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polymorphic forms can cause formulation problems. Phase transformations can cause changes in crystal size, which in suspensions can eventually cause caking, and in creams can cause detrimental changes in the feel of the cream. Changes in polymorphic form of vehicles, such as theobroma oil used to make suppositories, can result in unacceptable melting characteristics. Problems may also result from phase transformation when attempting to identify drugs using infrared spectroscopy. The most significant consequence of polymorphism is the possible difference in the bioavailability of the different polymorphic forms of a drug, as for example, in the case of polymorphs of chloramphenicol palmitate.

• When some drugs crystallise they may entrap solvent in their crystals and so form different crystal solvates. In some solvates the solvent plays an important role in holding the crystal together. These solvates, called polymorphic solvates, are very stable, and when they lose their solvent they recrystallise in a different crystal form. In other solvates, referred to as pseudopoly-morphic solvates, the solvent is not part of the crystal bonding and merely occupies voids in the crystal. These solvates can lose their solvent more readily and desolvation does not alter the crystal lattice. Solvated and anhydrous forms of a drug differ in

References

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2. J. W. Mullin. Crystallization, 4th edn, ButterworthHeinemann, London, 2001

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their aqueous solubilities. Anhydrous forms are generally more soluble than hydrates of the same drug, but less soluble than non-aqueous solvates of the drug. The dissolution rates of the various solvates of a drug may differ significantly, and with poorly soluble drugs this may result in differences in their absorption rates.

• The rate of dissolution of a solid can be increased by reduction in the particle size, providing that this does not induce changes in polymorphic form which could alter the drug's solubility. The reduction of particle size of some drugs to below 0.1 ^m can cause an increase in the intrinsic solubility. This is the basis of a method for increasing the rate of dissolution and solubility of poorly soluble drugs such as griseofulvin, by forming a eutectic mixture or solid dispersion with a highly soluble carrier compound.

• The contact angle is an indicator of the ability of a liquid to wet a solid surface; for complete, spontaneous wetting the contact angle should be zero. There are two types of wetting - spreading wetting, in which a liquid spreads over the surface of a solid, and immersional wetting, which is the initial wetting process that occurs when a solid is immersed in a liquid. Several pharmaceutical powders have been identified which, because of their high contact angle, present wetting problems.

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8. A. J. Aiguiar and J. E. Zelmer. Dissolution behaviour of polymorphs of chloramphenicol palmitate and mefanamic acid. J. Pharm. Sci., 58, 983-7 (1969)

9. J. H. Chapman, J. E. Page, A. C. Parker, et al. Polymorphism of cephaloridine. J. Pharm. Pharmacol., 20, 418-29 (1968)

10. G. Volkheimer. Persorption of particles: physiology and pharmacology. Adv. Pharmacol. Chemother, 14, 163-87 (1977)

11. A. T. Florence. The oral absorption of micro- and nanoparticulates: neither exceptional nor unusual. Pharm. Res, 14, 259-66 (1997)

12. R. M. Atkinson, C. Bedford, K. J. Child and E. G. Tomich. Effect of particle size on blood griseo-fulvin-levels in man. Nature, 193, 588-9 (1962)

13. T. R. D. Shaw, J. E. Carless, M. R. Howard and K. Raymond. Particle size and absorption of digoxin. Lancet, 2, 209-10 (1973)

14. J. F. Nash, L. D. Bechtel, L. R. Lowary, etal. Relation between the particle size of dicumarol and its bioavailability in dogs. I. Capsules. Drug Dev. Commun., 1, 443-57 (1975)

15. J. H. Fincher. Particle size of drugs and its relationship to absorption and activity. J. Pharm Sci., 57, 1825-35 (1968)

16. B. F. J. Broberg and H. C. A. Evers. Local anaesthetic emulsion cream. Eur. Pat. 0 002 425 (1981)

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