Ph

Figure 6.19 pH profile for the sorption of benzocaine by nylon 6 powder from buffered solutions at 30°C and ionic strength 0.5 mol dm03 (O) and the corresponding drug dissociation curve (•).

Reproduced from N. E. Richards and B. J. Meakin, J. Pharm. Pharmacol., 26, 166 (1974) with permission.

Of the two effects, the solubility effect is usually the stronger. Thus, in the adsorption of hyoscine and atropine on magnesium tri-silicate it was noted5 that hyoscine, although in its completely unionised form, was less strongly adsorbed than atropine, which at the pH of the experiment was 50% ionised. The reason for this apparently anomalous result is clear when the solubilities of the two bases are considered. Hyoscine base is freely soluble (1 in 9.5 parts of water at 15°C) compared with atropine base (1 in 400 at 20°C). Even when 50% ionised, atropine is less soluble than hyoscine and consequently is more strongly adsorbed.

Nature of the adsorbent

The physicochemical nature of the adsorbent can have profound effects on the rate and capacity for adsorption. The most important property affecting adsorption is the surface area of the adsorbent; the extent of adsorption is proportional to the specific surface area. Thus the more finely divided or the more porous the solid, the greater will be its adsorp-tive capacity. Indeed, adsorption studies are frequently used to calculate the surface area of a solid.

Adsorbent-adsorbate interactions are of a complex nature and beyond the scope of this book. Particular adsorbents have affinities for particular adsorbates for a wide variety of reasons. The surfaces of adsorbent clays such as bentonite, attapulgite and kaolin carry cation-exchange sites and such clays have strong affinities for protonated compounds, which they adsorb by an ion-exchange process. In many cases, different parts of the surface of the same adsorbent have different affinities for different types of adsorbents. There is evidence, for example, that anionic materials are adsorbed on the cationic edge of kaolin particles while cationics are adsorbed on the cleavage surface of the particles, which are negatively charged. An example of the differing affinities of a series of adsorbents used as antacids is shown in Fig. 6.20. The adsorptive capacity of a particular adsorbent often depends on the source from which it was prepared and also on its pretreatment.

Figure 6.20 Adsorption of digoxin by some antacids at 37 ± 0.1 °C: (■) magnesium trisilicate, (A) aluminium hydroxide gel BP (Aludrox was used in the concentration range 2.5-10% v/v), (▲) light magnesium oxide, (O) light magnesium carbonate, (•) calcium carbonate. Initial concentration of the glycoside: 0.25 mg%.

Reproduced from S. A. H. Khalil, J. Pharm. Pharmacol., 26, 961 (1974) with permission.

Figure 6.20 Adsorption of digoxin by some antacids at 37 ± 0.1 °C: (■) magnesium trisilicate, (A) aluminium hydroxide gel BP (Aludrox was used in the concentration range 2.5-10% v/v), (▲) light magnesium oxide, (O) light magnesium carbonate, (•) calcium carbonate. Initial concentration of the glycoside: 0.25 mg%.

Reproduced from S. A. H. Khalil, J. Pharm. Pharmacol., 26, 961 (1974) with permission.

Temperature

Since adsorption is generally an exothermic process, an increase in temperature normally leads to a decrease in the amount adsorbed. The changes in enthalpy of adsorption are usually of the order of those for condensation or crystallisation. Thus small variations in temperature tend not to alter the adsorption process to a significant extent.

Some medical and pharmaceutical applications and consequences of adsorption

Adsorption at the solid/liquid interface plays a crucial role in preparative and analytical chro-matography, and in heterogeneous catalysis, water purification and solvent recovery. These applications are, however, outside the scope of this book and we will be concerned with examples of the involvement of adsorption in more medical and pharmaceutical situations.

