Cellets 700 is a subtype of pellets made of microcrystalline cellulose. The size ranges from 700 µm to 1000 µm. Find more product information and technical specifications.

Benefits of multilayer high drug-loaded amorphous solid dispersions

Introduction on amorphous solid dispersions

What is the benefit of multilayer amorphous solid dispersions? Recently, several studies had been performed on amorphous solid dispersions working spheres or starter beads. Starter beads, such as MCC (Microcrystalline Cellulose) spheres are employed due to their high friability and chemical inertness. Some studies are even working on solventless pelletization and amorphization using high shear granulator techniques [1].

Amorphization of poorly water-soluble drugs is a promising approach to improve the solubility and dissolution rate as amorphous solids lack a crystal lattice with long-range order [2]. Unfortunately, a high chemical potential compared to crystalline forms makes amorphous forms thermodynamically unstable. Thus, amorphous drugs exhibit low physical stability and finally lack of recrystallization [3,4]. In turn, surface crystallization is to be minimized.

Multilayer amorphous solid dispersions

This is the key focus of a publication by Eline Boel and Guy Van den Mooter: They had been investigating a promising solution of multilayer high-drug load amorphous solid dispersions, as follows [5]:

Inhibiting surface crystallization is an interesting strategy to enhance the physical stability of amorphous solid dispersions (ASDs), still preserving high drug loads. The aim of this study was to investigate the potential surface crystallization inhibitory effect of an additional polymer coating onto ASDs, comprising high drug loads of a fast crystallizing drug, layered onto pellets. For this purpose, bilayer coated pellets were generated with fluid-bed coating, of which the first layer constitutes a solid dispersion of naproxen (NAP) in poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in a 40:60 or 35:65 (w/w) ratio, and ethyl cellulose (EC) composes the second layer. The physical stability of these double-layered pellets, in comparison to pellets with an ASD layer only, was assessed under accelerated conditions by monitoring with X-ray powder diffraction (XRPD) at regular time intervals. Bilayer coated pellets were however found to be physically less stable than pellets with an ASD layer only. Applying the supplementary EC coating layer induced crystallization and heterogeneity in the 40:60 and 35:65 (w/w) NAP-PVP-VA ASDs, respectively, attributed to the initial contact with the solvent. Caution is thus required when applying an additional coating layer on top of an ASD layer with fluid-bed coating, for instance for controlled release purposes, especially if the ASD consists of high loads of a fast crystallizing drug.

Read more on doi:10.1016/j.ijpharm.2022.122455.

How about following up studies on ASD formulation with starter beads? Simply, contact us für MCC spheres, such as CELLETS® 700 (700-1000 µm, US mesh 18/25).

Your technology and formulation partner for amorphous solid dispersions:

Glatt in amorphous solid dispersions

References

[1] K. Kondo, T. Rades, European Journal of Pharmaceutics and Biopharmaceutics 181 (2022) 183–194 doi:10.1016/j.ejpb.2022.11.011

[2] B.C. Hancock, M. Parks, Pharm. Res. 17 (2000) 397-404.

[3] L.I. Blaabjerg, E. Lindenberg, T. Rades, H. Grohganz, K. Lobmann, Int. J. Pharm. 521 (2017) 232-238.

[4] A. Singh, G. Van den Mooter, Adv. Drug Deliv. Rev. 100 (2016) 27-50.

[5] E. Boel, G. Van den Mooter, International Journal of Pharmaceutics (2022) 122455. doi:10.1016/j.ijpharm.2022.122455

 

Abstract

This case study is a short abstract on spouted bed characteristics, following closely findings in the publication by J. Vanamu and A. Sahoo [1].

Spouted bed systems are of highest importance for all powder processing industries, and more specific in pharmaceutical industry for coating and drying in pellet technologies [2]. These systems offer manufacturing particularly fine and temperature-sensitive particles from small to large scale: laboratory systems are capable of processing product volumes of very few grams, while production systems can handle capacities of several tons [3].

But how to control conditions in spouted beds for efficient process applications, like mixing, coating, or drying?

There might be certain reasons, that the hydrodynamic behavior of the spouted bed in the pharmaceutical industries is less investigated. The referred publication shed some light on the hydrodynamic characteristics of a spouted bed where the MCC Spheres (CELLETS®) are adopted as the bed material. These starter cores are ideal model systems due to their perfect sphericity and zero-level friability. At the same time, smooth and defined surface structure initiate perfect modelling conditions in the spouted bed dynamics.

