Correlation between Chemical Reactivity and the Hammett Acidity Function in Amorphous Solids Using Inversion of Sucrose as a Model Reaction

Chatterjee, Koustuv; Shalaev, Evgenyi; Suryanarayanan, Raj; Govindarajan, Ramprakash

doi:10.1002/jps.21081

Cited by 20 publications

(15 citation statements)

References 43 publications

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“…Where the ratio of ionized to unionized species of pH indicator dye, measured by UV-vis diffuse reflectance (DR) spectrophotometer, provides solid state acidity for lyophiles. The relationships between the Hammett acidity function and solid-state degradation were demonstrated for several small molecular weight compounds [2,12,17,22,29]. Expect that similar relationships between the Hammett acidity function and degradation rate of acidsensitive protein molecules would be observed for freeze-dried protein formulations as well, although publications in this area are lacking.…”

Section: Characterization Methodsmentioning

confidence: 89%

“…This effect was demonstrated in studies which used sucrose as a model of acid-sensitive compound which was lyophilized using citrate buffer and several different lyoprotectors [12,29]. Freeze-dried formulations, containing sucrose and co-solute (lactose, polyvinyl pyrrolidone (PVP), and dextran of different molecular weights) at 1:10 weight ratio, were prepared from solutions of the same pH with citrate buffer, and the rate of acid-catalyzed sucrose inversion was determined during storage of the lyophiles.…”

Section: Carboxylic Acid Buffersmentioning

confidence: 90%

“…Ultraviolet (UV)-visible spectrophotometry was used to probe the extent of proton transfer of bromophenol blue in the citrate buffer systems in solution and the amorphous solid state. This work was extended to focus on measurement of the apparent acidity using pH indicators, with the acidity expressed as the Hammett acidity function (Equation below), and to establish relationships between the Hammett acidity function and the degradation rate of acid-sensitive molecules in the amorphous freeze-dried formulations [12]. Figure 1 below shows the main principle and example of Hammett acidity function measurement in lyophile.…”

Section: Characterization Methodsmentioning

confidence: 99%

“…2 Pseudo-first-order rate constants of sucrose inversion in PVP ( squares), lactose ( triangles), and dextran ( circles) lyophiles as a function of Hammett acidity function. The line reflects the correlation between the rate constant (logarithmic scale) and the Hammett acidity function ( Blue symbols are for datapoints from Chatterjee et al [12] and black symbols from Lu et al [29]) been reported for glycines depending on the technique and sample tested [27]. Specifically, using a low-temperature pH probe, Larsen showed no pH change at pH 2.8 and moderate increase from 9.3 to 10.2.…”

Section: Amines and Amino Acidsmentioning

confidence: 95%

See 3 more Smart Citations

Advance Understanding of Buffer Behavior during Lyophilization

Shamblin

Varshney³

et al. 2015

Lyophilized Biologics and Vaccines

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Section: Characterization Methodsmentioning

confidence: 89%

Section: Carboxylic Acid Buffersmentioning

confidence: 90%

Section: Characterization Methodsmentioning

confidence: 99%

Section: Amines and Amino Acidsmentioning

confidence: 95%

See 2 more Smart Citations

Advance Understanding of Buffer Behavior during Lyophilization

Shamblin

Varshney³

et al. 2015

Lyophilized Biologics and Vaccines

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“…Note that the present study was focused on correlating properties of neat excipients and their impact on API stability in heterogeneous powder mixtures with API. The relationships between solidstate stability and acid-base milieu in single-phase API-excipient mixtures (such as amorphous freeze-dried materials) are covered elsewhere (21,22).…”

Section: Introductionmentioning

confidence: 99%

Surface Acidity and Solid-State Compatibility of Excipients with an Acid-Sensitive API: Case Study of Atorvastatin Calcium

et al. 2014

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Abstract. The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pH eq ) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pH eq . No lactone formation was observed in mixtures with excipients having pH eq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50°C/20% RH) with excipients exhibiting pH eq < 3. The three pH eq regions (> 6, 3-6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pH eq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid-sensitive API, were identified based on pH eq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API.

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Freeze‐Drying, Pharmaceuticals

Liu

2010

Encyclopedia of Industrial Biotechnology

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This article provides an overview of the fundamental aspects for pharmaceutical freeze‐drying, including the rationale for freeze‐drying process design and control, the basics of formulation development for freeze‐drying, the importance of the container‐closure system, and a general description of pharmaceutical freeze‐dryers. In the second part of this article, the challenges in freeze‐drying scale‐up and transfer, freezing control, use of cosolvent, freeze‐drying in syringes, process analytical technology, and quality‐by‐design in freeze‐drying have been discussed, and some new advancements related to these aspects are also highlighted.

show abstract

Correlation between Chemical Reactivity and the Hammett Acidity Function in Amorphous Solids Using Inversion of Sucrose as a Model Reaction

Cited by 20 publications

References 43 publications

Advance Understanding of Buffer Behavior during Lyophilization

Advance Understanding of Buffer Behavior during Lyophilization

Surface Acidity and Solid-State Compatibility of Excipients with an Acid-Sensitive API: Case Study of Atorvastatin Calcium

Freeze‐Drying, Pharmaceuticals

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