Publications

Authors: Wei Meng, Lalith Kotamarthy, Savitha Panikar, Maitraye Sen, Shankali Pradhan, Michaelis Marc, James D.Litsterd, Fernando J.Muzzio, Rohit Ramachandran

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Abstract: This study is concerned with identifying the design space of two different continuous granulators and their respective granulation mechanisms. Performance of a continuous high shear granulator and a twin screw granulator with paracetamol formulations were examined by face-centered cubic design, which focused on investigating key performance metrics, namely, granule size, porosity, flowability and particle morphology of granules as a function of essential input process parameters (liquid content, throughput and rotation speed). Liquid and residence time distribution tests were also performed to gain insights into the liquid-powder mixing and flow behavior. The results indicated that continuous high shear granulation was more sensitive to process variation and produced spherical granules with monomodal size distribution and distinct internal structure and strength variation. Twin screw granulation with such a particular screw configuration showed narrower design space and granules were featured with multimodal size distribution, irregular shape, less detectible porosity difference and tighter range of strength. Granulation mechanisms explored on the basis of nucleation and growth regime maps revealed that for most cases liquid binder was uniformly distributed with fast droplet penetration into the powder bed and that granule consolidation and coalescence mainly took place in the nucleation, steady growth and rapid growth regimes.

Authors: Ashutosh Tamrakar, Alfeno Gunadi, Patrick M.Piccione, Rohit Ramachandran

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Abstract: One of the serious challenges with the operation of an agitated filter dryer (AFD) is the issue of undesired agglomeration which often plagues the unit operation during the agitated drying cycles. Experimental analyses of the lumped powder formation at various operating conditions are now being used to gain insight into minimizing such activity; however, there is still a lack of understanding into the fundamental processes prompting such behavior and the effectiveness of suggested mitigation measures. This study aims to investigate the underlying agglomeration mechanisms induced during the agitated drying phase of an AFD operation. Through parametric study and granule growth regime map analysis, the dynamic drying and agglomeration profiles were studied for a model cohesive powder, micronized acetaminophen, at various process conditions. The granule growth regime map analysis showed that induction and nucleation type of granule enlargement where the dynamics of wetting dictates the formation of granules is predominant during agitated drying. Depending on the amount of time the drying experiment remains in the specific growth regime, the dynamic agglomeration profile differs drastically. In addition, through parametric investigation, the choice of wash solvent and the presence of critical residual moisture content at the start of the drying cycle showed dominant influence on agglomerate formation. Wash solvents which have high fluid viscosity seem to form stronger agglomerates that retain their structure through the drying process. In terms of the amount of residual moisture content, a critical moisture content range is noticeable for different wash solvents where the agglomerates formed possess superior strength. For prevention of agglomerates, such critical moisture levels and use of high viscous solvents must be avoided.

Authors: Andrés D.Román-Ospino, Ravendra Singh, Marianthi Ierapetritou, Rohit Ramachandran, Rafael Méndez, Carlos Ortega-Zuñiga, Fernando J.Muzzio, Rodolfo J.Romañach

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Abstract: Near infrared spectroscopic (NIRS) calibration models for real time prediction of powder density (tap, bulk and consolidated) were developed for a pharmaceutical formulation. Powder density is a critical property in the manufacturing of solid oral dosages, related to critical quality attributes such as tablet mass, hardness and dissolution. The establishment of calibration techniques for powder density is highly desired towards the development of control strategies. Three techniques were evaluated to obtain the required variation in powder density for calibration sets: 1) different tap density levels (for a single component), 2) generating different strain levels in powders blends (and as consequence powder density), through a modified shear Couette Cell, and 3) applying normal forces during a compressibility test with a powder rheometer to a pharmaceutical blend. For each variation in powder density, near infrared spectra were acquired to develop partial least squares (PLS) calibration models. Test samples were predicted with a relative standard error of prediction of 0.38%, 7.65% and 0.93% for tap density (single component), shear and rheometer respectively. Spectra obtained in real time in a continuous manufacturing (CM) plant were compared to the spectra from the three approaches used to vary powder density. The calibration based on the application of different strain levels showed the greatest similarity with the blends produced in the CM plant.

