Isomerization and Racemization

Reported examples of isomerization of drug substances include trans-cis isomerization of amphotericin B (Scheme 33),148 N,O-acyl rearrangement of cyclosporin A (Scheme 34),149 and dienone-phenol rearrangement of steroids such as tirilazad (Scheme 35).150

Scheme 25. Hydrolysis of 5-azacytidine and cytarabine.

cytarabine

Scheme 25. Hydrolysis of 5-azacytidine and cytarabine.

Scheme 26. Other drug substances that are susceptible to hydrolysis, including alkyl halides, sulfides, and platinum compounds.

2',3'-dideoxyguanosine Scheme 27. Hydrolysis of nucleosides.

i-(hydroxymethyl)-2-furfural Scheme 28. Dehydration of glucose.

Parole Giapponese Tatto
Scheme 29. Dehydration of erythromycin.

Scheme 30. Dehydration and isomerization of prostaglandin E2.

Scheme 30. Dehydration and isomerization of prostaglandin E2.

Scheme 31. Ring closure following dehydration of batanopride.
Scheme 32. Dehydration of streptovitacin A.
Scheme 33. Trans-cis Isomerization of amphotericin B.

CH(CH3)2

Scheme 34. N,O-Acyl rearrangement of cyclosporin A.

Scheme 35. Dienone-phenol rearrangement of tirilazad.

ergotamine

Scheme 36. Representative drug substances susceptible to epimerization.

Scheme 37. Epimerization and hydrolysis of etoposide.

stoposide

Scheme 37. Epimerization and hydrolysis of etoposide.

Racemization and epimerization, which are reversible conversions between optical isomers, have been reported for many drug substances. As shown in Scheme 36, pilocarpine undergoes epimerization by base catalysis,36-38 whereas tetracyclines151152 such as rolitetracycline,153154 and ergotamine155 exhibit epimerization by acid catalysis. Etoposide converts reversibly to picroetoposide, a cw-lactone, and then hydrolyzes to cis-hydroxy acid in the alkaline pH region, as shown in Scheme 37.156-157 Epinephrine is oxidized (see Section 2.1.5) and undergoes racemization under strongly acidic conditions (Scheme 38).158 Other drug substances susceptible to racemization include benzodiazepines, penicillins, and cephalosporins. Oxazepam undergoes racemization through a rapid equilibrium reaction in the neutral-to-alkaline pH region (Scheme 39).159 Moxalactam exhibits epimerization of its side chain as well as hydrolysis of the B-lactam ring (Scheme 40).160-162 Hetacillin exhibits epimerization of the lactam ring, hydrolysis of the side chain, and P-lactam ring cleavage (Scheme 41).163 Similar racemization and hydrolysis have been reported for carbe-nicillin,164,165 cefsulodin,166 cefotaxime,167 and dalvastatin.39

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Responses

  • JENNIFER
    How isomerization effect the drug stability?
    2 months ago

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