A solution, 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.
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.
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: for example, oral, otic (ear), and parenteral. Solutions are also classified by the nature of the formulation. They can also be classified by the traditional name, which relates to the solvent system used, such as syrups, elixirs, spirits, and tinctures.
Whilst 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, and 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.
Components of pharmaceutical solutions
Pharmaceutical solutions have three essential ingredients: the solvent system, the drug, and the excipients.
The solvent system
The majority of pharmaceutical solutions are waterbased. Water is the most commonly used solvent due to its many advantages, such as its lack of toxicity and low cost.
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 ability to dissolve drugs may therefore be added to water to enhance drug solubility. These liquids are called cosolvents. Commonly used examples include glycerol, propylene glycol, ethanol and polyethylene glycol. Cosolvents 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.
Nonaqueous 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. Nonaqueous solutions are, however, limited to certain delivery routes, such as intramuscular and topical, due to their unpalatability, toxicity, irritancy or immiscibility with physiological fluids. Although there are a huge number of organic liquids in which drugs can dissolve, the majority are toxic, and consequently only a few are used in pharmaceutical solutions. Examples of commonly used organic liquids (such as: alcohols, Fixed vegetable oils, Esters, Dimethyl sulfoxide, Glycofurol, Ethyl ether). These liquids are used as cosolvents with water, as cosolvents with other organic liquids, or on their own.
The drug
The drug may be a small (low molecular weight) molecule such as aspirin, or a large biotherapeutic molecule, such as insulin or an antibody. The drug is present in a solution 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 so as to avoid the possibility of the drug precipitating out of the solvent as a result of subsequent temperature changes during storage and use.
The excipients
Excipients are substances other than the drug or prodrug that are included in pharmaceutical solutions. Excipients are used for a number of reasons, such as enhancing product stability, bioavailability, or patient acceptability, or aiding in product manufacture and/or identification. Each excipient has a clear function in the product; thus, the choice of an excipient depends on the requirements of the pharmaceutical product. The excipient must be nontoxic, nonsensitizing, nonirritating, and compatible with all other components of the formulation. The route of administration is important; many excipients are acceptable for certain routes but not all. For example, the preservative benzalkonium chloride is used in oral but not nebulizer solutions, as it causes bronchoconstriction. Like the drug, excipients may be small (e.g., sucrose) or large (e.g., hydroxypropyl methylcellulose) molecules.
Solution Stability
Pharmaceutical solutions must maintain their physical, chemical, microbiological, therapeutic, and toxicological properties throughout their shelf life to ensure efficacy and safety. Solutions offer dose uniformity and ease of administration, particularly for those who have difficulty swallowing, like children and older adults. They are also easier to manufacture compared to other dosage forms.
However, many drugs are unstable in solution, and this instability is often exacerbated by factors such as temperature, pH, and exposure to light. Additionally, solutions can be challenging to formulate due to the poor solubility of some drugs in water and the increased bulkiness of liquids compared to solid forms. To enhance stability, solutions are formulated at pH levels that favor stability, with the addition of excipients like antioxidants and preservatives. Packaging also plays a crucial role in maintaining stability by protecting the solution from light and oxygen. Despite these efforts, the formulation of a solution may not be feasible for certain drugs due to inherent instability. The quality and compatibility of all excipients are essential to ensure that the solution remains effective throughout its shelf life.
Enhancement of Drug Solubility
As mentioned already, water is the most commonly used vehicle in pharmaceutical solutions. Many drugs are water soluble, solubility being defined as the concentration of the drug in a solution when equilibrium exists between dissolved and undissolved drug.
Drug solubility in water depends on a number of factors, such as the drug’s molecular structure, crystal structure, particle size and pKa and the pH of the medium (if the drug is a weak acid/base or a salt).
