Posts

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.

Abstract

Amorphous solid dispersions layered pellets solve a problem of poorly water soluble drugs. Speaking about oral drug formulations, drug carrier solutions based on starter cores are suitable for several drug classes and open new opportunities for modified drug release profiles. Layering and coating techniques, such as Wurster fluid bed process at different batch sizes, are well established.

However, an increasing number of poorly water soluble drugs challenges modern formulations. A novel approach improving the solubility of those drugs is to formulate them as amorphous solid dispersions (ASD) with a suitable polymer candidate [1]. In this study, Nifedipine was used as a model drug. Nifedipine manages angina, high blood pressure, Raynaud’s phenomenon, and premature labor [2].

Formulation & techniques

ASD formulations can be performed by hot-melt extrusion or spray drying technique. Both techniques have disadvantages such that hot-melt extrusion cannot be employed for temperature-sensitive drugs [3], and spray drying needs a further compaction step not to result in fine powder with poor flowability, broad particle size distribution and high sensitivity to electrostatic charge. Therefore, a further compaction step is required to obtain a freely flowable product [4].

In this context, two techniques for the preparation of ASDs are compared: A 6”-Wurster fluid bed with Type-C bottom plate (Glatt, Germany) and spouted bed (ProCell5™ with Zig-Zag-sifter, Glatt, Germany) are used.

A: GF3™ (fluidized bed); B: ProCell5™ (spouted bed)

Fig. 1: A: 6”-Wurster fluid bed; B: ProCell5™ spouted bed.

The formulation contains the drug and a stabilizing co-polymer (Kollidon®, KVA64, BASF, Germany). Nifedipine and Kollidon are mixed resulting in a drug load of 40 % (w/w) and dissolved in Acetone (30 % w/w solid content).

Parameter FB SB
Spray rate [g/min] 20 20-35
Product temp. [°C] 50-60 50-60
Process gas temp. [°C] 65 80
Process air flow [m³/h] 180-200 65-120
Spraying nozzle diameter [mm] 1.2 1.2
Spraying pressure [bar] 2.0 0.5

Table 1: Manufacturing parameters for fluid bed (FB) and spouted bed (SB).

In the fluid bed process, microcrystalline pellets (Cellets® 500, IPC Dresden, Germany) were layered with the spraying solution such that a drug load of 21.8 % (w/w) is reached. In the spouted bed process, fine powder is generated by spray drying, further agglomeration and layering. An overview on the process parameters is given in Table 1.

Dissolution Tests

Dissolution tests were conducted in a PBS buffer at pH 6.8 and 37 °C (± 0.5 °C). A physical mixture of Nifedipine and KVA64 (40 % w/w drug load) is used as reference.

Results

In the following, results from both experiments, which are amorphous solid dispersions layered pellets (fluid bed) and ASD pellets from direct palletization (spouted bed) are compared.

Flowability and particle size

ASD layered pellets show a better sphericity, higher level of monodispersity and better flowability properties than the ASD pellets from direct palletization (Figure 2). Nonetheless, it has to be pointed out that both techniques result in a high particle quality for capsule filling. Analysis data is shown in Table 2.

Parameter FB SB
10 [µm] 824 ± 23 559 ± 28
D50 [µm] 943 ± 13 732 ± 50
D90 [µm] 1091 ± 11 1374 ± 410
Bulk density [g/L] 427 280
Flowability [s/100g] 12.1 16.2

Table 2: Analysis of ASD layered pellets (FB) and ASD pellets from direct compaction (SB).

SEM images of processed pellets. A: ASD layered pellets based on Cellets® (FB)

Fig. 2a: SEM images of processed pellets. A: ASD layered pellets based on Cellets® (FB)

SEM images of processed pellets. B: ASD pellets from direct palletization (SB)

Fig. 2b: SEM images of processed pellets. B: ASD pellets from direct palletization (SB)

Dissolution profiles

Independent from the processing technique, pellets achieved an approximately factor 2 higher end concentration than the physical mixture. Pellets obtained from the fluid bed process showed a clear supersaturation phase after 1 hour and a generally higher dissolution rate than pellets obtained from the spouted bed process. Contrarily, the dissolution rate of the latter pellets approaches the supersaturation phase more continuously after 3 hours.

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.

