Factors Affecting Physical Stability

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The physical stability of pharmaceuticals is affected by many of the same variables that affect chemical stability. Specifically, the physical stability of solid pharmaceuticals is affected by the plasticizing effect of water, presumably owing to increases in molecular

60 70 80 90 100

Figure 141. Moisture adsorption of a sucrose-potassiumbromide mixture plotted according to Eq. (3.1). (25°C). (Reproduced from Ref. 602 with permission.)

60 70 80 90 100

Figure 141. Moisture adsorption of a sucrose-potassiumbromide mixture plotted according to Eq. (3.1). (25°C). (Reproduced from Ref. 602 with permission.)

Figure 142. Glass-transition temperature (Tg , —) and NMR relaxation-based critical mobility temperature ( TmIj

-) of lyophilized formulations. O • a,p$-Poly(N-hydroxyethyl)-L-aspartamide; A, a polyvinylpyrrolidane; □

■ , dextran. (Reproduced from Ref. 607 with permission.)

Figure 142. Glass-transition temperature (Tg , —) and NMR relaxation-based critical mobility temperature ( TmIj

-) of lyophilized formulations. O • a,p$-Poly(N-hydroxyethyl)-L-aspartamide; A, a polyvinylpyrrolidane; □

■ , dextran. (Reproduced from Ref. 607 with permission.)

mobility. Amorphous indomethacin,603 nifedipine,604 and lamotrigine mesylate all show decreased Tg values and increased crystallization in the presence of absorbed moisture.605

The decrease in Tg caused by the plasticizing effect of water was explained on the basis of free-volume theory and generally described by Gordon-Taylor/Kelly-Bueche relationships.606 Although Tg is useful in representing the molecular mobility of amorphous pharmaceuticals, the NMR relaxation-based critical mobility temperature ( Tmc) is also useful as a measure of molecular mobility. Tmc is the critical temperature of appearance of Lorentzian relaxation due to protons in the liquid state in pharmaceutical solids607 As shown in Fig. 142, Tmc is generally lower than Tg, indicating that glassy pharmaceutical solids exhibit significant molecular mobility even at temperatures below Tg.

Enthalpy relaxation time, determined by differential scanning calorimetry,608 and mechanical relaxation, determined by dynamic mechanical analysis,609 can also be used as measures of molecular mobility of amorphous pharmaceutical solids.

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