Solutions
Sudaxshina Murdan
Chapter contents
Advantages of pharmaceutical solutions
Enhancement of drug solubility
Complexation with cyclodextrins
Key points
• All the components in a solution are dispersed as molecules or ions.
• As the drug is already dissolved, it is immediately available for action or absorption.
• Solutions have many advantages, for example, oral solutions are easy to swallow.
Introduction
This chapter concentrates on solution dosage forms and it is recommended that it be read in conjunction with Chapters 2 and 3 where the science of formation of solutions and their properties are discussed.
A solution, as defined in Chapter 2, is a homogeneous, molecular, mixture of two or more components. The simplest solution consists of two components, a solute dissolved in a solvent. The solute and the solvent could be in the solid, liquid or gaseous states of matter. Most commonly, pharmaceutical solutions are preparations in which the solid solutes, i.e. drug and excipients, are dissolved in a liquid solvent system. Water is the most common solvent, although organic solvents are used in combination with water or on their own. All the components of a solution are dispersed as molecules or ions, and the solution is optically clear. Solutions can be prepared by simple mixing of the solutes with the solvent system. In industry, solutions are prepared in large mixing vessels which are thermostatically controlled should a specific temperature be desired.
The solvent system
Aqueous solvents
The majority of pharmaceutical solutions are water-based. Water is the most commonly used solvent due to its many advantages, such as its lack of toxicity and low cost. Different types of ‘water’ have been defined in the pharmacopoeias, related to its purity. Those defined in the British Pharmacopoeia are given as representative examples in Table 24.1. Other pharmacopoeias, such as the United States Pharmacopoeia, have additional types, such as ‘Bacteriostactic Water for Injection’.
Table 24.1
Different types of water, as defined by the British Pharmacopoeia
| Type of water | Use |
| Purified Water | Used for the preparation of medicines that do not have to be sterile and apyrogenic. |
| Highly Purified Water | Used for the preparation of medicines where water of high biological quality is needed, except where Water for Injections is required. |
| Water for Injections | Used for medicines for parenteral administration. Must be pyrogen-free. |
| Sterilized Water for Injections | Used for medicines for parenteral administration. Water has been sterilized by heat and is suitably packaged. |
Tap (drinking) water is not normally used for the manufacture of pharmaceutical solutions or for extemporaneous compounding, as it contains dissolved substances which could interfere with the formulation, for example, reduce drug solubility and stability. Tap water is therefore purified, for example, by distillation, ion exchange or reverse osmosis to produce Purified Water. The latter is used for the preparation of non-parenteral solutions. For parenteral solutions, tap water is further purified in order to remove pyrogens (water-soluble, fever-producing compounds) thereby producing Water for Injections. In certain instances, for example, in extemporaneous dispensing, drinking tap (potable) water, freshly drawn from a mains supply, boiled and cooled, can be used to prepare oral or external solutions that are not intended to be sterile.
On its own, water does not dissolve many drug compounds to a sufficient degree to enable the preparation of a pharmaceutical solution. Other water-miscible liquids with greater drug solubility may therefore be added to water to enhance drug solubility. These liquids are called co-solvents. Commonly used examples include glycerol, propylene glycol, ethanol and poly(ethylene glycol). Co-solvents are generally less innocuous than water and the concentration used in an aqueous solution is limited primarily by their toxicity, by drug solubility in the formulation and finally cost. The mechanism of action of co-solvents is discussed in greater detail below.
Non-aqueous solvents
Non-aqueous solvent systems are used when the drug is insufficiently soluble or stable in aqueous systems, or when a solution is intended for specific properties, such as sustained drug absorption. Non-aqueous solutions are however limited to certain delivery routes, such as intramuscular and topical, due to their unpalatibility, toxicity, irritancy or immiscibility with physiological fluids. Although there is a huge number of organic liquids in which drugs can dissolve, the majority are toxic, and only a few are used in pharmaceutical solutions. Examples of commonly used organic liquids are shown in Table 24.2. These liquids are used as co-solvents with water, as co-solvents with other organic liquids, or on their own.
