Coating and layering processes allow adding API and excipients onto carrier systems such as starter beads. Several goals can be satisfied, such as modified drug release, taste-masking, color, and more.

Posts

Cellets list of publication
, , , , , ,

Scientific literature on MCC pellets (CELLETS)

Selected Scientific literature

Please, find scientific literature on CELLETS®, MCC spheres. 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 – Publications with MCC spheres, 2024

Research article
In vitro validation of colon delivery of vitamin B2 through a food grade multi-unit particle system
Wageningen Academic (2024), eISSN: 1876-2891; doi:10.1163/18762891-bja00045
R.E. Steinert, W. Sybesma, R. Duss, A. Rehman, M. Watson, T.C. van den Ende, E. Funda

Research article
Homogeneity and mechanical properties of orodispersible films loaded with pellets
Eur. J. Pharm. Biopharm. 2024, 114537; doi:10.1016/j.ejpb.2024.114537
K. Centkowska, M. Szadkowska, M. Basztura, M. Sznitowska

Patent
Extended-release compositions comprising atomoxetine
A1

Patent
Extended release compositions comprising pyridostigmine
A1

Research article
The development of an innovative method to improve the dissolution performance of rivaroxaban
Heliyon 2024, (10)12; doi:10.1016/j.heliyon.2024.e33162
M. Langner, F. Priese, and B. Wolf

Research article
Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control
Pharmaceutics 2024, 16(10), 1307; doi:10.3390/pharmaceutics16070945
M. Langner, F. Priese, and B. Wolf

Thesis
Characterization of dense granular flows using a continuous chute flow rheometer
Purdue University, School of Materials Engineering, West Lafayette, Indiana, posted on 2024-07-20, 03:12
Kayli Lynn Henry

Research article
The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer
Pharmaceutics (2024), 16(7), 945; doi:10.3390/pharmaceutics16070945
A. Paulausks, T. Kolisnyk, V. Mohylyuk

Research article
The development of an innovative method to improve the dissolution performance of rivaroxaban
Heliyon 10 (2024) e33162; doi:10.1016/j.heliyon.2024.e33162
E.A. Ozon, E. Mati, O. Karampelas, V. Anuta, I. Sarbu, A.M. Musuc, R.-A. Mitran, D.C. Culita, I. Atkinson, M. Anastasescu, D. Lupuliasa, M.A. Mitu

Thesis
Uniform and homogenous hot-melt coating in a Wurster fluidized bed
TUM School of Life Sciences der Technischen Universität München, 2024
B. M. Wörthmann

Thesis
Modelling the disintegration of pharmaceutical tablets: integrating a single particle swelling model with the discrete element method
University of Strathclyde, Strathclyde Institute of Pharmacy and Biomedical Sciences, CMAC National Facility, 2024, Thesis identifier T16863
M. Soundaranathan

List – Publications with MCC spheres, 2023

Research article
Paediatric solid oral dosage forms for combination products: Improving in vitro swallowability of minitablets using binary mixtures with pellets
European Journal of Pharmaceutical Sciences (2023), 187, 106471; doi:10.1016/j.ejps.2023.106471
A. Avila-Sierra, A. Lavoisier, C. Timpe, P. Kuehl, L. Wagner, C. Tournier, M. Ramaioli

Research article
Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating
Pharmaceuticals (2023), 16(8), 1064; doi:10.3390/ph16081064
A. Kara, D. Kumar 2, A.M. Healy, A. Lalatsa, and D.R. Serrano

Research article
High-Speed Tableting of High Drug-Loaded Tablets Prepared from Fluid-Bed Granulated Isoniazid
Pharmaceuticals (2023), 15(4), 1236; doi:10.3390/pharmaceutics15041236
V. Mohylyuk, and D. Bandere

Research article
The Effect of Design and Size of the Fluid‑Bed Equipment on the Particle Size‑Dependent Trend of Particle Coating Thickness and Drug Prolonged‑Release Profile
AAPS PharmSciTech (2023) 24, 93. doi:10.1208/s12249-023-02540-9
T. Brezovar, G. Hudovornik, M. Perpar, M. Luštrik, R. Dreu

Research article
Amorphous Solid Dispersions Layered onto Pellets—An Alternative to Spray Drying?
Pharmaceutics (2023) 15(3), 764. doi:10.3390/pharmaceutics15030764
M. Neuwirth, S.K. Kappes, M.U. Hartig, K.G. Wagner

Research article
Optimization of Fluidized-Bed Process Parameters for Coating Uniformity and Nutrient-Release Characteristics of Controlled-Release Urea Produced by Modified Lignocellulosic Coating Material
Agronomy (2023) 13(3), 725. doi:10.3390/agronomy13030725
A.M. Ali, B. Azeem, A.M. Alghamdi, K. Shahzad, A. Ahmad Al-Zahrani, M. Imtiaz Rashid, A. Binti Mahpudz, A. Jamil

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

List – Publications with MCC spheres, 2022

Research article
Product-Property Guided Scale-Up of a Fluidized Bed Spray Granulation Process Using the CFD-DEM Method
Processes (2022) 10(7), 1291. doi:10.3390/pr10071291
P. Kieckhefen, S. Pietsch-Braune, S. Heinrich

Research article
Influence of In Situ Calcium Pectinate Coating on Metoprolol Tartrate Pellets for Controlled Release and Colon-Specific Drug Delivery
Pharmaceutics (2022) 14(5), 1061. doi:10.3390/pharmaceutics14051061
P. Wanasawas, A. Mitrevej, N. Sinchaipanid

Research article
Delamination and wetting behavior of natural hot-melt coating materials
Powder Technology (2022) 404, 117443. doi:10.1016/j.powtec.2022.117443
B.M. Woerthmann, L. Totzauer, H. Briesen

Research article
A systematic approach for assessing the suitability of enteral feeding tubes for the administration of controlled-release pellet formulations
International Journal of Pharmaceutics (2022) 612, 121286. doi:10.1016/j.ijpharm.2021.121286
F. Karkossa, N. Lehmann, S. Klein

Research article
Spray-freeze-dried lyospheres: Solid content and the impact on flowability and mechanical stability
Powder Technology (2022) 411, 117905. doi:10.1016/j.powtec.2022.117905
A. Rautenberg, A. Lamprecht

Conference proceedings
Assessment of the effect of microcrystalline cellulose (MCC) spheres size on the flow via powder rheology
The FORGE, 2022 – pure.qub.ac.uk
V. Mohylyuk, R. Dattani

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
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

List – Publications with MCC spheres, 2021

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
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
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

List – Publications with MCC spheres, 2020

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

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

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

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
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
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
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
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
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
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
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
Fixed-bed-column studies for Methylene blue removal by Cellulose CELLETS
Environmental Engineering and Management Journal, Volume 19 (2), March 2020, 269-279
Iulia Nica, Gabriela Biliuta, Carmen Zaharia, Lacramioara Rusu, Sergiu Coseri, Daniela Suteu

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

List – Publications with MCC spheres, 2019

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
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
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
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 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
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
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
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 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
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
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
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
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

List – Publications with MCC spheres, 2018

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
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
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
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
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
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
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
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
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

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
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
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
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
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
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
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

List – Publications with MCC spheres, 2017

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
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
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

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

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
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
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
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
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
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

List – Publications with MCC spheres, 2016

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
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
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
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
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

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
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

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

List – Publications with MCC spheres, 2015

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
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
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
Cellulose CELLETS as new type of adsorbent for the removal of dyes from aqueous media
Environmental Engineering and Management Journal, Volume 14, Issue 3, March 2015, Pages 525-532
Daniela Suteu, Gabriela Biliuta, Lacramioara Rusu, Sergiu Coseri, Gabriela Nacu

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
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
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

List – Publications with MCC spheres, 2014

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
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
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
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
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
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
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

List – Publications with MCC spheres, 2013

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
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
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
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
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
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
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
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
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
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
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

List – Publications with MCC spheres, 2012

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
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
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
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
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
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
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

List – Publications with MCC spheres, 2011

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
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
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
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
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
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
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

List – Publications with MCC spheres, 2010

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
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
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
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

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
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

List – Publications with MCC spheres, 2009

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

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
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
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
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)

List – Publications with MCC spheres, 2008 and earlier

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
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
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
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
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
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
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
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

 

/by
colon delivery of vitamin B2
,

In vitro validation of colon delivery of vitamin B2 through a food grade multi-unit particle system

Colon delivery of vitamin B2

This article “In vitro validation of colon delivery of vitamin B2 through a food grade multi-unit particle system” discusses a novel method for delivering active ingredients, particularly riboflavin, to the colon in a food-grade, environmentally friendly form using a double-layer coated multi-unit particle system (MUPS). The MUPS uses a shellac outer layer, alginate inner layer, and cellulose core, maintaining integrity through upper digestive processes. Tests showed it releases about 90% of riboflavin in the colon, enhancing gut health by promoting beneficial short-chain fatty acids. This sustainable approach addresses rising demand for effective colon-targeted health products and aligns with EU regulations limiting microplastic use in consumable goods.

The MUPS containing riboflavin, branded as Humiome® B2 by DSM-Firmenich, utilizes cellulose pellets known as CELLETS® as the core material. The manufacturing process involves a fluid bed layering method, where riboflavin and pectin are applied as a binder onto the Cellets. The MUPS is then coated with layers of sodium alginate and hardened with calcium chloride, followed by a shellac outer layer. This design ensures a controlled, colonic release, offering an efficient, food-grade delivery system for active nutrients.

The study demonstrates the efficacy of a shellac-alginate MUPS for targeted delivery of riboflavin to the colon, using food-grade materials that align with environmental standards. In vitro models validated its effectiveness, with around 90% of riboflavin reaching the colonic region. Results show promise for health benefits linked to microbiome modulation and short-chain fatty acid production. Future clinical studies will focus on the impact of this delivery system on microbiome and host health, supporting its potential in functional foods, supplements, and medical nutrition.

Abstract

Colon target delivery of active ingredients is frequently applied in pharmaceutical products. However, in functional food and beverage applications, dietary supplements, and medical nutrition, formats targeting colonic delivery to improve human health are rare. Nevertheless, there is emerging evidence for beneficial effects of colonic delivered nutrients on gut microbiota and host health which increases the demand for sustainable food grade materials that are regulatory approved for application. In this paper, we describe a double layer coated multi-unit particle system (MUPS) with a diameter of approximately 730 microns consisting of food grade materials: shellac as outer layer, alginate as inner layer, cellulose as a core and riboflavin as active ingredient. The suitability of the MUPS for colonic delivery was tested in three well-established in vitro digestion and fermentation models: the USP Apparatus 3 and the TNO Intestinal Models 1 and 2 (TIM-1 and TIM-2). All systems confirmed the integrity of the MUPS under simulated upper gastrointestinal tract conditions with approximately 90% of the active ingredient being released under simulated ileal-colonic conditions. The TIM-2 model also showed the effects of riboflavin loaded MUPS on the microbiome composition with an increase in the production of short-chain fatty acids, acetate and butyrate. The results of these experiments provide a reliable basis for validation of this vitamin-loaded food grade MUPS in future human clinical trials. In addition, following the recent announcement of the European Commission to restrict intentionally added microplastics to products, the materials used in the described formulation offer an environmentally friendly alternative to often applied methyl acrylate based coatings.

