J S

1/illumination intensity (xlO"3 Ix"1)

Figure 90. Effect of illumination intensity on the degradation of menatetrenon (25°C). Light source: White fluorescent lamp. (Reproduced from Ref. 407with permission.)

2.2.11. Crystalline State and Polymorphism in Solid Drugs

The chemical stability of solid drugs is affected by the crystalline state of the drug. Drugs in the crystalline state have lower ground-state free energy and exhibit higher AGt (Eq. 2.7) and, therefore, slower reactivity. This is exemplified by the solid-state chemical degradation of various vitamin A derivatives as shown in Fig. 91, where a linear relationship between the observed degradation rate constant and the inverse of the melting point of the derivative can be seen.190

Many drug substances exhibit polymorphism. Each crystalline state has a different ground-state free-energy level and a different chemical reactivity. For example, ramified crystals of 5-nitroacetylsalicylic acid are more susceptible to hydrolysis than are column-

2.2 2.4 2.6 2.8 3.0 1/Tm (xlO^K *')

Figure 91.

Relationship between the degradation rates of various vitamin A derivatives at 50°C and their melting (Reproduced from Ref. 190 with permission.)

shaped crystals.409 Solid-state hydrolysis of carbamazepine from needle-shaped crystals with a higher Crystalline order is faster than that of beam-shaped and prismatic forms.410 Reactivity of carbamazepine to light also depends on the crystalline form of the drug.411 Differences in reactivity among different crystalline forms have also been reported for photodegradation of furosemide.412

The stability of drugs in their amorphous form is generally lower than that of drugs in their crystalline form, because of the higher free-energy level of the amorphous state. The relationship between degradation rate and crystallinity determined from heats of dissolution for B-lactam antibiotics such as sodium cefazolin indicates that a drug with low crystallinity tends to have decreased chemical stability.413

Decreased chemical stability of solid drugs brought about by mechanical stresses such as grinding is said to be due to a change in crystalline state. For example, grinding of aspirin increased its degradation rate in suspension form. A relationship between the stability and grinding time was reported414 (Fig. 92) and was attributed to the increased solubility of aspirin due to a change in its crystalline state rather than to any increase in surface area.

The chemical stability of solid drugs is also affected by the crystalline state of the drug through differences in surface area. For reactions that proceed on the solid surface of the drug, an increase in the surface area can increase the amount of drug participating in the reaction. For example, in a study of the reaction between solid-state sulfacetamide and phthalic anhydride, the percent of the drug that reacted within 3 h increased with increasing surface area, as shown in Fig. 93.415

2.2.12. Effect of Moisture and Humidity on Solid and Semisolid Drugs

Drug degradation in heterogeneous systems such as solids and semisolid states is affected by moisture. The effect of moisture and humidity on the degradation kinetics of various drug substances including ascorbic acid,416417 thiamine salts,418419 aspirin,420 vitamin A421 (Fig. 94), and ranitidine hydrochloride,422 to name a few examples, has been reported.

Moisture plays two primary roles in catalyzing chemical degradation. First, water participates in the drug degradation process itself as a reactant, leading to hydrolysis,

5 10 15 20 grinding time (h)

Figure 92. Effect of grinding time on the degradation of aspirin in suspension at 40°C. o, Zero-order rate constant; • , solubility. (Reproduced from Ref. 414 with permission.)

5 10 15 20 grinding time (h)

Figure 92. Effect of grinding time on the degradation of aspirin in suspension at 40°C. o, Zero-order rate constant; • , solubility. (Reproduced from Ref. 414 with permission.)

40 60 80 100 120 140 surface area (cm2)

Figure 93. Effect of surface area on the reaction between sulfacetamide andphthalic anhydride. The plotted values are the percentages of the drug that reacted during 3 h at 95°C. (Reproduced from Ref. 415 with permission.)

hydration, isomerization, or other bimolecular chemical reactions. In these cases, the degradation rate is directly affected by the concentrations of water, hydronium ion, or hydroxide ion according to Eq. (2.4). Second, water adsorbs onto the drug surface and forms a moisture-sorbed layer in which the drug is dissolved and degraded. Water adsorption may also change the physical state of drugs, thereby affecting their reactivity. Thus, water affects drug degradation indirectly by providing a favorable environment for degradation.

