Theophylline solvates

The intrinsic dissolution rate method is most useful where the equilibrium method cannot be used. For example, when one wishes to examine the inLuence of crystal habit, solvates and hydrates, polymorphism, and crystal defects on apparent solubility, the intrinsic dissolution rate method will usually avoid the crystal transitions likely to occur in equilibrium methods. However, crystal transitions can still occur at the surface as in the case of anhydrous theophylline (De Smidt, 1986), where the anhydrous form converts to the hydrate and the intrinsic dissolution rate changes over time. In these cases, the application oflaer optical probe, which permits the detection of the drug concentration every few seconds, may prove to be very advantageous. 

Many drags can associate with solvents to produce crystalline forms called solvates. When the solvent is water, the crystal is termed a hydrate. Thus more rapid dissolution rates are often achieved with the anhydrous form of a drag. For example, the anhydrous forms of caffeine, theophylline and glutethimide dissolve more rapidly in water than do the hydrous forms of these drags and the anhydrous form of ampicillin is about 25% more soluble in water at 37 °C than the trihydrate. 

During their preparation, drug crystals may incorporate one or more solvent molecules to form solvates. The most common solvate is water. If water molecules are already present in a crystal structure, the tendency of the crystal to attract additional water to initiate the dissolution process is reduced, and solvated (hydrated) crystals tend to dissolve more slowly than anhydrous forms. Significant differences have been reported in the dissolution rate of hydrated and anhydrous forms of ampicillin, caffeine, theophylline, glutethimide, and mercaptopurine. The clinical significance of these differences has not been examined but is likely to be slight. 

A pharmaceutical cocrystal is composed of an API and complementary molecules including excipients (non-toxic ingredients) or other APIs. Cocrystals may include two or more different components and in most cases to date, two and three component systems are reported with the latter being mostly cocrystalline solvates, e.g., theophylline 5-fluorouracil hydrate. Table 1 presents some examples of pharmaceutical cocrystals and solvates. The term cocrystal generally refers to components that in their pure states are solids at room temperature. It is important to note that a... 

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 dmg 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. 

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