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

Sampada Koranne; Rahul Lalge; Raj Suryanarayanan

doi:10.1021/acs.molpharmaceut.0c00024

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

Sampada Koranne, Rahul Lalge, Raj Suryanarayanan

Pharmaceutics

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10 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1324-1334
Number of pages	11
Journal	Molecular pharmaceutics
Volume	17
Issue number	4
DOIs	https://doi.org/10.1021/acs.molpharmaceut.0c00024
State	Published - Apr 6 2020

Bibliographical note

Funding Information:
The work was partially funded by the William and Mildred Peters endowment fund. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Dr. Wenqian Xu for the help with the use of the 17BM beamline. The laboratory XRD studies were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program.

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Keywords

X-ray diffractometry
lattice disorder
magnesium stearate
microenvironmental acidity
organic acids
pH indicators
salt disproportionation
salt stability
synchrotron

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

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title = "Modulation of Microenvironmental Acidity: A Strategy to Mitigate Salt Disproportionation in Drug Product Environment",

abstract = "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 pHeq), governed the disproportionation reaction. In the current work, we hypothesized that the addition of an organic acid, by lowering the pHeq, 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 pHeq of the powder blends was measured via ionization of probe molecules deposited on the surface. In general, the stronger the acid, the lower the pHeq 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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note = "Funding Information: The work was partially funded by the William and Mildred Peters endowment fund. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Dr. Wenqian Xu for the help with the use of the 17BM beamline. The laboratory XRD studies were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

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N2 - 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 pHeq), governed the disproportionation reaction. In the current work, we hypothesized that the addition of an organic acid, by lowering the pHeq, 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 pHeq of the powder blends was measured via ionization of probe molecules deposited on the surface. In general, the stronger the acid, the lower the pHeq 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.

AB - 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 pHeq), governed the disproportionation reaction. In the current work, we hypothesized that the addition of an organic acid, by lowering the pHeq, 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 pHeq of the powder blends was measured via ionization of probe molecules deposited on the surface. In general, the stronger the acid, the lower the pHeq 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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Modulation of Microenvironmental Acidity: A Strategy to Mitigate Salt Disproportionation in Drug Product Environment

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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