Material

CELLETS®, made of 100% Microcrystalline Cellulose, have been used as bed material. The physical properties of the CELLETS® are shown in Table 1. The CELLETS® particle morphology is represented in Figure 1.

Parameter Value
CELLETS® 700 and CELLETS® 1000
Size distribution 700-1000 µm (CELLETS® 700)

1000-1400 µm (CELLETS® 1000)

Bulk density 800 kg/m3
Particle sphericity > 0.9
Void fraction 0.42
Geldart classification B

Table 1: Physical properties of the CELLETS®.

SEM micrographs of CELLETS® 700

Figure 1: SEM micrographs of CELLETS® 700, found in [1].

Spouted bed: experiment setup

There are some international players on the market of spouted bed technologies, such as Glatt which seems to be the major one (Figure 2). In this framework, a self-made setup is used for experiments. The experiments that have been carried out in a column, which is fabricated from a Perspex sheet. This column consists of a cylindrical section of height 0.53 m and a diameter of the cylinder of 0.135 m. The column further converged the diameter of the cylinder to 0.05 m as a conical bottom having a length of 0.47 m. The spouting air is supplied by a compressed air line is controlled by a gas regulator. The airflow is controlled by a gate valve and a mesh plate having a mesh size less than the size of the bed material is employed as a separator preventing the backflow of the bed material. Images are captured using a high-speed video camera to gain more details of the hydrodynamic characteristics of the flow pattern inside the spouted bed geometry.

Spouted bed

Figure 2: Scheme of a spouted bed (Glatt, Germany).

Experiments & spouted bed results

Experiments are carried out with three different static bed heights of shallow depth wherein the bed height is in the range of factor 2-3 of the Inlet diameter using two different particle distribution classes at 500-710 µm and 700-1000 µm, respectively. Analyzed parameters are the pressure drop across the bed, the bed expansion ratio, and the clusters concerning the superficial gas velocity are focused in the following.

J. Vanamu et al. found that the “bed expansion ratio increases with increasing superficial gas velocity until the onset of external spouting, further increase in the superficial gas velocity, the bed expansion ratio decreases. With increasing the volume of bed, the bed expansion ratio decreases. In a larger volume of bed, the particles tend to spout into the freeboard region rather than expanding with higher superficial gas velocity”. Initial spouting is symmetric, but with increasing superficial gas velocity spouting becomes asymmetric, and asymmetry is more pronounced or starts at lower superficial gas velocities for smaller particles. This agrees with existing theories of hydrodynamic behavior in a fluidized environment. Respecting the necessarity of a proper flow behavior for mixing, coating or drying applications in drug processing, symmetric spouting is essential. In turn, the superficial gas velocity may be kept low.

In case that high superficial gas velocity regimes are required for the operations a draft tube may be installed within the column to achieve the symmetric spout formation.

Summary

This case study highlights the Hydrodynamic behavior of MCC spheres in a spouted bed using image processing method. MCC spheres in the range between 500-710 µm and 700-1000 µm had been employed. All spheres showed a symmetric and asymmetric spouting in the spouted bed. With increasing superficial gas velocity, the fully suspended particles are limited to a certain height in the freeboard region due to the gas-solid crossflow. A change from symmetric to asymmetric spouting is observed with increasing superficial gas velocity.

Keeping the conditions efficient for the mixing, coating or drying applications requires finally to suppress high superficial gas velocities, or changing the setup in such way, that symmetric spouting conditions are kept upright even at higher superficial gas velocities.

References

[1] J. Vanamu and A. Sahoo, Particuology 76 (2023) 101

[2] L. A. P. de Freitas, Particuology 42 (2019) 126

[3] Glatt GmbH, Binzen, Germany. Online on Nov 8, 2022: Spouted bed systems – Glatt – Integrated Process Solutions

Great thanks to Arihant Innochem Pvt. Ltd. who supplied and donated CELLETS® for this study.

Cellets list of publication

Selected Scientific literature

Please, find scientific literature on CELLETS®. This list is constantly updated and does not claim to be complete. If you are author, scientist or R&D specialist, please submit your present publication to us for improving the visibility.