Summary

Both techniques, fluid bed and spouted bed as well, can be employed for manufacturing amorphous solid dispersions with good flow properties and dissolution profiles. Both techniques can be scaled up to pilot and production scale for batch or continuous manufacture of freely flowable ASDs. Cellets® serve stable and reliable cores for this venture.

Acknowledgement

We gratefully acknowledge Dr. Annette Grave and Dr. Norbert Pöllinger (Glatt Pharmaceutical Services, Germany), and Prof. Karl G. Wagner and Marius Neuwirth (University Bonn, Germany).

References

[1] T. Vasconcelos, B. Sarmento, and P. Costa, Drug Discovery Today, 12(23): 1068-1075 (2007)

[2] “Nifedipine”. The American Society of Health-System Pharmacists. Retrieved: Sept 17, 2019.

[3] J. Breitenbach, European Journal of Pharmaceutics and Biopharmaceutics, (54)2: 107-117 (2002)

[4] I. Weuts et al., Journal of Pharmaceutical Sciences, (100)1: 260-274 (2011)

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
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
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
Multiple-unit orodispersible mini-tablets
International Journal of Pharmaceutics, Volume 511, Issue 2, 25 September 2016, Page 1128
Anna Kira Adam, Christian Zimmer, Stefan Rauscher, Jörg Breitkreutz

Research article
A novel method of quantifying the coating progress in a three-dimensional prismatic spouted bed
Particuology, Volume 42, February 2019, Pages 137-145
Swantje Pietsch, Finn Ole Poppinga, Stefan Heinrich, Michael Müller, Michael Schönherr, Frank Kleine Jäger

Research article
Dynamic rearrangement of disulfide bridges influences solubility of whey protein coatings
International Dairy Journal, Volume 18, Issue 5, May 2008, Pages 566-573
René Floris, Igor Bodnár, Fanny Weinbreck, Arno C. Alting

Research article
Study of the preparation of a multiparticulate drug delivery system with a layering technique
Powder Technology, Volume 205, Issues 1–3, 10 January 2011, Pages 155-159
Krisztina Nikowitz, Péter Kása Jr., Klára Pintye-Hódi, Géza Regdon Jr.

Research article
Simulation of pellet coating in Wurster coaters
International Journal of Pharmaceutics, Volume 590, 30 November 2020, 119931
Hamid Reza Norouzi

Research article
Evaluation of in-line spatial filter velocimetry as PAT monitoring tool for particle growth during fluid bed granulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 76, Issue 1, September 2010, Pages 138-146
A. Burggraeve, T. Van Den Kerkhof, M. Hellings, J.P. Remon, C. Vervaet, T. De Beera

Short communication
Raman spectroscopic investigation of film thickness
Polymer Testing, Volume 28, Issue 7, October 2009, Pages 770-772
T. Sovány, K. Nikowitz, G. Regdon Jr., P. Kása Jr., K. Pintye-Hódi

Research article
A redispersible dry emulsion system with simvastatin prepared via fluid bed layering as a means of dissolution enhancement of a lipophilic drug
International Journal of Pharmaceutics, Volume 549, Issues 1–2, 5 October 2018, Pages 325-334
Mitja Pohlen, Luka Pirker, Matevž Luštrik, Rok Dreu

Research article
The influence of rolling friction on the shear behaviour of non-cohesive pharmaceutical granules – An experimental and numerical investigation
European Journal of Pharmaceutical Sciences, Volume 49, Issue 2, 13 May 2013, Pages 241-250
Ann-Sofie Persson, Göran Frenning

Research article
Development of an enteric-coated, layered multi-particulate formulation for ileal delivery of viable recombinant Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 61, Issue 3, October 2005, Pages 134-141
Nathalie Huyghebaert, An Vermeire, Pieter Rottiers, Erik Remaut, Jean Paul Remon

Research article
Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form
International Journal of Pharmaceutics, Volume 567, 15 August 2019, 118416
Federica Ronchi, Antonio, Sereno, Maxime Paide, Pierre Sacré, George Guillaume, Vincent Stéphenne, Jonathan Goole, Karim Amighi

Research article
Particle size and packing characterization by diffuse light transmission
Particuology Volume 10, Issue 5, October 2012, Pages 619-627
Henrik Ehlers, Jyrki Heinämäki, Jouko Yliruusi

