The effect of crosslinker structure upon the rate of hydroperoxide formation in dried, crosslinked poly(vinylpyrrolidone)

Abstract

The hydroperoxide levels of two commercial types of crosslinked poly(vinylpolypyrrolidinone) (or crospovidone) disintegrants were studied as a function of time and temperature using the titanyl sulfate titration method. It was noted that the two crospovidone types exhibited significantly different rates of hydroperoxide buildup and that this difference increases with increasing temperature. While the chemical and physical structures of these commercial types are essentially the same, they are known to be different with respect to their crosslinkers which represent nominally 2% of the total mass. These crosslinkers are 3-ethylidene-N-vinyl-2-pyrrolidinone and N,N 0 -divinylimidazolidinone. While both contain lactam type rings, the latter possesses two nitrogen atoms versus one in the former. It was hypothesized that this difference in the number of heteroatoms results in a greater susceptibility to oxidative attack at carbon positions vicinal to these nitrogen atoms. To test this hypothesis, model compounds representing the two crosslinker ring structures were subjected to oxidative attack and analyzed for hydroperoxide buildup over time and at several temperatures. The results of the model compound study were consistent with the observations made for hydroperoxide buildup in the corresponding crospovidone types thereby supporting this hypothesis.

Evaluation of the physicochemical characteristics of crospovidone that influence solid dispersion preparation

“…All of the products are USP grade; however, it is well known that the characteristics of a polymer differ among commercial sources (Tallon et al, 2008). Thus, the behavior of XL and CL with regard to SD preparation was compared.…”

“…The reaction processes for manufacturing XL and CL are different (Tallon et al, 2008). XL is made using alkali metal hydroxide and a small amount of added water, whereas CL is produced using N,Ndivinylimidazolidone as a crosslinker.…”

Effect of Antioxidants and Silicates on Peroxides in Povidone

“…12 Free-radical-mediated oxidation reactions tend to be self-propagating until the substrate is depleted. These reactions could be initiated by the presence of an initiator, such as heavy metal, peroxides, or oxygen, along with environmental stresses such as heat or light.…”

“…The peroxy radical can then participate in an autocatalytic cycle by abstraction of hydrogen atom from another reactant to form a hydroperoxide while generating another free-radical carbon. 12 The O O bond in peroxides is particularly weak and can cleave to form alkoxy (RO•) and hydroxy (•OH) free radicals. Peroxides and free radicals can also lead to formation of other reactive oxygen species such as superoxide anion (O 2-•), hydrogen peroxide (H 2 O 2 ), and organic hydroperoxides (R OOH).…”

“…13 In studies where peroxides in excipients were implicated in the oxidative degradation of drugs in their formulations, control of initial peroxide concentration was recommended for drug product stabilization. 1,9,13 Approaches for reducing peroxides from excipients include use of enzymes, 14 metals, 14 or other additives, 15 chemical modification of crosslinker, 12 supercritical fluid extraction, 16 and vacuum drying. 17 However, the peroxide impurities in excipients, such as povidone, tend to increase upon storage.…”