The mechanisms for these effects of water are complicated and are determined by the physical state of water molecules. For example, for drugs that form hydrates, water of crystallization is trapped in the crystals and, generally, cannot participate in chemical reactions. This is exemplified by the discoloration of glucuronic acid derivatives.423 As shown in Fig. 95, addition of water in amounts that form water of crystallization does not cause discoloration; however, addition of excess water does accelerate the discoloration at a rate proportional to the amount of water not involved in hydrate formation.

Figure 94. Effect of water content on the degradation of vitamin A tablets. (Reproduced from Ref. 421 with permission.)

Figure 94. Effect of water content on the degradation of vitamin A tablets. (Reproduced from Ref. 421 with permission.)

log (water content)

log (water content)

0 15 20

water content (%)

Figure 95. Effect of water content on the discoloration rate of potassium glucuronate. (Reproduced from Ref. 423 with permission.)

0 15 20

water content (%)

Figure 95. Effect of water content on the discoloration rate of potassium glucuronate. (Reproduced from Ref. 423 with permission.)

Water of crystallization can participate in drug degradation when it is released from the crystalline state by actions such as grinding. This has been reported for the hydrolysis of sodium prasterone sulfate424 and ampicillin trihydrate.425 The degradation rate of ampicillin trihydrate increased with increasing grinding time as shown in Fig. 96. Similarly, cefixime trihydrate exhibited decreased stability as a result of grinding,426 and rapid degradation was seen when its crystalline structure was disordered by dehydration upon storage under humidity conditions below the critical relative humidity.427

The effect of moisture on drug degradation has also been studied for various pharmaceuticals in the presence of excipients. This will be described in the next section.

A general equation analogous to the Arrhenius and Eyring equations for the effect of temperature on chemical degradation has not been developed to describe the effect of humidity. A linear relationship between the logarithm of the rate constant (or a constant

0 2 4 6 8 10 12 14 16 storage period (weeks)

0 2 4 6 8 10 12 14 16 storage period (weeks)

Figure 96. Effect of grinding on the degradation of ampicillin trihydrate during storage at 40°C. Grinding time:

o, 0, t, 15 min;D, 30 min; »,60 min;*120 min; A, 180 min. (Reproduced from Ref. 425 with permission.)

30 40 50 60 70 RHM

Figure 97. Effect of humidity on the degradation of nitrazepam. (Reproduced from Ref. 428 with permission.)

30 40 50 60 70 RHM

Figure 97. Effect of humidity on the degradation of nitrazepam. (Reproduced from Ref. 428 with permission.)

related to rate such as 1/^) and relative humidity has been used empirically to describe the effect of humidity on degradation rate. For example, the effect of humidity on the degradation rate constants of nitrazepam (Fig. 97),428 mecilliname (Fig. 98),429 and penicillins430 has been described by where RH is relative humidity and C is a constant. However, Eq. (2.112) cannot be applied in all cases. For example, a linear relationship was not observed for the degradation rates of acetyl-5-nitrosalicylic acid and glutathione with changing humidity, as shown in Fig. 99.431 The effect of humidity on the solid-state degradation rates of propantheline bromide and meclofenoxate hydrochloride has been described by

0.01

0.01

0 20 40

80 100

Figure 99. Effect of humidity on the degradation of acetyl-5-nitrosalicylic acid (a) and glutathione (O) at 80°C. (Reproduced from Ref. 431 with permission.)

where P is the vapor pressure of water and s is a constant. The constant k, calculated according to Eq. (2.58), was related to temperature and the vapor pressure of water using Eq. (2.1 13).432433 As shown in Fig. 100, the time course of degradation was well represented by Eq. (2.1 14), which was obtained by combining Eqs. (2.113) and (2.58):

where x is the ratio of drug degraded at time t, and xo is the ratio of drug degraded at 25°C and 100% RH (P = 23.756 mm Hg) when t = 50 (day).

where x is the ratio of drug degraded at time t, and xo is the ratio of drug degraded at 25°C and 100% RH (P = 23.756 mm Hg) when t = 50 (day).