Research article
In-line spatial filtering velocimetry for particle size and film thickness determination in fluidized-bed pellet coating processes
European Journal of Pharmaceutics and Biopharmaceutics, Volume 88, Issue 3, November 2014, Pages 931-938
Friederike Folttmann, Klaus Knop, Peter Kleinebudde, Miriam Pein

Research article
Liquid absorption capacity of carriers in the food technology
Powder Technology, Volume 134, Issue 3, 30 September 2003, Pages 201-209
Heidi Lankes, Karl Sommer, Bernd Weinreich

Research article
Asymmetric distribution in twin screw granulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 106, September 2016, Pages 50-58
Tim Chan Seem, Neil A. Rowson, Ian Gabbott, Marcelde Matas, Gavin K. Reynolds, AndyIngram

Review article
Overview of PAT process analysers applicable in monitoring of film coating unit operations for manufacturing of solid oral dosage forms
European Journal of Pharmaceutical Sciences, Volume 111, 1 January 2018, Pages 278-292
Klemen Korasa, Franc Vrečer

Research article
Effect of annealing time and addition of lactose on release of a model substance from Eudragit® RS coated pellets produced by a fluidized bed coater
Chemical Engineering Research and Design, Volume 89, Issue 6, June 2011, Pages 697-705
Ulrich M. Heckötter, Anette Larsson, Pornsak Sriamornsak, Mont Kumpugdee-Vollrath

Research article
Modeling of particle velocities in an apparatus with a draft tube operating in a fast circulating dilute spout-fluid bed regime
Powder Technology, Volume 319, September 2017, Pages 332-345
Wojciech Ludwig, Daniel Zając

Research article
On the properties and application of beeswax, carnauba wax and palm fat mixtures for hot melt coating in fluidized beds
Advanced Powder Technology, Volume 29, Issue 3, March 2018, Pages 781-788
M.G. Müller, J.A. Lindner, H. Briesen, K. Sommer, P. Foerst

Research article
Characteristics of pellet flow in a Wurster coater draft tube utilizing piezoelectric probe
Powder Technology, Volume 235, February 2013, Pages 640-651
Matevž Luštrik, Rok Šibanc, Stanko Srčič, Matjaž Perpar, Iztok Žun, Rok Dreu

Research article
Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility
International Journal of Pharmaceutics, Volume 581, 15 May 2020, 119217
Matteo Cerea, Anastasia Foppoli, Luca Palugan, Alic Melocchi, Lucia Zema, Alessandra Maroni, Andrea Gazzaniga

Research article
UV imaging of multiple unit pellet system (MUPS) tablets: A case study of acetylsalicylic acid stability
European Journal of Pharmaceutics and Biopharmaceutics, Volume 119, October 2017, Pages 447-453
Anna Novikova, Jens M. Carstensen, Thomas Rades, Claudia S. Leopold

Research article
Suspension pellet layering using PVA–PEG graft copolymer as a new binder
International Journal of Pharmaceutics, Volume 412, Issues 1–2, 30 June 2011, Pages 28-36
L. Suhrenbrock, G. Radtke, K. Knop, P. Kleinebudde

Research article
Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane
International Journal of Pharmaceutics, Volume 480, Issues 1–2, 1 March 2015, Pages 15-26
Sheng-Feng Hung, Chien-Ming Hsieh, Ying-Chen Chen, Cheng-Mao Lin, Hsiu-O Ho, Ming-Thau Sheu

Research article
In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 73, Issue 2, October 2009, Pages 280-284
Nele Poelvoorde, Hans Verstraelen, Rita Verhelst, Bart Saerens, Ellen De Backer, Guido Lopes dos Santos Santiago, Chris Vervaet, Mario Vaneechoutte, Fabienne De Boeck, Luc Van Borteld, Marleen Temmerman, Jean-Paul Remon

Research article
Dry Coating Characterization of Coverage by Image Analysis: Methodology
Procedia Engineering, Volume 102, 2015, Pages 81-88
Olivier Lecoq, Fredj Kaouach, Alain Chamayou

Research article
In-line particle sizing for real-time process control by fibre-optical spatial filtering technique (SFT)
Advanced Powder Technology, Volume 22, Issue 2, March 2011, Pages 203-208
Petrak Dieter, Dietrich Stefan, Eckardt Günter, Köhler Michael

Research article
Dry Powder Coating in a Modified Wurster Apparatus
Procedia Engineering, Volume 42, 2012, Pages 437-446
W. Ludwig, R.G. Szafran, A. Kmiec, J. Dziak

