Solute Crystallization in Mannitol–Glycine Systems—Implications on Protein Stabilization in Freeze‐Dried Formulations

Pyne, Abira; Chatterjee, Koustuv; Suryanarayanan, Raj

doi:10.1002/jps.10487

Cited by 56 publications

(37 citation statements)

References 19 publications

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“…Stability and retention of labile biomolecules during drying and later storage are often dependent on their encapsulation in an amorphous matrix formed during dehydration processes [23,107]. Amorphous sugars are effective encapsulating agents.…”

Section: Degradation Of Encapsulated Hydrophobic Componentsmentioning

confidence: 99%

“…However, obtaining pure amorphous mannitol by rapid cooling of a hot solution or by freeze-drying of an aqueous mannitol solution, while possible, is not practical, because amorphous mannitol is physically unstable and will transform into a more stable crystalline form, even under ambient conditions [159,163]. Another, more practical approach is the freeze-drying or rapid cooling of mannitol in combination with other amorphous components [107,159]. Molecular-level mixing with other components may limit the spatial rearrangement of mannitol molecules required for crystallization.…”

Section: Pharmaceutical Systemsmentioning

confidence: 99%

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State diagrams for improving processing and storage of foods, biological materials, and pharmaceuticals (IUPAC Technical Report)

Buera

Roos

Levine

et al. 2011

Pure and Applied Chemistry

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Supplemented temperature/composition phase diagrams include the non-equilibrium glass-transition temperature (T g ) curve and equilibrium ice-melting and solubility curves. The inclusion of the non-equilibrium curve allows one to establish relationships with the time coordinate and, thus, with the dynamic behavior of systems, provided that the thermal history of such systems is known.The objective of this report is to contribute to the potential applications of supplemented state diagrams for aqueous glass-formers, in order to describe the influence of water content, nature of vitrifying agents, and temperature on the physico-chemical properties of foods and biological and pharmaceutical products. These data are helpful to develop formulations, processing strategies, or storage procedures in order to optimize the stability of food ingredients and pharmaceutical formulations. Reported experimental data on phase and state transitions for several food and pharmaceutical systems were analyzed. Some methodological aspects and the effect of phase and state transitions on the main potential chemical reactions that can alter those systems during processing and/or storage are discussed.

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Section: Degradation Of Encapsulated Hydrophobic Componentsmentioning

confidence: 99%

Section: Pharmaceutical Systemsmentioning

confidence: 99%

State diagrams for improving processing and storage of foods, biological materials, and pharmaceuticals (IUPAC Technical Report)

Buera

Roos

Levine

et al. 2011

Pure and Applied Chemistry

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“…However, it can be seen that there is a tendency for samples containing excipients to result in higher moisture contents when analysed by KF titration than by the NIR model, indicating that NIR might underestimate the moisture content in the presence of excipients. A possible explanation can be given as follows: It has been reported in the literature that both sodium chloride and the amino acid glycine can inhibit the crystallisation of mannitol [20,21]. Based on these findings it can be assumed that sodium chloride and the amino acid histidine can lead to an increase in the amount of amorphous mannitol in the samples thus increasing the amount of absorbed water compared to surface water.…”

Section: Resultsmentioning

confidence: 96%

Role of excipients in the quantification of water in lyophilised mixtures using NIR spectroscopy

Grohganz

Fonteyne

Skibsted

et al. 2009

Journal of Pharmaceutical and Biomedical Analysis

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The ratio between mannitol and sucrose in a freeze-dried formulation has a major impact on the processing and the stability of a lyophilised product. The ratio of these common excipients influences a critical quality attribute of the system, namely the overall amount of water, due to the different nature of their water-solid interactions. For this experiment samples containing various ratios of mannitol and sucrose and several other additives were freeze-dried, stored under different conditions and measured by NIR. Different spectral pre-processing methods and wavelength selections were tested. Multivariate analysis was applied to correlate the Karl Fischer titration to the NIR spectra. It was found that standard normal variate (SNV) transformation of the wavenumber range 4200 7400 cm -1 yielded prediction errors close to the accepted measurement error of the Karl Fischer titration, when measuring samples of up to 5.5% (w/w) water. It was further found that there was a slight tendency for samples containing inorganic salts or histidine to be underestimated in the NIR measurements. However, no influence was found to be caused by the varying mannitol-sucrose ratio. By reducing the sample set to those samples containing up to around 2% of water, the error was found to be below the uncertainty originating from the reference method. Due to this it can no longer be determined whether the deviation originates from the NIR method or the reference method. It can therefore be concluded the NIR is a suitable tool for quantification of the water content in lyophilised samples with varying mannitol-sucrose ratios.

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“…The reason may be as follows: It has been reported that both NaCl and the amino acid glycine can influence the crystallisation of mannitol [18,19]. Differences in crystallisation behaviour can thus result in the formation of for instance mannitol hemihydrate, amorphous mannitol and other polymorphic forms of mannitol, which in turn would show differences in the three dimensional microstructure on molecular level of the formulation and thus influence the strength of the C-H bonds.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, several formulation substances have been found to influence the crystallisation behaviour of mannitol, e.g. polysorbate 80 [17], glycine and Na 2 HPO 4 [18], NaCl and alditols [19], or boric acid [20].…”

Section: Introductionmentioning

confidence: 99%

Classification of lyophilised mixtures using multivariate analysis of NIR spectra

Grohganz

Fonteyne

Skibsted

et al. 2010

European Journal of Pharmaceutics and Biopharmaceutics

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Excipient selection is critically affecting the processing and the stability of a lyophilised product. Near infra-red (NIR) spectroscopy was applied to investigate freeze-dried samples containing varying ratios of the commonly used excipients mannitol and sucrose.Further variation in the formulation was achieved by adding NaCl, CaCl 2 and histidine and by exposing the samples to different conditions. Untreated NIR spectra are strongly affected by the physical nature of samples and can thus be useful for detecting production outliers. Applying standard normal variate (SNV) transformation highlights chemical information. The obtained NIR spectra of the freeze-dried samples were clustered by principal component analysis (PCA) after applying SNV correction in the range 4200 to 7400 cm -1 (1350 2380 nm). Relative humidity under storage and the mannitol-sucrose ratio were clearly represented in the first two principal components, while influence of other excipients was observed in the 3 rd and 4 th principal component. It was investigated whether this could be due to an influence of the excipients on the mannitol crystallisation behaviour. Performing PCA with 2 principal components of SNV-corrected spectra in the range 4200 4500 cm -1 (2220 1380 nm) led to the following observation: While the 1 st principal component closely resembled the spectra of b-mannitol, the 2 nd principal component contained additional features that were not attributable to b-mannitol but correlated well to the main absorbance band of d-mannitol and mannitol hemihydrate.Therefore, it seems feasible that NIR can analyse versatile freeze-dried samples and classify these according to composition, water content and solid-state properties.

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Solute Crystallization in Mannitol–Glycine Systems—Implications on Protein Stabilization in Freeze‐Dried Formulations

Cited by 56 publications

References 19 publications

State diagrams for improving processing and storage of foods, biological materials, and pharmaceuticals (IUPAC Technical Report)

State diagrams for improving processing and storage of foods, biological materials, and pharmaceuticals (IUPAC Technical Report)

Role of excipients in the quantification of water in lyophilised mixtures using NIR spectroscopy

Classification of lyophilised mixtures using multivariate analysis of NIR spectra

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