Source of Abstract

In vitro validation of colon delivery of vitamin B2 through a food grade multi-unit particle system in: Beneficial Microbes- Vorabveröffentlichung

 

/by
packaged modified release gamma-hydroxybutyrateadobe firefly
,

Patent on packaged modified release gamma-hydroxybutyrate formulations having improved stability

The patent WO2019123269A1, titled “Packaged modified release gamma-hydroxybutyrate formulations having improved stability“ presents innovative formulations and packaging methods designed to enhance the dissolution and chemical stability of gamma-hydroxybutyrate (GHB), a treatment for narcolepsy. Current GHB treatments, like XYREM®, require patients to wake up mid-sleep for a second dose, making this method cumbersome. This patent aims to develop a once-nightly, modified-release GHB form that maintains stability through advanced packaging, which controls relative humidity to ensure long-term effectiveness and prevent chemical degradation of GHB into gamma-butyrolactone (GBL).

Key Innovations:

  1. Modified Release Formulation: The patent includes an immediate and modified release component, both containing GHB or a pharmaceutically acceptable salt. The modified release form is designed to control the release of GHB over time, providing sustained therapeutic effects throughout the night without the need for a second dose. This formulation helps improve patient convenience and adherence to treatment.
  2. Stability Issues with GHB: GHB is highly hygroscopic and chemically unstable, which leads to degradation, especially in high humidity environments. Its instability results in the formation of GBL, a degradation product that reduces the drug’s effectiveness. The patent addresses these challenges by creating a formulation with stable dissolution profiles and chemical stability, even under stressful storage conditions (e.g., high temperature and humidity).
  3. Packaging Innovation: To further enhance the stability, the GHB formulations are packaged in a way that maintains a specific relative humidity range (29% to 54%) within the package. This careful control of humidity is crucial to prevent GHB from degrading into GBL. The packaging material has a low water vapor transmission rate, reducing moisture exposure and ensuring the drug remains stable over time.
  4. Hydrophobic Coating: The patent uses a hydrophobic coating (e.g., glyceryl tristearate, hydrogenated vegetable oil) and methacrylic acid copolymers for the modified release component. These coatings help control the release rate of GHB and protect it from moisture, ensuring a steady release and preventing premature degradation.
  5. Pharmaceutical Composition: The GHB composition in the patent includes varying ratios of immediate and modified release components. These compositions are tailored to provide a sufficient therapeutic dose while maintaining stability. The sizes of the particles and the specific formulation ratios (e.g., 40/60 to 60/40) are key factors in achieving the desired pharmacokinetics and release profiles.

The primary innovation lies in controlling the relative humidity within the packaging, alongside a modified release formulation with hydrophobic coatings to maintain the drug’s chemical stability and effectiveness. These advancements make GHB therapy more convenient by eliminating the need for a second nightly dose and addressing the stability challenges that have plagued previous formulations.

In this patent, CELLETS® play a crucial role as inert cores used in the formulation of modified release or the active or salts thereof. These starter spheres serve as carriers for the active ingredient by providing a surface for multi-layer drug layering. Their primary function is to ensure uniform drug distribution and control the release profile of GHB. The benefits include enhancing dissolution stability, maintaining the integrity of the dosage form over time, and helping to modulate the release rate of the drug for once-nightly dosing convenience. For these aspects, MCC starter sphere types where employed: CELLETS® 90, CELLETS® 100, CELLETS® 127. Glatt ProCell™ technique is used for spraying molten API.

Document information

Document Type and Number: (“Packaged modified release gamma-hydroxybutyrate formulations having improved stability”).
Kind Code: A1

Inventors:

Hervé GUILLARD

Disclaimer

This text was partly generated by chatGPT engine version GPT‑4o, on Oct 21, 2024. Image was generated with Adobe Firefly.

/by
Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets

Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control

This article “Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control” was published on Pharmaceutics 2024, 16(10), 1307; https://doi.org/10.3390/pharmaceutics16101307, under free licence on October 08, 2024 by Marcel Langner, Florian Priese, and Bertram Wolf.

Abstract

Background/Objectives: Coated drug pellets enjoy widespread use in hard gelatine capsules. In heterogeneous pellets, the drug substance is layered onto core pellets. Coatings are often applied to generate a retarded release or an enteric coating. Methods: In the present study, the thickness of a polymer coating layer on drug pellets was correlated to the drug release kinetics. Results: The question should be answered whether it is possible to stop the coating process when a layer thickness referring to an intended drug release is achieved. Inert pellets were first coated with sodium benzoate and second with different amounts of water insoluble polyacrylate in a fluidized bed apparatus equipped with a Wurster inlet. The whole process was controlled in-line and at-line with process analytical technology by the measurement of the particle size and the layer thickness. The in-vitro sodium benzoate release was investigated, and the data were linearized by different standard models and compared with the polyacrylate layer thickness. With increasing polyacrylate layer thickness the release rate diminishes. The superposition of several processes influencing the release results in release profiles corresponding approximately to first order kinetics. The coating layer thickness corresponds to a determined drug release profile. Conclusions: The manufacturing of coated drug pellets with intended drug release is possible by coating process control and layer thickness measurement. Preliminary investigations are necessary for different formulations.

1. Introduction

The drug dissolution of solid formulations depends on the solubility and dissolution rate of the drug substances and—in case of release—a number of parameters additionally influence the release kinetics: for example, drug substance interaction with formulation components (excipients), compression force and hardness in case of tablets and kind of binder in granulates, pellets and generally in polymer coatings. The knowledge of the dissolution rate and the release kinetics is essential and indispensable for optimum pharmacotherapy. Dissolution of solid substances runs approximately with first order kinetics due to diffusion processes. Certain drug formulations show zero order release with equal amounts released in equal time intervals. The superposition of several processes, for example, wetting of the solid drug dosage form, dissolution of the solid drug substance, diffusion of the drug molecules out of the dosage form, swelling of the dosage form in case of matrix formulations and swelling and water uptake of insoluble films leads to kinetic processes not meeting unambiguous zero or first order or square or cubic root equations. The release data are linearized by several models to evaluate the best approach. The coefficient of determination CoD of the linearized curve gives hints to the best adaptation and to the probability of the dominating process [1,2,3,4,5,6].
The model-independent parameters difference factor f1 and similarity factor f2 are used for release profile comparison; f1 describing the relative error between two release profiles calculated from the cumulatively released amounts at a certain time T for a test and a reference formulation or in general between two formulations—for example in the drug’s development. f2 is based on the sum of deviation squares of the released drug amounts of two release profiles [4,5,7,8,9].
Increasing attention is given to drug-loaded pellets and their release control by slowly swelling matrix systems or a final functional coating. The release of drug substances from matrix pellets prepared by extrusion/spheronization and finally coated with different amounts and types of insoluble ethylcellulose has been investigated [10,11,12]. Other authors report on the influence of the filler type on the drug release [13], the effect of the pH value of the release fluid [4], the storage conditions of drug and methylcellulose matrix pellets [14], the amount of enteric polymer coating [15] and the salt concentration of the release fluid [16]. The influence of talc and hydrogenated castor oil on the dissolution behaviour of metformin-loaded matrix pellets with an acrylic-based sustained release coating [17], the sustained release of Lisinopril from mucoadhesive matrix pellets [18] and the sustained-release of sinomenine hydrochloride from pellets manufactured by a novel whirlwind fluidized bed process have all been investigated [19].
Drug-layered inert pellets coated with polymer (heterogeneous pellets) were investigated in a similar way regarding the influence of the release kinetics by different modifications of the ethylcellulose coating [20], by ethylcellulose mixed with different amounts of polyvinylpyrrolidone (PVP) as pore former for controlled drug release [21], by alternating layers of ethylcellulose and polyvinylacetate [22], by various ethylcellulose coating levels and final curing [23] and by ethyl cellulose coating of acetaminophen-layered sugar pellets [24]. With a polyacrylate coating, the drug release from layered pellets was found to be retarded [7,25]. Variation of polymer type and layer thickness permits the control of the release rate in a wide range [8].
In our own earlier investigations heterogeneous pellets were manufactured by fluidized bed technology with a Wurster inlet. Inert microcrystalline cellulose pellets were coated with excipients and the easily water-soluble model drug sodium benzoate [26,27,28]. These sodium benzoate pellets (SB pellets) exhibited a narrow particle size distribution, high sphericity and homogeneous layers and gave very quick sodium benzoate release. For retarded release, the SB pellets were coated in a second step with different amounts of ethylcellulose, once more by fluidized bed technology with a Wurster inlet [29]. The release rate diminished with increasing layer thickness, as expected. Furthermore, the fluidized bed processes were controlled by in-line particle size measurement with the spatial filter velocimetry SFV probe [27,28] for process control regarding particle size, particle size distribution and ethylcellulose layer thickness.
The aim of the present project was the manufacturing of heterogeneous pellets in the fluidized bed with a Wurster inlet, the control of the process by in-line particle size and coating layer thickness measurements, the investigation of the kinetics of sodium benzoate release considering different kinetic models, the interpretation of the partial processes involved in the release, the correlation of the release rate with the polymer layer thickness and the detection of the coating process endpoint for the improvement of the pellet product quality regarding controlled drug release. For drug pellet manufacturing, a similar experimental approach as the one in [26,27,28] was chosen. Relatively small initial inert pellets (Cellets®175, median 170 µm), referring to a large specific surface area, were coated with a solution of sodium benzoate and a low amount of the water soluble PVP as a binder to improve the mechanical stability of the layer. In a second step (see [29]), the SB pellets were coated with different amounts of insoluble but slowly swelling polyacrylate for retarded release. The risk of undesirable agglomeration of those small pellets during sodium benzoate and polymer coating was practically eliminated by adjusting the process parameters and adding talcum to the coating fluid as an antistick agent. The SFV probe was installed for in-line particle size measurement and detection of agglomerates. The drug release was investigated and discussed applying zero order, first order, square root and cubic root equation kinetic models. Finally, the most probable release kinetics model was identified by the calculation of curve parameters—area under the curve (AUC), dissolution efficiency (DE) and mean dissolution time (MDT)—and by comparison of the CoD of the different kinetic models. The difference of the release profiles and the similarity of different polyacrylate layered pellet lots were calculated by the difference factor f1 and similarity factor f2. The linearization approach of the dissolution profiles is suitable for first order kinetics; for other release profiles a nonlinear approach can describe the dissolution curves more accurately and with a smaller standard deviation of the fitting parameter than the linearization-based calculation method [30].

2. Materials and Methods

2.1. Materials

Pellets of microcrystalline cellulose (Cellets®175, particle size range 150–200 µm, median 170 µm, IPC, Dresden, Germany), sodium benzoate (Applichem, Darmstadt, Germany, solubility 57 g in 100 g water at room temperature), PVP (Kollidon®25, Carl Roth, Karlsruhe, Germany), talcum (Talkum Pharma, C. H. Erbslöh, Krefeld, Germany), magnesium stearate (VEG Pharma, Rome, Italy) and polyacrylate dispersion (Eudragit®NE 30D, Evonik Industries, Darmstadt, Germany, containing ethylacrylate- methylmethacrylate copolymer 30% w/w) were used. All substances conform to European Pharmacopoeia (Ph.Eur.) quality [31].