Research article
Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics
Journal of Controlled Release, Volume 287, 10 October 2018, Pages 247-256
Matteo Cerea, Alessandra Maroni, Luca Palugan, Marco Bellini, Anastasia Foppoli, Alice Melocchi, Lucia Zema, Andrea Gazzaniga

Research article
Role of plasticizer in membrane coated extended release oral drug delivery system
Journal of Drug Delivery Science and Technology, Volume 44, April 2018, Pages 231-243
Pinak Khatri, Dipen Desai, Namdev Shelke, Tamara Minko

Research article
New hybrid CPU-GPU solver for CFD-DEM simulation of fluidized beds
Powder Technology, Volume 316, 1 July 2017, Pages 233-244
H.R. Norouzi, R. Zarghami, N. Mostoufi

Research article
On-line monitoring of fluid bed granulation by photometric imaging
European Journal of Pharmaceutics and Biopharmaceutics, Volume 88, Issue 3, November 2014, Pages 879-885
Ira Soppela, Osmo Antikainen, Niklas Sandler, Jouko Yliruusi

Research article
Optimization and tracking of coating processes of pellets with polyvinylpyrrolidone solutions in an acoustic levitator
Powder Technology, Volume 360, 15 January 2020, Pages 1126-1133
Doris L. Wong, Anna-Lena Wirsching, Kai Betz, Andreas Reinbeck, Hans-Ulrich Moritz, Werner Pauer

Research article
Passive acoustic emissions monitoring of the coating of pellets in a fluidized bed—A feasibility analysis
Powder Technology, Volume 283, October 2015, Pages 373-379
Taylor Sheahan, Lauren Briens

Research article
A top coating strategy with highly bonding polymers to enable direct tableting of multiple unit pellet system (MUPS)
Powder Technology, Volume 305, January 2017, Pages 591-596
Frederick Osei-Yeboah, Yidan Lan, Changquan Calvin Sun

Research article
Evaluation of pellet cycle times in a Wurster chamber using a photoluminescence method
Chemical Engineering Research and Design, Volume 132, April 2018, Pages 1170-1179
Domen Kitak, Rok Šibanc, Rok Dreu

Research article
Application properties of oral gels as media for administration of minitablets and pellets to paediatric patients
International Journal of Pharmaceutics
Volume 460, Issues 1–2, 2 January 2014, Pages 228-233

Anna Kluk, Malgorzata Sznitowska

Research article
Influence of perforated draft tube air intake on a pellet coating process
Powder Technology, Volume 330, 1 May 2018, Pages 114-124
Matevž Luštrik, Rok Dreu, Matjaž Perpar

Research article
New insight into modified release pellets – Internal structure and drug release mechanism
Journal of Controlled Release, Volume 128, Issue 2, 4 June 2008, Pages 149-156
Simon Ensslin, Klaus Peter Moll, Kurt Paulus, Karsten Mäder

Research article
In-line monitoring of pellet coating thickness growth by means of visual imaging
International Journal of Pharmaceutics, Volume 470, Issues 1–2, 15 August 2014, Pages 8-14
Nika Oman Kadunc, Rok Šibanc, Rok Dreu, Boštjan Likar, Dejan Tomaževič

Research article
Optical microscopy as a comparative analytical technique for single-particle dissolution studies
International Journal of Pharmaceutics, Volume 469, Issue 1, 20 July 2014, Pages 10-16
Sami Svanbäck, Henrik Ehlers, Jouko Yliruusi

Research article
Synthesis and melt processing of cellulose esters for preparation of thermoforming materials and extended drug release tablets
Carbohydrate Polymers, Volume 177, 1 December 2017, Pages 105-115
Sanna Virtanen, Riku Talja, Sauli Vuoti

Research article
Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs
European Journal of Pharmaceutics and Biopharmaceutics, Volume 87, Issue 1, May 2014, Pages 107-113
Lieselotte De Smet, Lien Saerens, Thomas De Beer, Robert Carleer, Peter Adriaensens, Jan Van Bocxlaer, Chris Vervaet, Jean PaulRemon

Research article
Downstream drug product processing of itraconazole nanosuspension: Factors influencing drug particle size and dissolution from nanosuspension-layered beads
International Journal of Pharmaceutics, Volume 524, Issues 1–2, 30 May 2017, Pages 443-453
Johannes Parmentier, En Hui Tan, Ariana Low, Jan Peter Möschwitzer

