Kf kJilCD kfcATCDr 1tftfy l [CDr

The term [CD] is the total concentration of CD present in solution, and k„bs is the observed pseudo-first-order rate constant of the degradation of drug. Data such as those shown in Fig. 122 can be fitted to Eq. (2.119) (and variations of this equation) to yield estimates of K and kc. The value of kf can also be estimated by curve fitting, but it is best determined by direct measurement of drug degradation in the absence of added cyclodextrin.

Stabilization of prostacyclin and prostaglandins in solution and in the solid state by various CD derivatives is well known. Figure 122 shows the effect of the addition of a-, P-and y-CDs on the hydrolysis of prostacyclin in aqueous solution. The methyl ester of

Figure 121. Interaction of free drug molecules (Df) with the cavity of cyclodextrins. The formation of an "inclusion" complex can lead to either stabilization of the drug or catalysis of its breakdown.

CD concentration (x10"3m)

Figure 122. Stabilization of prostacyclin by increasing concentrations of a-CD (•) P -CD(A)i andy-CD (A )(pH 7.0, 15°C). (Reproduced from Ref. 524 with permission.)

prostacyclin is stabilized to an even larger extent.524 This differential stabilizing effect has been explained by the fact that ionization of the terminal carboxylic acid of prostacyclin inhibits complex formation. The methylation of the various hydroxyl groups on cyclodex-trins has a variable effect on stability. For example, heptakis(2,3-di-0-methyl)-P -CD (DM-P-CD) shows a larger stabilizing effect on prostacyclin than does heptakis(2,3,6-tri-C-methyl)-P-CD (TM-P-CD) (Fig. 123)^

Prostaglandin E, in neutral and alkaline solutions is destabilized by P-CD but stabilized by O-carboxymethyl-O-ethyl-P-CD(CME-P-CD) (Fig. 124).526 This stabilizing effect has been observed in a fatty alcohol propylene glycol ointment. Dehydration of prostaglandin E, and isomerization of prostaglandin A2 are enhanced by P -CD but inhibited by DM- P-CD and TM-P-CD (Fig. 125).527 HP-P -CD exhibits an inhibiting effect on degradation only in the acidic pH region.528

Stabilization of prostaglandins in the solid state by CDs and their derivatives has also been reported. The stability of 16,1 6-dimethyl-trans-A2-prostaglandin E1 methyl ester against dehydration and isomerization in the solid state is increased by complex formation with P -CD.529 As shown in Fig. 126, the stability of prostaglandin Ei is decreased by the

CD concentration (x10"3u)

Figure 123. Stabilization of prostacyclin by increasing concentrations ofTM- P-CD (a,) P-CD (»,)and DM-P-CD (A ) (pH 7.0, 15°C). (Reproduced from Ref. 525 with permission.)

CD concentration (x10"3u)

Figure 123. Stabilization of prostacyclin by increasing concentrations ofTM- P-CD (a,) P-CD (»,)and DM-P-CD (A ) (pH 7.0, 15°C). (Reproduced from Ref. 525 with permission.)

Figure 124. Effect of CD concentration on observed degradation rate constant of prostaglandin E, (pH 11.0, 60°C). A. P-CD; ■. CME-P-CD. (Reproduced from Ref. 526 with permission.)
Figure 125. Effect of CD concentration on the rate of dehydration of prostaglandin E2 (a) and the rate of isomerization of prostaglandin A, (b) (pH 1.0.60°C). A. P-CD; •, TM-P-CD; o.DM-P-CD. (Reproduced from Ref. 527 with permission.)
Figure 126. Stabilization of prostaglandin Ej in the solid state by various CDs versus no CD and a mannitol control at 60°C. [Drug]:[CD]=l:32 (by weight). &-P-CD; P-CD.n no CD; A. mannitol. (Reproduced from Ref. 530 with permission.)

Figure 127. Stabilization of bencyclane fumarate by various CDs (37°C, 0.1N HC1). The drug and CD were present in equimolar amounts. [3- C D ; ■ , y-CD; a-CD; o no CD. (Reproduced from Ref. 531 with permission.)

Figure 127. Stabilization of bencyclane fumarate by various CDs (37°C, 0.1N HC1). The drug and CD were present in equimolar amounts. [3- C D ; ■ , y-CD; a-CD; o no CD. (Reproduced from Ref. 531 with permission.)

addition of mannitol upon freezing in the presence of citric acid but increased by the addition of P -CD and 6-O-oeD-maltosyl-P-CD (G2-P-CD).530 This stabilizing effect has been explained by formation of inclusion complexes, as well as possibly by the fact that moisture, which participates in the degradation, is adsorbed by the CDs.

