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a Selected values from C. F. Lerk etal., J. Pharm. Sci., 65, 843 (1976); J. Pharm. Sci., 66, 1481 (1977).

a Selected values from C. F. Lerk etal., J. Pharm. Sci., 65, 843 (1976); J. Pharm. Sci., 66, 1481 (1977).

and the normal method of improving wettability is by the inclusion of surfactants in the formulation. The surfactants not only reduce yL/A but also adsorb onto the surface of the powder, thus reducing yS/A. Both of these effects reduce the contact angle and improve the dispersibility of the powder.

1.8 Solid dispersions

Over the past few years interest has been shown in solid solutions of drugs in attempts to change the biopharmaceutical properties of drugs which are poorly soluble or difficult to wet. The object is usually to provide a system in which the crystallinity of the drug is so altered as to change its solubility and solution rate, and to surround the drug intimately with water-soluble material. A solid solution comprises solute and solvent - a solid solute molecularly dispersed in a solid solvent. These systems are sometimes termed mixed crystals because the two components crystallise together in a homogeneous one-phase system. For understanding of the systems and their potential use, an arbitrary system might be considered.

In Fig. 1.18, the melting temperature of mixtures of A and B is plotted against mixture composition. On addition of B to A or of A to B, melting points are reduced. At a particular composition the eutectic point is reached, the eutectic mixture (the composition at that point) having the lowest melting point of any mixture of A and B. Below the eutectic temperature, no liquid phase exists. The phenomenon is important because of the change in the crystallinity at this point. If we cool a solution of A and B which is richer in A than the eutectic mixture (see M in Fig. 1.18), crystals of pure A will appear. As the solution is cooled further, more and more A crystallises out and the solution becomes richer in B. When the eutectic temperature is reached, however, the remaining solution crystallises out, forming a microcrystalline mixture of pure A and pure B, differing markedly at least in superficial characteristics from either of the pure solids. This has obvious pharmaceutical possibilities. This method of obtaining microcrystalline dispersions for administration of drugs involves the formation of a eutectic mixture composed of drug and a substance readily soluble in water. The soluble 'carrier' dissolves, leaving the drug in a fine state of solution in vivo, usually in a state which predisposes to rapid solution.

Composition (mole fraction)

Figure 1.18 Phase diagram (temperature versus composition) showing boundaries between liquid and solid phases, and the eutectic point, E.

Composition (mole fraction)

Figure 1.18 Phase diagram (temperature versus composition) showing boundaries between liquid and solid phases, and the eutectic point, E.

This technique has been applied to several poorly soluble drugs such as griseofulvin. A griseofulvin-succinic acid (soluble carrier) system has a eutectic point at 0.29 mole fraction of drug (55% w/w griseofulvin) (Fig. 1.19a). The eutectic mixture consists here of two physically separate phases; one is almost pure griseofulvin, while the other is a saturated solid solution of griseofulvin in succinic acid. The solid solution contains about 25% griseofulvin; the eutectic mixture, which has a fixed ratio of drug to carrier, thus comprises 60% solid solution and 40% almost pure griseofulvin. As can be seen from Fig. 1.19(b), which shows the solution profiles of the different forms, the solid solution dissolves 6-7 times faster than pure griseofulvin.

The simplest eutectic mixtures are usually prepared by the rapid solidification of the fused liquid mixture of the components which show complete miscibility in the liquid state and negligible solid-solid solubility. In addition to the reduction in crystalline size, the following factors may contribute to faster dissolution rate of drugs in eutectic mixtures:

• An increase in drug solubility because of the extremely small particle size of the solid

• A possible solubilisation effect by the carrier, which may operate in the diffusion layer immediately surrounding the drug particle

• Absence of aggregation and agglomeration of the particles

• Improved wettability in the intimate drug-carrier mixture

• Crystallisation in metastable forms

Where more complex solubility patterns emerge, as with the griseofulvin and succinic acid phase, the phase diagram becomes correspondingly more complex. Figure 1.20 shows one example of a system in which each component dissolves in the other above and below the eutectic temperature.

