Degradation Of The Drug May Make The Product Esthetically Unacceptable

Chemical Stability of Drug Substances

The most easily understood and most studied form of drug instability is the loss of drug through a chemical reaction resulting in a reduction of potency. Loss of potency is a well-recognized cause of poor product quality.

In this chapter, the quantitation of chemical drug loss is discussed and analyzed. However, loss of drug potency per se by various pathways is only one of many possible reasons for quantitating drug loss. Identification of the product(s) formed provides a better understanding of the mechanism(s) of these chemical reactions as well as other valuable information. Other reasons for quantitating drug loss include the following.

1. The drug may degrade to a toxic substance. Therefore, it is important to determine not only how much drug is lost with time but also what are its degradants. In some cases, the degradants may be of known toxicity. For example, the drug pralidoxime degrades via two parallel, pH-sensitive pathways. Under basic pH conditions, the toxic product cyanide is formed (Scheme 1).1 For other drugs, the toxicity of degradants is initially unknown. For example, a degradant of tetracycline is epianhydrotetracycline, known to cause Fanconi syndrome (Scheme 2).23

Sometimes, reactive intermediates are formed that are known or suspected to be toxic. For example, penicillins rearrange under acidic pH conditions to penicillenic acids, which are suspected to contribute to the allergenicity of penicillins (Scheme 3).4 Gosselin et al.

Scheme 1. Parallel degradation pathways for pralidoxime leading to cyanide formation under basic pH conditions. (Reproduced from Ref. 1 with permission.)

tetracycline epianhydrotetracycline

Scheme 2. Dehydration and epimerization of tetracycline, leading to formation of epianhydrotetracycline, known to be associated with Fanconi syndrome. (Reproduced from Refs. 2 and 3 with permission.)

tetracycline epianhydrotetracycline

Scheme 2. Dehydration and epimerization of tetracycline, leading to formation of epianhydrotetracycline, known to be associated with Fanconi syndrome. (Reproduced from Refs. 2 and 3 with permission.)

proposed a protecting group for phosphates that produces episulfide, a sulfur analog of ethylene oxide of unknown toxicity.5

2. Degradation of the drug may make the product esthetically unacceptable. Products are presumed to be adulterated if significant changes in, for instance, color or odor have occurred with time. For example, epinephirine is oxidized to adrenochrome (Scheme 4), a highly colored red material. Any epinephrine-containing product that develops a significant pink tinge is usually considered adulterated.

Recently, one of the authors was asked to comment on the acceptability of a drug substance that degraded to volatile, odor-producing, sulfur-containing degradant. Even minor degradation of the drug produced an unacceptable odor. This was of specific concern because one intended route of drug administration was via a nasal spray.

3. Even though a drug may be stabilized in its intended formulation, the formulator must show that the drug is also stable under the pH conditions found in the gastrointestinal tract, if the drug is intended for oral use. Most drug substances are fairly stable at the neutral pH values found in the small intestine (disregarding enzymatic degradation) but can be unstable at pH values found in the stomach. Examples of drugs that are very acid-labile are various penicillins,46 erythromycin and some of its analogs7 and the 2',3'-dideoxypurine nucleoside anti-AIDS drugs.8 Knowledge of the stability of a drug in the pH range of 1-2 at 37°C is important in the design of potentially acid-labile drugs and their dosage forms.