Authors: Anik Chaturbedi, Chinmay Pathak, Kapil Deshpande, Nina Shapley, Rohit Ramachandran

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Abstract: The properties of heteroaggregates (aggregates of particles that are different in various aspects such as size, surface charge) depend on the properties of the particles along with the initial relative concentration of the particles. In this article, the heteroaggregation of two different types of oppositely charged hydrogel particles, alginate microparticles and chitosan nanoparticles were studied. A population balance model (PBM), popularly used to model particulate processes was developed based on the inter-particle interactions such as van der Waals, electrostatic and hydration in order to study the effect of initial relative concentration of alginate and chitosan on the final heteroaggregate size distribution. The presence of three different regimes (namely, ‘dispersed, uncoated’, ‘agglomerated’ and ‘dispersed, coated’) based on the initial concentration of alginate and chitosan was observed both from the model calculations and the experiments. In addition, to better understand these interactions, the effect of various process parameters on the aggregation kinetics were studied.

Authors: M.O. Besenhard, S.K. Karkala, E.Faulhammer, S.Fathollahi, R. Ramachandran, J.G. Khinast

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Abstract: Precise and effective feeding of small powder quantities remains a challenge in many fields, including pharmaceutical development and production. This paper demonstrates that a simple feeding principle can be applied to accomplish stable micro feeding (<100 mg/s) and describes a gravimetric powder feeding system with a vibratory sieve mounted on a chute. Feeding was induced via vertical vibrations that can be adjusted within a broad range of frequencies and amplitudes. The feeding system was studied using different frequencies, amplitudes, sieves and powder properties. Feeding was characterized by means of a dynamic scale and high-speed camera recordings. The feeding system provided effective powder feeding even in a range of 1–2 mg/s. It was shown that powder properties require special attention when the vibratory sieve-chute system operates at higher feed rates (or feeding times >30 min), i.e., feeding at a higher throughput.

Authors: Manogna Adepu, Siddhi Hate, Angelique Bétard, Sarang Oka, Marek Schongut, Maitraye Sen. Yadvaindera Sood, Dorit Wolf, Stefan Wieland, Frantisek Stepanek, Fernando Muzzio, Benjamin Glasser, Rohit Ramachandran

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Abstract: The objective of this work was to study the granulation behavior of three different types of zirconium hydroxide, each varying in particle size and density. Different concentrations of yttrium (III) nitrate hexahydrate (Y(NO3)3·6H2O) solutions were used as a doping agent and also acted as binder. Experiments were performed using a high shear wet granulation process by adjusting two parameters, 1. liquid to solid mass ratio and 2. impeller speed, to obtain four parameter settings (referred as bounds in the paper) for a two factorial design of experiment for each powder. To understand the granule growth behavior, a regime map analysis using the growth regime map first proposed by Iveson and Litster (1998) , was carried out on the bounds. The granule growth behavior observed experimentally was compared with the regime map results. Different growth behavior was observed for different powders. Furthermore, an attempt was made to obtain a steady growth for those parameter settings that initially resulted in an induction growth. A surfactant, SDS (Sodium dodecyl sulfate), was used to improve the wetting properties of the powder and its addition to the binder solution resulted in a steady growth that is more controllable for granulation manufacturing operations compared to induction growth.

Authors: Suyang Wu, Savitha S. Panikar, Ravendra Singh, Jun Zhang, Benjamin Glasser, Rohit Ramachandran

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Abstract: The optimal design of sensor location and setup is essential to ensure the accuracy and precision of in-line process monitoring of water/moisture content. This manuscript presents a systematic framework of using Near Infrared (NIR) spectroscopy to monitor moisture content in an alumina mulling process that is commonly used in the upstream operation of catalyst supports production. For this, the optimal conditions of NIR sensor setup and critical quality attributes (CQAs) of a mulling process have been first identified and then calibration models for monitoring moisture at various conditions were developed and validated. The results suggest that there is a strong relationship between sensor setup and prediction accuracy. Therefore, optimal conditions such as operating distance of the NIR sensor, sample thickness and acquisition number need to be identified prior to installment of the sensor into the manufacturing plant. In mulling processes, the particle size distribution (PSD) and surface roughness/smoothness can also vary during operation, making the monitoring of moisture content a difficult task. In this study, the effects of PSD and powder surface characteristics on moisture content measurement has been investigated and it has been found that if suitable raw data preprocessing has been applied, the effect of agglomerate size and sample surface characteristics on the accuracy of the in-line measurements can be significantly minimized. This will allow the use of a single calibration model for a range of PSDs and powder bed smoothness/roughness and that will save a significant amount of time and resources. Here, a mulling process where a microNIR sensor has been used for monitoring of moisture content has been considered as a demonstrative example. However, the approach is generic and can be applied for any combination of process and sensor.