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

Koranne, Sampada; Lalge, Rahul; Suryanarayanan, Raj

doi:10.1021/acs.molpharmaceut.0c00024

Cited by 11 publications

(9 citation statements)

References 29 publications

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“…Salt disproportionation is a function of the pH max of the salt (i.e., levothyroxine sodium) and the “pH” of the microenvironment. This is the pH of the microscopic sorbed water layer on the surface of the particles in which the solid has dissolved and formed a saturated solution. , The propensity for disproportionation increased as a function of the strength of the acid. Given the evidence of salt disproportionation even with stearic acid, it is reasonable to expect free acid formation with citric acid (pH eq of citric acid <1.6) …”

Section: Resultsmentioning

confidence: 99%

“…In the presence of routinely used excipients, disproportionation of salts in the solid-state has been documented. 41 The risk of excipientinduced salt disproportionation is especially high in the present case since excipients essentially constitute the entire dosage form. We believe that this is the first report of salt disproportionation in LSP tablets.…”

Section: ■ Introductionmentioning

confidence: 95%

“…For salts of weak acids (such as LSP), if the pH of the microenvironment drops below the pH max , salt disproportionation will occur. In the presence of routinely used excipients, disproportionation of salts in the solid-state has been documented . The risk of excipient-induced salt disproportionation is especially high in the present case since excipients essentially constitute the entire dosage form.…”

Section: Introductionmentioning

confidence: 97%

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Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate

Kaur

Suryanarayanan

2021

Mol. Pharmaceutics

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A range of tablet excipients were evaluated for their influence on the physical form and chemical stability of levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O). LSP–excipient binary powder blends were stored under two conditions: (a) in hermetically sealed containers at 40 °C and (b) at 40 °C/75% RH. By use of synchrotron X-ray diffractometry, the disappearance of LSP could be quantified and the appearance of crystalline levothyroxine (free acid) could be identified. Under hermetically sealed conditions (40 °C) hygroscopic excipients such as povidone induced partial dehydration of LSP to form levothyroxine sodium monohydrate. When stored at 40 °C/75% RH, acidic excipients induced measurable disproportionation of LSP resulting in the formation of levothyroxine (free acid). HPLC analyses of drug–excipient mixtures revealed that lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium caused pronounced chemical decomposition of LSP. On the other hand, magnesium stearate, sodium stearyl fumarate, and alkaline pH modifiers did not affect the physical and chemical stability of the API following storage at 40 °C/75% RH. HPLC, being a solution based technique, revealed chemical decomposition of the API, but the technique was insensitive to physical transformations. Excipient properties such as hygroscopicity and microenvironmental acidity were identified to be critical determinants of both physical and chemical stability of LSP in a drug product. For drugs exhibiting both physical and chemical transformations, simultaneous solid-state and solution based analyses will enable comprehensive stability evaluation.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

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Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate

Kaur

Suryanarayanan

2021

Mol. Pharmaceutics

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“…Citric acid (CA) is a widely used pH modifier in pharmaceutical formulations, primarily to adjust the microenvironmental pH of tablet matrices . pH modifiers, such as citric acid, have been used previously as an effective tool to modulate the microenvironmental pH to enhance stability ,− and minimize salt disproportionation during manufacturing and dissolution. − Lactose monohydrate (LM) and magnesium stearate (MgSt) are widely used functional excipients in solid-dosage forms . It is well-documented that magnesium stearate induces and accelerates disproportionation reactions when blended with weak base salts due to its alkaline nature. ,,, …”

Section: Resultsmentioning

confidence: 99%

Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging

et al. 2021

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We have employed a bespoke setup combining confocal Raman microscopy and an ultraviolet–visible (UV–Vis) spectroscopy flow cell to investigate the effect of excipients on the disproportionation kinetics of Pioglitazone HCl (PioHCl) in tablets during dissolution. Three binary formulations of PioHCl, containing citric acid monohydrate (CA), lactose monohydrate (LM), or magnesium stearate (MgSt), respectively, were used as models to study the influence of excipients’ physicochemical properties on the rate of salt disproportionation kinetics and dissolution performance in different aqueous pH environments. It was found that formulation excipients can induce or prevent salt disproportionation by modulating the microenvironmental pH regardless of the pH of the dissolution media. Incorporating CA in PioHCl tablets preserves the salt form and enhances the dissolution performance of the salt in the acidic medium (pH = 1.2). In contrast, LM and MgSt had a detrimental effect on in vitro drug performance by inducing salt disproportionation in the tablet during dissolution in the same acidic medium. Dissolution in the neutral medium (pH = 6.8) showed rapid formation of the free base upon contact with the dissolution medium. The Raman maps of the cross-sectioned tablets revealed the formation of a shell consisting of the free base around the edge of the tablet. This shell decreased the rate of penetration of the dissolution medium into the tablet, which had significant implications on the release of the API into the surrounding solution, as shown by the UV–vis absorption spectroscopy drug release data. Our findings highlight the utility of the Raman/UV–vis flow cell analytical platform as an advanced analytical technique to investigate the effect of excipients and dissolution media on salt disproportionation in real time. This methodology will be used to enhance our understanding of salt stability studies that may pave the way for more stable multicomponent formulations.

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“…If salt ingredients are introduced in the formulation of an immediate release dosage forms, it will decrease the dissolution of less soluble compounds. To achieve a pH-independent release for the extended release of weak acidic or basic drugs, pH modifiers may be introduced, which can be combined with a basic drug for example to enhance the solubility significantly at high pH values [21] .…”

Section: Extended Release Mini Tabletsmentioning

confidence: 99%

Pharmaceutical Mini-Tablets Overview

2021

IJFMT

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Oral dosage forms are considered as the most preferred dosage forms to various age groups of patients. However, conventional solid dosage forms (tablets and capsules) have been associated with some issues; such fluctuation in the plasma drug concentration and swallowing difficulty for some patients. This advocates the need for the continuous development and improvement of tablets and capsule to enhance therapeutic efficacy and increase patient acceptance. Mini tablets technology has been developed to minimize these problems. It aims to facilitate oral administration with minimal swallowing difficulty (especially in pediatrics and geriatrics) and deliver a therapeutic agent, selectively and effectively, to be targeted in a certain position in the body. The most benefit of this technique is the ease of production with facilitated control of stability problems. The size and shape uniformity, with smooth surface area, make minitablets attractive to be incorporated with different medications for the efficient treatment of chronic diseases. This overview outlines properties, production requirements, formulation options and evaluation methods of mini tablets.

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

Cited by 11 publications

References 29 publications

Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate

Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate

Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging

Pharmaceutical Mini-Tablets Overview

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