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Title: Switching from batch to continuous granulation: A case study of metoprolol succinate ER tablets

Journal Article · · International Journal of Pharmaceutics
 [1];  [2];  [2];  [2];  [3];  [2];  [2];  [2]
  1. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research, Office of Pharmaceutical Quality; Rutgers Univ., Piscataway, NJ (United States)
  2. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research, Office of Pharmaceutical Quality
  3. Rutgers Univ., Piscataway, NJ (United States)
+ Show Author Affiliations

Continuous manufacturing (CM) has been used to produce several immediate release drug products. No extended-release (ER) product manufactured employing CM technology has been approved yet. Herein this study investigated the critical aspects of switching from the batch mode of high shear granulation to the continuous operation of twin-screw granulation for extended-release tablets. Metoprolol succinate ER tablets was used as a model ER formulation for this purpose. A central composite design (CCD) was employed to determine the effects of high shear granulator (HSG) parameters, namely impeller speed, granulation time, and binder liquid feeding rate, on the critical granulation characteristics important for product performance. These critical granulation characteristics served as a guide for switching from the batch processing to the continuous operation for achieving the same breaking strength and dissolution for this ER metoprolol tablets. The granulation time was the most critical factor affecting the bulk properties of granules which contributed to tablet dissolution. The higher density and lower compressibility of granules were attained at the longest granulation time of 5.4 min with the fastest liquid feeding rate of 75 g/min. The granules’ density was the primary factor negatively affecting the dissolution of metoprolol tablets. However, the breaking strength of tablets confounded the effect of granules density on metoprolol dissolution. Switching the processing parameters of high shear granulation to twin-screw granulation achieved similar dissolution profiles (F2 greater than 50). The screw speed was not found to affect bulk properties of granules. The root cause of granulation failures in twin-screw granulation, such as premature consolidation, excessive swelling, poor cohesion, inconsistent shearing effects, and formation of deformed agglomerates, were identified. In conclusion, the use of critical granulation characteristics through a performance-based approach of ER tablets facilitated the switching of manufacturing of an ER formulation form batch to continuous operation.

Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE; USDOE Office of Science (SC)
Grant/Contract Number:
SC0014664
OSTI ID:
1981637
Journal Information:
International Journal of Pharmaceutics, Journal Name: International Journal of Pharmaceutics Journal Issue: C Vol. 617; ISSN 0378-5173
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

References (30)

Granulation rate processes in the kneading elements of a twin screw granulator journal August 2013
Nucleation regime map for liquid bound granules journal February 2003
Transfer from High‐Shear Batch to Continuous Twin Screw Wet Granulation: A Case Study in Understanding the Relationship Between Process Parameters and Product Quality Attributes journal October 2014
Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review journal June 2001
Growth regime map for liquid-bound granules: further development and experimental validation journal June 2001
Wet granulation: the effect of shear on granule properties journal February 2003
Effect of process parameters on compressibility of granulation manufactured in a high-shear mixer journal March 2000
DEM modeling of high shear wet granulation of a simple system journal May 2018
Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis journal May 2019
A comprehensive review on process and engineering aspects of pharmaceutical wet granulation journal November 2017
The combined effect of wet granulation process parameters and dried granule moisture content on tablet quality attributes journal September 2016
Massing in high shear wet granulation can simultaneously improve powder flow and deteriorate powder compaction: A double-edged sword journal May 2011
Twin screw granulation: Steps in granule growth journal November 2012
Impact of screw configuration on the particle size distribution of granules produced by twin screw granulation journal February 2015
Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: Effect of process parameters on critical granule attributes and granulation mechanisms journal November 2016
Optimization of critical quality attributes in continuous twin-screw wet granulation via design space validated with pilot scale experimental data journal June 2017
Application of continuous twin screw granulation for the metformin hydrochloride extended release formulation journal August 2017
Modelling and understanding powder flow properties and compactability of selected active pharmaceutical ingredients, excipients and physical mixtures from critical material properties journal October 2017
The role of the screw profile on granular structure and mixing efficiency of a high-dose hydrophobic drug formulation during twin screw wet granulation journal February 2020
Systematic study of paracetamol powder mixtures and granules tabletability: Key role of rheological properties and dynamic image analysis journal October 2021
Development of an international standard for shear testing journal September 2006
Twin screw wet granulation: Influence of formulation parameters on granule properties and growth behavior journal April 2013
A method to analyze shear cell data of powders measured under different initial consolidation stresses journal June 2016
Mechanistic understanding of granule growth behavior in bi-component wet granulation processes with wettability differentials journal May 2020
Comparison between twin-screw and high-shear granulation - The effect of filler and active pharmaceutical ingredient on the granule and tablet properties journal October 2020
A review of high shear wet granulation for better process understanding, control and product development journal March 2021
Mixing of low-dose cohesive drug and overcoming of pre-blending step using a new gentle-wing high-shear mixer granulator journal May 2018
The application of povidone in the preparation of modified release tablets journal June 2016
Understanding the Effect of Granulation and Milling Process Parameters on the Quality Attributes of Milled Granules journal June 2020
Formulation and design of sustained release matrix tablets of metformin hydrochloride: Influence of hypromellose and polyacrylate polymers journal January 2013

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Continuous manufacturing
Design space
Extended-release tablets
Formulation
High-shear granulation
Oral solid dosage processing
Pharmacology & Pharmacy
Twin-screw granulation