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a Modified from R. Bouche and M. Draguet-Brughmans, J. Pharm. Belg., 32, 347 (1977) with additions. b Tertiary butyl acetate (tebutate). c Trimethyl acetate.

a Modified from R. Bouche and M. Draguet-Brughmans, J. Pharm. Belg., 32, 347 (1977) with additions. b Tertiary butyl acetate (tebutate). c Trimethyl acetate.

differences in crystal habit (see section 1.2). Since polymorphs frequently have different habits, they too will be subject to these same problems. However, polymorphs also have different crystal lattices and consequently their energy contents may be sufficiently different to influence their stability and biopharmaceutical behaviour.

As the different polymorphs arise through different arrangement of the molecules or ions in the lattice, they will have different interaction energies in the solid state. Under a given set of conditions the polymorphic form with the lowest free energy will be the most stable, and other polymorphs will tend to transform into it. We can determine which of two polymorphs is the more stable by a simple experiment in which the polymorphs are placed in a drop of saturated solution under the microscope. The crystals of the less stable form will dissolve and those of the more stable form will grow until only this form remains. Figure 1.12 shows this process occurring with the two polymorphs of paracetamol discussed earlier. Figure 1.12(a) shows the presence of both forms of paracetamol at room temperature in saturated benzyl alcohol. Over a time interval of 30 min the less stable of the two forms, the orthorhombic Form 2, has completely converted to the more stable mono-clinic Form 1 (Fig. 1.12b). For drugs with more than two polymorphs we need to carry out this experiment on successive pairs of the polymorphs of the drug until we eventually arrive at their rank order of stability.

Transformations

The transformation between polymorphic forms can lead to formulation problems. Phase transformations can cause changes in crystal size in suspensions and their eventual caking. Crystal growth in creams as a result of phase transformation can cause the cream to become gritty. Similarly, changes in polymorphic forms of vehicles, such as theobroma oil used to make suppositories, could cause products with different and unacceptable melting characteristics.

Analytical issues

For analytical work it is sometimes necessary to establish conditions whereby different forms of a substance, where they exist, might be converted to a single form to eliminate differences in the solid-state infrared spectra which result from the different internal structures of the crystal forms. As different crystal forms arise through different arrangements of the molecules or ions in a three-dimensional array, this implies different interaction energies in the solid state. Hence one would expect different melting points and different solubilities (and of course different infrared spectra). Changes in infrared spectra of steroids due to grinding with KBr have been reported; changes in the spectra of some substances have been ascribed to conversion of a crystalline form into an amorphous form (as in the case of digoxin), or into a second crystal form. Changes in crystal form can also be induced by solvent extraction methods used for isolation of drugs from formulations prior to examination by infrared spectroscopy. Difficulties in identification arise when samples that are thought to be the same substance give different spectra in the solid state; this can happen, for example, with cortisone acetate, which exists in at least seven forms, or dexamethasone acetate, which exists in four. Therefore, where there is a likelihood of polymorphism it is best where possible to record solution spectra if chemical identification only is required. The normal way to overcome the effects of polymorphism is to convert both samples into the same form by recrystallis-ation from the same solvent, although obviously this technique should not be used to hide the presence of polymorphs.

Consequences

The most important consequence of polymorphism is the possible difference in the bioavailability of different polymorphic forms of a drug; particularly when the drug is poorly soluble. The rate of absorption of such a drug is often dependent upon its rate of dissolution. The most stable polymorph usually has the lowest solubility and often the slowest dissolution rate. Fortunately, the difference in the bioavailability of different polymorphic forms of a drug is usually insignificant. It has been proposed that when the free energy differences between the polymorphs are small there may be no significant differences in their biopharmaceutical behaviour as measured by the blood levels they achieve. Only when the differences are large may they affect the extent of absorption. For example, A GB 2 A for the transition of chloramphenicol palmitate

Form B to Form A is 03.24 kJ mol1; AH is 027.32 kJ mol01. For mefenamic acid AGII21 is 01.05 kJ mol01 and AH is 04.18 kJ mol 01. Whereas differences in biological activity are shown by the palmitate polymorphs, no such differences are observed with the mefenamic acid polymorphs. When little energy is required to convert one polymorph into another, it is likely that the forms will inter-convert in vivo and that the administration of one in place of the other form will be clinically unimportant.

Particle size reduction may lead to fundamental changes in the properties of the solid. Grinding of crystalline substances such as digoxin can lead to the formation of amorphous material that has an intrinsically higher rate of solution and therefore apparently greater activity. Such is the importance of the polymorphic form of poorly soluble drugs that it has to be controlled. For instance, there is a limit on the inactive polymorph of chloram-phenicol palmitate. Of the three polymorphic forms of chloramphenicol palmitate Form A has a low biological activity because it is so slowly hydrolysed in vivo to free chloram-phenicol.7 We can see from Fig. 1.13 that the maximum blood levels attained with 100% Form B polymorph are about seven times greater than with 100% Form A polymorph, and that with mixtures of A and B the blood levels vary in proportion to the percentage of B in the suspension. 8

During formulation development it is vital that sufficient care is taken to determine polymorphic tendencies of poorly soluble drugs. This is so that formulations can be designed to release drug at the correct rate and so that intelligent guesses can be made before clinical trial about possible influences of food and concomitant therapy on drug absorption. As will be seen later, particle characteristics (of nitrofurantoin, for example) can affect drug interaction as well as drug absorption. Above all, it is important that during toxicity studies care is given to the characterisation of the physical state of the drug, and that during development the optimal dosage form is attained. It is insufficient that drug is 'available' from the dosage form; on both economic

Figure 1.13 Comparison of serum levels (¡jg cm03) obtained with suspensions of chloramphenicol palmitate after oral administration of a dose equivalent to 1.5 g of chloramphenicol.

