Implementation of a Process Analytical Technology System in a Freeze-Drying Process Using Raman Spectroscopy for In-Line Process Monitoring

Beer, T.R.M. De; Allesø, Morten; Goethals, F; Coppens, Alexander; Heyden, Yvan Vander; Diego, Heidi Lopez de; Rantanen, Jukka; Verpoort, Francis; Vervaet, Chris; Remon, Jean Paul; Baeyens, Willy R. G.

doi:10.1021/ac070549h

Cited by 109 publications

(126 citation statements)

References 35 publications

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“…Moreover, a small peak at 9.90°, selective for δ-mannitol, in the diffractograms of runs 5, 12, 13, 18 and 19 indicated a significant residual percentage of δ-mannitol in these samples [21,22,30,34,36,37]. The overall lower intensity of the peaks in the diffractograms of the granules was attributed to a different crystal habit of the granules in comparison to the reference materials (powders) [38].…”

Section: Solid State Characterizationmentioning

confidence: 95%

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Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation

Vanhoorne

Bekaert

Peeters

et al. 2016

International Journal of Pharmaceutics

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To refer to or to cite this work, please use the citation to the published version:Vanhoorne V., Bekaert B., Peeters E., De Beer T., Remon J.P., Vervaet C. (2016) Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation. International Journal of Pharmaceutics 506 13-24 DOI: 10.1016/j.ijpharm.2016.04.025 AbstractIn most formulations processed via continuous twin screw granulation microcrystalline cellulose (MCC) and/or lactose are used as excipients, but mannitol is also a preferred excipient for wet granulation and tableting due to its non-hygroscopicity and inertness.Therefore, the aim of the current study was to investigate the influence of process parameters on critical quality attributes of granules (moisture content, solid state, morphology, size distribution, specific surface area, friability, flowability and hygroscopicity) and tablets (tensile strength and friability) after twin screw granulation of δ-mannitol. The δ-polymorph was selected since a moisture-induced transformation to β-mannitol was observed during batch wet granulation, which exhibited a unique morphology with a large surface area and improved tabletability. A full factorial experimental design was performed, varying screw speed (400 -900 rpm), granulation temperature (25 -40 °C), number of kneading elements (6 or 12) and liquid-to-solid (L/S) ratio, on the granulation unit of a ConsiGma TM -25 line (a continuous powder-to-tablet manufacturing system). After tray drying the granules were milled and tableted. The results showed that the polymorphic transition from δ-to β-mannitol also occurred during twin screw granulation, although the residence time and L/S ratios were much lower in continuous twin screw granulation compared to batch processing. However, the polymorphic transition was not complete in all experiments and depended on the L/S ratio, screw speed and number of kneading elements. Nevertheless all granules exhibited the unique morphology linked to the polymorphic transition and had a superior tabletability compared to granules produced with β-mannitol as starting material. This was attributed to enhanced plastic deformation of the granules manufactured using δ-mannitol as starting material. In addition, it was concluded that mannitol was granulated via a different mechanism than other, lesssoluble, excipients (e.g. lactose, microcrystalline cellulose) due to its high solubility and dissolution rate as the influence of process parameters on the mannitol granule characteristics was different.

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Section: Solid State Characterizationmentioning

confidence: 95%

“…Magnesium stearate (Fagron, Waregem, Belgium) was used as lubricant for tableting. Raman spectra of reference materials of α-, β-and δ-mannitol were adopted from De Beer et al [30].…”

Section: Methodsmentioning

confidence: 99%

Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation

Vanhoorne

Bekaert

Peeters

et al. 2016

International Journal of Pharmaceutics

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Section: Introductionmentioning

confidence: 99%

“…Raman spectroscopy was applied to describe mannitol polymorphic forms for instance [12], and on-line measurements during freezedrying have been performed [13,14]. NIR has also been applied for on-line freeze-drying measurements [15] and the NIR spectra of a-, b-and d-mannitol as well as mannitol hemihydrate have been reported [9,13]. The potential of NIR to detect various forms is highly relevant for the quality assurance of lyophilised mannitol products as it has been shown that the freeze-drying conditions can influence the solid state form in the product [2,16].…”

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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“…Therefore, it is not surprising that several models can be found in the literature describing the use of NIR for the determination of water in freezedried products. Though usually the final product is characterised, the use of both Raman and NIR spectroscopy for in-line spectroscopic measurements during freeze-drying has recently been described [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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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Implementation of a Process Analytical Technology System in a Freeze-Drying Process Using Raman Spectroscopy for In-Line Process Monitoring

Cited by 109 publications

References 35 publications

Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation

Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation

Classification of lyophilised mixtures using multivariate analysis of NIR spectra

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

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