2.2. Formulation of Sodium Benzoate-Coated Pellets

Microcrystalline cellulose pellets were coated with an aqueous solution of sodium benzoate 30% (w/w), PVP 1.5% (w/w) and talcum 0.5% (w/w) in a first coating step (Table 1). Sodium benzoate and PVP were dissolved one after another in purified water and finally talcum was suspended under agitation with a blade stirrer.
Table 1. Sodium benzoate pellet formulation.
Content (%)
Sodium benzoate 32.6
Microcrystalline cellulose 65.3
PVP 1.6
Talcum 0.5
100.0

2.3. Formulation of Polyacrylate-Coated Sodium Benzoate Pellets

In a second coating step, SB pellets were layered with polyacrylate in three different concentration lots P1 (11.1% w/w PVP), P2 (14.3% w/w) and P3 (17.6% w/w). Magnesium stearate and talcum were added to the coating fluid as a plasticizer and an antistick agent, respectively (Table 2). The polyacrylate coating fluid contains a polyacrylate copolymer 13.3% (w/w), magnesium stearate 1.3% (w/w) and talcum 5.3% (w/w). A Eudragit®NE 30D dispersion was added to a beaker, and magnesium stearate and talcum were added one after another under strong agitation and homogenization by a disperser (Ultra Turrax T50 standard, Janke & Kunkel, IKA Labortechnik, Staufen, Germany, disperser length 225 mm, diameter 18 mm, rotation 5000 rpm).
Table 2. Polyacrylate coated sodium benzoate pellet.
Lot P1 P2 P3
Content (%)
Sodium benzoate 25.9 24.4 22.9
Microcrystalline cellulose 55.7 52.6 49.3
PVP 1.3 1.2 1.1
Polyacrylate 11.1 14.3 17.6
Talcum 4.9 6.1 7.4
Magnesium stearate 1.1 1.4 1.7
100.0 100.0 100.0

2.4. Fluidized Bed Pellet Coating

The coating process was performed in a batch laboratory fluidized bed apparatus (GPCG 1.1, Glatt, Binzen, Germany) with a Wurster inlet and SFV probe installed into the process chamber [27]. A 1.0 mm diameter spray nozzle with a nozzle cap position of 2.5 scales was used. The distance of the lower end of the cylinder from the perforated bottom plate B was fixed to 20 mm. The process air volume rate was variable and adapted to the increasing weight of the pellets during the coating process in a range of 40–60 m3/h.
Cellets®175 were coated with the sodium benzoate/PVP/talcum aqueous fluid in a first step (Table 3). The second coating step with polyacrylate dispersion was performed under smooth conditions (lower spray rate and reduced process air temperature) to avoid the risk of the pellets adhering and sticking together. The polyacrylate coated pellets were finally tempered (one hour, 30 °C) in a tray dryer as a thin layer on a steel dish for coalescence and film forming completion.
Table 3. Process parameters of pellet fluidized bed coating with sodium benzoate (first step) and polyacrylate (second step).
Parameter First Step Second Step
Sodium benzoate Polyacrylate
Pellet batch (g) 300
Process air temperature (°C) 80 40
Product temperature (°C) 40 25
Process air volume rate (m3/h) 40–60
Spray rate (g/min) 20 6
Spray pressure (bar) 3

2.5. Particle Size Coating Layer Thickness Measurement with SFV Probe

The particle size and thickness of the coating layer were measured in-line by the SFV probe (IPP 70, Parsum, Chemnitz, Germany). The probe was directly installed into the down-bed zone of the process chamber. Details of probe measurement are described elsewhere [27,28].

2.6. Sodium Benzoate Release and Content Investigation

The release was investigated with the dissolution tester (PTW 2, Pharmatest, Hainburg, 6 vessels, 1.0 L purified water, 37 °C, blade rotation 75 rpm). The sampling was performed after 10, 20, 30, 45, 60, 120 and 180 min. Samples were withdrawn and refilled by purified water. Sodium benzoate was analysed with a UV–Vis-Spectrophotometer (Spekol 1300, Analytik Jena, Germany, 1 cm quartz cuvette, wave length 220 nm).
For the sodium benzoate content investigation, 50 mg pellets (13.5 mg of which being sodium benzoate) were dispersed in 1.0 L purified water. The sodium benzoate dissolution and release were proved to be complete after 4 h and the content was analysed as above.

2.7. Linearization of Release Curves

The evaluation of the release curves was performed according to the different models of release kinetics also used by a number of authors [1,3,5,6,9,14]. In the first step of the release evaluation, the amount of cumulative released substance is plotted versus time. Linear curves arise in the case of zero order kinetics, i.e., equal amounts of the drug are released in equal time intervals (Equation (1)).

Mt = −k0 ∗ t + M0

First order release kinetics are typical for the release of slightly soluble drugs from solid preparations like tablets, pellets and granules dominated by slow dissolution and diffusion control. The release rate is highest at the beginning of the process, according to the large concentration gradient being the most important factor in Fick’s first law for the transport flow density by diffusion (Equation (2)), and diminishes with a decreasing concentration gradient in the course of the process.

1/A ∗ dn/dt = −D ∗ dc/dx

The released amount Mt at the moment t refers to (Equation (3)), and linearization results in the Sigma minus function (Equation (4)).

Mt = M0 ∗ (1 − exp(−k1∗t))
ln (M0 − Mt) = ln (M0) − k1 ∗ t

The Weibull function (Equation (5)) and its linearized form (Equation (6)) presuppose first order kinetics.

Mt = M0 ∗ (1− exp (−t b/a)
ln (−ln (1−Mt/M0)) = b ∗ ln (t) − ln (a)

Square root kinetics occurs at non-disintegrating solid matrix formulations (Equation (7)).

Mt = kq ∗ √ t

Cubic root kinetics are observed in the case of spherical multiparticulate formulations (linearized form, Equation (8)).

Mt⅓ = M0⅓ − kc ∗ t

2.8. Model Independent Parameters: Difference Factor f1 and Similarity Factor f2

The difference factor f1 describes the relative error between two release profiles calculated from the cumulative released amounts Ri and Ti at distinct moments for the reference and test formulations (Equation (9)). The similarity factor f2 is based on the sum of deviation squares of the released drug amounts (Equation (10)) and describes the statistical similarity between two release profiles. The value is 100 in case of identical profiles and 50–100 for similar profiles. Both factors are used to compare the release profiles of generic and standard drug product in order to decide whether the profile of the generic drug product surpasses that of the standard. In this study, both factors are used to evaluate the differences and similarities between sodium benzoate release profiles with different polymer coatings.

Eq9

(9)

Eq10

(10)

2.9. Microscopically Investigation

Coated pellets were placed on black paper for an improved contrast. Size and shape were investigated with a stereo light microscope (Stemi 2000-C, Carl Zeiss, Oberkochen, Germany, ocular: W-PI, 10×/23, magnification: 5.0, 50 scale = 1 mm). Photographs were shot by mobile.

2.10. Sphericity

The sphericity of the pellet lots was measured by digital image processing (Camsizer®, Retsch, Haan, measuring particle size range 40–3000 µm, measured particles 20,000 per second). The chord length was used for the evaluation of particle size and particle size distribution.

2.11. SFV Measurement

The SFV probe was installed directly into the process chamber of the fluidized bed apparatus between the inner chamber wall and the Wurster inlet. Details are described elsewhere [27].

3. Results and Discussion

3.1. Properties of Sodium Benzoate and Polyacrylate Coated Pellets

SB pellets are received as a free-flowing material. The coating process runs without disturbances, and the special fluidized bed pattern with a Wurster inlet was homogeneous. The product shows a narrow particle size distribution [27]. The median x50.3 increases from 170 µm of uncoated Cellets®175 to 200 µm, and the sphericity of both initial Cellets®175 and SB pellets is above 0.9.
The polyacrylate coating of SB pellets is performed without undesired agglomeration; only very few twins and triplets are detected by microscopic observation (Figure 1). The median of polyacrylate pellets grows to 232.2 µm and the layer thickness to 16.1 µm (Table 4, P3, 17.6% polyacrylate content). The product yield losses and the incomplete sodium benzoate recovery derive from a material precipitation at the textile filter and the inner chamber wall. A sphericity above 0.9 indicates the existence of spherical products and a homogeneous processing.
Figure 1. SEM photograph of a polyacrylate coated SB pellet.
Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets

Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets

Table 4. Median, polyacylate layer thickness, product yield, sodium benzoate content and sphericity of polyacrylate coated SB pellets.
X50.3 (µm) Polyacrylate
Layer
Thickness (µm)		 Yield (%) Sodium
Benzoate
Content (%)		 Sphericity
(-)
P1 213.0 6.5 84 92 0.91
P2 221.0 10.5
P3 232.2 16.1

3.2. Sodium Benzoate Release Kinetics

3.2.1. Double Linear Diagram (Zero Order Release Kinetics)

After five minutes, more than 90% of the sodium benzoate is dissolved from SB pellets without a polymer layer due to a high solubility and a high dissolution rate. Showing properties of a strong electrolyte (sodium salt of benzoic acid with pKa of 4.19, indicating a strong acid [31]), a considerable dissociation into sodium cations and benzoate anions takes place. The release from polyacrylate coated pellets is characterized by exponential curves (Figure 2). In general, the release rate decreases with the increasing polyacrylate layer thickness. The insoluble polyacrylate acts as a release barrier. After ten minutes, 30% sodium benzoate at low coating (P1), 20% at medium coating (P2) and 8% at high coating (P3) is released. The sodium benzoate dissolution rate is rather implausible as a release controlling process step. The diffusion of sodium benzoate molecules and sodium and benzoate ions out of the polymer layer forced by a high concentration gradient in the initial phase seems to be the rate controlling process. The release process starts with a high rate, and, in the terminal phase, the rate diminishes due to a nearly complete sodium benzoate release and a low concentration gradient across the polyacrylate film. In the case of the low polyacrylate coating, the CoD of the zero order kinetics amounts to 0.57 (Table 5, P1), giving no probability for zero order release kinetics at all. The diffusion process referring to first order kinetics seems to be the rate controlling step. Otherwise, the zero order CoD increases with the increasing polyacrylate layer thickness (P2: 0.70, P3: 0.93), indicating the growing influence and interaction of other processes like polymer swelling and retarded diffusion over a prolonged diffusion distance. With an increasing polyacrylate amount the release rate decreases, as indicated by the decreasing AUC, decreasing DE and increasing MDT (Table 6).
Figure 2. Double linear plot of the sodium benzoate release, SB pellets without polyacrylate layer, experimental release from polyacrylate-coated lots P1, P2 and P3 with increasing layer thickness and calculated release P1cal, P2cal and P3cal.
Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets 002

Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets 002

Table 5. CoD of sodium benzoate release profiles, kinetic models of zero order, first order, square root and cubic root; lots P1, P2 and P3.
CoD (R2)
Model P1 P2 P3
Zero order 0.57 0.70 0.93
First order Sigma minus 0.98 0.98 0.95
First order Weibull 0.87 0.99 0.99
Square root 0.81 0.88 0.94
Cubic root 0.68 0.80 0.98
Table 6. Area under the curve, AUC, dissolution efficiency, DE, and mean dissolution time, MDT, of sodium benzoate release; lots P1, P2 and P3.
AUC (%∗min) DE (-) MDT (min)
P1 14,820 0.82 32
P2 13,927 0.77 41
P3 11,587 0.64 63
The release profiles of lots P1 and P2 (Figure 2) differ only slightly, so the f1 of 12 (Table 7) is in the range below 15 and indicates equivalence between P1 and P2; whereas the deviation of the profiles of P1/P3 and P2/P3 is much more pronounced due to thicker polyacrylate coating layers leading to an f1 above 15 and to the evaluation “not equivalent” regarding the relative error between both release profiles calculated from the cumulative released amounts Ri and Ti at certain moments. The increasing coating layer thickness leads to clearly different release profiles.
Table 7. Difference factor and similarity factor of sodium benzoate release profiles, comparison of lots P1, P2 and P3.
Parameter Evaluation P1/P2 P1/P3 P2/P3
Difference factor f1 “equivalent”
0–15		 12 24 25
Similarity factor f2 “similar”
50–100		 74 63 67
The similarity factor f2 decreases with the increasing layer thickness and diminished release rate, which is obvious comparing P1 with P2 (74) and P1 with P3 (63). Nevertheless, both f2s confirm the similarity of the release profiles.
Release curves (P1cal, P2cal and P3cal, Figure 2) were calculated according to first order kinetics (Equation (2)) and by use of the experimental release rate constants of P1, P2 and P3 (Table 5) from the Sigma minus plots (Figure 3).
Figure 3. First order Sigma minus function of the experimental and calculated (cal) sodium benzoate release, lots P1, P2 and P3.
Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets 003

Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets 003

The double linear drawn calculated curves (grey colour) meet roughly the corresponding experimental curves (black colour, Figure 2). The deviation of the experimental from the calculated curve is highest for P3 with the thick polyacrylate layer due to an increased coincidence of the following processes and circumstances: slow polyacrylate film wetting and swelling, slow water molecule uptake and diffusion through the polyacrylate film to the sodium benzoate layer, dissolution of sodium benzoate and diffusion through the swollen polymer film into the release fluid. The high thickness of the polyacrylate layer and therefore the long diffusion path and change of the sodium benzoate concentration gradient via the polyacrylate layer with the ongoing process is of important influence on the release rate.

3.2.2. First Order Kinetics, Sigma Minus Function

The Sigma minus function gives linear trends of the sodium benzoate release (Figure 3) according to first order kinetics and a CoD above 0.9 (Table 5). The release rate constant k1 decreases with growing polyacrylate coating (Table 8). The calculated curves P1cal and P2cal (Equation (3)) meet the experimental curves of P1 and P2, respectively (Figure 3). The diffusion of sodium benzoate through the polyacrylate layer and to some extent the polymer swelling are the rate controlling steps. The more pronounced deviation of the experimental from the calculated curve in case of P3 is explained by the reasons mentioned above.
Table 8. First order release parameters of the Sigma minus and Weibull function, lots P1, P2 and P3.
k1 (1/min) Sigma Minus b (-)
Weibull		 1/a (-)
Weibull		 t63.2% (min)
Weibull
P1 0.036 1.08 0.25 30
P2 0.030 1.58 0.17 40
P3 0.020 1.36 0.17 70

3.2.3. First Order Kinetics, Weibull Function

The Weibull function gives linear curves (Figure 4) comparable to the Sigma minus function (Figure 3) with coefficients of determination of 0.99 for P2 and P3 (higher polyacrylate coating) and a value of 0.87 for P1 (Table 5) due to the fast release in the initial phase and finally the slow release rate after 45 min (x-axis value 3.8, Figure 5).
Figure 4. First order Weibull function of the experimental sodium benzoate release, lots P1, P2 and P3.
Pharmaceutics 16 01307 g004
Figure 5. Weibull function release parameter t63.2% versus coating layer thickness, lots P1 (coefficient of determination 0.87, polyacrylate content 6.5%), P2 (0.99, 10.5%) and P3 (0.99, 16.1%).
Pharmaceutics 16 01307 g005
A shape parameter of 1 indicates a monophasic and b > 1 a multiphasic release process with an initial lag time due to a wetting and a swelling of the polyacrylate film in the present case and an accelerated release rate up to the inflection point by high concentration gradient followed by a slower release rate due to a concentration gradient decrease when the drug dissolution and the release are finished. P1 with low coating gives nearly monophasic release kinetics (shape parameter 1.08, Table 8) whereas P2 (1.58) and P3 (1.36) give hints of a pronounced multiphasic release. The scale parameter (1/a) refers numerically to the rate constant and decreases with the increasing coating layer thickness (Table 8). The time parameter t63.2% is the moment when 63.2% of sodium benzoate is released. The value ascends with the increasing polyacrylate layer thickness from 30 to 70 min (Table 8 and Figure 5, compare also Figure 2).
The polyacrylate coating layer thickness (Table 4) proves to have a strong influence on the release kinetics. The manufacturing of coated pellet products with the intended drug release may be realized in the following way: pellet lots are manufactured with an increasing coating layer thickness in a preliminary step on a laboratory scale. The layer thickness is measured by the SFV probe. The in vitro drug release of these lots is investigated and correlated with the polymer coating layer thickness. The coating process in the production scale is interrupted when the desired coating layer thickness is detected.

3.2.4. Square Root Function

The cumulative release plot versus the square root of time gives straight lines in case of a drug release by diffusion from non-disintegrating matrices like matrix tablets and semisolid systems (ointments, creams). Lots P1 and P2 show nearly straight lines in the time interval 10 to 60 min (Figure 6). The initial phase up to 10 min and the terminal phase after 60 min do not meet the square root model. CoDs reach values between 0.81 (P1) and 0.94 (P3, Table 5). This model is not suitable to describe the release profile in the present case of drug pellets with an insoluble but swellable polymer coating.
Figure 6. Square root function of the experimental sodium benzoate release, lots P1, P2 and P3.
Pharmaceutics 16 01307 g006

3.2.5. Cubic Root Function

The cubic root function is valid for a dissolution of spherical particles due to reduction of weight and surface area. The difference of cubic roots of dose and cumulative released substance plotted versus time should give straight lines. This is not the case with the sodium benzoate release from polyacrylate coated pellets (Figure 7). The deviation from the linearity is pronounced for P1 and P2 in the terminal release phase after 45 min (CoD 0.68 and 0.80, respectively, Table 5) whereas the slow releasing P3 gives a curve with a DoD of 0.98. Only at a thick polyacrylate layer does the cubic root model seem to be suitable to describe the release kinetics, whereas the lower coated lots P1 and P2 do not refer to cubic root kinetics and dissolution of spheres.
Figure 7. Cubic root function of the experimental sodium benzoate release, lots P1, P2 and P3.
Pharmaceutics 16 01307 g007

4. Conclusions

Inert Cellets®175 were coated in a first step with the model drug sodium benzoate and in a second step with a water insoluble polyacrylate dispersion in a fluidized bed with a Wurster inlet. Particle size increase and coating layer thickness were measured in-line over the whole processes by the SFV probe and detected at each moment of the process. The in vitro sodium benzoate release was investigated and release profiles were linearized and evaluated with different kinetic models.
With the increasing polyacrylate coating layer thickness, the sodium benzoate release rate decreases, as evaluated by release parameters, release rate constants, AUC, MDT and DE. A difference factor f1 above 15 showed dissimilar release rate profiles for lower coated (P1, P2) compared with high coated (P3) polyacrylate SB pellets, indicating a significant influence of the coating layer thickness on the sodium benzoate release. The similarity factors f2 of 67 to 74 refer to similar release profiles of the lots P1, P2 and P3.
The high CoD of linearized sodium benzoate release profiles in the case of the polyacrylate coating predetermined first order kinetics as the most applicable, which is explained by the significant influence of the sodium benzoate diffusion through the swollen polyacrylate film outside of the pellets. With the increasing coating layer thickness, the polymer swelling, the long-distance diffusion process for both water and sodium benzoate and the increase of the concentration gradient become stronger influences on the release profiles.
The detailed investigation of the release rate profiles as dependent on the polymer coating layer thickness permits the detection of the coating process endpoint and the manufacturing of a custom-made coated drug pellet product with a defined drug release.

Authors and affiliations

Marcel Langner (1), Florian Priese (2), and Bertram Wolf (2)
1 IDT Biologika, Am Pharmapark, 06861 Dessau-Roßlau, Germany
2 Department of Applied Biosciences and Process Engineering, Anhalt University of Applied Sciences, Bernburger Straße 55, 06366 Köthen, Germany

Author Contributions

Conceptualization, B.W.; methodology, M.L.; data curation, B.W.; writing—original draft preparation, M.L.; writing—review and editing, F.P. and B.W.; supervision, F.P.; project administration, B.W.; funding acquisition, F.P. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Federal Ministry of Education and Research of Germany (BMBF) within the research project WIGRATEC+ and the German Research Foundation (Deutsche Forschungsgemeinschaft DFG)—project number 491460386—plus the Open Access Publishing Fund of Anhalt University of Applied Sciences.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All relevant data are available in the article.

Conflicts of Interest

The authors declare no conflicts of interest.

Notations

M0 initial drug dose, drug content (%)
Mt released drug amount at time (%)
AUC area under the curve (%*min)
DE dissolution efficiency (-)
MDT mean dissolution time (min)
Ti released drug amount at moment t test formulation (%)
Ri released drug amount at moment t reference formulation (%)
n number of time points (-)
I release time point (min)
T moment of drug release (min)
k0 release rate constant, zero order release kinetics (%/min)
k1 release rate constant, first order release kinetics (1/min)
kq release rate constant, square root release kinetics (-)
kc release rate constant, cubic root release kinetics (-)
1/a scale parameter of Weibull function (-)
b shape parameter of Weibull function (-)
x50.3 median of volume density distribution (µm)
R2 coefficient of determination (CoD) (-)
A cross section area (m2]
D diffusion coefficient (cm2/s)
dn/dt transport flow (mol/min)
dc/dx concentration gradient (mol/l*m)
f1 difference factor (-)
f2 similarity factor (-)

Abbreviations

CoD coefficient of determination
P1, P2, P3 coated pellet lots, experimental release
P1cal, P2cal, P3cal coated pellet lots, calculated release
Ph.Eur. European Pharmacopoeia
pKa logarithmic acid dissociation constant
PVP polyvinylpyrrolidone
rpm rotation per minute
SB pellets sodium benzoate coated pellets
SFV spatial filter velocimetry

