Drug Excipient and Drug Drug Interactions

As will be seen in Chapter 4, drugs are rarely formulated as just the drug substance itself. Often, additives or excipients are present in the formulation. Quite often, reactions can occur between the drug and one or more additives. Similarly, two drugs might be formulated in the same product and react with each other.

CHrfi CHj nicardipine

Scheme 55. Photodegradation leading to dehydrogenation of nifedipine, reserpine, and nicardipine. Reactions of Bisulfite, an Antioxidant

In the 1950s, it was reported that epinephrine, a catecholamine, undergoes displacement of its hydroxy group by bisulfite, as shown in Scheme 64.231 Dexamethasone 21-phosphate, an a/p-unsaturated ketone, is known to undergo addition by bisulfite (Scheme 64)232 Reaction of Amines with Reducing Sugars

Reducing sugars readily react with primary amines, including those of amino acids, through the Maillard reaction. Drug substances with primary or secondary amine groups

Stability Benzydamine
Scheme 56. Photodegradation of nimodipine.
Stability Benzydamine

Scheme 57. Some unusual photochemically induced reactions.

Stability Benzydamine
Scheme 58. Degradation of chlordiazepoxide.
Stability Benzydamine
Scheme 59. Photochemically induced elimination/hydrolysis.

Scheme 60. Photodegradation of meclofenamic acid.

Image Grenouille Colorier
Scheme 61. Photodegradation leading to oxidation of a hydroxy group.

CHjPh oa



Scheme 62. Photodegradation of benzydamine.

Scheme 63. Photooxidation of menadione.
dexamethasone 21-phosphate Scheme 64. Representative drug substances susceptible to substitution and addition reactions by bisulfite.

undergo this addition/rearrangement reaction, also called the "browning" reaction because of the resulting discoloration. Examples are the reaction of amphetamine,233 isoniazid,234 dextroamphetamine sulfate,235 236 and norphenylephrine237 with sugars such as lactose and the degradation products of sugars, such as 5-(hydroxymethyl)furfural. Sulpyrine forms an addition product with glucose.238 Transesterification Reactions

In the presence of drug substances with hydroxy groups, aspirin undergoes a reversible transacylation reaction to form salicylic acid, while acetylating the drug substance. For example, codeine239 and sulfadiazine240 are acetylated by aspirin, as shown in Scheme 65. Similar acetylation reactions with aspirin have been reported for acetaminophen241 and the excipient polyethylene glycol.242 243 Another example of transesterification is the reaction of benzocaine with polyvinyl acetate phthalate (Scheme 66).244


Scheme 65. Representative drug substances susceptible to acetylation by aspirin.


Scheme 65. Representative drug substances susceptible to acetylation by aspirin.

Scheme 66. Interaction of benzocaine and polyvinyl acetate phthalate.

Scheme 66. Interaction of benzocaine and polyvinyl acetate phthalate.

2.2. Factors Affecting Chemical Stability

In the previous section, the chemical degradation pathways for many drug substances were classified according to various pathways and mechanisms. In this section, factors that affect the rates of chemical degradation are elaborated.

Factors determining the chemical stability of drug substances include intrinsic factors such as the molecular structure of the drug itself and environmental factors, such as temperature, pH, buffer species, ionic strength, light, oxygen, moisture, additives, and excipients. In the case of solid-state degradation, the solid-state properties of the drug such as melting point, crystallinity, and hygroscopicity are very important. In addition, mechanical forces such as pressure and grinding applied to drug substances may affect their chemical as well as physical stability. By applying well-established kinetic concepts, it is possible not only to summarize, numerically, the role that each variable might play in altering the kinetics of degradation but also to provide valuable insight into the mechanism(s) of degradation.

Continue reading here: Basic Kinetic Principles

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