A surface is the outer boundary of a material. In reality, each surface is the boundary between two phases: an interface, which can be solid/liquid (SL), solid/vapour (SV) or liquid/vapour (LV); or a boundary between two immiscible phases of the same state, i.e. liquid/liquid or solid/solid interfaces. There cannot be vapour/vapour interfaces, as two vapours would mix, rather than form an interface.

Pharmaceutically we often think of materials in terms of their bulk properties, such as solubility, particle size, density and melting point. However, surface material properties often bear little relationship to bulk properties, for example materials can be readily wetted by a liquid but not dissolve in it, i.e. they could have water loving surfaces but not be soluble; an example of this is glass. As contact between materials occurs at interfaces, a knowledge of surface properties is necessary if interactions between two materials are to be understood (or predicted). Indeed every process, reaction, interaction, whatever it may be, either starts, or fails to start, due to the extent of interfacial contact.

Surface tension

If we compare the forces acting on a molecule in the bulk of the liquid with one at the interface (see Fig. 4.1), in the bulk, the molecules are surrounded on all sides by other liquid molecules and will consequently have no net force acting on them (all attractive forces generally being balanced). At the surface, however, each liquid molecule is surrounded by other liquid molecules to the sides and below (essentially in a hemisphere below the molecule), whilst above the molecule the interactions will be with gas molecules from the vapour; these will be much weaker than those between the liquid molecules. As the molecule at the liquid surface has balanced forces pulling sideways, the imbalance is a net inward attraction in a line perpendicular to the interface. Due to the net inward force exerted on liquids, the liquid surface will tend to contract, and to form a sphere (the geometry with minimum surface area to volume ratio). The contracted liquid surface is said to exist in a state of tension – known as surface tension. The value of surface tension for a liquid will be related to the strength of the pull between the liquid molecules. The interfacial interactions are a consequence of long range forces which are electrical in nature and consist of three types: dipole, induced dipole and dispersion forces.

Fig. 4.1 The balance of forces on molecules at the surface and in the bulk of a liquid. Molecules (depicted here as large circles) in the bulk of a liquid have neighbours on all sides and a net balance of forces. Molecules at the surface have neighbours to each side, but no balance for the attraction of molecules from below, giving a net inward force into the body of the liquid – this is the basis of surface tension.

Dipole forces are due to an imbalance of charge across the structure of a molecule. This situation is quite common, certainly most drugs are ionizable, and have such an asymmetric charge distribution, as do many macromolecules and proteins. Such materials are said to have permanent dipoles, and interactive forces are due to attraction between the negative pole of one molecule when in reasonably close contact with the positive pole of another. Hydrogen bonding interactions are a specific sort of this type of bonding, resulting from the fact that hydrogen consists of only one proton and one electron, making it very strongly electronegative. When hydrogen bonds, its electron is ‘lost’, leaving an ‘exposed’ proton (i.e. one without any surrounding electrons). This unique situation causes a strong attraction between the proton and an electronegative region from another atom. The strength of the hydrogen bond results in drastically different properties of interaction, exemplified by the fact that water has such a high surface tension, melting and boiling point (in comparison with non-hydrogen bonded materials).

A bond between carbon and oxygen would be expected to be dipolar, however, if the molecule of carbon dioxide is considered (OCO), it can be seen that the molecule is in fact totally symmetrical, the dipole on each end of the linear molecule being in perfect balance with that on the other end. Even though these molecules do not carry a permanent dipole, if they are placed in the presence of a polarized material, a dipole will be induced on the (normally symmetrical) molecule, such that interaction can occur (dipole – induced dipole, or Debye interactions).

London – van der Waals forces are termed dispersion forces. These are interactions between molecules which do not have a charge imbalance, and which do not have the ability to have an induced dipole either. Essentially these are interactions between non-polar materials. These dispersion forces occur between all materials, and thus, even though the interaction forces are weak, they make a very significant contribution to the overall interaction between two molecules. Dispersion forces can be understood in a simplistic fashion by considering the fact that the electrons which spin around two neighbouring non-polarized atoms will inevitably not remain equally spaced. This will result in local imbalances in charge that lead to transient induced dipoles. These induced dipoles, and the forces which result from them will be constantly changing, and obviously the magnitude of these interactions is small compared to the permanent and induced dipole situations described above. Dispersion forces are long range, in the order of 10 nm which is significantly longer than a bond length.

Measurement of surface tension

The surface tension of a liquid is the combined strength of polar and dispersion forces that are pulling on the molecules in the surface of the liquid. There are a number of methods by which surface tension can be measured, including the rise of a liquid in a capillary, but more usually the force experienced by the surface is measured using a microbalance. To do this, an object either in the form of a thin plate (Wilhelmy plate) or ring (Du Nouy ring), is introduced to the surface and then pulled free, with the force at detachment being measured. For the Wilhelmy plate method, a plate (usually very clean glass or platinum) is positioned edge on in the surface whilst suspended from a microbalance arm, the force is then measured as the plate is pulled out of the liquid. The surface tension is obtained by dividing the measured force at the point of detachment by the perimeter of the plate.