Research article
Attrition strength of water-soluble cellulose derivative coatings applied on different core materials
Powder Technology, Volume 222, May 2012, Pages 71-79
Katarzyna Nienaltowska, Frédéric Depypere, Giacomo Perfetti, Gabrie M.H. Meesters, Frederik Ronsse, Jan G. Pieters, Koen Dewettinck

Research article
Modulating pH-independent release from coated pellets: Effect of coating composition on solubilization processes and drug release
European Journal of Pharmaceutics and Biopharmaceutics, Volume 72, Issue 1, May 2009, Pages 111-118
Simon Ensslin, Klaus Peter Moll, Hendrik Metz, Markus Otz, Karsten Mäder

Research article
Estimating coating quality parameters on the basis of pressure drop measurements in a Wurster draft tube
Powder Technology, Volume 246, September 2013, Pages 41-50
Matjaž Perpar, Matevž Luštrik, Rok Dreu, Stanko Srčič, Iztok Žun

Research article
An experimental evaluation of the accuracy to simulate granule bed compression using the discrete element method
Powder Technology, Volume 219, March 2012, Pages 249-256
Ann-Sofie Persson, Göran Frenning

Research article
Measurement of particle concentration in a Wurster coater draft tube using light attenuation
Chemical Engineering Research and Design, Volume 110, June 2016, Pages 20-31
R. Šibanc, I. Žun, R. Dreu

Research article
Influence of separation properties and processing strategies on product characteristics in continuous fluidized bed spray granulation
Powder Technology, Volume 342, 15 January 2019, Pages 572-584
Daniel Müller, Andreas Bück, Evangelos Tsotsas

Research article
Flowability of surface modified pharmaceutical granules: A comparative experimental and numerical study
European Journal of Pharmaceutical Sciences, Volume 42, Issue 3, 14 February 2011, Pages 199-209
Ann-Sofie Persson, Göran Alderborn, Göran Frenning

Research article
Mechanics of Pharmaceutical Pellets—Constitutive Properties, Deformation, and Breakage Behavior
Journal of Pharmaceutical Sciences, Volume 107, Issue 2, February 2018, Pages 571-586
Alexander Russell, Rok Šibanc, Rok Dreu, Peter Müller

Research article
Global monitoring of fluidized-bed processes by means of microwave cavity resonances
Measurement, Volume 55, September 2014, Pages 520-535
Johan Nohlert, Livia Cerullo, Johan Winges, Thomas Rylander, Tomas McKelvey, Anders Holmgren, Lubomir Gradinarsky, Staffan Folestad, Mats Viberg, Anders Rasmuson

Research article
Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating
European Journal of Pharmaceutics and Biopharmaceutics, Volume 124, March 2018, Pages 13-27
Dolores R. Serrano, David Walsh, Peter O’Connell, Naila A. Mugheirbi, Zelalem Ayenew Worku, Francisco Bolas-Fernandez, Carolina Galiana, Maria Auxiliadora Dea-Ayuela, Anne Marie Healy


Research article

Research article
Dry Particle High-Impact Coating of Biopowders: Coating Strength
Particulate Science and Technology, Volume 27(4), 2009
S. Ötles, O. Lecoq, J. A. Dodds


Research article

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)

 

Abstract

Cellets are inert starter cores made of microcrystalline cellulose (MCC). They play an important role in new formulations of solid dosage forms. As a carrier system for actives, the chemical inertness and surface smoothness are crucial parameters. Additionally, high level of robustness and sphericity simplify formulations and technical processes, such as fluidized bed technologies for coating and layering. In a joint study between the University of Hertfordshire and Freeman Technology (a Micromeritics company), the effect of pellets’ size on the behavior in a Wurster process is explained. Wurster fluid bed coating of Cellets with particle size larger than 400 µm is unproblematic. However, decreasing the particle size begins to complicate the coating process. So, powder rheology was used to compare Cellets with different particle sizes in terms of their effect on the powder flow in the Wurster fluid bed coater. For deeper knowledge, we strongly recommend reading investigations by V. Mohylyuk et al. [1]

Materials

Cellets® 90, 100, 200 and 350 (D50-size from 94 µm to 424 μm, Ingredientpharm, Switzerland). MCC powder Avicel® PH-102 (supplied by IMCD UK Ltd., UK) is included in the investigations, as it is widely used in industry and can be used by readers for comparison with other studies.