Unfortunately, many drugs are not sufficiently soluble in water, and aqueous drug solubility must be increased by the inclusion of other solvents/chemicals. The nature of the solubility enhancer depends on the drug molecule and the route of administration, as well as the intended patient population. Certain enhancers may be safely administered via the oral route, but not parenterally due to their greater toxicity when administered parenterally. Different approaches to enhancing drug solubility are:
pH adjustment
Most existing drugs are either weak acids or weak bases. In solution, an equilibrium exists between the undissociated drug molecules and their ions. The equilibrium may be represented as:
$$ weak\;acid:\;HA⇌H^++A^-\\weak\;base:\;B+H^+⇌BH^+ $$
Depending on the circumstances these equilibria will shift towards either the undissociated form or the dissociated form. Since ions are more soluble in water than neutral molecules, changing the pH of the medium to increase ionization of the drug is a common technique for increasing drug solubility in an aqueous medium. Weakly acidic drugs are ionized when the pH of the solvent is increased. Conversely, lowering the pH favours ionization of weakly basic drugs. The pH required to achieve drug ionization can be calculated using the Henderson–Hasselbalch equations and the pH can be adjusted using acids or alkalis, or by using buffers such as citrate, acetate, phosphate and carbonate buffers. Extremes of pH should be avoided however so that the solution is physiologically acceptable; the pH ranges tolerated for the different routes.
The selected pH should not adversely affect the stability of the drug and excipients. The rate of chemical reactions which lead to degradation can be pH dependent. The pH for optimal drug solubility may not be the same as that for optimal stability. The pH can also be important for the optimal functioning of excipients. For example, the ionization and subsequently the activity of a preservative may be influenced by the pH of the medium. Bioavailability of the drug should also not be compromised by a change in pH, un-ionized drug molecules being absorbed to a greater extent through biological membranes than their ionized counterparts. The pH of a pharmaceutical solution is thus a compromise between drug solubility, stability and bioavailability, the function of excipients, and physiological acceptability of the product.
Cosolvents
Cosolvents are often used to increase the water solubility of drugs which do not contain ionizable groups and whose solubility can thus not be increased by pH adjustment. The principle ‘like dissolves like’, polar drugs generally dissolve in polar solvents and nonpolar drugs generally dissolve in nonpolar solvents. Thus nonpolar drugs are poorly soluble in water – a polar solvent. To increase the solubility of such drugs in water, the latter’s polarity should be lowered. This can be achieved by addition of a third component such as a water-miscible organic liquid with a low polarity. Such a liquid, when used in this context, is called a cosolvent.
Most water-miscible organic liquids are toxic, and only a few are used as cosolvents in pharmaceutical solutions. Examples include glycerol, propylene glycol, ethanol and the low molecular weight polyethylene glycols. The solubility of nonpolar drugs in water can be increased by several orders of magnitude with cosolvents. Typically, a linear increase in cosolvent fraction results in logarithmic increases in drug solubility. The concentration of the cosolvent is, however, limited by its physiological acceptability. The cosolvent must be nontoxic at the concentrations used, and for the route of administration.
Surfactants and micelles
Surfactants (surface-active agents) and amphiphiles are molecules which have two distinct regions in their chemical structure. One region is hydrophilic and the other is hydrophobic. Because of this, such molecules tend to accumulate at the boundary between two phases, such as water–air or water–oil interfaces. They reduce the surface tension of liquids, and self-assemble to form micelles once the critical micellar concentration (CMC) is reached. Poorly water-soluble drugs can be solubilized in micelles to enhance their aqueous solubility.
The location of the solubilizate (the drug which is solubilized within the micelles) depends on its nature: nonpolar solubilizates are located within the micelles’ hydrophobic interior cores, solubilizates containing polar groups are oriented with the polar group at the micellar surface and slightly polar solubilizates partitions between the micelle surface and the core. Solubilizates may also be found in the palisade layer of nonionic surfactant micelles. The maximum amount of solubilizate which can be incorporated into a given system at a fixed concentration is known as the maximum additive concentration (MAC).
The aqueous solubility of a wide range of drugs has been increased by surfactants, especially for oral administration and parenteral administration. For example, solubilization of steroids with polysorbates has allowed their formulation in aqueous ophthalmic preparations, and solubilization of the water-insoluble vitamins A, D, E and K has enabled the preparation of aqueous injections. The surfactant chosen for a particular drug must solubilize the drug and be compatible with it and all the other components of the solution. For example, the surfactant should not adversely influence the drug’s stability. The surfactant must also be nontoxic at the concentration used for the particular route of administration.
Reference:
- Aulton, M. (2018). Aulton’s pharmaceutics, the design and manufacture of medicines. Edinburgh. : Elsevier.
