Drs.i nyoman kadjeng widjaja

drug instability

loss of drug

reduction of

potency

poor

product quality

loss of drug potency

various pathways

only onequantitating

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

penicillenic acids

reactive intermediates

acidic pH

allergenicity of penicillins

rearrange

penicillins

degradants

The drug may

degrade

??

toxic substance

color or odor

Cholinesterase Reactivator

Organophosphorous pesticides

Exp.1.DEGRADANT

Exp.2.DEGRADANT

Fanconi syndrom

e

degradants

The drug may

degrade

??

the product

esthetically

unacceptable

Adrenalin, stimulan of sympathetic nervous system

a highly colored red

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

Drug substances used as pharmaceuticals

have diverse molecular structures and are,

therefore, susceptible to many and variable degradation pathways

Degradation pathways include hydrolysis,

dehydration, isomerization and

racemization, elimination, oxidation,

photodegradation, and complex interactions with excipients and

other drugs

design of stability studiesearliest stages

of drug development

minimize chemical

degradation

Parenteral products (contact with water) solid dosage forms,

(moisture)

hydrolysis

procaine, aspirin,

chloramphenicol,atropine,and

methyl-phenidate

Hydrolysis is often the main

degradation pathway for drug substances having ester and amide functional

groups within their

structure.

.

Ester bond

a carboxylic acid and

various alcohols

carbamic, sulfonic,

and sulfamic acids

and various alcohols

These ester compounds are primarily hydrolyzed

through nucleophilic attack

of hydroxide ion or water at the este

The degradation rate depends on the substituents R1 and R2,

in that electron-withdraw-ing groups enhance hydrolysis

whereas electron-donating groups inhibit hydrolysis

• Carboxylic acid esters that are susceptible to hydrolysis are shown include ethylparaben, benzocaine, procaine, oxathiin carboxanilide , aspirin, atropine, scopolamine, methylphenidate, meperidine, steroid esters such as hydrocortisone sodium succinate and methylprednisolone sodium succinate, and succinylcholine chloride.

• 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.

• 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.

• Other Esters. • Carbamic acid esters such as chlorphenesin carbamate and carmethizole,

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.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, a sulfonic acid ester, and sulfamic acid 1,7-heptanediyl ester ,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. Representative sulfonic esters and sulfamic esters susceptible to hydrolysis.

• Phosphoric acid esters such as hydrocortisone disodium phosphate and echothio-phate iodide are known to hydrolyze (Scheme 9).

• Although nitric esters such as nitroglycerin and nicorandil undergo hydrolysis, nitroglycerin is relatively stable (Scheme 9).

• Amide bonds are commonly found in drug molecules. Amide bonds are less susceptible to hydrolysis than ester bonds because the carbonyl carbon of the amide bond is less electrophilic (the carbon-to-nitrogen bond has considerable double bond character) and the leaving group, an amine, is a poorer leaving group (Scheme 10).

• Figure 3 shows the structure of acetaminophen, chloramphenicol, lincomycin, indomethacin, and sulfacetamide, all of which are known to produce an amine and an acid through hydrolysis of their amide bonds; moricizine, a derivative of phenothiazine, which undergoes hydrolysis of its amide bonds followed by oxidation; and HI-6, a bis(pyridimium)aldoxime having an amide bond, which exhibits fast hydrolysis in concentrated aqueous solutions owing to the acidifying effect of a strongly acidic oxime group.

β-Lactam

• β-Lactam antibiotics such as penicillins and cephalosporins, which are cyclic amides or lactams, undergo rapid ring opening due to hydrolysis. Ring opening of the β-lactam group has been reported or penams, such as, benzylpenicillin, ampicillin, amoxicillin, carbenicillin,phenethicillin,and methicillin (Scheme 11),

• For cephems, such as cephalothin cefadroxil, cephradine, and cefotaxime (Scheme12). These drug substances have both a lactam and an amide bond in their molecular structure, the former being considerably more susceptible to hydrolysis cephalothin and cefotaxime are also acetoxy esters, and opening of their lactam ring competes with hydrolysis of the ester bond. Decomposition products produced by hydrolysis of penam and cephem β-lactams are still reactive and undergo various side

reactions.

For example, condensation products were formed upon hydrolysis of cefaclor, and dimeric products were detected upon hydrolysis of loracarbef, as shown in Scheme 13, as well as of ampicillin.

• Cycloserine, which can be considered a cyclic amide, undergoes opening of its isoxazolidone ring due to hydrolysis in acidic media, as shown in Scheme 14. Like loracarbef and ampicilllin, it also undergoes self-condensation.