References

  1. Koch, H.P. Die Technik der Dissolutionsbestimmung. Teil 2. Experimentelle Methodik, Auflösungsgesetze, Auswertung und graphische Darstellung der Ergebnisse, Kenngrößen der Dissolution, Korrelation. Pharm. Acta Helv. 1984, 59, 130–139. [Google Scholar]
  2. Yonezawa, Y.; Kawase, S.; Sasaki, M.; Shinohara, I. Dissolution of solid dosage form. V. New form equations for the non-sink dissolution of a monodisperse system. Chem. Pharm. Bull. 1995, 43, 304–310. [Google Scholar] [CrossRef]
  3. Pereira de Almeida, L.; Simões, S.; Brito, P.; Portugal, A.; Figueiredo, M. Modeling dissolution of sparingly soluble multisized powders. J. Pharm. Sci. 1997, 86, 726–732. [Google Scholar] [CrossRef] [PubMed]
  4. Liu, Y.; Sun, Y.; Sun, J.; Zhao, N.; Sun, M.; He, Z. Preparation and in vitro/in vivo evaluation of sustained-release venlafaxine hydrochloride pellets. Int. J. Pharm. 2012, 426, 21–28. [Google Scholar] [CrossRef]
  5. Javadzadeh, Y.; Monajjemzadeh, F.; Safaei, E.; Adibkia, K.H. Release kinetics of sodium diclofenac from controlled release device. Pharm. Ind. 2014, 76, 1786–1793. [Google Scholar]
  6. Viswanadha, L.S.; Arcot, Y.; Lin, Y.-T.; Akbulut, M.E.S. A comparative investigation of release kinetics of paclitaxel from natural protein and macromolecular nanocarriers in nanoscale drug delivery systems. J. Colloid Interf. Sci. Open 2024, 15, 100120. [Google Scholar] [CrossRef]
  7. Wang, J.; Sun, Y.; Li, B.; Fan, R.; Li, B.; Yin, T.; Rong, L.; Sun, J. Preparation and evaluation of tamsulosin hydrochloride sustained-release pellets modified by two-layered membrane techniques. Asian J. Pharm. Sci. 2015, 10, 31–39. [Google Scholar] [CrossRef]
  8. Kovacevic, J.; Mladenovic, A.; Djuris, J.; Ibric, S. Evaluation of powder, solution and suspension layering for the preparation of enteric coated pellets. Eur. J. Pharm. Sci. 2016, 85, 84–93. [Google Scholar] [CrossRef]
  9. Cascone, S. Modeling and comparison of release profiles: Effect of the dissolution method. Eur. J. Pharm. Sci. 2017, 106, 352–361. [Google Scholar] [CrossRef]
  10. Marucci, M.; Andersson, H.; Hjärtstam, J.; Stevenson, G.; Baderstedt, J.; Stading, M.; Larsson, A.; Corswant, C. New insights on how to adjust the release profile from coated pellets by varying the molecular weight of ethyl cellulose in the coating film. Int. J. Pharm. 2013, 458, 218–223. [Google Scholar] [CrossRef]
  11. Xu, M.; Liew, C.V.; Heng, P.W.S. Evaluation of the coat quality of sustained release pellets by individual pellet dissolution methodology. Int. J. Pharm. 2015, 478, 318–327. [Google Scholar] [CrossRef]
  12. Villar López, E.; Luzardo Álvarez, A.; Blanco Méndez, J.; Otero Espinar, F.J. Cellulose-polysaccharide film-coating of cyclodextrin based pellets for controlled drug release. J. Drug Deliv. Sci. Technol. 2017, 42, 273–283. [Google Scholar] [CrossRef]
  13. Sousa, J.J.; Sousa, M.J.; Moura, M.J.; Podczeck, F.; Newton, J.M. The influence of core materials and film coating on the drug release from coated pellets. Int. J. Pharm. 2002, 233, 111–122. [Google Scholar] [CrossRef] [PubMed]
  14. Krueger, C.; Thommes, M.; Kleinebudde, P. Influence of storage conditions on properties of MCC II-based pellets with theophylline-monohydrate. Eur. J. Pharm. Biopharm. 2014, 88, 483–491. [Google Scholar] [CrossRef]
  15. Albanez, R.; Nitz, M.; Pereira Taranto, O. Influence of the type of enteric coating suspension, coating layer and process conditions on dissolution profile and stability of coated pellets of diclofenac sodium. Powder Technol. 2015, 269, 185–192. [Google Scholar] [CrossRef]
  16. Kazlauske, J.; Cafaro, M.M.; Caccavo, D.; Marucci, M.; Lasson, A. Determination of the release mechanism of theophylline from pellets coated with Surelease®—A water dispersion of ethyl cellulose. Int. J. Pharm. 2017, 528, 345–353. [Google Scholar] [CrossRef]
  17. Hiew, T.N.; Siew, L.W.; Wannaphatchaiyong, S.; Elsergany, R.N.; Pichayakorn, W.; Boonme, P.; Heng, P.W.S.; Liew, C.V. Influence of talc and hydrogenated castor oil on the dissolution behavior of metformin-loaded pellets with acrylic-based sustained release coating. Int. J. Pharm. 2023, 640, 122984. [Google Scholar] [CrossRef]
  18. Alagili, M.F.; AlQuadeib, B.T.; Ashri, L.Y.; Ibrahim, M.A. Optimization and evaluation of Lisinopril mucoadhesive sustained release matrix pellets: In-vitro and ex-vivo studies. Saudi Pharm. J. 2023, 31, 101690. [Google Scholar] [CrossRef]
  19. Wu, S.; Zeng, Q.; Zhang, Z.; Zhang, X.; Hou, Y.; Li, Z.; Jia, C.; Liu, Y.; Li, W. Development of sinomenine hydrochloride sustained-release pellet using a novel whirlwind fluidized bed. J. Drug Deliv. Sci. Technol. 2022, 78, 103956. [Google Scholar] [CrossRef]
  20. Muschert, S.; Siepmann, F.; Leclercq, B.; Carlin, B.; Siepmann, J. Prediction of drug release from ethylcellulose coated pellets. J. Control Release 2009, 135, 71–79. [Google Scholar] [CrossRef]
  21. Yang, M.; Xie, S.; Li, Q.; Wang, Y.; Chang, X.; Shan, L.; Sun, L.; Huang, X.; Gao, C. Effects of polyvinylpyrrolidone both as a binder and pore-former on the release of sparingly water-soluble topiramate from ethylcellulose coated pellets. Int. J. Pharm. 2014, 465, 187–196. [Google Scholar] [CrossRef] [PubMed]
  22. Dekyndt, B.; Verin, J.; Neut, C.; Siepmann, F.; Siepmann, J. How to easily provide zero order release of freely soluble drugs from coated pellets. Int. J. Pharm. 2015, 478, 31–38. [Google Scholar] [CrossRef] [PubMed]
  23. Thapa, P.; Thapa, R.; Choi, D.H.; Jeong, S.H. Effect of pharmaceutical processes of the quality of ethylcellulose coated pellets: Quality by Design approach. Powder Technol. 2018, 339, 25–38. [Google Scholar] [CrossRef]
  24. Kaur, S.; Sivasankaran, S.; Wambolt, E.; Jonnalagadda, S. Determinants of zero-order release kinetics from acetaminophen-layered Suglet® pellets, Wurster-coated with plasticized Aquacoat® ECD (ethyl cellulose dispersion). Int. J. Pharm. 2020, 573, 118873. [Google Scholar] [CrossRef]
  25. Kállai, N.; Luhn, O.; Dredán, J.; Kovács, K.; Lengyel, M.; Antal, I. Evaluation of drug release from coated pellets based on isomalt, sugar and microcrystalline cellulose inert cores. AAPS PharmSciTech 2010, 11, 383–391. [Google Scholar] [CrossRef]
  26. Priese, F.; Wolf, B. Development of high drug loaded pellets by Design of Experiment and population balance model calculation. Powder Technol. 2013, 241, 149–157. [Google Scholar] [CrossRef]
  27. Wiegel, D.; Eckardt, G.; Priese, F.; Wolf, B. In-line particle size measurement and agglomeration detection of pellet fluidized bed coating by Spatial Filter Velocimetry. Powder Technol. 2016, 301, 261–267. [Google Scholar] [CrossRef]
  28. Petrak, D.; Eckardt, G.; Dietrich, S.; Köhler, M.; Wiegel, D.; Wolf, B.; Priese, F.; Jacob, M. In-line measurement of layer thickness, agglomerate fraction and spray drying during pellet coating in the fluidized bed. Pharm. Ind. 2018, 80, 262–270. [Google Scholar]
  29. Priese, F.; Frisch, T.; Wolf, B. Comparison of film-coated retarded release pellets manufactured by layering technique or by fluidized bed rotor pelletization. Pharm. Dev. Technol. 2015, 20, 417–424. [Google Scholar] [CrossRef]
  30. Juhász, A.; Ungor, D.; Berta, K.; Seres, L.; Csapó, E. Spreadsheet-based nonlinear analysis of in vitro release properties of a model drug from colloidal carriers. J. Mol. Liq. 2021, 328, 115405. [Google Scholar] [CrossRef]
  31. European Pharmacopoeia 11.5, 2024. Available online: https://pheur.edqm.eu/subhome/11-5 (accessed on 29 August 2024).
/by
Titelbild Brezovar-2023
,

The Effect of Design and Size of the Fluid-Bed Equipment on the Particle Size-Dependent Trend of Particle Coating Thickness and Drug Prolonged-Release Profile

Abstract

The focus of the current work is to study and demonstrate the impact of the design, the scale, and settings of fluid-bed coating equipment on the differences in pellet coating thickness, which in case of prolonged-release pellets dictates the drug release. In the first set of coating experiments, the pellet cores were coated with the Tartrazine dye with the aim of estimating the coating equipment performance in terms of coating thickness distribution, assessed through color hue. In the second set, drug-layered pellets were film-coated with prolonged-release coating and dissolution profile tests were performed to estimate the thickness and uniformity of the coating thickness among differently sized pellets. In both study parts, film coating was performed at the laboratory and the pilot scale and essentially two types of distribution plate and different height adjustments of the draft tube were compared. The dye coating study proved to be extremely useful, as the results enable process correction and the optimal use of the process equipment in combination with the appropriate process parameters. Preferential film coating of larger drug-containing pellets was confirmed on the laboratory scale, while on the pilot scale, it was possible to achieve preferential coating of smaller pellets using rational alternatives of settings, which is desirable in terms of particle size-independent drug release profile of such prolonged-release dosage forms. […]

Materials

In the first part of the study, neutral MCC pellets (CELLETS 700, IPC Process Center GmbH, Germany) were coated with water solution composed of 8% w/w HPMC 6 mPas (Shin-Etsu Chemical, Japan), 1% w/w Macrogol 6000 (Clariant Produkte GmbH, Glendorf site, Germany), 1% w/w coloring agent Tartrazine (Sigma-Aldrich, USA), and purified water (90%, w/w).

In the second part of coating experiments, API-coated pellets containing Diclofenac sodium were coated with water-based sustained release coating dispersion containing Eudragit RS 30D (9.6% w/w), Eudragit RL 30 D (19.2% w/w) (Evonic Nutrition Care GmbH, Germany), 1.7% w/w triethyl citrate (Vertellus LLC, USA), and 10.4% w/w talc.