The stabilizing effect of CDs and their derivatives has been observed with many other drug substances. Hydrolysis of bencyclane fumarate is inhibited by a-, P- and y-CD, as shown in Fig. 127.531 The reduction of the hydrolysis rate of a hydrophobic drug, a dihydropyndine derivative of benzylpenicillin, by HP-P-CD is shown in Fig. 128.532 Among the numerous other reported examples are the stabilization of doxorubicin533 and mitomycin C534 by y-CD, aspartame by P -CD,535 daunorubicin in acidic aqueous solution by oc-takis(2,6-di-O-methyl)-y-CD (DM-y-CD),536 estramustine537 and thymoxamine538 by DM-

time (min)

Figure 128. Stabilization of a benzylpenicillin prodrug by HP-P -CD (pH 6.93,40°C). HP-P-CD concentration:

■, 0; a, 0.5% 1%. (Reproduced from Ref. 532 with permission.)

time (min)

Figure 128. Stabilization of a benzylpenicillin prodrug by HP-P -CD (pH 6.93,40°C). HP-P-CD concentration:

■, 0; a, 0.5% 1%. (Reproduced from Ref. 532 with permission.)

Scheme 77. Reaction pathway leading to melphalan degradation through a polar cyclic ethyleneimmonium intermediate. (Reproduced from Ref. 543 with permission.)

P-CD, thalidomide by HP- P-CD,539 tauromustine by HP-a-CD,540 and medroxyprogesterone acetate and megestrol acetate by HP-P -CD and methyl-P-CD.541 The stabilizing effect of P -CD against the oxidation of 2-[8-methyl-10,11-dihydro-11-oxodibenz[b,/]oxepin-2-yl]propionic acid in ointments has also been reported.542

Recently, Ma et at.543 studied the stability of the very unstable alkylating agent melphalan in the presence of (SBE)7m-P-CD and HP-P -CD. Melphalan undergoes an intramolecular displacement reaction through a very polar cyclic ethyleneimmonium intermediate (Scheme 77). The very polar transition state leading to this intermediate involves considerable charge separation. Both (SBE),7m-P-CD and HP-P -CD stabilized melphalan to chemical degradation.543 What is interesting in this case is that both (SBE)7m-P-CD and HP- P-CD have similar binding constants for melphalan and the same K values, as defined in Scheme 76, but k was significantly smaller in the case of (SBE)vm-P-CD (Table 7). One would intuitively feel that similar binding constants should yield similar positional binding in the cyclodextrin cavity and perhaps similar kc values. Ma et atJ43 were able to demonstrate that the melphalan bound to (SBE)7m-P-CD was in a more hydrophobic environment and that there was a small but significant difference in the position of binding of melphalan to (SBE)7m-P-CD versus HP-P-CD.

Although the degradation-inhibiting effects of CDs and their derivatives through complex formation can be used as a method for stabilizing pharmaceuticals, CDs and their derivatives may also enhance drug degradation, depending on the reaction mechanisms and the steric arrangement of the drug in the complex. For example, P -CD inhibits the alkaline hydrolysis of benzocaine (ethyl p-aminobenzoate)544 but enhances that of aspirin (Table 8).545 This has been explained by assuming that complex formation protects the ester bond of ethyl ^-aminobenzoate from attack by the hydroxide ion nucleophile. In the case of

Table 7. Estimated Values ofK, kf, and kc for the Degradation of Melphalan at 25°C (pH 7.5) in the Presence of (SBE)7M-P-CD and HP- P -CD, in Accordance with Scheme 76a

Cyclodextrin

K (M->)

k/e-1)

kc (h-1)

kf/kc

(SBEVP-CD

360

0.2

1.8 x 10-3

114

HP-P-CD

382

0.2

1.1 x 10-2

Table 8. Effect of P -CD on the Second-Order Rate Constants for the Hydrolysis of Benzocaine andAspirin"

Table 8. Effect of P -CD on the Second-Order Rate Constants for the Hydrolysis of Benzocaine andAspirin"

Benzocaine 30°C, [OH] = 0.04N

Aspirin 35°C, pH 10

0.00

0.666

0.258

0.25

0.358

0.530

0.50

0.229

0.807

0.75

1.085

1 .00

0.129

Reference 545.

aspirin, ester bond cleavage is accelerated by the attack of one of the cyclodextrin hydroxyl groups. HP-P-CD, a derivative of P -CD in which some of the hydroxyl groups are masked, stabilizes aspirin (Fig. 129).546 y-CD stabilizes anthracyclines such as daunorubicin in the acidic pH region but destabilizes them in the alkaline pH region, as shown in Fig. 130.547 The destabilizing effect of y-CD has also been reported for hydrolysis of doxorubicins.548

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