42 Physical Pharmacy chapter 4 7. Indicate which of the following statements relating to the effect of pH on drug stability are true: a. The rate of acid-catalysed decomposition of a drug increases with pH. Surfactants b. The rate of base-catalysed decomposition of a drug increases with the concentration of hydroxyl ions. c. The effect of buffer components on decomposition is referred to as general acid–base catalysis. Overview d. A plot of the observed-rate constant (as ordinate) against pH (as abscissa) for an acid-catalysed reaction has a gradient equal to k +. In this chapter we will: H Ⅲ see why certain molecules have the ability to lower the surface and interfacial tension and how the surface activity of a molecule is related to its molecular structure 8. What is the remaining concentration (a – x) in mg ml–1 of a drug (initial Ⅲ look at the properties of some surfactants that are commonly used in pharmacy –1 concentration a = 7 mg ml ) after a time equivalent to 3 half-lives assuming Ⅲ examine the nature and properties of monolayers formed when insoluble surfactants are that the decomposition follows fi rst-order kinetics? spread over the surface of a liquid a. 2.33 Ⅲ look at some of the factors that infl uence adsorption onto solid surfaces and see how b. 3.5 experimental data from adsorption experiments may be analysed to gain information on c. 1.75 the process of adsorption Ⅲ d. 0.875 see why micelles are formed, examine the structure of ionic and non-ionic micelles and look at some of the factors that infl uence micelle formation e. 1.167 Ⅲ examine the properties of liquid crystals and surfactant vesicles Ⅲ discuss the process of solubilisation of water-insoluble compounds by surfactant micelles 9. The time taken for 5% of a drug to decompose by fi rst-order kinetics is: and its applications in pharmacy. a. 0.022/k1 b. 0.051/k1 c. 0.105/k1 d. k /0.051 1 Some typical surfactants KeyPoint e. 0.105 k 1 Surfactants have two distinct Depending on their charge characteristics regions in their chemical structure, the surface-active molecules may be one of which is water-liking or anionic, cationic, zwitterionic (ampholytic) hydrophilic and the other of which or non-ionic. Examples of surfactants that is water-hating or hydrophobic. are used in pharmaceutical formulation are These molecules are referred to as follows: as amphiphilic or amphipathic molecules or simply as surfactants or surface active agents. Anionic surfactants: Sodium Lauryl Sulphate BP Ⅲ is a mixture of sodium alkyl sulfates, the chief of which is – + sodium dodecyl sulfate, C12 H25 SO4 Na Ⅲ is very soluble in water at room temperature, and is used pharmaceutically as a preoperative skin cleaner, having bacteriostatic action against gram-positive bacteria, and also in medicated shampoos Ⅲ is a component of emulsifying wax. Cationic surfactants Ⅲ The quaternary ammonium and pyridinium cationic surfactants are important pharmaceutically because of their 43 44 Physical Pharmacy Surfactants 45 bactericidal activity against a wide range of gram-positive and Reduction of surface and interfacial KeyPoints tension some gram-negative organisms. Ⅲ The molecules at the surface Ⅲ They may be used on the skin, especially in the cleaning of When surfactants are dissolved in water they of water are not completely wounds. orientate at the surface so that the hydrophobic surrounded by other molecules Ⅲ Their aqueous solutions are used for cleaning contaminated regions are removed from the aqueous as they are in the bulk of the utensils. environment, as shown in Figure 4.1a. The water. Ⅲ As a result there is a net inward reason for the reduction in the surface tension Non-ionic surfactants force of attraction exerted when surfactant molecules adsorb at the water on a molecule at the surface Ⅲ Sorbitan esters are supplied commercially as Spans and are surface is that the surfactant molecules replace from the molecules in the mixtures of the partial esters of sorbitol and its mono- and some of the water molecules in the surface and bulk solution, which results in di-anhydrides with oleic acid. They are generally insoluble the forces of attraction between surfactant and a tendency for the surface to in water (low hydrophile–lipophile balance (HLB) value) water molecules are less than those between two contract. This contraction is and are used as water-in-oil emulsifi ers and as wetting water molecules, hence the contraction force is spontaneous and represents a minimum free energy state. agents. reduced. Ⅲ Ⅲ We express the strength of Polysorbates are complex mixtures of contraction by the work required Figure 4.1 Orientation of amphiphiles at (a) solution– Tip partial esters of sorbitol and its mono- to increase the surface area by vapour interface and (b) hydrocarbon–solution interface. HLB stands for hydrophile–lipophile and di-anhydrides condensed