Methods

Pellet Film-Coating Experiments with Tartrazin

Coating experiments using Tartrazine dye were performed on two laboratory-sized fluid-bed coaters (GPCG1, Glatt GmbH, Germany and BX FBD10, Brinox d.o.o., Slovenia) and on one pilot-sized (BX FBD30, Brinox d.o.o., Slovenia) fluid-bed coater. In case of both laboratory coaters, the type of distribution plate and the gap between the plate and the draft tube were varied. The pilot-scale setup with three swirl generators and draft tubes was used, while only the size of the gap was varied during coating experiments (Table I). All other process parameters were comparable within each coating process scale. […]

Size distributions of uncoated CELLETS® 700 used in Tartrazine coating experiments and of drug-layered pellets used in PR coating experiments

Size distributions of uncoated CELLETS® 700 used in Tartrazine coating experiments and of drug-layered pellets used in PR coating experiments

Conclusion

Considering the results of the coating process evaluation with the dye-coated pellet approach, based on previous research, it can be said that the obtained positive slopes of size preferential coating in the laboratory-scale CW process chamber are within the expected performance of this type of coater design. The values of the slope of the size preferential coating were always lower in the case of the SW distribution plate in comparison with the CW design of the distribution plate. However, within the laboratory-scale coater designs, different performances of swirl generator equipped flat and funnel-shaped distribution plates were identified, the latter exhibiting the least size dependent preferential coating performance. This was attributed to a less expressed dead zone effect enabling mixing and elimination of any segregation in the pellet bed region of the coater. On the pilot film-coating scale, coater equipped with flat SW distribution plates exhibited negative size preferential coating slope, meaning that smaller pellets obtained more coating than larger ones, which is unprecedented result. Moreover, the extent of the negative size preferential coating slope depended on the dynamics of the pressure drop fluctuations. This finding was effectively translated to the prolonged-release coating application, where the right extent of the negative size preferential coating ensures pellet size-independent drug release profiles, thus improving robustness of such multiple unit prolonged-release formulation. By lowering the air flow rate and using bimodal size distribution, rich in smaller drug-layered pellets, led to rather surprising results, where performance of prolonged drug release-coated pellets did not resemble size preferential coating results from the dye coating study part.

These results confirm the fact that we must have a good knowledge of the coater performance characteristics in combination with the process variables and even formulation properties, if we want to produce coated multiple-unit solid pharmaceutical products of the highest quality.

Disclaimer

Excerpt from: AAPS PharmSciTech, 24, 93 (2023), https://doi.org/10.1208/s12249-023-02540-9. by T. Brezovar, G. Hudovornik, M. Perpar, M. Luštrik, and R. Dreu.
/by
Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating
, ,

Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating

Abstract on Continuous Manufacturing

Using cocrystals has emerged as a promising strategy to improve the physicochemical properties of active pharmaceutical ingredients (APIs) by forming a new crystalline phase from two or more components. Particle size and morphology control are key quality attributes for cocrystal medicinal products. The needle-shaped morphology is often considered high-risk and complex in the manufacture of solid dosage forms. Cocrystal particle engineering requires advanced methodologies to ensure high-purity cocrystals with improved solubility and bioavailability and with optimal crystal habit for industrial manufacturing. In this study, 3D-printed microfluidic chips were used to control the cocrystal habit and polymorphism of the sulfadimidine (SDM): 4-aminosalicylic acid (4ASA) cocrystal. The addition of PVP in the aqueous phase during mixing resulted in a high-purity cocrystal (with no traces of the individual components), while it also inhibited the growth of needle-shaped crystals. When mixtures were prepared at the macroscale, PVP was not able to control the crystal habit and impurities of individual mixture components remained, indicating that the microfluidic device allowed for a more homogenous and rapid mixing process controlled by the flow rate and the high surface-to-volume ratios of the microchannels. Continuous manufacturing of SDM:4ASA cocrystals coated on beads was successfully implemented when the microfluidic chip was connected in line to a fluidized bed, allowing cocrystal formulation generation by mixing, coating, and drying in a single step.

Conclusions

SDM:4ASA cocrystal particle engineering has been successfully achieved using 3D-printed microfluidic chips. The addition of PVP in the aqueous phase during mixing has allowed the inhibition of needle-shaped crystals and the generation instead of spherical crystal habits with higher purity compared to conventional mixing. A successful continuous manufacturing method for the fabrication of cocrystal-coated particles has been demonstrated by the combination of microfluidic chips with a fluidized bed, allowing the process intensification of mixing and drying in one step.

Authors:

Aytug Kara, Dinesh Kumar, Anne Marie Healy, Aikaterini Lalatsa, and Dolores R. Serrano.

Read more

Read more on continuous manufacturing of cocrystals by Kara et al. here and find out the functionality of CELLETS® 500 (pellets made of microcrystalline cellulose, size: 500-710 µm).
/by

Investigating the Influence of Fluid-Bed Equipment Design and Size on Particle Coating Thickness Trends and Drug Prolonged-Release Profiles Linked to Particle Size

The primary objective of this research is to investigate the design and size on particle coating thickness. Furthermore,  illustrate how the design, size, and configurations of fluid-bed coating machinery influence variations in pellet coating thickness. This parameter plays a crucial role in governing the release of medication in prolonged-release pellets. Initially, the scientists conducted a series of coating experiments where the pellet cores were coated with Tartrazine dye. The aim was to evaluate the performance of the coating equipment in terms of the distribution of coating thickness, which was assessed based on color hue.

In the subsequent set of experiments, drug-layered pellets underwent film-coating with prolonged-release material. Brezovar et al. conducted dissolution profile tests to gauge the uniformity and thickness of the coating among pellets of different sizes. Pellets of kind CELLETS® 700 (IPC Dresden, Germany) had been employed. This investigation encompassed both laboratory and pilot scale applications. Laboratory-sized fluid-bed coaters GPCG1 (Glatt GmbH, Germany and BX FBD10, Brinox d.o.o., Slovenia) and a pilot-sized (BX FBD30, Brinox d.o.o., Slovenia) fluid-bed coater are used for these tests. The group made comparisons between two types of distribution plates and various adjustments in the height of the draft tube.

The dye coating study yielded highly valuable insights. The results provided the basis for refining the process and optimizing the utilization of process equipment, especially in conjunction with the appropriate process parameters. On the laboratory scale, we observed a preference for film coating larger drug-containing pellets. However, on the pilot scale, we achieved a preferential coating of smaller pellets through judicious adjustments, a development that holds significance in achieving a drug release profile independent of particle size for prolonged-release dosage forms.

Link to publication:

The Effect of Design and Size of the Fluid‑Bed Equipment on the Particle Size‑Dependent Trend of Particle Coating Thickness and Drug Prolonged‑Release Profile
AAPS PharmSciTech (2023) 24, 93. doi:10.1208/s12249-023-02540-9
T. Brezovar, G. Hudovornik, M. Perpar, M. Luštrik, R. Dreu

/by
Preparation and characterization of controlled-release doxazosin mesylate pelletsingredientpharm

Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique

Abstract

Pellets are one of multiparticulate pharmaceutical forms and can offer numerous technical and biopharmaceutical advantages compared with single dose unit formulations, e.g. tablets and capsules. This study aimed at formulation of controlled-release pellets of doxazosin mesylate (DM), a widely used treatment for antihypertensive and benign prostatic hyperplasia. DM was loaded onto microcrystalline cellulose CELLETS® pellets using hydroalcoholic solution and alcoholic suspension layering techniques to achieve a minimum drug load of 4 mg DM/g pellets. DM-layered CELLETS were coated by Aquacoat dispersion (ready-made ethylcellulose dispersion) using a coating pan technique as a simple and widely utilized technique in pharmaceutical industry. Controlled-release DM-layered pellets showed a release profile comparable to the controlled-release commercial product Cardura® XL Tablet. Also, the mechanism of DM release from Aquacoat CELLETS® was mathematically modeled and imaged by scanning electron microscopy to elucidate drug release mechanisms from the prepared pellet formulations. Accelerated stability studies of the prepared pellets were performed under stress conditions of 40 °C, and 75 % RH for 3 months. In conclusion, preparation of controlled-release DM-layered CELLETS® is feasible using a simple and conventional coating pan technology. Read more about controlled-release doxazosin mesylate pellets.

References

H. A. Hazzah, M. A. EL-Massik, O. Y. Abdallah & H. Abdelkader, Journal of Pharmaceutical Investigation (2013), 43:333–342. doi:10.1007/s40005-013-0077-0

Additional information

CELLETS® are perfect starter beads for coating and layering of API, such as doxazosin mesylate. Multilayer formulation attempts enable defined release profiles and improved bioavailability. Check different pellet sizes from 100 µm to 1400 µm which fit to your formulation.

Need formulation services?

Contact our partner Glatt Pharmaceutical Services!

/by
Pore Former basic drugs

Design and Optimization of a Nanoparticulate Pore Former as a Multifunctional Coating Excipient for pH Transition-Independent Controlled Release of Weakly Basic Drugs for Oral Drug Delivery

Abstract

Bioavailability of weakly basic drugs may be disrupted by dramatic pH changes or unexpected pH alterations in the gastrointestinal tract. Conventional organic acids or enteric coating polymers cannot address this problem adequately because they leach out or dissolve prematurely, especially during controlled release applications. Thus, a non-leachable, multifunctional terpolymer nanoparticle (TPN) made of cross-linked poly(methacrylic acid) (PMAA)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) was proposed to provide pH transition-independent release of a weakly basic drug, verapamil HCl (VER), by a rationally designed bilayer-coated controlled release bead formulation. The pH-responsive PMAA and cross-linker content in the TPN was first optimized to achieve the largest possible increase in medium uptake alongside the smallest decrease in drug release rate at pH 6.8, relative to pH 1.2. Such TPNs maintained an acidic microenvironmental pH (pHm) when loaded in ethylcellulose (EC) films, as measured using pH-indicating dyes. Further studies of formulations revealed that with the 1:2 VER:TPN ratio and 19% coating weight gain, bilayer-coated beads maintained a constant release rate over the pH transition and exhibited extended release up to 18 h. These results demonstrated that the multifunctional TPN as a pHm modifier and pH-dependent pore former could overcome the severe pH-dependent solubility of weakly basic drugs.