Adsorption of poisons/toxins The 'universal antidote' for use in reducing the effects of poisoning by the oral route is composed of activated charcoal, magnesium oxide and tannic acid. A more recent use of adsorbents has been in dialysis to reduce toxic concentrations of drugs by passing blood through a haemodialysis membrane over charcoal and other adsorbents. Several drugs are adsorbed effectively by activated charcoal. These include chlorphenamine, dextropro-poxyphene hydrochloride, colchicine, pheny-toin and aspirin. Some of these are easily recognisable as surface-active molecules (chlorphenamine, dextropropoxyphene) and will be expected to adsorb onto solids. Highly ionised substances of low molecular weight are not well adsorbed, neither are drugs such as tolbutamide that are poorly soluble in acidic media. The formation of a monolayer of drug molecules covering the surface of the charcoal particles through nonpolar interactions is indicated.

The direct application of in vitro data for estimating doses of activated charcoal for antidotal purposes may lead to use of inadequate amounts of adsorbent.6 In an animal study, charcoal: drug ratios of 1:1, 2:1, 4:1 and 8 : 1 reduced absorption of drugs as follows: pentobarbital sodium, 7%, 38%, 62% and 89%; chloroquine phosphate 20%, 30%, 70% and 96%; isoniazid 1.2%, 7.2%, 35% and 80%. Activated charcoal, of course, is not effective in binding all poisons. Biological factors such as gastrointestinal motility, secretions and pH may influence charcoal adsorption. While 5 g of activated charcoal has been said to be capable of binding 8 g of aspirin in vitro, 7 30 g of charcoal in vivo was reported to inhibit the gastrointestinal absorption of 3 g of aspirin by only 50%8. The surface area of the charcoal is a factor in its effectiveness; charcoal tablets have been found to be approximately half as effective as powdered material.

Taste masking

The intentional adsorption of drugs such as diazepam onto solid substrates should be mentioned, the object being to minimise taste problems. Desorption of the drug in vivo is essential but should not occur during the shelf-life of the preparation. Desorption may be a rate-limiting step in absorption. Diaze-pam adsorbed onto an inorganic colloidal magnesium aluminium silicate (Veegum) had the same potency in experimental animals as a solution of the drug, but when adsorbed onto microcrystalline cellulose (Avicel) its efficacy was much reduced. Flocculation of the cellulose in the acidic environment of the stomach probably retards the desorption process.

Haemoperfusion

Carbon haemoperfusion is an extracorporeal method of treating cases of severe drug overdoses, and originally involved perfusion of the blood directly over charcoal granules. Although activated charcoal granules were very effective in adsorbing many toxic materials, they were found to give off embolising particles and also to lead to removal of blood platelets. Microencapsulation of activated charcoal granules by coating with biocompatible membranes such as acrylic hydrogels was found to be a successful means of eliminating charcoal embolism and to lead to a much reduced effect on platelet count. In vitro tests showed that the coated granules had a reduced adsorption rate although the adsorptive capacity was unchanged.9 A large proportion of drug overdoses in Great Britain involve barbiturates, and the applicability of carbon haemoper-fusion in the treatment of such cases has been demonstrated.10 Many other drugs taken as overdoses are also present in the plasma at sufficiently high concentration to allow removal by this technique.

Adsorption in drug formulation

Examples of the adsorption of drugs and excipients on to solid surfaces are found in many aspects of drug formulation, some of which, for example the adsorption of surfactants and polymers in the stabilisation of suspensions, are considered elsewhere in this book (see section 7.4). An interesting approach to the improvement of the dissolution rate of poorly water-soluble drugs is to adsorb very small amounts of surfactant on to the drug surface. For example, the adsorption of Pluronic F127 onto the surface of the hydro-phobic drug phenylbutazone significantly increased its dissolution rate when compared with untreated material.11