List

 

Research article
Solventless amorphization and pelletization using a high shear granulator. Part II; Preparation of co-amorphous mixture-layered pellets using indomethacin and arginine
European Journal of Pharmaceutics and Biopharmaceutics (2022) 181, 183-194. doi: 10.1016/j.ejpb.2022.11.011
K. Kondo, T. Rades

Research article
Solventless amorphization and pelletization using a high shear granulator. Part I; feasibility study using indomethacin
European Journal of Pharmaceutics and Biopharmaceutics (2022) 181, 147-158. doi: 10.1016/j.ejpb.2022.11.010
K. Kondo, T. Rades

Research article
Hydrodynamic behaviour of CELLETS® (Ph.Eur./USP) in a spouted bed using image processing method
Particuology (2023), 76, 101-112, doi:10.1016/j.partic.2022.07.009
J. Vanamu, A. Sahoo

Research article
Application of different models to evaluate the key factors of fluidized bed layering granulation and their influence on granule characteristics
Powder Technology (2022), 408:117737. doi: 10.1016/j.powtec.2022.117737
R. Maharjan, S. H. Jeong

Research article
Evaluation of gravitational consolidation of binary powder mixtures by modified Heckel equation
Powder Technology (2022), 408:117729. doi: 10.1016/j.powtec.2022.117729
P. Svačinová, O. Macho, Ž. Jarolímová, M. Kuentz, Ľ. Gabrišová and Z. Šklubalová

Research article
Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing
Pharmaceutics (2022), 14(5)1058. doi: 10.3390/pharmaceutics14051058
M. W. Stocker, M. J. Harding, V. Todaro, A. M. Healy and S. Ferguson

Research article
Relative bioavailability enhancement of simvastatin via dry emulsion systems: comparison of spray drying and fluid bed layering technology
Eur J Pharm Biopharm (2021), S0939-6411(21)00353-2. doi: 10.1016/j.ejpb.2021.12.004
M. Pohlen, J. Aguiar Zdovc, J. Trontelj, J. Mravljak, M. G. Matjaž, I. Grabnar, T. Snoj and R. Dreu

Research article
Correlating Granule Surface Structure Morphology and Process Conditions in Fluidized Bed Layering Spray Granulation
KONA Powder and Particle Journal (2021), DOI:10.14356/kona.2022016
M. Orth, P. Kieckhefen, S. Pietsch and S. Heinrich

Research article
Measurement of hydrogen peroxide vapor in powders with potassium titanium oxide oxalate loaded cellulose pellets as probes
AAPS PharmSciTech, Volume 21(1):3, 11 Nov 2019
Maria H. Kastvig, Johan P. Bøtker, Ge Ge, Mogens L. Andersen

Research article
Wurster Fluidised Bed Coating of Microparticles: Towards Scalable Production of Oral Sustained-Release Liquid Medicines for Patients with Swallowing Difficulties
AAPS PharmSciTech, Volume 21(1):3, 11 Nov 2019
Valentyn Mohylyuk, Kavil Patel, Nathan Scott, Craig Richardson, Darragh Murnane, Fang Liu

Research article
Assessment of the effect of Cellets’ particle size on the flow in a Wurster fluid-bed coater via powder rheology
Journal of Drug Delivery Science and Technology, Volume 54, December 2019, 101320
Valentyn Mohylyuk, Ioanna Danai Styliari, Dmytryi Novykov, Reiss Pikett, Rajeev Dattani

Research article
Measuring segregation characteristics of industrially relevant granular mixtures: Part II – Experimental application and validation
Powder Technology, Volume 368, 15 May 2020, Pages 278-285
Alexander M. Fry, Vidya Vidyapati, John P. Hecht, Paul B. Umbanhowar, Julio M. Ottinoa, Richard M. Lueptow

Research article
Influence of Non-Water-Soluble Placebo Pellets of Different Sizes on the Characteristics of Orally Disintegrating Tablets Manufactured by Freeze-Drying
Journal of Pharmaceutical Sciences, Volume 102, Issue 6, June 2013, Pages 1786-1799
Ulrike Stange, Christian Führling, Henning Gieseler

Short communication
Introduction of the energy to break an avalanche as a promising parameter for powder flowability prediction
Powder Technology, Volume 375, 20 September 2020, Pages 33-41
Žofie Trpělková, Hana Hurychová, Martin Kuentz, Barbora Vraníková, Zdenka Šklubalová

Research article
Particle electrification in an apparatus with a draft tube operating in a fast circulating dilute spout-fluid bed regime
Particuology, Volume 42, February 2019, Pages 146-153
Wojciech Ludwig