2.1. Pathways of Chemical Degradation

Drug substances used as pharmaceuticals have diverse molecular structures and are, therefore, susceptible to many and variable degradation pathways. Possible degradation pathways include hydrolysis, dehydration, isomerization and racemization, elimination, oxidation, photodegradation, and complex interactions with excipients and other drugs. It would be very useful if we could predict the chemical instability of a drug based on its molecular structure. This would help both in the design of stability studies and, at the earliest benzylpeniclllin benzylpenicillenic acid

Scheme 3. Representative example of the rearrangement of penicillins to their penicillenic acids under acidic pH conditions. (Reproduced from Ref. 4 with permission.)

benzylpeniclllin benzylpenicillenic acid

Scheme 3. Representative example of the rearrangement of penicillins to their penicillenic acids under acidic pH conditions. (Reproduced from Ref. 4 with permission.)

ePinePhrine adrenoehrome

Scheme 4. Oxidation of epinephrine to the highly colored adrenochrome.

ePinePhrine adrenoehrome

Scheme 4. Oxidation of epinephrine to the highly colored adrenochrome.

stages of drug development, in identifying ways in which problematic drugs could be formulated to minimize chemical degradation. The immense chemical and pharmaceutical literature is probably underutilized as a source of such information. Expert systems are also being developed for predicting stability.

Below, the major-degradation pathways in relation to molecular structure are discussed and examples provided.

2.1.1. Hydrolysis

For most parenteral products, the drug comes into contact with water and, even in solid dosage forms, moisture is often present, albeit in low amounts. Accordingly, hydrolysis is one of the most common reactions seen with pharmaceuticals. Many researchers have reported extensively on the hydrolysis of drug substances. In the 1950s, elegant studies, especially considering the lack of high-throughput analytical techniques, concerning the hydrolysis of procaine,910 aspirin,1112 chloramphenicol,13-15 atropine,16-18 and methyl-phenidate19 were reported. Hydrolysis is often the main degradation pathway for drug substances having ester and amide functional groups within their structure.

Many drug substances contain an ester bond. Traditional esters are those formed between a carboxylic acid and various alcohols. Other esters, however, include those formed between carbamic, sulfonic, and sulfamic acids and various alcohols. These ester compounds are primarily hydrolyzed through nucleophilic attack of hydroxide ion or water at the ester, as shown in Scheme 5 for the case of a carboxylic acid ester.

The degradation rate depends on the substituents R1 and R2, in that electron-withdrawing groups enhance hydrolysis whereas electron-donating groups inhibit hydrolysis. As shown in Table 1, substituted benzoates having an electron-withdrawing group, such as a nitro group, in the para position of the phenyl ring (R1) exhibit higher decomposition rates than the unsubstituted benzoate. On the other hand, the decomposition rate decreases with increasing electron-donating effect of the alkyl group (in the alcohol portion of the ester (R2)) (e.g., it decreases in the order methyl > ethyl > «-propyl). Replacing a hydrogen atom

Scheme 5. Hydrolysis of a carboxylic acid ester.

Table 1. Second-Order Rate Constants for the Hydrolysis of Various Benzoic Acid Esters through Nucleophilic Attack of Hydroxide Ion, in Accordance with Scheme 5 (R, = R'-

Table 1. Second-Order Rate Constants for the Hydrolysis of Various Benzoic Acid Esters through Nucleophilic Attack of Hydroxide Ion, in Accordance with Scheme 5 (R, = R'-

R'

R2

Second-order rate constant K OH (x 10-4 m-1 s-1)°

H

CH3

6.08

H

C2H5

1.98

H

«-C3H7

1.67

H

¿S0-C3H7

0.319

H

Phenyl

33.6

H

CH4C1

12.4

ch3

CH3

2.65

F

CH3

12.1

C1

CH3

19.1

C1

C2H5

6.51

C1

n-QH,

5.11

C1

iso-C3H7

1.21

C1

Phenyl

103

NO2

CH3

276

NO2

C2H5

98.8

NO2

n-C3H7

76.0

NO2

iso-C3H7

19.6

NO2

Phenyl

1140

aIn 50% acetonitrile-0.02Mphosphate buffer solution; 25°C.

aIn 50% acetonitrile-0.02Mphosphate buffer solution; 25°C.

with an electron-withdrawing halogen such as chlorine, e.g., -C2H5 versus -C2H4CI, also increases the rate of decomposition.20

Another way of viewing this reaction is by considering leaving-group ability. The mechanism of ester hydrolysis can be considered an addition/elimination reaction, the leaving group being R2OH. The rate of the elimination step will be determined in part by the ability of the leaving alcohol to sustain the buildup of negative charge on the oxygen atom. This will also be reflected in the pKa of the alcohol. For example, hydrolysis of phenyl benzoate is much faster than that of ethyl benzoate (Table 1) because the pKa values of ethanol and phenol are 18 and 10, respectively.