In addition to the beneficial use of surfactants in the preparation of formulations, we should also be aware of problems that can arise as a result of inadvertent adsorption occurring both in the manufacture and storage of the product and in its subsequent usage. Problems arising from the adsorption of medicaments by adsorbents such as antacids which may be taken simultaneously by the patient, or which may be present in the same formulation, are discussed in section 10.7. Problems also arise from the adsorption of medicaments onto the container walls. Containers for medicaments, whether glass or plastic, may adsorb a significant quantity of the drug or bacteriostatic or fungistatic agents present in the formulation and thereby affect the potency and possibly the stability of the product. The problem is particularly significant where the drug is highly surface active and present in low concentration. With plastic containers the process is often referred to as sorption rather than adsorption since it often involves significant penetration of the drug into the polymer matrix. Plastics are a large and varied group of materials and their properties are often modified by various additives, such as plasticisers, fillers and stabilisers (see Chapter 8). Such additives may have a pronounced effect on the sorption characteristics of the plastics. The sorption of the fungistatic agent sorbic acid from aqueous solution by plastic cellulose acetate and cellulose triacetate shows an appreciable pH dependence, the sorption declining to zero in the vicinity of the point of maximum ionisation of the sorbic acid. The sorption of local anaesthetics by polyamide and polyethylene depends on the kind of plastic, the reaction conditions and the chemical structure of the drugs. As with sorbic acid, significant sorption was observed only when the drugs were in their unionised forms.

6.3 Micellisation

As the concentration of aqueous solutions of many amphiphilic substances increases, there is a pronounced change in the physical properties of the solution. For example, we have seen in section 6.2.2 that a sharp inflection appears in surface tension plots of surfactant solutions at a critical concentration (the critical micelle concentration, cmc) which is attributable to the self-association of the amphiphile into small aggregates called micelles. Similar inflection points are observed when other physical properties such as solubility, conductivity, osmotic pressure and light scattering intensity are plotted as a function of concentration (see Fig. 6.21).

The idea that molecules should come together at a critical concentration to form aggregates in solution was quite novel when first proposed by McBain in 1913, but the concept of micellisation has long gained universal acceptance. The micelles are in dynamic equilibrium with free molecules (monomers) in solution; that is, the micelles are continuously breaking down and reforming. It is this fact that distinguishes micellar solutions from other types of colloidal solution and this difference is emphasised by referring to micelle-forming compounds as association colloids.

The primary reason for micelle formation is the attainment of a state of minimum free energy. At low concentration, amphiphiles

Figure 6.21 Solution properties of an ionic surfactant as a function of concentration, c. A, Osmotic pressure (against c); B, solubility of a water-insoluble solubilisate (against c); C, intensity of light scattered by the solution (against c); D, surface tension (against log c); E, molar conductivity (against c1'2).

Figure 6.21 Solution properties of an ionic surfactant as a function of concentration, c. A, Osmotic pressure (against c); B, solubility of a water-insoluble solubilisate (against c); C, intensity of light scattered by the solution (against c); D, surface tension (against log c); E, molar conductivity (against c1'2).

can achieve an adequate decrease in the overall free energy of the system by accumulation at the surface or interface, in such a way as to remove the hydrophobic group from the aqueous environment. As the concentration is increased, this method of free energy reduction becomes inadequate and the monomers form into micelles. The hydrophobic groups form the core of the micelle and so are shielded from the water.

The free energy change of a system is dependent on changes in both the entropy and enthalpy; that is, A G = AH - T AS. For a micellar system at normal temperatures the entropy term is by far the most important in determining the free energy changes (T AS constitutes approximately 90-95% of the A G value). Micelle formation entails the transfer of a hydrocarbon chain from an aqueous to a nonaqueous environment (the interior of the micelle). To understand the changes in enthalpy and entropy that accompany this process, we must first consider the structure of water itself.

6.3.1 Water structure and hydrophobic bonding

Water possesses many unique features that distinguish it from other liquids. These arise from the unusual structure of the molecule in which the O and H atoms are arranged at the apices of a triangle (see Fig. 6.22).

Each of the covalent bonds between a hydrogen atom and the oxygen atom of the water molecule involves the pairing of the electron of the hydrogen atom with an electron in the oxygen atom's outer shell of six

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