Introduction

Many existing active pharmaceutical ingredients (APIs) (drug compounds) are either weak acids or weak bases; their water solubility can change significantly with the lumen pH changes along the gastrointestinal tract (GIT) as a result of variation in the ionization degree. Severe pH-dependent solubility could pose a great challenge to achieving consistent and predictable performance of oral dosage forms, as abrupt changes in release rate may result in unexpected dissolution, absorption, and bioavailability of the drug, leading to increased risks of adverse side effects or decreased therapeutic efficacy. This problem may be pronounced for weakly basic drugs with low solubility at high pH, especially those with a narrow therapeutic index, or requiring prolonged release, because in the lower GIT the pH is >6.8 [1]. Furthermore, food intake, disease state (e.g., inflammatory bowel disease, gastritis, colitis), concomitant medication (e.g., proton pump inhibitors), and inter- and intra-individual variations, among other factors, can alter the pH in the GIT, which deviates from the pH of simulated gastric and intestinal fluid for in vitro testing and prediction [2,3,4]. Hence, novel strategies to formulate weakly basic drugs with extreme pH-dependent solubility in controlled release forms could enhance the repertoire of advanced medications available to patients.
To compensate for the varying pH values in the GIT, several approaches have been employed. One approach is the addition of small-molecule pH modifiers to the immediate vicinity of the drug to change the microenvironmental pH (pHm), thus enhancing the drug solubility. For example, organic acids (e.g., adipic, fumaric, and succinic acids) have been introduced into formulations of weakly basic drugs, reducing the pHm sufficiently, thereby facilitating drug dissolution, irrespective of the pH of the bulk solvent [5,6,7,8,9,10,11]. Drug release will depend on the compatibility of the organic acid with the drug in terms of the buffering capacity of organic acids and the pKa of the drug. Nevertheless, the incorporation of organic acids remains challenging as they are prone to leach out from the formulation, leading to inefficient pH modulation over time [12]. Therefore, large amounts of organic acids are required in order to achieve prolonged pH-independent drug release [5,13], which often makes this approach inadequate for controlled release formulations.
Another approach to compensate for the reduction in drug solubility is the use of enteric coating polymers on tablets, pellets, or beads as permeability modifiers, which can increase drug permeability at higher pH. In such coatings, polymers with pH-dependent solubility or swellability are employed, either alone or incorporated in a hydrophobic polymer (e.g., ethylcellulose (EC)) that acts as a membrane barrier to drug diffusion, resulting in slowed drug release. For example, methacrylic acid–ethyl acrylate copolymer (Eudragit® L) and hydroxypropyl methylcellulose acetate succinate are frequently incorporated into these membranes as pore forming materials for pH-dependent release [13,14,15,16,17,18,19,20,21,22,23]. At a pH above their pKa’s, the pore formers dissolve and leach out of the membrane film to form channels that facilitate drug diffusion. However, as pore formers leach out, the film becomes more porous and weaker, increasing the risk of dose dumping due to weakened structure or ruptures of the coating [24].
Recent advances using biopolymer-based nanomaterials, molecular imprinted polymers, and mathematical and computational models have been used to address the various challenges of drug delivery systems [25,26,27,28,29]. Biopolymers such as starch, collagen, chitosan, etc., are useful for their biocompatibility, biodegradability, and ease of synthesis and modifications [25]. Controlled release dosage forms capable of being flexible, releasing drugs in a timely manner, with desired duration and dosage, are more important than ever, and mathematical and computational models also function as influential tools in addressing the potential mechanisms or impediments of drug delivery systems [26,27,28,29].
Previously, a crosslinked terpolymer nanoparticle (TPN), consisting of poly(methacrylic acid)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) [30,31,32,33], was incorporated into ethylcellulose films (TPN-EC) to respectively reduce or enhance the permeability of the film coating by a pH-dependent shrinking (at low pH) and swelling (at high pH) mechanism [34]. Unlike other soluble polymeric pore-formers, the TPN did not increase the viscosity of EC dispersions for coating, attributable to its crosslinking structure [31,32,33]. For the same reason, TPN did not leach out from cast TPN-EC films, maintaining good mechanical properties compared to conventional Eudragit® L-EC films. When used as a membrane coating over beads loaded with a water-soluble drug, diltiazem HCl, TPN-EC provided faster drug release at pH 6.8 than at pH 1.2 [34]. The biocompatibility of TPN was demonstrated previously in vitro using isolated rat hepatocytes [32].
Inspired by previous findings regarding the pH-dependent properties of TPN, in this work, we explore the application of TPN for the first time to develop an advanced, controlled release bilayer-coated bead formulation for weakly basic drugs that exhibits severe pH-dependent water solubility. Verapamil HCl (VER) was selected as a model drug because it undergoes extreme decrease in solubility by several orders of magnitude when the media pH is increased from acidic to neutral and weakly basic conditions [9,35]. By exploiting the pH-dependence of TPN, we proposed that an increase in permeability at high pH could help compensate for the low solubility of the drug in its unionized form, thereby permitting a constant release rate when transitioning from gastric to intestinal pH. Additionally, we explored the ability of TPN to serve as a pHm modifier, owing to the presence of its acidic functional groups in MAA. Because TPN is retained within EC, unlike traditional leachable pHm modifiers when formulated together with the drug in a matrix, the source of the acidifying agent could be sustained throughout dissolution, while preserving dosage form integrity.
To investigate the effectiveness of combining both the permeability and the pHm modulation strategies of TPN, experiments were performed using EC matrix free-films incorporated with VER and TPN (VER-TPN-EC) and a bilayer-coated bead design consisting of an inner VER-TPN-EC matrix, surrounded by an outer membrane composed of TPN-EC. As illustrated in Figure 1, the TPN composition was first adjusted by varying the amounts of the pH-responsive monomer, MAA, and cross-linker, N,N′-methylenebis(acrylamide) (MBA) for pH-dependent swelling (medium uptake) and drug release via experiments using composite free-films. The best-performing TPN-containing films were then tested for their ability to lower pHm. Subsequently, the TPN was incorporated into a bilayer-coated bead design, where it was expected to lower the pHm in the matrix layer and regulate permeability in the membrane layer by its pH-dependent swelling. The effects of formulation parameters such as VER:TPN ratio within the matrix layer and membrane coating level on the pH-independence of dissolution rate in various pH conditions were evaluated.
Pharmaceutics 15 00547 g001 550
Figure 1. A flow chart of the optimization strategy to achieve pH transition-independent controlled release of VER from a TPN-containing bilayer-coated beads. Formulation strategy for TPN bilayer-coated beads containing weakly basic VER Optimization of TPN composition to achieve pHm modification and pH-dependent swelling, followed by strategic placement of TPN in the bilayer bead matrix and membrane layers are proposed to overcome pH-dependent solubility of VER. Figure created with BioRender.com (accessed on 15 December 2022).
Our cumulative research investigating the various applications of TPN (e.g., nanoparticle drug carrier in injectables, enteric coating agent and pore former in film coatings, recrystallization inhibitor in amorphous solid dispersions) is helping us widen the breadth of its capabilities. Namely, in the present research, the ability of TPN for pHm modification, pH-responsive swelling, nanoscale pore formation, interaction with drugs, and non-leachability comprise a set of multi-faceted features that set it apart from traditional excipients, which could improve the efficacy and quality of controlled release dosage forms for weakly basic drugs. As the landscape of new drug molecules continues to shift towards greater challenges (e.g., poor solubility, pH-dependent solubility, narrow therapeutic index, etc.) the need for more advanced, multifunctional excipients can be expected to increase.

Materials and Methods

2.1. Materials

Soluble corn starch, methacrylic acid (MAA), N,N′-methylenebisacrylamide (MBA), sodium thiosulfate (STS), potassium persulfate (KPS), sodium dodecyl sulfate (SDS), and sodium phosphate tribasic were purchased from Sigma Aldrich (Oakville, ON, Canada). Verapamil HCl (VER) was purchased from Spectrum Chemicals, (New Brunswick, NJ, USA). Hydrochloric acid (HCl) was purchased from Caledon (Georgetown, ON, Canada). SNARF-4F (#S23920) was purchased from Fisher Scientific (Ottawa, ON, Canada). Bromocresol green was purchased from Sigma Aldrich (Oakville, ON, Canada). Ethylcellulose (Surelease® E-7-19040) was kindly donated by Colorcon (West Point, PA, USA). Polyvinylpyrrolidone (PVP) (Kollidon®/PVPK30) was kindly donated by BASF (Ludwigshaven, Germany). Polysorbate 80 (Tween 80-LQ-(CQ)) was kindly donated by Croda (Edison, NJ, USA). Microcrystalline cellulose (MCC) beads ([…] annotation from the publisher: for example: CELLETS® 700) were used as the coating substrate […].

Conclusions

In this work, the multifunctionality of a nanogel TPN was investigated as a non-leachable pHm modifier and pH-responsive pore former in a bilayer-coated bead formulation for the pH transition-independent controlled release of weakly basic drugs. The results demonstrated that incorporation of TPN, comprised of pH-sensitive MAA and cross-linker MBA, enables the inner matrix layer of VER-TPN-EC to maintain a pHm approximately 1.5 unit lower than the external buffer pH, which may be further enhanced by coating with a TPN-EC membrane. In a simulated gastric and intestinal pH transition condition (i.e., from pH 1.2 to 6.8), the bilayer-coated beads with 16% to 19% WG resulted in a constant release rate during the pH transition, followed by a sustained release of VER up to 18 h, beyond the extent achieved when tested in single pH media. This ability to overcome the poor solubility of VER at high pH can be ascribed to the combinatory effects of the pH-dependent swelling of TPN that increased permeability, preferred retention of protons in the TPN due to Donnan equilibrium, pH-dependent complexation between MAA and VER, and the barrier to diffusion of buffer ions by the outer coating. This work suggests that the multifunctionality and tunability of TPN-EC formulations and the formulation design strategy may be expanded to tackle the challenges faced by other drugs with severe pH-dependence of water solubility.

Disclaimer

Excerpt from: Pharmaceutics 2023, 15(2), 547; https://doi.org/10.3390/pharmaceutics15020547. by Hao Han R. Chang, Kuan Chen, Jamie Anne Lugtu-Pe, Nour AL-Mousawi, Xuning Zhang, Daniel Bar-Shalom, Anil Kane, and Xiao Yu Wu.

