Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets

Fonteyne, Margot; Wickström, Henrika; Peeters, Elisabeth; Vercruysse, Jurgen; Ehlers, Henrik; Peters, Björn-Hendrik; Remon, Jean Paul; Vervaet, Chris; Ketolainen, Jarkko; Sandler, Niklas; Rantanen, Jukka; Naelapää, Kaisa; Beer, Thomas De

doi:10.1016/j.ejpb.2014.02.011

Cited by 74 publications

(33 citation statements)

References 35 publications

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“…This is in contrast to most literature reports (on a variety of formulations), indicating no correlation between screw speed and d 50 [1,7,16,17,29] or an inverse relationship [1,5,8]. They attributed the larger particle size at lower screw speeds to higher torque values, resulting in higher compressive forces in the granulator barrel.…”

Section: Size Analysiscontrasting

confidence: 85%

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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: Size Analysiscontrasting

confidence: 85%

“…Only a limited number of studies on twin screw granulation addressed formulation development while most studies focused on the influence of process parameters on granule quality [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. Moreover, most studies used formulations with lactose or microcrystalline cellulose as fillers.…”

Section: Introductionmentioning

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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“…Despite the similar primary particle size of lactose and powdered theophylline in formulations F4-6, theophylline was not evenly distributed over the size fractions of these formulations. This was also observed by Fonteyne et al after continuous granulation of an immediate release formulation [37]. However, no explanation was found for the observations.…”

Section: Influence Of Formulation Variables On Granule Qualitysupporting

confidence: 49%

“…the primary particle size of theophylline to differences in the GSD [37]. In the current study the inclusion of a high percentage of HPMC, which in addition to its function as matrix former also acts as binder, probably eliminated the effect of primary particle size on GSD.…”

Section: Influence Of Formulation Variables On Granule Qualitymentioning

confidence: 85%

Continuous twin screw granulation of controlled release formulations with various HPMC grades

Vanhoorne

Janssens

Vercruysse

et al. 2016

International Journal of Pharmaceutics

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HPMC is a popular matrix former to formulate tablets with extended drug release. Tablets with HPMC are preferentially produced by direct compression. However, granulation is often required prior to tableting to overcome poor flowability of the formulation. While continuous twin screw granulation has been extensively evaluated for granulation of immediate release formulations, twin screw granulation of controlled release formulations including the dissolution behavior of the formulations received little attention. Therefore, the influence of the HPMC grade (viscosity and substitution degree) and the particle size of theophylline on critical quality attributes of granules (continuously produced via twin screw granulation) and tablets was investigated in the current study. Formulations with 20 or 40% HPMC, 20% theophylline and lactose were granulated with water at fixed process parameters via twin screw granulation.The torque was influenced by the viscosity and substitution degree of HPMC, but was not a limiting factor for the granulation process. An optimal L/S ratio was selected for each formulation based on the granule size distribution. The granule size distributions were influenced by the substitution degree and concentration of HPMC and the particle size of theophylline. Raman and UV spectroscopic analysis on 8 sieve fractions of granules indicated an inhomogeneous distribution of theophylline over the size fractions. However, this phenomenon was not correlated with the hydration rate or viscosity of HPMC. Controlled release of theophylline could be obtained over 24 h with release profiles close to zero-order.The release of theophylline could be tailored via selection of the substitution degree and viscosity of HPMC.

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“…Earlier findings (Fonteyne et al, 2013b) from our research group showed indeed a bi-modal size distribution when evaluating granules produced with the twin screw granulator module of the ConsiGma™-25 (GEA Pharma systems nv, Collette, Wommelgem, Belgium), a fully continuous from powder-to-tablet manufacturing line. A recurring comment on twin screw granulation as an agglomeration technique is the short residence time of the processed material in the granulator barrel, resulting in a short interaction and mixing time between powder, binder and granulation liquid.…”

Section: Notementioning

confidence: 99%

Distribution of binder in granules produced by means of twin screw granulation

Fonteyne

Fussell

Vercruysse

et al. 2014

International Journal of Pharmaceutics

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Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets

Cited by 74 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

Continuous twin screw granulation of controlled release formulations with various HPMC grades

Distribution of binder in granules produced by means of twin screw granulation

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