Figure 100. Time courses of the degradation ratio of meclofenoxate hydrochloride defined according to EQ. (2.114). A, 9(1 C. 23.4% RH; c 70°C. 37.5% RH; V, 80°C. 22.6% RH; 60°C. 49.9% RH; ».60 C. 43.1% RH; Y 70°C. 22.0% RH. (Reproduced from Ref. 433 with permission.)

Estimates of Ea and S were obtained by nonlinear regression analysis. These equations appear to be useful for predicting the solid-state hydrolysis rate of water-soluble drugs as functions of changes in both temperature and humidity.

2.2.13. Excipients

The role that excipients play in drug stability has been extensively reported. Examples include the stabilizing effect of sugars on the degradation of ascorbic acid in aqueous solutions434; the accelerating effect of talc on the hydrolysis of thiamine hydrochloride powders435 436; the accelerating effect of magnesium stearate on discoloration of tablets containing amines and lactose437; and the effect of talc impurities,438 stearic acid,439440 and calcium succinate441 on the degradation of aspirin tablets. Additional information includes reports on the compatibility and incompatibility of drugs442-444; the incompatibility of flomoxef and sugars368; and the incompatibility of components of intravenous hyperalimen-tation fluids.445 However, detailed mechanistic studies on drug/excipient interactions and incompatibilities have not received much attention.

Excipients may affect drug stability via various mechanisms. The most obvious examples are those in which the excipients may participate directly in degradation as reactants, such as addition reactions with drugs. Excipients may also exhibit catalyzing effects toward drug degradation, as described in Section 2.2.6. This is exemplified by the nucleophilic catalysis effect of sugars (such as glucose and sucrose) and amines on the degradation of ester or amide drugs.387 388 Other mechanisms include the effect of moisture present in excipients, the effect of pH changes caused by excipients and other such effects. In following sections, the effects of excipients on chemical degradation, excluding their role as reactants or catalysts, are described.

2.2.13.1. Effect of the Amount of Moisture Present in Excipients

Excipients can affect drug stability by being a source of moisture. For example, owing to the high moisture content of polyvinylpyrrolidone and urea, aspirin hydrolysis was enhanced in solid dispersions with these excipients.446 Decreased drug stability caused by excipients having higher moisture-containing ability has been reported for tablets of aspirin and ascorbic acids,447 a urea-linoleic acid inclusion complex,448 powders of cysteine derivatives,449 and dry syrups of cephalexin.450

The effects of moisture from excipients on drug degradation rates are often difficult to interpret. Degradation of ascorbic acid in the presence of silica gel increased with increasing water content, as shown in Fig. 101.451 The higher degradation rate observed in the presence of silica gel compared to that for ascorbic acid alone at the same moisture content suggested an accelerating effect of silica gel itself or of one of its impurities. On the other hand, degradation decreased when the ratio of silica gel to ascorbic acid was increased. This suggested that most of the moisture was adsorbed onto the silica gel and that the entrapped water was unable to participate in the degradation. Thus, silica gel appeared to exhibit both an inhibiting effect via water entrapment and an accelerating effect toward ascorbic acid degradation. Similar inhibiting effects of excipients via water entrapment/adsorption were shown in tablets containing aspirin and colloidal silica.452

Degradation of thiamine hydrochloride in tablets containing magnesium stearate and microcrystalline cellulose exhibits a maximum at a water content of about 5%, as shown in

0 40 80 120 160 200 240 280 water content (mg)

Figure 101. Effect of silica gel and moisture content on the solid-state degradation of ascorbic acid during storage at 45°C for 3 weeks. O, 300 mg ascorbic acid; 300 mg ascorbic acid and 80 mg silica gel; X, 300 mg ascorbic acid and 640 mg silica gel. (Reproduced from Ref. 451 with permission.)

0 40 80 120 160 200 240 280 water content (mg)

Figure 101. Effect of silica gel and moisture content on the solid-state degradation of ascorbic acid during storage at 45°C for 3 weeks. O, 300 mg ascorbic acid; 300 mg ascorbic acid and 80 mg silica gel; X, 300 mg ascorbic acid and 640 mg silica gel. (Reproduced from Ref. 451 with permission.)