Wurster fluid-bed

Wurster process is a bottom-spray method, employed as a coating technology, for layering powder-like particles in a fluidized bed system (Figure 1). The process can be separated in different zones of mass flow, such as the down-flow zone or the horizontal transport zone. The flowability in these zones is crucial for homogeneous and efficient coating of the particles.

wurster_500x500

Figure 1: Wurster process is a bottom-spray method for layering powder-like particles in a fluidized bed system.

Hereby, the size of particles might play an important role. The narrow size distribution of MCC pellets is shown in Figure 2 and Figure 3. Measured data is presented in Table 1.

Figure-2

Volume weightened size distribution of Cellets 90 (red, diamonds), Cellets 100 (orange, triangles), Cellets 200 (blue, circles), Cellets 350 (green, squares).

The compact Cellets with fair sphericity, zero friability and a high level of surface smoothness show a fair mass flow rate which is almost independent of particle size at given experimental conditions and was determined by the gravitational funnel method. The reference MCC powder did not flow through the orifice.

Excipient PSD
[µm]
Span
[µm]
Flow rate
[g/s]
Avicel PH-102 115a 1.85 No flow
Cellets 90 94b 0.44 1.76
Cellets 100 163b 0.27 2.06
Cellets 200 270b 0.34 1.89
Cellets 350 424b 0.22 1.83

Table 1: Particle size distribution (D50) value and span by laser diffraction (a) and digital microscopy (b), and the mass flow rate by gravitational funnel method (5 mm diameter orifice) for the investigated excipients.

Impact of the Cellets’ size

The impact of the Cellets’ size on bulk powder behavior can only be estimated by screening additional parameters. In addition to the mass flow rate, standard pharmacopoeia methods such as bulk/tapped density were initially employed for the characterization of the powder’s properties. This was extended to rotating drum measurements providing the dynamic angle of repose and dynamic cohesivity index. Via powder rheology the conditioned bulk density, basic flowability energy, specific energy, pressure drop, permeability and compressibility (Figure 4) were obtained [1].

By picking the compressibility of Cellets at an applied force of 10 kPa normal stress, two key points need to be mentioned: (a) smaller particle size induces a higher rate of compressibility; (b) Cellets are less compressible than the reference MCC powder.

These findings are part of the open question on powder flow in a Wurster process. It is expected, that Cellets with a lower compressibility will result in better flow behavior in the fluidized bed.

Figure-3

Microscopic imaging of Cellets 100 (top left), 200 (top right), 350 (bottom left) with 1 mm scale bar and 100x magnification. Bottom right: surface of Cellets 350 in 1000x magnification.

Figure-4

Compressibility at 10 kPa normal stress on Cellets with varying particle size (D50) and Avicel® PH-102.

Summary

The flow of Cellets’ through a Wurster fluid-bed coater is likely to show improved performance as the Cellets’ particle size increases. Among others, a lower compressibility demonstrates a rheological behavior which is superior to MCC.

References

[1] Mohylyuk V, Styliari ID, Novykov D, Pikett R, Dattani R. Assessment of the effect of Cellets’ particle size on the flow in a Wurster fluid-bed coater via powder rheology. J D Deliv Sci Tec. 2019; 54: 101320, doi: 10.1016/j.jddst.2019.101320.

Author

Dr. Bastian Arlt, Glatt Pharmaceutical Services, Werner-Glatt-Straße 1, 79589 Binzen.

The renaissance of micropellets is promoting innovative technologies

In recent years, formulations based on pellets and micropellets have been the trend. New technologies make it possible to circumvent property rights for active ingredients and are therefore very popular with pharmaceutical customers. But which technologies are the most important?

Pellets are the jack-of-alltrades of solid dosage forms. Positioned somewhere between powder and granulate, they make bitter medicine more palatable and can even awaken a child’s instinct to play when the dosage forms are imaginative enough. One well-known example is the Xstraw, a plastic tube shaped like a drinking straw which is filled with pellets of active ingredient, through which children or elderly people can take in the medicine with water. Pellets in tablets are also making a splash – hybrids which combine all the advantages of both dosage forms. The pioneers in the development of these formulations, known as Multiple Unit Pellet Systems (or MUPS for short), was Astra Zeneca in 1999. Their move to embed the proton pump inhibitor Omeprazole in micropellets and then compress these pellets into immediate release tablets was an award-winning one at the time. The development of MUPS and Xstraw symbolizes the impetus pellets have fueled in recent years.

