Crystallization of Amorphous Drugs

Attempts are often made to formulate poorly water-soluble drugs in their amorphous state. This is because the solubility of amorphous materials is generally higher than that of the same substances in their crystalline state. However, because of the lower free energy of the crystalline state, amorphous substances tend to change to their more thermodynamically stable crystalline state with time. Therefore, crystallization of amorphous drug substances

Figure 136. Changes in dissolution behavior of nifedipine from amorphous nifdipine samples exposed to different storage conditions. Storage period at 40°C: (1) 0, (2) 3.5, (3) 6 months; (b) storage period at 21°C and 75% RH: (1) 0, (2) 0.5, (3) 1.5, (4) 4 months. (Reproduced from Ref. 566 with permission.)

Figure 136. Changes in dissolution behavior of nifedipine from amorphous nifdipine samples exposed to different storage conditions. Storage period at 40°C: (1) 0, (2) 3.5, (3) 6 months; (b) storage period at 21°C and 75% RH: (1) 0, (2) 0.5, (3) 1.5, (4) 4 months. (Reproduced from Ref. 566 with permission.)

may occur during long-term storage and may lead to drastic changes in the release characteristics of the drug and, hence, changes in its clinical and toxicological behavior. Changes in crystal habit during storage have been reported for many drug substances. Some examples are discussed below.

Amorphous nifedipine, coprecipitated with polyvinylpyrrolidone, undergoes partial crystallization during storage under high-humidity conditiods. This change from a largely amorphous state to a partially crystalline state resulted in altered dissolution and solubility behavior, as shown in Fig. 136.566 Amorphous nifedipine prepared by spray drying also exhibited time-dependent crystallization. This crystallization was inhibited by the addition of HP- P-CD.567 Oxyphenbutazone, which can exist in an amorphous state and three different crystalline states (anhydrous, monohydrate, and hemihydrate), exhibits crystallization and polymorphic transitions during storage depending on humidity, as illustrated in Scheme 78.568 Amorphous oxyphenbutazone converts to an anhydrous form with lower solubility during storage under conditions of high humidity. A similar crystallization at high humidity was observed with amorphous 6-methylenandrosta- 1,4-diene-3,17-dione prepared by grinding with P-CD.569 Amorphous halopredone acetate prepared by grinding with various excipients, namely, hydroxypropylcellulose (HPC), methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), and polyvinylalcohol (PVA), crystallized on subsequent storage at significantly different rates, depending on the excipient polymers, as shown in Fig. 137.570

The crystallization rate of amorphous frusemide prepared by spray drying depended on the preparation temperature; higher temperatures apparently provided a more stable amorphous state with a higher glass-transition temperature ( Tg ).571 A similar crystallization rate dependency on the spray-drying temperature of macrolide derivatives was seen. Spray

Scheme 78. Schematic representation of the polymorphic transitions of oxyphenbutazone. (Reproduced from Ref. 568 with permission.)

100 r

100 r

time (month)

Figure 137. Change in percent crystallinity with time of initially amorphous halopredone acetate prepared by grinding halopredone acetate with various polymeric excipients (40°C, 75% RH). 0.» HPC; □ MC; A,* , HPMC; <!>,♦, PVA. -, aluminum film;-, cellophane/polyethylene film. (Reproduced from Ref. 570 with pennission.)

time (month)

Figure 137. Change in percent crystallinity with time of initially amorphous halopredone acetate prepared by grinding halopredone acetate with various polymeric excipients (40°C, 75% RH). 0.» HPC; □ MC; A,* , HPMC; <!>,♦, PVA. -, aluminum film;-, cellophane/polyethylene film. (Reproduced from Ref. 570 with pennission.)

drying at a temperature between Ts and the temperature at which crystallization started yielded the most stable amorphous materials:572 573

Crystallization of amorphous excipients may also occur during the storage of pharmaceuticals. Freeze-dried amorphous sucrose undergoes crystallization at temperatures above its Tg. 574-576 Moisture adsorption upon storage under higher humidity conditions caused crystallization even at temperatures below the Ts owing to the plasticizing effect of the adsorbed moisture. The addition of excipients having a high Tr and low hygroscopicity, such as dextran, raises the Tr and inhibits the crystallization.577

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