Other systems that form eutectic mixtures are chloramphenicol-urea, sulfathiazole-urea, and niacinamide-ascorbic acid. The solid solution of chloramphenicol in urea was found to dissolve twice as rapidly as a physical mixture of the same composition and about four times as rapidly as the pure drug. In vivo, however, the system failed to display improved bioavailability. On the other hand, the eutectic mixture of sulfathiazole-urea did give higher blood levels than pure sulfonamide.

A formulation containing a eutectic

A topical preparation for intradermal anaesthesia to reduce the pain of venepuncture is available. The cream, Emla (Eutectic Mixture

(a)

Figure 1.19 (a) Griseofulvin-succinic acid phase diagram. (b) Rate of solution of griseofulvin solid solutions, eutectic and crystalline material.

Figure 1.19 (a) Griseofulvin-succinic acid phase diagram. (b) Rate of solution of griseofulvin solid solutions, eutectic and crystalline material.

of Local Anaesthetics) (AstraZeneca), contains a eutectic of procaine and lidocaine.16. The eutectic mixture (50 : 50 mixture) is an oil, which is then formulated as an oil-in-water emulsion. This allows much higher concentrations than would have been possible by using the individual drugs dissolved in an oil.

1.8.1 Eutectics and drug identification

As the eutectic temperature of a substance in mixtures with other compounds is, as a rule, different even when the other substances have the same melting point, this parameter can be used for identification purposes. Benzanilide

Figure 1.20 Melting point-composition plot for a system in which a and p are regions of solid solution formation. Each component dissolves the other component to some extent above the eutectic temperature. As the temperature is lowered, the solid solution regions become narrower.

(m.p. 163°C), phenacetin (m.p. 134.5°C) and salophen (m.p. 191°C) are often used as test substances. The eutectic temperatures of mixtures of benzanilide with various drugs are shown in Table 1.11. Substances of identical melting points can be distinguished by measurement of the eutectic temperature with another suitable compound.

Ternary eutectics are also possible. The binary eutectic points of three mixtures are as follows: for aminophenazone-phenacetin 82°C; for aminophenazone-caffeine 103.5°C; and for phenacetin-caffeine 125°C. The ternary eutectic temperature of aminophenazone-phenacetin-caffeine is 81°C. In this mixture the presence of aminophenazone and phenacetin can be detected by the mixed melting point test, but the caffeine causes little depression of the eutectic given by the other two components.

The possibility of determining eutectic temperatures of multicomponent mixtures has practical value in another respect. During tableting, for example, heat is generated in the punch and die and in the powder compact; measurement of the eutectic temperature can give information on whether this rise in temperature is likely to cause problems of melting and fusion.

Summary

• The crystal lattices of drugs are constructed from repeating units called unit cells. All unit cells in a specific crystal are the same size and contain the same number of molecules or ions arranged in the same way. For all crystals there are seven primitive unit cells: cubic, orthorhombic, monoclinic, hexagonal, tetragonal, triclinic and trigonal. Certain of these may also be end-centred, body-centred or face-centred, making a total of 14 possible unit cells or Bravais lattices. The various planes of the crystal lattice can be identified using the system of Miller indices.

• The external shape of the crystal can be described in terms of its habit, which is affected by the rate of crystallisation and by the presence of impurities, particularly surfactants. The habit of a crystal is of pharmaceutical importance, since it affects the compression characteristics and flow properties of the drug during tableting and also the ease with which the suspensions of insoluble drugs will pass through syringe needles.

• Many drugs exist in several polymorphic forms. The various polymorphs of a drug differ in the packing of the molecules in the crystal lattice or in the conformation of the molecules at the lattice sites. The different polymorphs have different physical and chemical properties and usually exist in different habits. The transformation between

Table 1.11 Eutectic temperatures

of drugs with

benzanilidea

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