<scp>Processing‐Induced</scp>Phase Transformations and Their Implications on Pharmaceutical Product Quality

Thakral, Seema; Govindarajan, Ramprakash; Suryanarayanan, Raj

doi:10.1002/9783527697847.ch12

Cited by 3 publications

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“…However, there is lattice disorder in many pharmaceutical solids. Moreover, pharmaceutical processing is also known to induce lattice disorder in solids . One consequence of introducing lattice disorder is an increase in the reactivity.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, pharmaceutical processing is also known to induce lattice disorder in solids. 29 One consequence of introducing lattice disorder is an increase in the reactivity. Recently, we demonstrated that lattice disorder (decrease in crystallinity) introduced by milling caffeine-oxalic acid cocrystals, for just 30 s, facilitated their dissociation.…”

Section: ■ Resultsmentioning

confidence: 99%

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Modulation of Microenvironmental Acidity: A Strategy to Mitigate Salt Disproportionation in Drug Product Environment

2020

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Disproportionation of pioglitazone hydrochloride (PioHCl), leading to the free base formation, was observed in tablet formulations containing basic excipients such as magnesium stearate (Koranne et al, Mol. Pharmaceutics, 2017, 14, 1133−1144. The nature and concentration of excipients, by modulating the microenvironmental acidity (measured as pH eq ), governed the disproportionation reaction. In the current work, we hypothesized that the addition of an organic acid, by lowering the pH eq , can stabilize PioHCl. Powder blends containing PioHCl, magnesium stearate and each oxalic, maleic, tartaric, fumaric, and glutaric acid were stored at 40 °C/75% RH for 15 days. The concentration of crystalline free base, a product of the disproportionation reaction, was quantified using synchrotron radiation. The pH eq of the powder blends was measured via ionization of probe molecules deposited on the surface. In general, the stronger the acid, the lower the pH eq of the formulation blend and more effective it was in stabilizing PioHCl and preventing disproportionation. Thus, controlling the microenvironmental acidity in a rational and systematic way provided an avenue to mitigate excipient-induced salt disproportionation. Even when the lattice of PioHCl was activated by milling, it remained stable in the presence of acid. The amount of water sorbed during tablet storage provided an indirect measure of the disproportionation.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%