Research article
Attrition and abrasion resistance of particles coated with pre-mixed polymer coating systems
Powder Technology, Volume 230, November 2012, Pages 1-13
G. Perfetti, F. Depypere, S. Zafari, P. van Hee, W.J. Wildeboer, G. M. H. Meesters

Research article
Dry particle high coating of biopowders: An energy approach
Powder Technology, Volume 208, Issue 2, 25 March 2011, Pages 378-382
S. Otles, O. Lecoq, J. A. Dodds

Research article
Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices
Chemical Engineering Journal, Volume 164, Issues 2–3, 1 November 2010, Pages 268-274
Jari T. T. Leskinen, Matti-Antero H. Okkonen, Maunu M. Toiviainen, Sami Poutiainen, Mari Tenhunen, Pekka Teppola, Reijo Lappalainen, Jarkko Ketolainen, Kristiina Järvinen

Research article
Development and evaluation of budesonide-based modified-release liquid oral dosage forms
Journal of Drug Delivery Science and Technology, Volume 54, December 2019, 101273
Federica Ronchi, Antonio Sereno, Maxime Paide, Ismaël Hennia, Pierre Sacré, George Guillaume, Vincent Stéphenne, Jonathan Goole, Karim Amighi

Research article
Water-mediated solid-state transformation of a polymorphic drug during aqueous-based drug-layer coating of pellets
International Journal of Pharmaceutics, Volume 456, Issue 1, 1 November 2013, Pages 41-48
Andres Lust, Satu Lakio, Julia Vintsevits, Jekaterina Kozlova, Peep Veski, Jyrki Heinämäki, Karin Kogermann

Research article
Two-dimensional particle shape analysis from chord measurements to increase accuracy of particle shape determination
Powder Technology, Volume 284, November 2015, Pages 25-31
D. Petrak, S. Dietrich, G. Eckardt, M. Köhler

Research article
Evaluation of in-line particle measurement with an SFT-probe as monitoring tool for process automation using a new time-based buffer approach
European Journal of Pharmaceutical Sciences, Volume 128, 1 February 2019, Pages 162-170
Theresa Reimers, Jochen Thies, Stefan Dietrich, Julian Quodbach, Miriam Pein-Hackelbusch

Research article
In-line particle size measurement and process influences on rotary fluidized bed agglomeration
Powder Technology, Volume 364, 15 March 2020, Pages 673-679
Marcel Langner, Ivonne Kitzmann, Anna-Lena Ruppert, Inken Wittich, Bertram Wolf

Research article
In vitro and sensory tests to design easy-to-swallow multi-particulate formulations
European Journal of Pharmaceutical Sciences, Volume 132, 30 April 2019, Pages 157-162
Marco Marconati, Felipe Lopez, Catherine Tuleu, Mine Orlu, Marco Ramaioli

Research article
Material specific drying kinetics in fluidized bed drying under mechanical vibration using the reaction engineering approach
Advanced Powder Technology, Volume 31, Issue 12, December 2020, Pages 4699-4713
Soeren E. Lehmann, Tobias Oesau, Alfred Jongsma, Fredrik Innings, Stefan Heinrich

Short communication
Novel production method of tracer particles for residence time measurements in gas-solid processes
Powder Technology, Volume 338, October 2018, Pages 1-6
Swantje Pietsch, Paul Kieckhefen, Michael Müller, Michael Schönherr, Frank Kleine Jäger, Stefan Heinrich

Research article
Quantitative bin flow analysis of particle discharge using X-ray radiography
Powder Technology, Volume 344, 15 February 2019, Pages 693-705
Sanket Bacchuwar, Vidya Vidyapati, Ke-ming Quan, Chen-Luh Lin, Jan D. Miller

Research article
Adjustment of triple shellac coating for precise release of bioactive substances with different physico-chemical properties in the ileocolonic region
International Journal of Pharmaceutics, Volume 564, 10 June 2019, Pages 472-484>
Eva-Maria Theismann, Julia Katharina Keppler, Jörg-Rainer Knipp, Daniela Fangmann, Esther Appel, Stanislav N. Gorb, Georg H. Waetzig, Stefan Schreiber, Matthias Laudes, Karin Schwarz

Research article
The effect of administration media on palatability and ease of swallowing of multiparticulate formulations
International Journal of Pharmaceutics, Volume 551, Issues 1–2, 15 November 2018, Pages 67-75
Felipe L. Lopez, Terry B. Ernest, Mine Orlu, CatherineTuleu

