Impact of Freeze-Drying on Ionization of Sulfonephthalein Probe Molecules in Trehalose–Citrate Systems

Govindarajan, Ramprakash; Chatterjee, Koustuv; Gatlin, Larry A.; Suryanarayanan, Raj; Shalaev, Evgenyi

doi:10.1002/jps.20620

Cited by 41 publications

(42 citation statements)

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“…The pH eq of the solid surface is defined as the pH of an aqueous solution in which the ratio of the peak absorbance signals of the ionized to the unionized forms of the indicator is the same as in the given solid sample. If the ratio of the extinction coefficients of the ionized and unionized species is similar in an aqueous solution and in the solid sample, as was shown for several sulfonephthalein indicators (11), the pH eq value closely approximates the H 2− (9).…”

Section: Introductionmentioning

confidence: 54%

“…The probe indicator method is more difficult from the measurement perspective and also has more experimental variables. These issues were addressed by Pudipeddi et al (12) and also in our earlier publications (9,11). For example, any particular probe molecule would cover only a narrow acidity range, and several indicators with different pK a values may be needed to measure acid-base properties of different excipients.…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, measurements are performed with solid materials, in which acid-base properties of the material are evaluated by monitoring protonation-dependent properties of various probe molecules with a corresponding detection method. Detection methods depend on the nature of a probe molecule and include NMR (2), fluorescence (3), attenuated total reflectance Fourier transform infrared spectroscopy (4), evanescent wave cavity ring-down spectroscopy (5), electron spin resonance (6), inverse gas chromatography (7), and diffuse reflectance visible spectroscopy (9)(10)(11). The last method usually utilizes common pH indicators (i.e., sulfonephthalein probe molecules) and represents the most common approach for pharmaceutical systems.…”

Section: Introductionmentioning

confidence: 99%

“…Limitations of both the approaches to measure apparent acidity for pharmaceutical solids have been discussed earlier (9,11,12). However, this is not a problem unique to solids; many liquid systems, such as mixed solvents and aqueous solutions with high salt or acid concentrations, do not have an established, thermodynamically rigorous, proton activity scale (13).…”

Section: Introductionmentioning

confidence: 99%

“…For example, any particular probe molecule would cover only a narrow acidity range, and several indicators with different pK a values may be needed to measure acid-base properties of different excipients. In addition, pH eq values were dependent on the probe molecule used, when the acidity values of the same material differed by 0.1-0.5 units when measured using different indicators (11).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 54%