title: Chemical reactivity in solid-state pharmaceuticals: formulation implications.
abstract: Solid-state reactions that occur in drug substances and formulations include solid-state phase transformations, dehydration/desolvation, and chemical reactions. Chemical reactivity is the focus of this chapter. Of particular interest are cases where the drug-substance may be unstable or react with excipients in the formulation. Water absorption can enhance molecular mobility of solids and lead to solid-state reactivity. Mobility can be measured using various methods including glass transition (T(g)) measurements, solid-state NMR, and X-ray crystallography. Solid-state reactions of drug substances can include oxidation, cyclization, hydrolysis, and deamidation. Oxidation studies of vitamin A, peptides (DL-Ala-DL-Met, N-formyl-Met-Leu-Phe methyl ester, and Met-enkaphalin acetate salt), and steroids (hydrocortisone and prednisolone derivatives) are discussed. Cyclization reactions of crystalline and amorphous angiotensin-converting enzyme (ACE) inhibitors (spirapril hydrochloride, quinapril hydrochloride, and moexipril) are presented which investigate mobility and chemical reactivity. Examples of drug-excipient interactions, such as transacylation, the Maillard browning reaction, and acid base reactions are discussed for a variety of compounds including aspirin, fluoxitine, and ibuprofen. Once solid-state reactions are understood in a pharmaceutical system, the necessary steps can be taken to prevent reactivity and improve the stability of drug substances and products.
authors.affiliation: Purdue University, West Lafayette, IN 47907, USA. sbyrn@pharmacy.purdue.edu
authors.forename: S R
authors.initials: SR
authors.lastname: Byrn
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: A W
authors.initials: AW
authors.lastname: Newman
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D005079:Excipients; D015416:Maillard Reaction; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D013256:Steroids / Q000737:chemistry*; D014801:Vitamin A / Q000737:chemistry*
chemical_list: D005079:Excipients; D010455:Peptides; D013256:Steroids; D014801:Vitamin A