Research article
Production of composite particles using an innovative continuous dry coating process derived from extrusion
Advanced Powder Technology, Volume 28, Issue 11, November 2017, Pages 2875-2885
Fanny Cavaillès, Romain Sescousse, Alain Chamayou, Laurence Galet

Research article
Regulating the pH of bicarbonate solutions without purging gases: Application to dissolution testing of enteric coated tablets, pellets and microparticles
International Journal of Pharmaceutics, Volume 585, 30 July 2020, 119562
Nathan Scott, Kavil Patel, Tariro Sithole, Konstantina Xenofontos, Valentyn Mohylyuk, Fang Liu

Research article
Solidification of carvedilol loaded SMEDDS by swirling fluidized bed pellet coating
International Journal of Pharmaceutics, Volume 566, 20 July 2019, Pages 89-100
J. Mandić, M. Luštrik, F. Vrečer, M. Gašperlin, A. Zvonar Pobirk

Research article
In-line particle size measurement and agglomeration detection of pellet fluidized bed coating by Spatial Filter Velocimetry
Powder Technology, Volume 301, November 2016, Pages 261-267
Dimitri Wiegel, Günter Eckardt, Florian Priese, Bertram Wolf

Research article
Easy to Swallow “Instant” Jelly Formulations for Sustained Release Gliclazide Delivery
Journal of Pharmaceutical Sciences, Volume 109, Issue 8, August 2020, Pages 2474-2484
Simmi Patel, Nathan Scott, Kavil Patel, Valentyn Mohylyuk, William J. McAuley, Fang Liu

Research article
Effect of formulation variables on oral grittiness and preferences of multiparticulate formulations in adult volunteers
European Journal of Pharmaceutical Sciences, Volume 92, 20 September 2016, Pages 156-162
Felipe L. Lopez, Alexandra Bowles, Mine Orlu Gul, David Clapham, Terry B. Ernest, Catherine Tuleu

Research article
Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique
Journal of Pharmaceutical Investigation (2013), 43:333–342. doi: 10.1007/s40005-013-0077-0
H. A. Hazzah, M. A. EL-Massik, O. Y. Abdallah & H. Abdelkader

Research article
A density based segmentation method to determine the coordination number of a particulate system
Chemical Engineering Science, Volume 66, Issue 24, 15 December 2011, Pages 6385-6392
Thanh T. Nguyen, Thanh N. Tran, Tofan A. Willemsz, Henderik W. Frijlink, Tuomas Ervasti, Jarkko Ketolainen, Kees van der Voort Maarschalk

Research article
X-ray micro tomography and image analysis as complementary methods for morphological characterization and coating thickness measurement of coated particles
Advanced Powder Technology, Volume 21, Issue 6, November 2010, Pages 663-675
Giacomo Perfetti, Elke Van de Casteele, Bernd Rieger, Willem J. Wildeboer, Gabrie M.H. Meesters

Research article
Development of high drug loaded pellets by Design of Experiment and population balance model calculation
Powder Technology, Volume 241, June 2013, Pages 149-157
Florian Priese, Bertram Wolf

Research article
Quantification of swelling characteristics of pharmaceutical particles
International Journal of Pharmaceutics, Volume 590, 30 November 2020, 119903
Mithushan Soundaranathan, Pattavet Vivattanaseth, Erin Walsh, Kendal Pitt, Blair Johnston, Daniel Markl

Research article
Numerical study of the hydrodynamics of fluidized beds operated under sub-atmospheric pressure
Chemical Engineering Journal, Volume 372, 15 September 2019, Pages 1134-1153
Sayali Zarekar, Andreas Bück, Michael Jacob, Evangelos Tsotsas

Research article
Granule size distribution of tablets
Journal of Pharmaceutical Sciences, Volume 99, Issue 4, April 2010, Pages 2061-2069
Satu Virtanen, Osmo Antikainen, Heikki Räikkönen, Jouko Yliruusi

Research article
Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations
International Journal of Pharmaceutics, Volume 540, Issues 1–2, 5 April 2018, Pages 120-131
Josefina Nordström, Göran Alderborn, Göran Frenning

Research article
New insights into segregation during tabletting
International Journal of Pharmaceutics, Volume 397, Issues 1–2, 15 September 2010, Pages 19-26
S. Lakio, S. Siiriä, H. Räikkönen, S. Airaksinen, T. Närvänen, O. Antikainen, J.Yliruusi