• The reactivity of these amides toward hydrolysis depends on the substituents R1, R2, and R3 (Scheme 10), as shown in Table 3.

• The β-lactam antibiotics, including penicillins and cephalosporins, undergo surprisingly facile hydrolysis compared to other amides. The most likely contributors to this facile hydrolysis are electronic factors, the relief of ring strain (a four-membered ring coupled to a five- or six-membered ring), and the lower double bond character between the carbonyl carbon and the amide nitrogen

• Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive.

• Barbituric acids such as barbital, phenobarbital, amobarbital, and metharbital undergo ring-opening hydrolysis, as shown in Scheme 15.

• Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation. The hydrolysis rates of these substances depend on the substituents R1, R2, and R3.

• For some allylbarbituric acids, the effects of these substituents on hydrolysis rates can be explained in terms of Hammett.s σ value. As shown in Scheme 16, the hydantoin allantoin is susceptible to hydrolysis, and the imide bonds in and (+)-1,2-bis(3,5-dioxopiperazinyl-l-yl)propane are hydrolyzed by parallel and successive reactions. The reactivity of the imide groups is intramolecularly affected by the tertiary amine groups in its structure.

• This conclusion was drawn from the observation that model compound A .As shown in Scheme 16, the hydantoin allantoin is susceptible to hydrolysis, and the imide bonds in and (+)-1,2-bis(3,5-dioxopiperazinyl-l-yl)propane are hydrolyzed by parallel and successive reactions. In the case of , the reactivity of the imide groups is intramolecularly affected by the tertiary amine groups in its structure. This conclusion was drawn from the observation that model compound A

OKSIDASI FOTOLISIS

• Oxidation is a well-known chemical degradation pathway for pharmaceuticals. Oxygen, which participates in most oxidation reactions, is abundant in the environment to which pharmaceuticals are exposed, during either processing or long-term storage. Oxidation of ascorbic acid (Scheme 44) was reported as early as 1940, and many factors affecting ascorbic acid oxidation have been discussed, including the role of metal ions

• Oxidation mechanisms for drug substances depend on the chemical structure of the drug and the presence of reactive oxygen species or other oxidants.

• Catechols such as methyl-dopa and epinephrine are readily oxidized to quinones, as shown in Scheme 45.

• 5-Aminosalicylic acid undergoes oxidation and forms quinoneimine, which is further degraded to polymeric compounds (Scheme 46).

• Ethanolamines such as procaterol are oxidized to formyl compounds (Scheme 47),

• Thiols such as 6-ercaptopurine, captopril, and derivative of thiocarbamic acid) are oxidized to disulfides (Scheme 48)

• Phenothiazines such as promethazine are oxidized via complex pathways and yield various products (Scheme 49)

• polyunsaturated molecules such as vitamin A, as well as other polyenes such as ergocalciferol, cholecalciferol, fumagillin, and filipin, are susceptible to oxidation

• Spiradoline is susceptible to oxidative degradation, resulting in the formation of an imidazolidine ring in addition to hydrolysis of the amide bond (Scheme 51)

• Sulfur atoms are becoming more common in new drug candidates and present a particular challenge owing to their propensity to oxidize to the corresponding sulfoxides and ultimately sulfones (Scheme 52)

Photodegradation

• Photodegradation has been reported for a large number of drug substances. The mechanisms for these reactions are generally very complex. As exemplified by chloroquine and primaquine, shown in Schemes 53 and 54, respectively, photodegradation generally yields numerous products through complex pathways. Photodegradation is often accompanied by oxidation in the presence of oxygen. Thus, drug substances such as Fumagillin, phenothiazines, and cholecalciferol,whose oxidation was described in the previous section, are degraded to different products in the presence and absence of light.

• Representative photodegradation routes for drug substances include dehydrogenation of nifedipine, reserpine,and nicardipine (Scheme 55)

• dehydrogenation accompanied by transmutation of a nitro group in nimodipine (Scheme 56)

• Rearrangement of chlordiazepoxide (Scheme 58)

• In addition, the following photoinduced degradation reactions have been reported:

• hydrolysis of mefloquine, furosemide, (Scheme 59); • elimination of hydrogen halide from meclofenamic acid (Scheme

60); • oxidation of a hydroxyl group of 2 l-cortisol tert-butylacetate and

a-[(dibutylamino)methy1]-6,8-dichloro-2-(3´,4´-dichlorophenyl)-4-quinoline methanol (Scheme 61); and rearrangement of benzydamine (Scheme 62).

• Oxidation of menadione is enhanced by light (Scheme 63)