Addition of Stabilizers Such as Antioxidants and Stabilization through the Use of Packaging

In the previous sections, positive methods for stabilizing pharmaceuticals, involving modification of the molecular structure or the microscopic environment in which the drug is formulated, have been described. On the other hand, the exclusion of some factors adversely affecting drug stability can also lead to the stabilization of pharmaceuticals. Because oxygen, light, and moisture often enhance drug degradation as described earlier, various methods for excluding these factors have been considered as means of stabilizing pharmaceuticals.

Often, the effect of oxygen can be eliminated by the addition of antioxidants. Oxidation of lovastatin in aqueous solution is inhibited by antioxidants such as a-tocopherol and butylated hydroxyanisole (BHA), as shown in Table 9.553 Similarly, the inhibition of the oxidation of cholecalciferol by a-tocopherol and ascorbic acid554 and the inhibition of the oxidation of NSC-629243 (an O-alkyl-N-aryl thiocarbamate; see Scheme 49) by thioglycolic acid187 have been reported. The ability to inhibit oxidative photodegradation of benzaldehyde has been utilized as a measure of the antioxidant effects of polyhydric phenols.555 Pharmaceuticals are often stabilized by the utilization of packaging containing an antioxidant.556 For example, the photooxidation of cianidanol in the solid state was inhibited by lowering the concentration of oxygen with the use of an oxygen absorbent, as illustrated in Figure 132.402

Figure 132. Stabilization of cianidanol against photodegradation (light source: mercury lamp) in the solid state by the use of an oxygen absorbent. 6 With oxygen absorbent; • without oxygen absorbent. (Reproduced from Ref. 402 with permission.)

Figure 133. Stabilization of sulfisomidine tablet coloration (light source: mercury lamp) by modifying film coating thickness and oxybenzone content. Samples were irradiated at a temperature below 27°C. Oxybenzone concentration: 10.5%; a, 1%; o, 2%; A, 5%;», 10%. (Reproduced from Ref. 557 with permission.)

Figure 133. Stabilization of sulfisomidine tablet coloration (light source: mercury lamp) by modifying film coating thickness and oxybenzone content. Samples were irradiated at a temperature below 27°C. Oxybenzone concentration: 10.5%; a, 1%; o, 2%; A, 5%;», 10%. (Reproduced from Ref. 557 with permission.)

The use of photoprotective films generally eliminates the effect of light. As shown in Fig. 133, a film coating containing oxybenzone inhibited coloration and photolytic degradation of sulfisomidine tablets. The extent of inhibition depended on the concentration of the W absorber and the thickness of the film.557 Titanium dioxide in a gelatin capsule shell stabilized indomethacin (Fig. 134),558 and film coatings containing titanium dioxide stabilized nifedipine in a tablet formulation.559 Incorporation of synthetic iron oxides resulted in the stabilization of uncoated tablets of nifedipine and sorivudine against phododegrada-tion.560 Stabilization of other pharmaceuticals against photodegradation by the use of

0 50 100 150

membrane thickness (nm)

Figure 134. Stabilization of indomethacin coloration (light source: mercury lamp) by the addition of titanium dioxide to gelatin capsule shells. Titanium dioxide concentration: 6,0; •.0.5%; A, 1.0%; 1.5%. The values of A' were calculated from the equation AE (color difference) = k( tK - 0.08). (Reproduced from Ref. 558 with permission.)

Figure 135. Stabilization of the photochemical degradation (at 290-700 nm) of daunorubicin solutions by the addition of various colorants: scarlet GN; A, amaranth; ponceau 6R; O, tartrazine; no colorant. (Reproduced from Ref. 561 with permission.)

Figure 135. Stabilization of the photochemical degradation (at 290-700 nm) of daunorubicin solutions by the addition of various colorants: scarlet GN; A, amaranth; ponceau 6R; O, tartrazine; no colorant. (Reproduced from Ref. 561 with permission.)

colorants has also been reported; for example, daunorubicin in solution was stabilized by the addition of various colorants (Fig. 135)561 and ubidecarenone in a dry emulsion was stabilized by the addition of a -(o-tolylazo)- P -naphthylamine.562

Various methods for protecting pharmaceuticals from the effect of moisture have been considered, with the use of moisture-proof packaging563 564 and film coatings565 being the techniques most often utilized. Further discussion of moisture permeability of packaging will be presented in Chapter 4.

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