Publications

Authors: Ashutosh Tamarkar, Sheng-Wen Chen, Rohit Ramachandran

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Abstract: Wet granulation is widely used in many particulate industries for its capability to improve flowability and handling of powder substances. A mathematical model using discrete element methodology (DEM) was developed to study two kinds of binder addition approaches commonly used during wet granulation in a batch high-shear granulator: wet binder addition (WBA) and dry binder addition (DBA). To define the complex interactions in the systems, a novel integrated DEM algorithm that incorporates powder wetting behavior, capillary and viscous liquid bridge formation as well as binder dissolution was developed. DEM simulation results show a significant difference between the viscous regions in the particle bed for the two systems: the WBA approach quickly wets the majority of the particle bed with a low viscosity fluid, while in the DBA approach fewer particles with higher viscous surface liquid are generated that are responsible for a delayed but faster granule growth rate. The difference in the viscosity of the surface liquid in the two systems lead to varying strengths and numbers of the liquid bridge formed between particles as well as particle velocities. In general, the high viscous areas are dependent on the binder and liquid dispersion which are affected by the mechanical agitation.

Authors: Wei Meng, Kallakuri Suparna Rao, Ronald D.Snee, Rohit Ramachandran, Fernando J.Muzzio

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Abstract: Nowadays twin-screw granulation has been emerging as an attractive continuous wet granulation technique. This study was geared towards better process design and understanding with emphasis on bridging the knowledge gap between input and output variables by employing sequential experimentation strategy. A low-dose formulation for granulation experiments contained anhydrous caffeine as the model drug. In the first phase of parameter screening, D-optimal design and stepwise regression were leveraged to develop interaction models following the examination of various quantitative and qualitative factors of potential importance. To maximize the design space dictated by predefined quality target values, several variables were fixed at optimum levels: 700 rpm screw speed, 60° kneading element staggering angle, 5 kneading elements and distributive feed screw in the screw configuration. In the second phase of characterization, response surface design was utilized to investigate the dependence of critical quality attributes of granules and tablets on selected critical process parameters (L/S ratio, throughput and barrel temperature). The results indicated that the influence of throughput and barrel temperature was relatively inferior to L/S ratio. Higher degree of liquid saturation led to granules with narrower size distribution, smaller porosity and enhanced flowability and tablets with declining tensile strength yet slackened drug release.

Authors: Tianxiang Gao, Arun Sundar S. Singaravelu, Sarang Oka, Rohit Ramachandran, František Štepánek, Nikhilesh Chawla, Heather Emady

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Abstract: Single drop impact of liquid on a static powder bed was studied to investigate the granule formation mechanism, droplet penetration time, as well as the characterization of granules (morphology, surface structure and internal structure). Water was used as the liquid and two pharmaceutical powders, microcrystalline cellulose (MCC) and acetaminophen (APAP), were mixed to make heterogeneous powder beds. The complete drop impact and penetration was recorded by a high speed camera. Two granule formation mechanisms that have been identified previously occurred: Spreading and Tunneling. Spreading occurred for mixtures with an APAP amount of less than 20%, while Tunneling started to occur when the APAP amount increased above 20%. With an increase of APAP concentration, the mean particle size decreased, drop penetration time increased, and the granules formed became smaller in size, which was in good agreement with previous literature. The granule morphology, surface structure, and internal structure were characterized by a prism method with image analysis, scanning electron microscopy (SEM), and X-ray microtomography, respectively. The Spreading mechanism produced flat disks with a porous internal structure, while the Tunneling mechanism produced round granules with a dense internal structure. There is a clear trend of decreasing porosity and increasing roundness of granules made from heterogeneous mixtures within the transition from Spreading to Tunneling. It is believed that the mean particle size of the powder bed and the powder-liquid contact angle are the predominant factors in influencing the formation mechanism, drop penetration time, and granule properties.

Authors: Glinka Cathy Pereira, Shashank Venkat Muddu, Andrés David Román-Ospino, Don Clancy, Benoit Igne, Christian Airiau, Fernando J. Muzzio, Marianthi Ierapetritou, Rohit Ramachandran & Ravendra Singh

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Abstract: Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical manufacturing to achieve a consistent predefined end-product quality.

Authors: Shashank Venkat Muddu, Ashutosh Tamrakar, Preetanshu Pandey, and Rohit Ramachandran

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Abstract: An experimental study in industry was previously carried out on a batch fluid bed granulation system by varying the inlet fluidizing air temperature, binder liquid spray atomization pressure, the binder liquid spray rate and the disintegrant composition in the formulation. A population balance model framework integrated with heat transfer and moisture balance due to liquid addition and evaporation was developed to simulate the fluid bed granulation system. The model predictions were compared with the industry data, namely, the particle size distributions (PSDs) and geometric mean diameters (GMDs) at various time-points in the granulation process. The model also predicted the trends for binder particle dissolution in the wetting liquid and the temperatures of the bed particles in the fluid bed granulator. Lastly, various process parameters were varied and extended beyond the region studied in the aforementioned experimental study to identify optimal regimes for granulation.