Fig. 102.453 It was proposed that the degradation proceeds through the catalyzing effect of an alkaline component on the dissolved drug. Thus, the degradation rate increases with increasing water content, as more drug is dissolved and comes into contact with the catalytic species. At higher water content, however, where the drug is completely dissolved, the degradation rate decreases with increasing water content as the two reactive species are diluted.453 A similar maximum degradation rate observed at a certain water content has been reported for the degradation of propantheline bromide in the presence of sodium aluminum gel (Fig. 103).454

Figure 102. Effect of water content on the degradation of thiamine hydrochloride tablets composed of magnesium stearate and microcrystalline cellulose. The percent of drug remaining after reaction equilibrium at 55°C is plotted versus water content. (Reproduced from Ref. 453 with permission.)

water content (ml/5g mixture)

water content (ml/5g mixture)

Figure 103. Effect of water content on degradation of propantheline bromide in the presence of sodium aluminum gel. The values of the rate constant (in units of h °5) calculated according to the Jander equation at 37°C. •, Moisture equilibrium; water added. (Reproduced from Ref. 454 with permission.)

2.2.13.2. Effect of the Physical State of Water Molecules in Excipients

As described earlier, the contribution of water to the chemical degradation of drug substances is determined by the physical state of water. This is also the case for drug-excipient mixtures. Recent studies have shown that water present in excipients exists in various physical states, being either weakly or strongly adsorbed to the excipient. The physical state of water can affect drug degradation.

Excipients having strong water-entrapping abilities tend to inhibit drug degradation, as exemplified by silica gel451 and colloidal silica.452 The hydrolysis rate of nitrazepam in the presence of various excipients such as microcrystalline cellulose was inversely proportional to the nitrogen-adsorption energy of the excipients, as shown in Fig. 104.455 This would suggest that excipients having higher adsorption energy decrease water reactivity and

nitrogen adsorption energy (kcal/mol)

Figure 104. Plot showing the relationship between the nitrogen-adsorption energy of various excipients and the hydrolysis rate of nitrazepam. The values of the rate constant (k ) have been normalized with respect to the specific surface area for the sample with 0.5% nitrazepam (70°C, 60% RH). (Reproduced from Ref. 455 with permission.)

nitrogen adsorption energy (kcal/mol)

Figure 104. Plot showing the relationship between the nitrogen-adsorption energy of various excipients and the hydrolysis rate of nitrazepam. The values of the rate constant (k ) have been normalized with respect to the specific surface area for the sample with 0.5% nitrazepam (70°C, 60% RH). (Reproduced from Ref. 455 with permission.)

cellulose (mg)

Figure 105. Effect of two cellulose forms on the degradation of aspirin (55°C, 75% RH). • , Microcrystalline cellulose; t, microfine cellulose. (Reproduced from Ref. 456 with permission.)

cellulose (mg)

Figure 105. Effect of two cellulose forms on the degradation of aspirin (55°C, 75% RH). • , Microcrystalline cellulose; t, microfine cellulose. (Reproduced from Ref. 456 with permission.)

thereby decrease the relative hydrolysis rates. However, the relationship between nitrogen-and water-adsorption energies requires further clarification.

The degradation rate of aspirin in the presence of cellulose compounds does not necessarily increase with an increase in the moisture-containing capacity of the com-pound.456 Microcrystalline cellulose provided a higher degradation rate constant per unit of water content than seen with microfine cellulose, suggesting a more highly reactive water content in the case of the microcrystalline material (Fig. 105). That is, this observation may be due to a lower proportion of strongly adsorbed water in microcrystalline cellulose. It has been reported that the amount of water that is strongly adsorbed on microcrystalline cellulose is only 0.856 mol/100 g and that most water in microcrystalline cellulose is only weakly adsorbed and, therefore, evaporates readily.457

The degradation rate of a drug substance can also depend on the time required to reach moisture-adsorption equilibrium, rather than on the amount of water adsorbed at equilib-rium.458 As shown in Fig. 106, the degradation of tablets of a proprietary drug formulated with various excipients such as microcrystalline cellulose decreased as the amount of water adsorbed by the excipients during storage increased. An explanation for this observation is

Figure 106. Effect of the amount of water adsorbed by excipients on the degradation of drug A (storage at 40°C, 80% RH for 4 weeks). (Reproduced from Ref. 458 with permission.)