Klaus N. Möller, Head of Business Development at Glatt in Binzen / Germany, explains: “New excipients, coating materials and sophisticated processes allow us to extend the patent protection period and to make the dosage form more attractive.“

The number of patents registered yearly for pellet-based formulations has increased exponentially and is set to continue. According to research performed by IMS Health, the market for OSD (Oral Solid Dosage Forms) is growing by 6 to 8 percent every year. The number of drugs approved by the FDA also reflect this trend: in 2015, more than half were solid products.

Pellets, as defined by pharmacy guru Prof. Peter Kleinbudde are “an isometric agglomerate of powder particles in an approximate spherical or cylindrical form”, and are a task for perfectionists. The smoother and rounder the pellets, the better they are at fulfilling their purpose. The equipment manufacturer Glatt and their specialists from Pharmaceutical Services have been actively ursuing the subject for years.

There are two fundamental ways of making active ingredient pellets: direct pelletization, in which the powdered active ingredient and excipient combine in a matrix, and active ingredient layering, in which uses side spray or Wurster technology to apply the active ingredient to a starter core of sugar or microcrystalline cellulose.

A case for the specialists

One interesting process variant for matrix pellets is the extrusion of wet granulate in a basket extruder and subsequent rounding in a spheronizer. Möller elucidates: “Continuous wet granulation, followed by extrusion, spheronization and drying now make it possible to perform continuous processes”. Active ingredient pellets made like this can then be covered with a functional coating, be continuously mixed with excipients and be directly compressed into a MUPS tablet. The challenge is to avoid separation of the ingredients and destruction of the tablets during pressing.

Glatt, whose portfolio comprises all granulation and pellet manufacturing techniques, has spent recent years developing additional ways of “fine tuning” the pellet process and has opened up a range of new, interesting possibilities for the lifecycle management of active ingredients.

Pellets and micropellets can be further processed into a wide range

Pellets and micropellets can be further processed into a wide range

Applying the final touches

But what differentiates the manufacturing of granulates from the manufacturing of pellets? From a pharmaceutical point of view, both processes are closely related and are only separated by the form of the particle, since the ideal shape for pellets is a sphere. There are also definite commonalities in procedure. As Möller explains: “The fluidized bed can be used for both granulation and pelletization. This is why we configure fluidized bed machines on request to be multipurpose installations which then allow the continuous manufacturing of pellets. The individual process modules for direct pelletization with rotor technology, for layering active ingredient and for pellet coating with Wurster technology or the simple drying of wet granulates can be added as necessary. Wurster technology has been used in practice for many years: it is a fluidized bed technique in which starter cores or active ingredient pellets are sprayed with a insists. Möller says: “This method is robust and, because the process is so stable, it’s generally the most popular way to process pellets.”

Depending on the composition of the tablets, processing can last anywhere between eight and ten hours. The knack is knowing how to optimize the efficiency and times of the production process. Additionally, Möller recommends timely expert assistance during the development of the pellet formulation and the production process: “Right from the beginning, it will help to avoid mistakes and to keep an eye on process times and manufacturing costs”.