Steric factors also play a role. Bulky groups on either R1 or R2 decrease the decomposition rate. For example, when an iso-propyl group is substituted for an n-propyl group on R2, the decomposition is five times slower (Table 1).

Attack of hydroxide ion on an ester bond is also affected by the presence of neighboring charges. For example, the hydrolysis rates of all ester bonds within poly(butylene tartrate) are not equal; the ester bonds close to the negatively charged, terminal carboxylate group are less reactive toward hydroxide-ion attack than are the ester groups removed from the negatively charged carboxylate group.21

2.1.1.1.a. Carboxylic Acid Esters of Pharmaceutical Relevance. Representative examples of carboxylic acid esters that are susceptible to hydrolysis are shown in Fig. 1. These include ethylparaben,22 benzocaine,10 23 24 procaine?9-10 oxathiin carboxanilide (NSC-

Pathways Benzoylecgonine

Figure 1. Representative examples of carboxylic acid esters of pharmaceutical interest, susceptible to hydrolysis.

hydrocortisone sodium succinate methylprednisolone sodium succinate

Figure 1. Representative examples of carboxylic acid esters of pharmaceutical interest, susceptible to hydrolysis.

615985),25 aspirin,1112 atropine,16-18-26 scopolamine,27 methylphenidate,19 meperidine,28 steroid esters such as hydrocortisone sodium succinate29 30 and methylprednisolone sodium succinate,31 and succinylcholine chloride.32 33 Cocaine has two ester bonds that hydrolyze to produce benzoylecgonine or ecgonine methyl ester, as shown in Scheme 6.3435 It is said to undergo parallel pathways of degradation. Shown in all future reaction schemes are the primary reaction pathways. As such, these are not meant to be complete; that is, some compounds undergo other competing reactions.

Based on the structures of these various esters, it can be readily seen that having information on the reactivity of one ester should provide valuable insight into that of a second

ecgonine methylester Scheme 6. Parallel hydrolysis pathways for cocaine.

ester. For example, ethylparaben and benzocaine are very similar in structure; both have a para electron-donating group and both are ethyl esters. Therefore, information about the reactivity of one of them could be the basis for predicting the stability of the other. Similarly, ester group hydrolysis in atropine should be similar in rate and pH dependency to that in scopolamine. Is it not reasonable to expect the hydrolysis of methylprednisolone sodium succinate to be similar to that of hydrocortisone sodium succinate? Therefore, if one is presented with a new drug substance containing a hydrolyzable ester moiety, it should be possible, using appropriate literature examples of similar drugs, to make a good estimate of the sensitivity of the ester group to hydrolysis.

Lactones, or cyclic esters, also undergo hydrolysis. As shown in Fig. 2, pilocarpine,36-38 dalvastatin,39 warfarin,4041 and camptothecin42 exhibit ring opening due to hydrolysis. Note that, unlike linear esters, lactones often exist in dynamic equilibrium with their carboxylic acid/carboxylate forms.

Apparent rate constants for the hydrolysis of various carboxylic acid esters are shown in Table 2 for the comparison of their reactivities. As these values were obtained under different conditions of temperature, pH, ionic strength, and buffer species, they are for rough comparison only. Nevertheless, they do point out the role that structure plays in the relative reactivity of the ester bond.

pilocarpine pilocarpi acid pilocarpine pilocarpi acid

Tracing Curved Lines Worksheets

C2H5 OH CjHJ OH

camptothecin

Figure 2. Representative lactones of pharmaceutical interest susceptible to hydrolysis. Note that, unlike esters, lactones often exist in dynamic equilibrium (pH dependent) with their carboxylate forms.