Figure 107. Effect of grinding of lactose monohydrate on the degradation rate of 4-methoxyphenylaminoacetate hydrochloride at 37°C. Mixtures of the drug and lactose monohydrate were prepared in four ways: ■, mixing at 10% RH; mixing at 80% PH; mixing after grinding lactose for 10 min; * mixing after grinding both drug and lactose for 10 min. (Reproduced from Ref. 459 with permission.)

Figure 107. Effect of grinding of lactose monohydrate on the degradation rate of 4-methoxyphenylaminoacetate hydrochloride at 37°C. Mixtures of the drug and lactose monohydrate were prepared in four ways: ■, mixing at 10% RH; mixing at 80% PH; mixing after grinding lactose for 10 min; * mixing after grinding both drug and lactose for 10 min. (Reproduced from Ref. 459 with permission.)

that an excipient that adsorbs more moisture adsorbs it more strongly. Thus, the amount of free water is less for the strongly adsorbing excipients before moisture-adsorption equilibrium is reached. Because of a decrease in free water, the relative reactivity is decreased.

As in the case of drugs that are hydrated, excipients that can form hydrates may enhance drug degradation by giving up their water of crystallization during grinding. For example, the excipient a-lactose hydrate has been reported to enhance degradation of 4-methoxyphenylaminoacetate hydrochloride upon grinding, as shown in Fig. 107.459

2.2.13.3. Effect of the Mobility of Water Molecules in Excipients on Drug Degradation

In the previous section, drug stability was shown to depend on the physical state of water in excipients. Detailed information on the physical state of water can be obtained by measuring the dynamics or the mobility of water molecules. The effect of water mobility on drug stability has been studied by determining water mobility in mixtures of water and polymers used as pharmaceutical excipients. Methods used include the measurement of spin-lattice relaxation time and spin-spin relaxation time by nuclear magnetic resonance (NMR) spectroscopy as well as of dielectric relaxation time by dielectric relaxation spec-troscopy.

The spin-lattice relaxation time, Tb of water (H217O) in aqueous solutions of water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, and gelatin depends on polymer concentration as shown in Fig. 108.460 T1 is inversely related to the correlation time, TC, which corresponds to the time required for the rotation of a water molecule. T1 increases with increasing rotation rate in this range of water content; thus, Ti can be used as a measure of water mobility. Ti can be described using Eq. (2.115) by assuming that there are two kinds of water molecules present, freely mobile water and water whose mobility is decreased by interaction with the polymer. In Eq. (2.113, Tl{l) and / represent the spin-lattice relaxation time and the fraction of freely mobile water, respectively, while T^) and /2 represent the corresponding values for water with restricted mobility. Assuming that the value of T^^is that of pure water, T°, rearrangement of Eq. (2.115) yields Eq. (2.116).

Figure 108. Spin-lattice relaxation time of water in aqueous solutions of polymer excipients. Polyvinylpyrrolidone; □, gelatin; polyethylene glycol (PEG) 20,000; i, PEG400; A, sucrose; o, glucose. T, Spin-lattice relaxation time of pure water. (Reproduced from Ref. 460 with permission.)

Since / is proportional to polymer concentration (weight of polymer/total weight of water), plotting the term on the left-hand side of Eq. (2.116) (T,°/T 1) against polymer concentration should yield a linear relationship. As shown in Fig. 108, the plots obtained for aqueous solutions of polyvinylpyrrolidone, polyethylene glycol, and gelatin exhibited nonlinear relationships at higher polymer concentrations, indicating that T1 of water in these polymer solutions cannot be adequately described in terms of two groups of water having constant T1 values (namely, T1(1) and T1(2)) and that both T1(1) and T1(2) decrease with increasing polymer concentration. This has been confirmed by measurements of the dielectric relaxation time of water with these polymer solutions.461 Polyvinylpyrrolidone exhibited the most significant increase in T1 °/T1 values with increasing polymer concentration, suggesting its stronger tendency to decrease water mobility.

Water mobility in polymer solutions, as assessed by the methods discussed above, appears to be related to drug degradation rate in the presence of the polymers. The rate of kanamycin-catalyzed hydrolysis of flomoxef in gelatin gels, which depends on the diffusion rates of the drug and the catalyst, was related to the molecular mobility of water as determined by measurements of its spin-lattice relaxation time.462 The decrease in the T1 of water with increasing polymer concentration may reflect an increase in the microviscosity of the gelatin gel, which would result in a decrease in the diffusion-controlled reaction rate.