Redrawn from reference 8.

Figure 1.13 Comparison of serum levels (¡jg cm03) obtained with suspensions of chloramphenicol palmitate after oral administration of a dose equivalent to 1.5 g of chloramphenicol.

Redrawn from reference 8.

and biological grounds, the maximum response must be achieved with the minimum amount of drug substance.

1.4 Crystal hydrates

When some compounds crystallise they may entrap solvent in the crystal. Crystals that contain solvent of crystallisation are called crystal solvates, or crystal hydrates when water is the solvent of crystallisation. Crystals that contain no water of crystallisation are termed anhydrates.

Crystal solvates exhibit a wide range of behaviour depending on the interaction between the solvent and the crystal structure. With some solvates the solvent plays a key role in holding the crystal together; for example, it may be part of a hydrogen-bonded network within the crystal structure. These solvates are very stable and are difficult to de-solvate. When these crystals lose their solvent they collapse and recrystallise in a new crystal form. We can think of these as polymorphic solvates. In other solvates, the solvent is not part of the crystal bonding and merely occupies voids in the crystal. These solvates lose their solvent more readily and desolvation does not destroy the crystal lattice. This type of solvate has been called a pseudopolymorphic solvate.

By way of illustration of this phenomenon, we return to the case of spironolactone which we considered earlier. As well as the two poly-morphs, this compound also possesses four solvates, depending on whether it is crystallised from acetonitrile, ethanol, ethyl acetate or methanol. Each of these solvates is transformed to the polymorphic Form 2 on heating, indicating that the solvent is involved in the bonding of the crystal lattice.

The stoichiometry of some of the solvates is unusual. Fludrocortisone pentanol solvate, for example, contains 1.1 molecules of pentanol for each steroid molecule, and its ethyl acetate solvate contains 0.5 molecules of ethyl acetate per steroid molecule. A succinylsulfathiazole solvate appears to have 0.9 moles of pentanol per mole of drug. Beclometasone dipropionate forms solvates with chlorofluorocarbon pro-pellants.

Infrared measurements show that cefalori-dine exists in a, ¡, 6, e, Z and ^ forms (that is, six forms after recrystallisation from different solvents). 9 Proton magnetic resonance spectroscopy showed that although the p form contained about 1 mole of methanol and the e form about 1 mole of dimethyl sulfoxide, ethylene glycol or diethylene glycol (depending on the solvent), the a, ¡, anhydrous 6 and e forms contained less than 0.1 mole, that is nonstoichiometric amounts of solvent. The a form is characterised by containing about 0.05 mole of N,N-dimethylacetamide. This small amount of 'impurity', which cannot be removed by prolonged treatment under vacuum at 10 5-10 06 torr, is apparently able to 'lock' the cefaloridine molecule in a particular crystal lattice.

example, water) can be represented as

where Ks is the equilibrium constant. This equilibrium will of course be influenced by the crystal form, as we have seen, as well as by temperature and pressure. For a hydrate AxH2 O, we can write

AxH2O(c)

Ksh is then the solubility of the hydrate. The process of hydration of an anhydrous crystal in water is represented by an equation of the type

1.4.1 Pharmaceutical consequences of solvate formation

Modification of the solvent of crystallisation may result in different solvated forms. This is of particular relevance because the hydrated and anhydrous forms of a drug can have melting points and solubilities sufficiently different to affect their pharmaceutical behaviour. For example, glutethimide exists in both an anhydrous form (m.p. 83°C, solubility 0.042% at 25°C) and a hydrated form (m.p. 68°C, solubility 0.026% at 25°C). Other anhydrous forms show similar higher solubilities than the hydrated materials and, as expected, the anhydrous forms of caffeine, theophylline, glutethimide and cholesterol show correspondingly higher dissolution rates than their hydrates.

One can assume that as the hydrate has already interacted intimately with water (the solvent), then the energy released for crystal break-up, on interaction of the hydrate with solvent, is less than for the anhydrous material. The nonaqueous solvates, on the other hand, tend to be more soluble in water than the nonsolvates. The n-amyl alcohol solvate of fludrocortisone acetate is at least five times as soluble as the parent compound, while the ethyl acetate solvate is twice as soluble.

The equilibrium solubility of the nonsol-vated form of a crystalline organic compound which does not dissociate in the solvent (for

AxH2O(c) (hydrate)

and the free energy of the process is written

AGtrans = RT ln Kr

A Gtrans can be obtained from the solubility data of the two forms at a particular temperature, as for theophylline and glutethimide in Table 1.3.

The dissolution rates of solvates can vary considerably. Table 1.4 shows the range of intrinsic dissolution rates reported for solvates of oxyphenbutazone into a dissolution medium containing a surface active agent (to avoid wetting problems). The superior

Table 1.3 Solubility of theophylline and glutethimide

forms at various temperatures'

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