Research article
Passive acoustic emission monitoring of pellet coat thickness in a fluidized bed
Powder Technology, Volume 286, December 2015, Pages 172-180
Taylor Sheahan, Lauren Briens

Research article
Attrition strength of different coated agglomerates
Chemical Engineering Science, Volume 63, Issue 5, March 2008, Pages 1361-1369
B. van Laarhoven, S.C.A. Wiers, S.H. Schaafsma, G.M.H. Meesters

Research article
A New Apparatus for Real‐Time Assessment of the Particle Size Distribution of Disintegrating Tablets
Journal of Pharmaceutical Sciences, Volume 103, Issue 11, November 2014, Pages 3657-3665
Julian Quodbach, Peter Kleinebudde

Research article
Particle sizing measurements in pharmaceutical applications: Comparison of in-process methods versus off-line methods
European Journal of Pharmaceutics and Biopharmaceutics, Volume 85, Issue 3, Part B, November 2013, Pages 1006-1018
Ana F.T. Silva, Anneleen Burggraeve, Quenten Denon, Paul Van der Meeren, Niklas Sandler, Tom Van Den Kerkhof, Mario Hellings, Chris Vervaet, Jean Paul Remon, João Almeida Lopes, Thomas De Beer

Research article
Effects of pharmaceutical processes on the quality of ethylcellulose coated pellets: Quality by design approach
Powder Technology, Volume 339, November 2018, Pages 25-38
Prakash Thapa, Ritu Thapa, Du Hyung Choi, Seong Hoon Jeong

Research article
Physical properties of pharmaceutical pellets
Chemical Engineering Science, Volume 86, 4 February 2013, Pages 50-60
Rok Šibanc, Teja Kitak, Biljana Govedarica, StankoSrčič Rok Dreu

Research article
Determination of the release mechanism of Theophylline from pellets coated with Surelease®—A water dispersion of ethyl cellulose
International Journal of Pharmaceutics, Volume 528, Issues 1–2, 7 August 2017, Pages 345-353
Jurgita Kazlauske, Maria Margherita Cafaro, Diego Caccavo, Mariagrazia Marucci, Gaetano Lamberti, Anna Angela Barba, Anette Larsson

Research article
The analysis of the influence of the normal restitution coefficient model on calculated particles velocities by means of Eulerian-Lagrangian approach
Powder Technology, Volume 344, 15 February 2019, Pages 140-151
Wojciech Ludwig, PaweƚPłuszka

Research article
Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen
International Journal of Pharmaceutics, Volume 499, Issues 1–2, 29 February 2016, Pages 271-279
Eva Julia Laukamp, Klaus Knop, Markus Thommes, Joerg Breitkreutz

Research article
A density-based segmentation for 3D images, an application for X-ray micro-tomography
Analytica Chimica Acta, Volume 725, 6 May 2012, Pages 14-21
Thanh N. Tran, Thanh T. Nguyen, Tofan A. Willemsz, Gijsvan Kessel, Henderik W. Frijlink, Kees van der Voort Maarschalk

Research article
Continuous pellet coating in a Wurster fluidized bed process
Chemical Engineering Science, Volume 86, 4 February 2013, Pages 87-98
N. Hampel, A. Bück, M. Peglow, E. Tsotsas

Research article
Measurement of granule layer thickness in a spouted bed coating process via optical coherence tomography
Powder Technology, Volume 356, November 2019, Pages 139-147
Swantje Pietsch, Anna Peter, Patrick Wahl, Johannes Khinast, Stefan Heinrich

Research article
Effects of humidity on cellulose pellets loaded with potassium titanium oxide oxalate for detection of hydrogen peroxide vapor in powders
Powder Technology, Volume 366, 15 April 2020, Pages 348-357
Maria H. Kastvig, Cosima Hirschberg, Frans W.J. Van Den Berg, Jukka Rantanen, Mogens L. Andersen

Research article
Euler-Lagrange model of particles circulation in a spout-fluid bed apparatus for dry coating
Powder Technology, Volume 328, 1 April 2018, Pages 375-388
Wojciech Ludwig, Paweł Płuszka

Research article
Direct Drug Loading into Preformed Porous Solid Dosage Units by the Controlled Particle Deposition (CPD), a New Concept for Improved Dissolution Using SCF-Technology
Journal of Pharmaceutical Sciences, Volume 97, Issue 10, October 2008, Pages 4416-4424
Ragna S. Wischumerski, Michael Türk, Martin A. Wahl