The rate of microviscosity as a factor affecting drug degradation rate has also been reported by Spancake et al.463 For example, the degradation rate of aspirin in Tetronic gels decreased with increasing polymer concentration owing to increasing microviscosity, as shown in Fig. 109. The decrease in degradation rate was less than expected based on the changes in macroviscosity. This was explained by assuming that the microviscosity did not

6.00

6.00

0 5 10 15 20 25 polymer concentration (%w/w)

Figure 109. Effect of polymer concentration on the degradation of aspirin in alkaline media as a function of Tetronic polymer concentration (pH 10.0, 50°C). (Reproduced from Ref. 463 with permission.)

0 5 10 15 20 25 polymer concentration (%w/w)

Figure 109. Effect of polymer concentration on the degradation of aspirin in alkaline media as a function of Tetronic polymer concentration (pH 10.0, 50°C). (Reproduced from Ref. 463 with permission.)

change as much as the macroviscosity, with water maintaining a high mobility within the gel structure.

Drug degradation rate in gels of lower water content was determined by the concentration of water with high mobility. The apparent hydrolysis rate of trichlormethiazide in gelatin gels increased with increasing water content at a water content of more than 15%, as shown in Fig, 110.462 Dielectric relaxation spectroscopy showed that there are three kinds of water with different mobilities within gelatin gels: water bound to gelatin (both strongly and weakly bound) and water with a high mobility close to that of pure, or bulk, water.461 The amount of water with high mobility as determined by dielectric relaxation spectroscopy, increased with increasing water content at a water content greater than 15%. This increase correlated well with the degradation rate.462

The effect of water with high mobility on drug degradation has also been demonstrated in the hydrolysis of a solid cephalothin mixture with microcrystalline cellulose.464 The hydrolysis rate was found to be proportional to the amount of water with high mobility rather than to the total amount of water, which included water with strongly reduced mobility.

The increase in drug degradation rate in solid polymer matrices with increasing water content can also be attributed to the plasticizing effect of water. As shown in Fig. 1 1 1 ,465 the

Figure 110. Effect of percent water content on the first-order degradation rate constant for trichlormethiazide in a gelatin gel at 27°C. •, Apparent first-order rate constant; □, [H,0]/ (concentration of free water). (Reproduced from Ref. 462 with permission.)
Figure 111. Effect of water content on the dehydration of misoprostol dispersed in hydroxymethyl cellulose (55°C) at a function of water content. (Reproduced from Ref. 465 with permission.)

dehydration rate of misoprostol dispersed in hydroxymethyl cellulose increased significantly as water content increased, presumably due to the plasticizing effect of water. Drugs in polymer matrices in a glassy state with low water content exhibit high stability owing to the restricted mobility, whereas those in polymer matrices plasticized by water exhibit increased degradation. Few studies have been performed on the plasticizing effect of water on the chemical degradation of pharmaceuticals. However, there are some studies on the plasticizing effect of water on physical degradation in relation to glass-transition temperature. This effect will be described in Chapter 3. It is difficult to make generalizations about the role of water in chemical degradation because of the multiple roles (reactant, plasticizer etc.) that water can play.

2.2.13.4. Other Properties of Excipients

Excipients can also affect drug stability by altering microclimate pH. The surface acidity of excipients has been reported to be a factor contributing to drug degradation, for example, in the isomerization of vitamin D2.466 Carboxylic acid groups on the solid surface furnish a representative example. Lomustine exhibited faster degradation in poly(<i,/-lactide) microspheres than in its pure crystalline state.467 Although this enhanced degradation has been attributed to molecular dispersion of the drug in the microspheres, the possibility that the terminal carboxylic acid groups of poly(d,/-lactide) effect micro-pH changes cannot be excluded. Degradation of etoposide entrapped in poly(Z-lactide) microspheres increased as the number of terminal carboxylic acid groups increased during poly(Z-lactide) decomposition, suggesting the degradation enhancing effect of these groups.468 Enhanced degradation of solid oxazolam in the presence of microcrystalline cellulose may be attributed to carboxylic acid groups on the cellulose surface in addition to the effect of moisture.469470

Excipients affect drug degradation via various mechanisms other than pH changes. The effect of stearate on the degradation of aspirin has been explained by a change in melting behavior rather than pH changes (Fig. 112).471 Dye excipients may enhance oxidation and photodegradation of drugs by producing singlet oxygen that participates in chain reactions. Examples are enhancement of the oxidation of phenylbutazone472 and ascorbic acid473 by dye excipients.