C2H5 OH CjHJ OH

camptothecin

Figure 2. Representative lactones of pharmaceutical interest susceptible to hydrolysis. Note that, unlike esters, lactones often exist in dynamic equilibrium (pH dependent) with their carboxylate forms.

Table 2. Apparent Rate Constants for the Hydrolysis of Various Carboxylic Acid Esters

k(s)

pH

Reference

Camptothecin

6.0 x l0-5 (25°C)

7.13

42

Aspirin

3.7 x 10-6 (25°C)

6.90

12

Methylprednisolone sodium succinate 2.5 x l0-7 (25°C)

7.30

31

Oxathiin carboxanilide

1.8 x lO-7 (25°C)

6.92

25

Benzocaine

5.7 x 10-8(25°C)

9.2

4

Ethylparaben

4.2 x 10-8 (25°C)

9.16

22

Cocaine

4.97 x 10-6 (30°C)

7.25

34

Succinylcholine

5.0 x 10-5(400°C)

8.00

32

Procaine

6 x 10-6 (40°C)»

8

9

Pilocarpine

1.7 x 10-6 (40°C>

8

36

Atropine

1.8 x 10-7 (40oC)

7.01

17

Methylphenidate

3.2 x 10-6 (50°C)

6.07

19

Hydrocortisone sodium succinate

9.0 x 10-6 (65.2°C)

7.0

29

1 x 10-7(25°C)b

29

Meperidine

1.8 x 10-7 (89.7°C)

6.192

28

aValue ofk estimated from plots in the reference.

bValue ofk estimated using the reported value of the activation energy (Ea ).

aValue ofk estimated from plots in the reference.

bValue ofk estimated using the reported value of the activation energy (Ea ).

2.1.1.1.b. Other Esters. Carbamic acid esters such as chlorphenesin carbamate43 and carmethizole,44 shown in Scheme 7, are known to undergo hydrolysis in strongly acidic and neutral-to-alkaline solutions, respectively. The two carbamate ester groups in carmethizole undergo hydrolysis at significantly different rates owing in large part to completely different mechanisms.44 The first carbamate group is cleaved by more of an elimination reaction via carbonium formation whereas the second carbamate linkage appears to hydrolyze via a normal hydrolysis mechanism.

Cyclodisone,45 a sulfonic acid ester, and sulfamic acid 1,7-heptanediyl ester (NSC-329680),46 a sulfamic acid ester, have been reported to hydrolyze in the neutral-to-alkaline pH range (Scheme 8). Both hydrolyze via carbon-oxygen bond cleavage rather than sulfur-oxygen bond cleavage.45 46

ci-/ \-och2chch2oconh2 oh chlorophenesin carbamate ci-f Voch2chch2oh oh n ch2oconhch3 n ch2oconhch3

y"XH2OCONHCH3

CH3 CH3

N"xh2OH

carmethizole

Scheme 7. Representative carbamic acid esters of pharmaceutical relevance susceptible to hydrolysis.

o cyclodisone

o cyclodisone

H2NS020(CHJ)70S02NH2 —*■ H2NS020(CH2)t0H —- HO(CH2)TOH NSC-329680

Scheme 8. Representative sulfonic esters and sulfamic esters susceptible to hydrolysis.

Phosphoric acid esters such as hydrocortisone disodium phosphate4748 and echothio-phate iodide49 are known to hydrolyze (Scheme 9). Although nitric esters such as nitroglycerin50 and nicorandil51 undergo hydrolysis, nitroglycerin is relatively stable (Scheme 9). Phosphatidylcholine and phosphatidylethanolamine in intravenous lipid emulsion and aqueous liposome dispersions have been reported to hydrolyze in the neutral pH range.5253

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