Formation and Growth of Crystals

Molecules in a crystal, and the crystals themselves, should not be considered static. Crystals can grow or decrease in size provided that there is a medium across which the molecules can travel. This could be a liquid phase or a gaseous phase into which the molecules can sublime. For example, drug substances and excipients in solid dosage forms, such as tablets and granules, may recrystallize or sublime onto the surface of the dosage form during storage. So-called "whisker" crystallization was observed in tablets of ethenzamide and caffeine anhydride.588589 This crystallization was enhanced in porous tablets and at higher temperatures. Some kinetic studies on the formation and growth of whisker crystals as a function oftemperature have been reported. Whisker formation in ethenzamide tablets conformed to apparent zero-order kinetics, and the rate constant followed Arrhenius behavior in the temperature range 20-65°C, as shown in Fig. 138.588 The effect of humidity on whisker crystallization was complex in that crystallization of ethenzamide and caffeine anhydride tablets was enhanced at higher and lower humidity, respectively, as shown in Fig. 139. Aspirin tablets exhibited whisker crystallization of salicylic acid, a degradation product. This was found to change the tablet strength and to be

Figure 138. Arrhenius plot of whisker crystal growth kinetics in ethenzamide tablets. (Reproduced from Ref. 588 with permission.)

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Figure 139. Whisker formation of anhydrous caffeine (a) and ethenzamide (b) in tablet dosage forms at 60°C. (Reproduced from Ref. 589 with permission.)

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Figure 139. Whisker formation of anhydrous caffeine (a) and ethenzamide (b) in tablet dosage forms at 60°C. (Reproduced from Ref. 589 with permission.)

dependent on tablet pore size.590 591 Particles of a valproate-synthetic aluminum silicate mixture formed whiskers comprised of valproic acid and sodium valproate (1:1) on their surface.592 Some excipients may also participate in crystal formation. Tablets containing lactose andmannitol excipients have been shown to form whiskers.593

Carbamazepine tablets containing stearic acid formed column-shaped crystals on the tablet surface during storage at high temperature.594 This crystallization was ascribed to the recrystallization of carbamazepine promoted by the solvent, melted stearic acid.

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