Figure 112. Relationship between degradation rate and melting point of aspirin in the presence of various stearate salts. (0) No additive; (1) 3% Zn salt; (2) Al salt; (3) Na salt; (4) Ca salt; (5) and (8) Mg salt; (6) 1% Mg salt; (7) 2% Mg salt; (9) 5% Mg salt. The values of k were calculated according to the equation [1 - (1-x)K]2 = kt. (Reproduced from Ref. 471 with permission.)

Figure 112. Relationship between degradation rate and melting point of aspirin in the presence of various stearate salts. (0) No additive; (1) 3% Zn salt; (2) Al salt; (3) Na salt; (4) Ca salt; (5) and (8) Mg salt; (6) 1% Mg salt; (7) 2% Mg salt; (9) 5% Mg salt. The values of k were calculated according to the equation [1 - (1-x)K]2 = kt. (Reproduced from Ref. 471 with permission.)

Metal ions used as pharmaceutical excipients, or present as impurities, often catalyze drug degradation. Metal ions are well known to be catalysts of oxidation and photodegradation of drugs, as described in 2.1.5 and 2.1.6. Metal ions may also cause drug degradation by forming complexes with drugs. A good example is the rearrangement reaction of fosinopril caused by magnesium ion.474

The role that surfactants play in drug degradation has received considerable attention.475 Mechanisms for the effect of surfactants are complex and depend on various factors. For example, the effect of cetyltrimethylammonium bromide (CTAB) on the kinetics of the hydrolysis of phenyl acetates and ethyl benzoates varied depending on the substituent on the phenyl ring of these esters (amino or nitro groups etc.) (Fig. 1 13).476 The observation that alkaline hydrolysis of acetylcholine is decreased by dodecyltrimethylammonium chloride (DTAC), as shown in Fig. 114, has been explained by assuming that the drug molecule penetrates the micellar phase and is shielded from the attack of hydroxide ion.477 However, it is hard to imagine why the polar acetylcholine should have an affinity for the hydrophobic core of the micelle. Alkaline hydrolysis of benzocaine is inhibited by cetyltrimethylam-monium chloride (CTAC)478 Alkaline hydrolysis of indomethacin is inhibited by nonionic surfactants such as ethoxylated lanolin and anionic surfactants such as sodium dodecyl sulfate but enhanced by a cationic surfactant, CTAB, as shown in Fig. 1 15.479480 The latter enhancing effect has been explained by increased concentration of the reactants upon micelle formation. This effect decreased at higher concentrations of surfactant. Similar enhancing effects of CTAB have been reported for hydrolysis of various naphthyl481 and carbaryl esters.482

1,4-Benzodiazepines undergo hydrolysis of the azomethine and amide groups by acid catalysis. Anionic surfactants such as sodium dodecyl sulfate inhibited hydrolysis of the

Figure 113. Effect of CTAB on the degradation rate of various acetate and benzoate esters. The ratio of the rate constant in the presence of CTAB (k) to that in its absence (A'„) is plotted as a function of CTAB concentration. □, />-Nitrophenyl acetate (pH 9.2,25°C); ■, ethyl p-nitrobenzoate (pH 10.64,25°C); a, />-aminophenolacetate (pH 10.64,50°C); • ethyl />-aminobenzoate (pH 10.55,50°C). (Reproduced from Ref. 476 with permission.)