Water is the liquid with the highest value for its surface tension of all commonly used liquids in the pharmaceutical field (although metals have much higher surface tensions than water, e.g. mercury with 380 mN m⁻¹). Water is also of great pharmaceutical interest, being the vehicle used for the large majority of liquid formulations, and being the essential component of all biological fluids. At the standard reporting temperature, the surface tension of water is 72.6 mN m⁻¹.

The addition of small quantities of impurities will alter the surface tension. In general, organic impurities are found to lower the surface tension of water significantly. Take for example the addition of methanol to water. The surface tension of methanol is 22.7 mN m⁻¹, but the surface tension of a 7.5% solution of methanol in water is 60.9 mN m⁻¹ (Fig. 4.2). On the basis of a linear reduction in surface tension in proportion to the concentration of methanol added, the surface tension of this mixture would be expected to be about 68.9 mN m⁻¹, thus the initial reduction in surface tension upon addition of an organic impurity is dramatic, and cannot be explained by the weighted mean of the surface tensions of the two liquids. Methanol has been used as the example here, as it is one of the more polar organic liquids, containing just 1 carbon, attached to a polar hydroxyl group. However, it is its hydrophobicity that causes the significant reduction in surface tension. The reason for the large effect on surface tension is that the water molecules have a greater attraction to each other than to methanol, consequently the methanol is concentrated at the water/air interface, rather than in the bulk of the water. The methanol here is said to be surface active (surface active agents are discussed elsewhere in this book; in particular in Chapters 5 and 27). Water obtained directly from a tap can have a surface tension greater than 72.6 mN m⁻¹, due to the presence of ionic impurities, such as sodium chloride, which are concentrated preferentially in the bulk of water rather than at the surface. Inorganic additives also strengthen the bonding within water, so the surface tension is increased in their presence.

Fig. 4.2 The surface tension of mixtures of methanol and water (•) and sodium chloride and water (×). Based on data from Weast (1988).

Solid wettability

The vast majority of pharmaceutically active compounds exist in the solid state at standard temperatures and pressures. Inevitably, the solid drug will come into contact with a liquid phase, either during processing, and/or in the formulation, and also ultimately during use in the body. Consequently, the solid/liquid interface is of great importance. Here the term wettability is used to assess the extent to which a solid will come into contact with a liquid. Obviously a material which is potentially soluble, but which is not wetted by the liquid (i.e. the liquid does not spread over the solid) will have limited contact with the liquid and this will certainly reduce the rate at, and potentially the extent to, which the solid will dissolve. When formulating an active pharmaceutical ingredient, it is important that the powder ultimately becomes wetted by body fluids in order that it will dissolve.

As with liquid surfaces, there is a net imbalance of forces in the surface of a solid, and so solids will have a surface energy. The surface energy of a solid is a reflection of the ease of making new surface, and in simple terms can be considered to be the same as surface tension for a liquid. With liquids, the surface molecules are free to move, and consequently surface levelling is seen, resulting in a consistent surface tension/energy over the entire surface. However, with solids the surface molecules are held much more rigidly, and are consequently less able to move. The shape of solids is dependent upon previous history (perhaps crystallisation or milling techniques). These processes may yield rough surfaces with different regions of the same solid’s surface having different surface energies. Certainly different crystal faces and edges can all be expected to have a different surface nature due to the local orientation of the molecules presenting different functional groups at the surface of different faces of the crystal – some more and some less polar, and therefore some regions more water loving and other regions less so.

Contact angle

The properties of solids raise many problems with respect to surface energy determination, not least the fact that it is not possible to measure directly the forces exerted on the surface. The methods that are used for liquid surface tension measurement, such as immersing a Wilhelmy plate and measuring the force as it is pulled from the liquid, cannot be used as the plate cannot gain access into the solid. This means that surface properties of solids must be derived from techniques such as contact angle measurement. The tendency for a liquid to spread is estimated from the magnitude of the contact angle (θ), which is defined as the angle formed between the tangent drawn to the liquid drop at the three phase interface and the solid surface, measured through the liquid (Fig. 4.3). The contact angle is a consequence of a balance of the three interfacial forces; γ_SV acting to aid spreading; γ_SL acting to prevent spreading and γ_LV which acts along the tangent to the drop. The interfacial forces are related to contact angle by Young’s equation:

(4.1)

A low value for the contact angle indicates good wettability, with total spreading being described by an angle of 0 degrees. Conversely, a high contact angle indicates poor wettability, with an extreme being total non-wetting with a contact angle of 180 degrees. The contact angle provides a numerical assessment of the tendency of a liquid to spread over a solid, and as such is a measure of wettability.