Table 24.2
Examples of non-aqueous solvents used in pharmaceutical solutions
| Solvent | Use |
| Alcohols, including polyhydric ones (i.e. those containing more than one hydroxyl group per molecule) | Ethanol is the most common organic solvent used in pharmaceutical solutions. It is often used as a co-solvent in oral, topical and parenteral solutions. Propylene glycol (CH3CH(OH)CH2OH) contains 2 hydroxyl groups per molecule. It is often used as a co-solvent in oral, topical, parenteral and otic solutions. Glycerol contains 3 hydroxyl groups per molecule. It is widely used as a solvent or co-solvent with water, in oral and parenteral solutions. Low molecular weight polyethylene glycols (PEGs) with the general formula HOCH2(CH2CH2O)nCH2OH. These are used as solvents or co-solvents with water or ethanol. Used in parenteral solutions. |
| Fixed vegetable oils | Fixed oils are expressed from the seeds, fruit or pit/stone/kernel of various plants. They are non-volatile oils and are mainly triglycerides of fatty acids. Examples include olive oil, corn oil, sesame oil, arachis oil, almond oil, poppyseed oil, soya oil, cottonseed oil, castor oil. Historically, they have been used for intramuscular administration. They are used to a lesser extent now due to their irritancy and the possibility of allergic reactions to certain oils. They are being replaced by synthetic alternatives such as ethyl oleate. |
| Esters, such as ethyl oleate, benzyl benzoate, ethyl ethanoate | These are used as a vehicle in certain intramuscular injections. |
| Dimethyl sulfoxide | Used as a carrier for idoxuridine for topical application to the skin. |
| Glycofurol | Used as a co-solvent in parenteral solutions for intramuscular or intravenous injection. |
| Ethyl ether | Used as a co-solvent with ethanol in collodions. |
The drug
The drug could be a small molecule like aspirin, or a large biotherapeutic molecule, such as insulin or an antibody. As defined in Chapter 2, the drug is present as molecules or ions throughout the solvent. It is usual to ensure that the drug concentration in a pharmaceutical solution is well below its saturation solubility in order to avoid the possibility of drug precipitating out of the solvent as a result of subsequent temperature changes during storage and use.
The excipients
Excipients – substances other than the drug or prodrug which are included in pharmaceutical solutions – are used for a number of reasons, such as to enhance product stability, bioavailability or patient acceptability, aid product manufacture and/or identification. Each excipient has a clear role in the product, thus, the nature of an excipient used depends on the requirements of the pharmaceutical product. The excipient must be non-toxic, nonsensitizing, nonirritating, as well as compatible with all the other components of the formulation. The route of administration is important; many excipients are acceptable by certain, but not all, routes. For example, the preservative benzalkonium chloride is used in oral, but not nebulizer, solutions, as it causes bronchoconstriction. Like the drug, excipients could be small (e.g. sucrose) or large (e.g. hydroxypropyl methylcellulose) molecules.
Pharmaceutical solutions
Solutions are one of the oldest pharmaceutical formulations. They are administered by many different routes; they are often therefore classified by the intended route (e.g. oral, otic (ear), parenteral). Solutions are also classified by the nature of the formulation, or by the traditional name which relates to the solvent system used, such as syrups, elixirs, spirits and tinctures. The latter terms are described in Table 24.3. While all pharmaceutical solutions must be stable, and acceptable to patients, other requirements of solutions administered by the different routes vary. For example, parenteral and ocular solutions must be sterile, oral solutions must be palatable, solutions which come into contact with body fluids must be isotonic and at physiological pH, especially if large volumes are used. Multidose products often contain preservatives to ensure that the growth of any microorganisms that are accidentally introduced during product use is inhibited. The requirements of the different types of pharmaceutical solutions are detailed in Table 24.4. These requirements are achieved by the inclusion of a number of excipients, as detailed in Table 24.5.
Table 24.3
Traditional terms for different pharmaceutical solutions
| Traditional term | Description |
| Aromatic Waters | Saturated aqueous solutions of volatile oils or other aromatic or volatile substances. |
| Elixirs | Many oral solutions that contain alcohol as a cosolvent have traditionally been designated as elixirs. However, many other oral solutions containing significant amounts of alcohol are not designated as elixirs. |
| Spirits | Alcoholic or hydro-alcoholic solutions of volatile substances. Some spirits are used as flavouring agents, others are medicinal. |
| Syrups |