Figure 113. Effect of CTAB on the degradation rate of various acetate and benzoate esters. The ratio of the rate constant in the presence of CTAB (k) to that in its absence (A'„) is plotted as a function of CTAB concentration. □, />-Nitrophenyl acetate (pH 9.2,25°C); ■, ethyl p-nitrobenzoate (pH 10.64,25°C); a, />-aminophenolacetate (pH 10.64,50°C); • ethyl />-aminobenzoate (pH 10.55,50°C). (Reproduced from Ref. 476 with permission.)

azornethine group while enhancing amide hydrolysis.483 The inhibiting effect increased as the hydrophobicity of the surfactants increased.484

The effect of surfactants on the degradation of P -lactam antibiotics is difficult to interpret. As shown in Fig. 116, acid degradation of propicillin in solutions was inhibited by polyoxyethylene-23-laurylether (a nonionic surfactant) and CTAB (a cationic surfactant) but enhanced by sodium lauryl sulfate (an anionic surfactant).485 Degradation of cefaclor (an a-aminophenyl cepalosporin) was enhanced by CTAB. The dependence on salt concentration suggests a complex mechanism for the effect of surfactants on degradation of cefaclor.486

DTAC to intial drug ratio

Figure 114. Effect of DTAC on the degradation of acetylcholine (pH 9.0,25°C). Initial drug concentration: <* 3 mM, o 5 mM, ■ 10 mA 1. (Reproduced from Ref. 477 with permission.)

0.0 0.2 0.4 0.6 0.8 1.0 surfactant concentration (%)

Figure 115. Effect of surfactants on the degradation of indomethacin (30.3°C, [OH-] = 5 inM). • Ethoxylated lanolin; E CTAB. (Reproduced from Ref. 479 with permission.)

0.0 0.2 0.4 0.6 0.8 1.0 surfactant concentration (%)

Figure 115. Effect of surfactants on the degradation of indomethacin (30.3°C, [OH-] = 5 inM). • Ethoxylated lanolin; E CTAB. (Reproduced from Ref. 479 with permission.)

Phospholipid liposomes can affect drug degradation. The hydrolysis rate of procaine free base decreased in the presence of liposomes (Fig. 1 17).487488 The inhibiting effect of liposomes has also been reported for alkaline hydrolysis of various esters such as aspirin.489-491 An electron spin resonance (ESR) study confirmed that the decrease in rate is due to partitioning of the drug substances into the liposomes, thus altering the reactant concentration in the aqueous phase, where the hydrolysis reaction is presumed to occur.492 Liposomes inhibited the degradation of the free base of 2-diethylaminoethyl p-nitrobenzoate but enhanced the degradation of the protonated form of the drug. An explanation is the differing interaction between drug and liposome, depending on the charge of the drug molecule.493

Excipients such as cyclodextrins, which form inclusion complexes with drug substances, can have a significant effect on drug stability. These effects will be described in

0.75

0.75

10 20 30 40 50 surfactant concentration (xlO^M)

Figure 116. Effect of surfactants on the degradation of propicillin at 37°C. Polyoxyethylene-23-laurylether, pH 1.10; a, sodium lauryl sulfate, pH 3.00; ■ CTAB, pH 1.10. (Reproduced from Ref. 485 with permission.)

10 20 30 40 50 surfactant concentration (xlO^M)

Figure 116. Effect of surfactants on the degradation of propicillin at 37°C. Polyoxyethylene-23-laurylether, pH 1.10; a, sodium lauryl sulfate, pH 3.00; ■ CTAB, pH 1.10. (Reproduced from Ref. 485 with permission.)

Figure 117. Effect of a liposome formulation on the degradation of procaine (pH 10.2, 40°C). concentration: o 0; • 1.01 x 10~=M (Reproduced from Ref. 487 with permission.)

Lecithin greater detail in Section 2.3. Some polymers affect drug stability by mechanisms different from those described earlier. For example, it has been proposed that hydroxypropyl methyl cellulose decreased the rate of dehydration of prostaglandin E1 by protecting the drug from water through entanglement of the drug in a polymer environment.494

Detailed mechanisms are not clear in other reports of the effects of excipients on drug stability. For example, bropirimine was destabilized by solubilizers (such as polyethylene glycol),495 whereas water adsorbed on porous montmorillonite exhibited a catalyzing effect on the degradation of aspirin.496 Some excipients appear to have minimal effects on drug stability; for example, fluocinolone acetonide in a cream formulation exhibited the same degradation as in aqueous solution without the excipients present in the cream formulation.497

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