References

  1. Dvořáčková, K.; Doležel, P.; Mašková, E.; Muselík, J.; Kejdušová, M.; Vetchý, D. The effect of acid pH modifiers on the release characteristics of weakly basic drug from hydrophlilic-lipophilic matrices. AAPS Pharmscitech 2013, 14, 1341–1348. [Google Scholar] [CrossRef] [PubMed]
  2. Bassi, P.; Kaur, G. pH modulation: A mechanism to obtain pH-independent drug release. Expert Opin. Drug Deliv. 2010, 7, 845–857. [Google Scholar] [CrossRef]
  3. Sun, Y.; Koyama, Y.; Shimada, S. Measurement of intraluminal pH changes in the gastrointestinal tract of mice with gastrointestinal diseases. Biochem. Biophys. Res. Commun. 2022, 620, 129–134. [Google Scholar] [CrossRef] [PubMed]
  4. Vinarov, Z.; Abdallah, M.; Agundez, J.A.G.; Allegaert, K.; Basit, A.W.; Braeckmans, M.; Ceulemans, J.; Corsetti, M.; Griffin, B.T.; Grimm, M.; et al. Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. Eur. J. Pharm. Sci. 2021, 162, 105812. [Google Scholar] [CrossRef] [PubMed]
  5. Thoma, K.; Ziegler, I. The pH-independent release of fenoldopam from pellets with insoluble film coats. Eur. J. Pharm. Biopharm. 1998, 46, 105–113. [Google Scholar] [CrossRef]
  6. Bolourchian, N.; Dadashzadeh, S. PH-independent release of propranolol hydrochloride from HPMC-based matrices using organic acids. Daru 2008, 16, 136–142. [Google Scholar]
  7. Nie, S.; Pan, W.; Li, X.; Wu, X. The effect of citric acid added to hydroxypropyl methylcellulose (HPMC) matrix tablets on the release profile of vinpocetine. Drug Dev. Ind. Pharm. 2004, 30, 627–635. [Google Scholar] [CrossRef] [PubMed]
  8. Espinoza, R.; Hong, E.; Villafuerte, L. Influence of admixed citric acid on the release profile of pelanserin hydrochloride from HPMC matrix tablets. Int. J. Pharm. 2000, 201, 165–173. [Google Scholar] [CrossRef]
  9. Streubel, A.; Siepmann, J.; Dashevsky, A.; Bodmeier, R. pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets. J. Control. Release 2000, 67, 101–110. [Google Scholar] [CrossRef] [PubMed]
  10. Obaidat, A. Modulation of the micro-environmental pH and its influence on the gel layer behavior and release of theophylline from hydrophilic matrices. Int. J. Pharma. Bio Sci. 2013, 4, P794–P802. [Google Scholar]
  11. Siepe, S.; Lueckel, B.; Kramer, A.; Ries, A.; Gurny, R. Assessment of tailor-made HPMC-based matrix minitablets comprising a weakly basic drug compound. Drug Dev. Ind. Pharm. 2008, 34, 46–52. [Google Scholar] [CrossRef] [PubMed]
  12. Siepe, S.; Lueckel, B.; Kramer, A.; Ries, A.; Gurny, R. Strategies for the design of hydrophilic matrix tablets with controlled microenvironmental pH. Int. J. Pharm. 2006, 316, 14–20. [Google Scholar] [CrossRef] [PubMed]
  13. Akiyama, Y.; Yoshioka, M.; Horibe, H.; Hirai, S.; Kitamori, N.; Toguchi, H. pH-independent controlled-release microspheres using polyglycerol esters of fatty acids. J. Pharm. Sci. 1994, 83, 1600–1607. [Google Scholar] [CrossRef]
  14. Lecomte, F.; Siepmann, J.; Walther, M.; MacRae, R.J.; Bodmeier, R. Blends of enteric and GIT-insoluble polymers used for film coating: Physicochemical characterization and drug release patterns. J. Control. Release 2003, 89, 457–471. [Google Scholar] [CrossRef]
  15. Sakellariou, P.; Rowe, R.C.; White, E.F.T. Polymer/polymer interaction in blends of ethyl cellulose with both cellulose derivatives and polyethylene glycol 6000. Int. J. Pharm. 1986, 34, 93–103. [Google Scholar] [CrossRef]
  16. Sakellariou, P.; Rowe, R.C. Phase separation and morphology in ethylcellulose/cellulose acetate phthalate blends. J. Appl. Polym. Sci. 1991, 43, 845–855. [Google Scholar] [CrossRef]
  17. Lecomte, F.; Siepmann, J.; Walther, M.; MacRae, R.J.; Bodmeier, R. pH-Sensitive polymer blends used as coating materials to control drug release from spherical beads: Elucidation of the underlying mass transport mechanisms. Pharm. Res. 2005, 22, 1129–1141. [Google Scholar] [CrossRef]
  18. Khan, M.Z.; Prebeg, Z.; Kurjaković, N. A pH-dependent colon targeted oral drug delivery system using methacrylic acid copolymers. I. Manipulation Of drug release using Eudragit L100-55 and Eudragit S100 combinations. J. Control. Release 1999, 58, 215–222. [Google Scholar] [CrossRef]
  19. John, R.; Howard, P.T. Controlled Release Formulation. U.S. Patent US4792452A, 20 December 1988. [Google Scholar]
  20. Amighi, K.; Timmermans, J.; Puigdevall, J.; Baltes, E.; Moës, A.J. Peroral sustained-release film-coated pellets as a means to overcome physicochemical and biological drug-related problems. I. In vitro development and evaluation. Drug Dev. Ind. Pharm. 1998, 24, 509–515. [Google Scholar] [CrossRef]
  21. Gruber, P.; Brickl, R.; Bozler, G.; Stricker, H. Dipyricamole Sustained Release Forms Comprising Lacquer-Coated Particles and the Preparation Thereof. U.S. Patent US4367217A, 4 January 1983. [Google Scholar]
  22. Cole, E.T.; Scott, R.A.; Connor, A.L.; Wilding, I.R.; Petereit, H.U.; Schminke, C.; Beckert, T.; Cadé, D. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int. J. Pharm. 2002, 231, 83–95. [Google Scholar] [CrossRef]
  23. Felton, L.A.; Porter, S.C. An update on pharmaceutical film coating for drug delivery. Expert Opin. Drug. Deliv. 2013, 10, 421–435. [Google Scholar] [CrossRef] [PubMed]
  24. Frohoff-Hülsmann, M.A.; Lippold, B.C.; McGinity, J.W. Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl-cellulose as coating material for diffusion pellets II: Properties of sprayed films. Eur. J. Pharm. Biopharm. 1999, 48, 67–75. [Google Scholar] [CrossRef] [PubMed]
  25. Jacob, J.; Haponiuk, J.T.; Thomas, S.; Gopi, S. Biopolymer based nanomaterials in drug delivery systems: A review. Mater. Today Chem. 2018, 9, 43–55. [Google Scholar] [CrossRef]
  26. Luliński, P. Molecularly imprinted polymers based drug delivery devices: A way to application in modern pharmacotherapy. A review. Mater. Sci. Eng. C 2017, 76, 1344–1353. [Google Scholar] [CrossRef] [PubMed]
  27. Shamsi, M.; Mohammadi, A.; Manshadi, M.K.D.; Sanati-Nezhad, A. Mathematical and computational modeling of nano-engineered drug delivery systems. J. Control. Release 2019, 307, 150–165. [Google Scholar] [CrossRef]
  28. Al Ragib, A.; Chakma, R.; Dewan, K.; Islam, T.; Kormoker, T.; Idris, A.M. Current advanced drug delivery systems: Challenges and potentialities. J. Drug Deliv. Sci. Technol. 2022, 76, 103727. [Google Scholar] [CrossRef]
  29. Davoodi, P.; Lee, L.Y.; Xu, Q.; Sunil, V.; Sun, Y.; Soh, S.; Wang, C.-H. Drug delivery systems for programmed and on-demand release. Adv. Drug Deliv. Rev. 2018, 132, 104–138. [Google Scholar] [CrossRef] [PubMed]
  30. Liu, Z.; Cheung, R.; Wu, X.Y.; Ballinger, J.R.; Bendayan, R.; Rauth, A.M. A study of doxorubicin loading onto and release from sulfopropyl dextran ion-exchange microspheres. J. Control. Release 2001, 77, 213–224. [Google Scholar] [CrossRef]
  31. Wong, H.L.; Bendayan, R.; Rauth, A.M.; Wu, X.Y. Development of solid lipid nanoparticles containing ionically complexed chemotherapeutic drugs and chemosensitizers. J. Pharm. Sci. 2004, 93, 1993–2008. [Google Scholar] [CrossRef]
  32. Shalviri, A.; Raval, G.; Prasad, P.; Chan, C.; Liu, Q.; Heerklotz, H.; Rauth, A.M.; Wu, X.Y. pH-Dependent doxorubicin release from terpolymer of starch, polymethacrylic acid and polysorbate 80 nanoparticles for overcoming multi-drug resistance in human breast cancer cells. Eur. J. Pharm. Biopharm. 2012, 82, 587–597. [Google Scholar] [CrossRef]
  33. Shalviri, A.; Chan, H.K.; Raval, G.; Abdekhodaie, M.J.; Liu, Q.; Heerklotz, H.; Wu, X.Y. Design of pH-responsive nanoparticles of terpolymer of poly(methacrylic acid), polysorbate 80 and starch for delivery of doxorubicin. Colloids Surf. B Biointerfaces 2013, 101, 405–413. [Google Scholar] [CrossRef] [PubMed]
  34. Chen, K.; Chang, H.H.R.; Shalviri, A.; Li, J.; Lugtu-Pe, J.A.; Kane, A.; Wu, X.Y. Investigation of a new pH-responsive nanoparticulate pore former for controlled release enteric coating with improved processability and stability. Eur. J. Pharm. Biopharm. 2017, 120, 116–125. [Google Scholar] [CrossRef] [PubMed]
  35. Yoshida, M.I.; Gomes, E.C.L.; Soares, C.D.V.; Cunha, A.F.; Oliveira, M.A. Thermal Analysis Applied to Verapamil Hydrochloride Characterization in Pharmaceutical Formulations. Molecules 2010, 15, 2439–2452. [Google Scholar] [CrossRef] [PubMed]
/by
Coating uniformity of hot-melt coated particles Figure 2 (pure)

Coating uniformity of hot-melt coated particles

Abstract

Coating uniformity is a critical parameter in coating processes in novel pharmaceutical formulations. Speaking about pellet technology, coating and layering are the main methods for implementing drug functionalities, such as modified release of the active, taste-masking properties and further more. Coating uniformity guaranties not only upholding functionalities of the formulation, but also prevent risks such as dose dumping.

This application note is based on a publication of Wörthmann et al. [1] and focuses on selected aspects which are related to starter cores.

Cellets 1000, magnification 100x

Figure 1: Microscopic image of Cellets® 1000, magnification 100x.

Materials and techniques

Coating was applied on highly spherical starter cores Cellets® 1000 (Figure 1). The pellets have a relatively narrow size distribution with a mean particle size of d­­­­50 = 1197 μm, a standard deviation of σ = 113 μm, and particle density of 1.4 g/cm3. For analyzing the coating uniformity, stearin (54 % stearic acid and palmitic acid) and hydrogenated palm oil were used. For the hot-melt coating experiments a lab-scale Wurster fluidized bed was used. The overspray rate was estimated to 8 % (w/w). Processed particles were analyzed by image analysis (Figure 2) and micro-computed-tomography (μCT) (Figure 3). 2D and 3D software analysis were further conducted for the evaluation of the sphere dimension, layer thickness and coating uniformity.

Figure 2 shows a wax-coated particle, where the coating thickness varies and delamination is clearly visible (Figure 3). Small pores and fractions of the coating layer area are obvious.

Coating uniformity of hot-melt coated particles Figure 1

Figure 2: Images of coated pellets are used for a stepwise evaluation of the particle shell thickness. A: original image; B: segmented coating layer. Further software calculation steps are not shown here.

These undesired artefacts result from imperfect parameters, such as spreading mechanism, temperature fluctuations, viscosity, or drop size.

The coating layer thickness is analyzed for three particles of the same batch (Figure 4) using 5 % (w/w) stearin at a spraying rate of 1 g/min. The layer thickness varies between approximately 2 µm to 30 µm. A mean coating thickness is found between 12 µm and 16 µm.

Coating uniformity of hot-melt coated particles Figure 2

Figure 3: Portion of a micro-computed-tomography image of a wax-coated particle showing.

Coating uniformity of hot-melt coated particles Figure 3

Figure 4: Relative frequency of the coating layer-thickness of three particle shells from the same batch using 5 % (w/w) stearin at a spraying rate of 1 g/min. Mean thicknesses: particle I (blue): 15.5 μm, particle II (red): 12.4 μm, and particle III (grey): 15.6 μm.

In terms of customer safety and of compliance aspects, not only statistical information about the layer thickness are of interest. In case of inhomogeneous layers, taste-masking functionalities or even uncontrolled dose dumping might occur. In this context, a single-particle analysis is mandatory. 3D µCT is a powerful tool, which is complementary to existing methods, such as laser imaging methods, 2D analysis or thickness estimations. The analyzed mean thickness deviates by approximately 13 % among these methods (Figure 5).

Coating uniformity of hot-melt coated particles Figure 4

Figure 5: Mean layer-thicknesses measured using different methods. Relative standard deviation: 13 %.

Summary

Microcrystalline cellulose pellets (Cellets®) are used to study coating uniformity. 3D μCT can be a powerful tool to assess the quality of the final product coating and facilitates the selection of an appropriate combination of core particles and coating material. 3D visualization methods allow a critical single-particle analysis with a resolution of up to 2 µm. Furthermore, the determination of the particle’s uncoated surface area can be specified.

Acknowledgement

Prof. Heiko Briesen, Mario Wörthmann (Technical University Munich) and team are gratefully acknowledged for serving content for this note.

Research was financially supported by the Ministry of Economics and Energy (BMWi) and FEI (Germany) via project AiF 19970 N. Equipment funded by Deutsche Forschungsgemeinschaft (DFG, Germany) 198187031.

References

[1] B.M. Woerthmann, J.A. Lindner, T. Kovacevic, P. Pergam, F. Schmid, H. Briesen, Powder Technology 378 (2021) 51–59

/by