Research article
A novel method for assessing the coating uniformity of hot-melt coated particles using micro-computed tomography
Powder Technology, Volume 378, Part A, 22 January 2021, Pages 51-59
B.M. Woerthmann, J.A. Lindner, T. Kovacevic, P. Pergam, F. Schmid, H. Briesen

Research article
New spout-fluid bed apparatus for electrostatic coating of fine particles and encapsulation
Powder Technology, Volume 225, July 2012, Pages 52-57
Roman G. Szafran, Wojciech Ludwig, Andrzej Kmiec

Research article
Impact of polymers on dissolution performance of an amorphous gelleable drug from surface-coated beads
European Journal of Pharmaceutical Sciences, Volume 37, Issue 1, 11 April 2009, Pages 1-10
Chon gFan, Rashmi Pai-Thakur, Wantanee Phuapradit, Lin Zhang, Hung Tian, Waseem Malick, Navnit Shah, M. Serpil Kislalioglu

Research article
Inline acoustic monitoring to determine fluidized bed performance during pharmaceutical coating
International Journal of Pharmaceutics, Volume 549, Issues 1–2, 5 October 2018, Pages 293-298
Allan Carter, Lauren Briens

Research article
Multivariate calibration of the degree of crystallinity in intact pellets by X-ray powder diffraction
International Journal of Pharmaceutics, Volume 502, Issues 1–2, 11 April 2016, Pages 107-116
Krisztina Nikowitz, Attila Domján, Klára Pintye-Hódi, Géza Regdon jr.

Research article
Tabletability Modulation Through Surface Engineering
Journal of Pharmaceutical Sciences, Volume 104, Issue 8, August 2015, Pages 2645-2648
Frederick Osei-Yeboah, Changquan Calvin Sun

Research article
Evaluation of extrusion/spheronisation, layering and compaction for the preparation of an oral, multi-particulate formulation of viable, hIL-10 producing Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 59, Issue 1, January 2005, Pages 9-15
Nathalie Huyghebaert, An Vermeire, Sabine Neirynck, Lothar Steidler, Eric Remaut, Jean Paul Remon

Research article
Recent advance in delivery system and tissue engineering applications of chondroitin sulfate
Carbohydrate Polymers, Volume 230, 15 February 2020, 115650
Jun Yang, Mingyue Shen, Huiliang Wen, Yu Luo, Rong Huang, Liyuan Rong, Jianhua Xie

Research article
In-line monitoring of multi-layered film-coating on pellets using Raman spectroscopy by MCR and PLS analyses
European Journal of Pharmaceutics and Biopharmaceutics, Volume 114, May 2017, Pages 194-201
Jin Hisazumi, Peter Kleinebudde

Short communication
Can encapsulation lengthen the shelf-life of probiotic bacteria in dry products?
International Journal of Food Microbiology, Volume 136, Issue 3, 1 January 2010, Pages 364-367
F. Weinbreck, I. Bodnár, M.L. Marco

Research article
Towards improving quality of video-based vehicle counting method for traffic flow estimation
Signal Processing, Volume 120, March 2016, Pages 672-681
Yingjie Xia, Xingmin Shi, Guanghua Song, Qiaolei Geng, Yuncai Liu

Research article
Sifting segregation of ideal blends in a two-hopper tester: Segregation profiles and segregation magnitudes
Powder Technology, Volume 331, 15 May 2018, Pages 60-67
Mariagrazia Marucci, Banien Al-Saaigh, Catherine Boissier, Marie Wahlgren, Håkan Wikström

Conference abstract
Multiple unit mini-tablets: Content uniformity issues
International Journal of Pharmaceutics, Volume 536, Issue 2, 5 February 2018, Pages 506-507
Anna Kira Adam, Jörg Breitkreutz

Research article
Study of the recrystallization in coated pellets – Effect of coating on API crystallinity
European Journal of Pharmaceutical Sciences, Volume 48, Issue 3, 14 February 2013, Pages 563-571
Krisztina Nikowitz, Klára Pintye-Hódi, Géza Regdon Jr.