Micropellets and more

Glatt’s development team demonstrated how to refine an established process with the fluidized bed agglomeration technique known as MicroPx. The trick is to use the Conti process, which was conceived in Pharmaceutical Services’ laboratories in Binzen: first, the active ingredient/excipient liquid is spray-dried to a very fine product dust in a fluidized bed and agglomerated into tiny primary particles. The micropellets then build up, layer by layer, until the desired size is reached. The heart of this technology is a zigzag classifier which continuously ejects particles of sufficient size from the process, while simultaneously allowing smaller particles to reenter the process chamber where they continue to grow. Möller explains that the result of this method are high dosage active ingredient pellets in the size range of 100 to 400 μm with a narrow particle size distribution and content uniformity of a consistent 90 to 95 percent. This means that one significant limitation of former times is now no longer an issue: for many years, the volume of a pellet- filled capsule was larger — and therefore much harder to swallow — than the equivalent tablet with the same dose and composition. The use of microencapsulation, which changes bitter-tasting active ingredients into tasteless microparticles, means the taste is much improved now, too. Micropellets can be also pressed into tablets or MUPS tablets which already begin disintegration in the mouth. But the reason pharmaceutical companies find the MicroPx process so exciting is that it makes completely new formulations possible and therefore allows the legal circumvention of property rights. The technology experts have long known the secret to the perfect pellet, too, an answer provided by Complex Perfect Spheres Technology (CPS). CPS is a souped-up rotor process for fluidized bed machines that uses direct pelletization to yield functionalized pellets and micropellets which are perfectly round and smooth. Unlike classic rotor technology, the modified technique uses a tapered rotating disc which allows the movement of particles to be directed and pelletization to be performed to a defined endpoint. The results are perfectly spherical pellets of exactly defined sizes of between 100 and 1500 μm and extremely narrow size distribution. This is how Glatt’s own Cellets of microcrystalline cellulose are created, which are used as starter cores for pellets and in the Wurster process, for example — thus completing the formulation cycle.

Author

Klaus Möller, Head of Business Development Glatt Process Technology Pharma

Abstract

Microcrystalline cellulose pellets (MCC) and sugar are well-known materials in pellet technology. Pellet technology describes the drug load onto starter pellets for controlled release formulations by Wurster process or others. Inert pellets are made of microcrystalline cellulose, while water soluble pellets are composed of sugar. Both material classes show desirable characteristics, such as a narrow particle size distribution, sphericity, surface smoothness. Also the batch-to-batch reproducibility and robustness of starter cores is high. A comparison does not seem to be that easy …

Starter cores in the micron range

Respecting the final application, the initial size of starter pellets defines the final size of the drug loaded pellet. In case of several layers of API and excipients, the initial size is factorized by the layering process. Pellet sizes in a range from 200 µm to 700 µm are frequently used (Table 1). We will focus on three size classes within this range and compare MCC pellets with those made of sugar.

Cellets_200-1-3

Figure 1: MCC pellets (here: Cellets® 200) are shown with good sphericity and striking surface smoothness.

Small-sized pellets starting at 200 µm

Small-sized pellets with sizes starting at 200 µm and larger, exhibit a comparably large surface-to-volume ratio. This can be beneficial in some applications. For example, taste-masking of bitter API is accessible.

Cellets_200-1-4

Figure 2: Sugar pellets (here: 50/70 mesh) are shown with moderate sphericity and reduced surface smoothness.

Figure 1 displays a microscopic image of MCC Cellets® 200 and Figure 2 displays the image of sugar pellets in 50/70 mesh, respectively. It is obvious, that for small-sized pellets, the sphericity and surface smoothness of MCC pellets is superior.

Size MCC Sugar
small Cellets® 200 50/70 mesh
Medium Cellets® 350 40/50 mesh
large Cellets® 500 25/30 mesh

Table 1: Size definition of MCC and sugar pellets.

Mid-sized pellets up to 500 µm

This class of pellets is frequently used for multi-layer coating technologies. Easy processing and reliable batch-to-batch control are positive aspects. Exemplary application is a hydrocortisone formulation for peadiatrics. Again, Figure 3 (MCC pellets) and Figure 4 (sugar pellets) show advantages in surface properties for the MCC material.

Cellets_350-1-3

Figure 3: MCC pellets (Cellets® 350) are shown.

Cellets_350-1-4

Figure 4: Sugar pellets (40/50 mesh) are shown

Large-sized pellets above 500 µm

In some applications, larger pellet sizes are requested. Let’s have short excurse into straws which can contain larger pellets in dry state. Upon use by sucking liquid through the straw, the API coating dissolves immediately while the pellet remains in the straw by simple filters.

In this size range the striking advantages of MCC pellets are not of immediate importance, but still visible.

Cellets_500-1-3

Figure 5: MCC pellet above 500 µm (Cellets® 500).

Cellets_500-1-4

Figure 6: Sugar pellet above 500 µm (25/30 mesh).

Summary

Microcrystalline cellulose pellets (Cellets®) show superior surface and sphericity properties compared to sugar pellets. In case of non-dissolving applications, MCC pellets are first choice. As sugar pellets exhibit strong dissolution in water, there is still a fair application range for them.

Authors

Dr. Bastian Arlt

Portfolio Items