with an 1 m2; this is referred to as the balance. Compounds with a high approximate number of moles of ethylene surface tension γ. HLB (greater than about 12) are oxide. They are supplied commercially Ⅲ Units of surface and interfacial –1 predominantly hydrophilic and as Tweens. The polysorbates are miscible Vapour phase tension are mN m . Aqueous solution water-soluble. Those with very low with water, as refl ected in their higher HLB values are hydrophobic and HLB values, and are used as emulsifying (a) water-insoluble. agents for oil-in-water emulsions. Ⅲ Poloxamers are synthetic block copolymers of hydrophilic Hydrocarbon poly(oxyethylene) and hydrophobic poly(oxypropylene) Aqueous solution with the general formula EmPnEm, where E = oxyethylene Hydrophobic group (OCH2CH2) and P = oxypropylene (OCH2CH(CH3)) and the subscripts m and n denote chain lengths. Properties such as (b) Hydrophilic group viscosity, HLB and physical state (liquid, paste or solid) are dependent on the relative chain lengths of the hydrophilic and hydrophobic blocks. They are supplied commercially Surfactants will also adsorb at the interface Tip as Pluronics and are labelled using the Pluronic grid, for between two immiscible liquids such as oil and When substituting values into example as F127 or L62, where the letter indicates the water and will orientate themselves as shown in equations it is important to convert physical state (F, P or L, denoting solid, paste or liquid, Figure 4.1b, with their hydrophilic group in the the values into the correct units. respectively). The last digit of this number is approximately water and their hydrophobic group in the oil. In the case of the Gibbs equation it is easy to forget to convert one-tenth of the weight percentage of poly(oxyethylene); the The interfacial tension at this interface, which concentration into mol m–3 fi rst one (or two digits in a three-digit number) multiplied arises because of a similar imbalance of attractive (1 mol l–1 = 1 mol dm–3 = 103 mol by 300 gives a rough estimate of the molecular weight of the forces as at the water surface, will be reduced by m–3). hydrophobe. this adsorption. There is an equilibrium between surfactant A wide variety of drugs, including the antihistamines and the molecules at the surface of the solution and those in the bulk of the tricyclic depressants, are surface-active. solution which is expressed by the Gibbs equation: 1 dγ Γ = – 2 xRT 2.303 d logc where Γ2 is the surface excess concentration, R is the gas constant 46 Physical Pharmacy Surfactants 47 –1 –1 –3 (8.314 J mol K ), T is temperature in kelvins, c is the concentration in mol m and x pressure π (π = γo – γm, where γo is the surface tension of the clean has a value of 1 for ionic surfactants in dilute solution. surface and γm is the surface tension of the fi lm-covered surface) The area A occupied by a surfactant molecule at the solution–air interface can be against area per molecule. calculated from A = 1/N Γ where N is the Avogadro number (6.023 × 1023 molecules A 2 A Figure 4.2 Langmuir trough. mol–1) and dγ/dlogc is the gradient of the plot of surface tension against logc measured at a concentration just below the critical micelle concentration (CMC). Tip The surface activity of a particular surfactant depends on the balance between its Fixed Remember when using Traube’s bar hydrophilic and hydrophobic properties. For rule that for every extra CH2 group in the compound you need 3 times a homologous series of surfactants: Film less of the compound to produce Ⅲ An increase in the length of the the same lowering of surface hydrocarbon chain (hydrophobic) tension. So if you add 2 extra CH 2 increases the surface activity. This groups you will require 9 times relationship between hydrocarbon chain less of the compound (not 6 times length and surface activity is expressed by Fixed less). bar Traube’s rule, which states that ‘in dilute Movable aqueous solutions of surfactants belonging bar to any one homologous series, the molar Side view Plan view Tip concentrations required to produce equal Remember that an increase in lowering of the surface tension of water surface activity means a decrease decreases threefold for each additional There are three main types of insoluble monolayers (Figure 4.3): in surface tension. Compounds Ⅲ CH2 group in the hydrocarbon chain of the Solid or condensed monolayers, in which the fi lm pressure that are most effective in lowering solute’. remains very low at high fi lm areas and rises abruptly when the surface tension are those with Ⅲ An increase of the length of the the molecules become tightly packed on compression. The a high surface activity. ethylene oxide chain (hydrophilic) of a extrapolated limiting surface area is very close to the cross- polyoxyethylated non-ionic surfactant sectional area of the molecule from molecular models.