–1.5 | |
Hypromellose (HPMC) 4,000 mPa.s | 1–1.5 | |
Methylcellulose 15 mPa.s | 2.5 | |
Tragacanth | 0.5 | |
Xanthan gum | 1–3 | Incompatible with polyvalent cations |
Using thickening agents of natural origin such as agar, tragacanth or gum Arabic the microbiological quality requires constant attention. The sterilisation of the raw materials with ethylene oxide is not allowed in pharmaceutical use and autoclaving a thickened base may decrease viscosity. Therefore an effective preservation is very important.
Xanthan gum and carrageenan are contained in the suspending base Ora-Plus®.
Some examples of the use of thickening agents are given.
In a potassium hydrogen tartrate suspension (Table 5.12) methylcellulose 15 mPa.s is applied as thickening agent. The pH of this suspension is 3.0–3.5. Cellulose derivatives, such as methylcellulose, may hydrolyse at low pH. The polymer chain is broken down and the viscosity will decrease. The shelf life is therefore limited to 3 months.
Table 5.12
Potassium Hydrogen Tartrate Oral Suspension 188 mg/mL [24]
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