Authors: Chaitanya Sampat, Franklin Bettencourt, Yukteshwar Baranwala, Ioannis Paraskevakos, Anik Chaturbedi, Subhodh Karkala, Shantenu Jha, Rohit Ramachandran, Marianthi Ierapetritoua

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Abstract: The accurate modeling of the physics underlying particulate processes is complicated and requires significant computational capabilities to solve using particle-based models. In this work, a unidirectional multi-scale approach was used to model the high shear wet granulation process. A multi-dimensional population balance model (PBM) was developed with a mechanistic kernel, which in turn obtained collision data from the discrete element modeling (DEM) simulation. The PBM was parallelized using a hybrid OpenMP+MPI approach. The DEM simulations were performed using LIGGGHTS, which was parallelized using MPI. Speedups of approximately 14 were obtained for the PBM simulations and approximately 12 for the DEM simulations. The uni-directional coupling of DEM to PBM was performed using middle-ware components (RADICAL-Pilot) that did not require modifications of the DEM or PBM codes, yet supported flexible execution on high-performance platforms. Results demonstrate scaling from 1 to 128 cores for the PBM and up to 256 cores for the DEM. The proposed method, implementations and middle-ware enable the modeling of high shear wet granulation process faster than existing approaches in literature.

Authors: Nirupaplava Metta, Maxim Verstraeten, Michael Ghijs, Ashish Kumar, Elisabeth Schafer, Ravendra Singh, Thomas De Beer, Ingmar Nopens, Philippe Cappuyns, Ivo Van Assche, Marianthi Ierapetritou, Rohit Ramachandran

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Abstract: The comilling process plays an important role in solid oral dosage manufacturing. In this process, the granulated products are comminuted to the required size distribution through collisions created from a rotating impeller. In addition to predicting particle size distribution, there is a need to predict other critical quality attributes (CQAs) such as bulk density and tapped density, as these impact tablet compaction behavior. A comprehensive modeling approach to predict the CQAs is needed to aid continuous process modeling in order to simulate interaction with the tablet press operation. In the current work, a full factorial experiment design is implemented to understand the influence of granule strength, impeller speed and residual moisture content on the CQAs. A population balance modeling approach is applied to predict milled particle size distribution and a partial least squares modeling approach is used to predict bulk and tapped density of the milled granule product. Good agreement between predicted and experimental CQAs is achieved. An  value of 0.9787 and 0.7633 is obtained when fitting the mean particle diameters of the milled product and the time required to mill the granulated material respectively.

Authors: Anik Chaturbedi, Preetanshu Pandey, Dilbir Bindra, Jay Poorna Reddy, Bo Lang, David Buckley, Rohit Ramachandran

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Abstract: In this work, a population balance model has been developed and calibrated with experimental data to be used as a predictive tool to replace or reinforce experimental studies of high shear wet granulation. The system studied also involves dry binder addition necessitating the incorporation of dissolution calculations, viscosity-binder correlations and drop penetration calculations to address some of the heterogeneities arising from the dry addition of binder. To address inhomogeneous liquid distribution in the powder bed, the granulator has been divided into two compartments, one with more liquid, less solid and the other one with the opposite. 27 wet granulation experiments were performed by varying liquid addition amount, liquid addition rate, impeller speed and wet massing time. Geometric mean diameter (GMD) in one case and d10 along with d50 in the other case for the 9 of these experiments were used to estimate the tuning parameters in the model. With the estimated parameters, GMD and d10, d50 were predicted for the remaining 18 experiments using the model and compared with experimental results. The model was able to predict the GMD of 8 experiments with a deviation of <10 μm and 4 more with <20 μm deviation. The model was also able to predict the d10 of 6 batches within 10 μm and 9 more batches within 20 μm. For d50 prediction, the deviation was <10 μm for 12 batches and <20 μm for 4 more batches. The model predicted particle size distribution (PSD) was also compared with the experimental PSD for two of the predicted sets as an example. It was seen that the model was able to replicate the PSD fairly well with the exception of the presence of some big granules seen in the experiments.

Authors: Huiyi Cao, Srinivas Mushnoori, Barry Higgins, Chandrasekhar Kollipara, Adam Fermier, Douglas Hausner, Shantenu Jha, Ravendra Singh, Marianthi Ierapetritou, Rohit Ramachandran

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Abstract: As the pharmaceutical industry seeks more efficient methods for the production of higher value therapeutics, the associated data analysis, data visualization, and predictive modeling require dependable data origination, management, transfer, and integration. As a result, the management and integration of data in a consistent, organized, and reliable manner is a big challenge for the pharmaceutical industry. In this work, an ontological information infrastructure is developed to integrate data within manufacturing plants and analytical laboratories. The ANSI/ISA-88.01 batch control standard has been adapted in this study to deliver a well-defined data structure that will improve the data communication inside the system architecture for continuous processing. All the detailed information of the lab-based experiment and process manufacturing, including equipment, samples and parameters, are documented in the recipe. This recipe model is implemented into a process control system (PCS), data historian, as well as Electronic Laboratory Notebook (ELN) system. Data existing in the recipe can be eventually exported from this system to cloud storage, which could provide a reliable and consistent data source for data visualization, data analysis, or process modeling.

Authors: Anjali Kataria, Sarang Oka, David Smrčka, Zdenek Grof, František Štěpánek, Rohit Ramachandran

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Abstract: This study investigates the extent of drug (active) migration in granules made via high shear wet granulation subject to factors such as the viscosity of the binder solution, particle size of the excipient and granule porosity. Due to the complexity of a qualitative comparison between granules having different sizes, shape and porosities, a quantification technique that is independent of these differences was developed. The radial distribution function (RDF), developed as part of this effort, quantifies the spatial distribution of the active ingredient in granules produced under different processing conditions.