Research article
Optimisation of an enteric coated, layered multi-particulate formulation for ileal delivery of viable recombinant Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 69, Issue 3, August 2008, Pages 969-976
Nele Poelvoorde, Nathalie Huyghebaert, Chris Vervaet, Jean-Paul Remon

Research article
Influence of gas inflow modelling on CFD-DEM simulations of three-dimensional prismatic spouted beds
Powder Technology, Volume 329, 15 April 2018, Pages 167-180
Paul Kieckhefen, Swantje Pietsch, Moritz Höfert, Michael Schönherr, Stefan Heinrich, Frank Kleine Jäger

Research article
Analysis of pellet coating uniformity using a computer scanner
International Journal of Pharmaceutics, Volume 533, Issue 2, 30 November 2017, Pages 377-382
Rok Šibanc, Matevž Luštrik, Rok Dreu

Conference abstract
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Book
Formulation and Analytical Development for Low-Dose Oral Drug Products
John Wiley & Sons , inc. (2009), ISBN 978-0-470-05609-7
Jack Zheng (Editor)

 

Metoprolol pellets

Abstract on Metoprolol pellets

Metoprolol Tartrate is a salt of Metoprolol, a selective β1-receptor blocker medication. The application is the treatment of high blood pressure, chest pain due to poor blood flow to the heart, and several conditions involving an abnormally fast heart rate [2]. In the following, an attempt is shown, wherein MCC spheres are used as starter cores for a multi-layer pellet formulation.

This case study is a short abstract of the publication by P. Wanasawas et al. [1] and presents controlled release Metoprolol Tartrate layered pellets achieving colon-specific drug delivery.

Pellet technology attempt

In the following, in-situ calcium pectinate-coated MCC pellets (CELLETS® 700) were proposed by applying an alternate coating method to drug-layered pellets to achieve colon-specific drug delivery. Using a centrifugal granulator, inert MCC pellets were layered by a Metoprolol Tartrate water-soluble model drug. A protective HPMC layer helps to strengthen cracks or delamination from the core in the later stage of the coating processes. Then, alternate coatings of pectin and calcium chloride layers were spray coated by fluidized bed bottom spray technology (GPCG-1, Glatt®, Germany). This technology allows achieving uniform coating layers. The subcoating with pectin and calcium pectinate polymers allow site-specific drug delivery targeting the colon due to their low water solubility. Both excipients additionally degraded completely by gut microflora [3].

By testing different composition in multilayer coatings with calcium and pectin, some interesting phenomena are stated:

  • the release behavior follows the Higuchi model
  • the drug release can be described by a diffusion control mechanism
  • the coating of the outermost layer defines the success in controlled drug release

The latter point issues the importance of the outermost layer which is whether composed by pectin or calcium. In case of calcium, the drug release was accelerated independently of the number of Ca/P layers, such that a 4-layer system (P/Ca/P/Ca) yield a faster drug release that a 3-alyer system (P/Ca/P), see Figure 1. This is explained by the effect of the calcium ions in the outermost layer, leading to a weakening in the calcium pectinate coating layer.

Metoprolol pellets

Figure 1: Metoprolol pellets. From left to right: Ca/P, P/Ca/P, Ca/P/Ca/P layered pellets. Colors: Cellets as MCC pellet (green), Metoprolol Tartrate (orange), Talcum (blue), Calcium (white), Pectin (grey).

Once, pectin is the component in the outermost layer, this led to a difference in drug release at neutral and slightly acidic conditions of the dissolution media. While in a neutral pH 7.4 buffer, the dissolution kinetics were comparable for a P/Ca/P-system and Ca/P-system, the situation changes in a slightly acidic buffer at pH 6.0. In a phosphate buffer at pH 6.0 the dissolution of a P/Ca/P-system was faster than of a Ca/P-system due to the almost complete ionization of pectin at pH 6.0.

Summary

This case study highlights the controlled release profile of Metoprolol Tartrate as a water-soluble model drug. The formulation is based on CELLETS® 700, which serve as inert MCC spheres. By a variation in the multi-layer composition of calcium and pectin, the dissolution kinetics and controlled release profiles were examined.

Acknowledgement

This research was funded by Thailand Research Fund through Royal Golden Jubilee Ph.D. Program, grant number PHD/00005/2541.

References

[1] P. Wanasawas, A. Mitrevej, N. Sinchaipanid, Pharmaceutics 14 (2022) 1061, https://doi.org/10.3390/pharmaceutics14051061

[2] The American Society of Health-System Pharmacists. Archived from the original on 12 March 2014. Retrieved 21 April 2014. https://web.archive.org/web/20140312062359/http://www.drugs.com/monograph/metoprolol-succinate.html

[3] M. Khotimchenko, Int. J. Biol. Macromol. 158 (2020) 1110-1124. https://doi.org/10.1016/j.ijbiomac.2020.05.002