Moisture Behavior of Pharmaceutical Powder during the Tableting Process

Abstract

The moisture content of pharmaceutical powder is a key parameter contributing to tablet sticking during the tableting process. This study investigates powder moisture behavior during the compaction phase of the tableting process. Finite element analysis software COMSOL Multiphysics^® 5.6 was used to simulate the compaction microcrystalline cellulose (VIVAPUR PH101) powder and predict temperature and moisture content distributions, as well as their evolution over time, during a single compaction. To validate the simulation, a near-infrared sensor and a thermal infrared camera were used to measure tablet surface temperature and surface moisture, respectively, just after ejection. The partial least squares regression (PLS) method was used to predict the surface moisture content of the ejected tablet. Thermal infrared camera images of the ejected tablet showed powder bed temperature increasing during compaction and a gradual rise in tablet temperature along with tableting runs. Simulation results showed that moisture evaporate from the compacted powder bed to the surrounding environment. The predicted surface moisture content of ejected tablets after compaction was higher compared to that of loose powder and decreased gradually as tableting runs increased. These observations suggest that the moisture evaporating from the powder bed accumulates at the interface between the punch and tablet surface. Evaporated water molecules can be physiosorbed on the punch surface and cause a capillary condensation locally at the punch and tablet interface during dwell time. Locally formed capillary bridge may induce a capillary force between tablet surface particles and the punch surface and cause the sticking.

Introduction

Tableting is the mechanical process adopted by the pharmaceutical industry to produce medicinal tablets. It involves direct compression of a powder mixture in a die using three steps: die filling, during which the formulation is delivered to the die cavity; compaction, during which pressure is applied to the formulation; and ejection, when the compacted tablet is ejected from the die cavity [1]. Up to 1 million tablets can be pressed per hour with one multi-die rotating press. The formulation compacted during the process is a mixture of active principal ingredients and excipients, such as ligands, binders, and lubricants, with a given moisture content.

The study of the physics of the tableting process is of great interest in order to understand the mechanism of consolidation of the granules during compaction, the punch-sticking phenomena, and the quality management of the pressed product. Several mathematical equations, such as Hekel’s [2], Kawakita’s [3], and Leuenberger’s [4] equations, have been developed to investigate the ability of formulations to flow, deform, and consolidate under pressure. These equations are usually used to predict how a formulation performs during the tableting process and minimize defects related to the pressing process. Although these equations are useful for preparing the best formulations for the tableting process, they do not provide a detailed insight of the phenomena occurring in the whole volume of the powder bed during the compaction process. Hence, simulation models based on the finite element method (FEM) have been developed to analyze in greater detail the powder bed behavior during compaction [5,6,7,8]. These phenomenological constituent methods are based on experimental calibrations using the variable physical properties of the compressed material. Several constitutive models have been developed, of which the DiMaggio–Sandler model [9], the Cam-Clay model [10], and the Drucker–Prager Cap (DPC) model [5,6] are well known. The DPC model is the most used for the pharmaceutical tableting process due to its ability to describe physical phenomena taking place during compression of a granular medium. It was first developed to investigate irreversible deformations of soils during compaction [5]. The DPC model was subsequently modified and adapted to pharmaceutical powder, and a calibration method was proposed to define all the involved parameters [11,12]. This modified DPC model was then used to study the mechanical behavior of powders, such as strain, stress, and density distribution, in the compact during compaction [13,14,15,16,17]. Thermomechanical analysis using the modified DPC model described how the heat generated during compaction progressively increased the powder bed temperature in all its volume [18,19,20] and was conclusive, along with results from previous experimental work [21,22,23].

During the tableting process, defects such as cracking, stretching, capping, lamination, chipping, restricting, and sticking may be present in the finally ejected tablets [1]. Coupling the FEM with the modified DPC allows determination of how the defects developed during compaction and helps to improve the understanding of the tableting process accordingly. Defects such as capping, cracking, lamination, and chipping have been intensively investigated and have been shown to originate from the inhomogeneous distribution of stress, relative density, and buildup of air pressure in the powder bed during compaction [24,25,26,27]. Furthermore, defects such as sticking, which is a persistent problem during the tableting process, were investigated to discover how the tableting process parameters, compressed material, compression tool properties, and ambient conditions contributed to the sticking defects [28,29,30,31,32,33,34,35,36]. Multivariate analysis, adhesion force measurement, push-off force measurements, material accumulation quantification, and the discrete element method have often been used for testing the propensity to stick [37,38,39,40,41,42,43]. (1) These studies identified the van der Waals forces and capillary forces to play a dominating role in the observed adhesion. The interplay between the interparticle cohesive force and wall–powder adhesion force results in localized attachment of the surface granules or layer of the tablet to the surface of the compression tool. Tableting force and speed, moisture level of the formulation, and properties of the compressed material govern the cohesivity of the tablet, and hence the tendency to stick. (2) From a phenomenological point of view, an increase in granule temperature during compaction may lead to the melting of some ingredients, such as ibuprofen and magnesium stearate, or of eutectic components present in the formulation, which may contribute to sticking. However, other studies have invalidated the melting hypothesis by showing that sticking still occurs when high-melting-point material, such as ibuprofen sodium, are compressed [44]. (3) Recent multivariate analysis of granulation and tableting process parameters [41,43] showed that the moisture level of the formulation plays a key role in the occurrence of sticking. While the results obtained from these studies provide good data to understand sticking, it is of interest to identify the phenomena that can trigger the development of sticking during compaction.

Near-infrared (NIR) spectroscopy is often used in the pharmaceutical industry as a faster, cheaper, and nondestructive way of analyzing pharmaceutical products. Its use is encouraged in process analytical technology (PAT) for on- and inline measurements and control of pharmaceutical products. The overall objective of its use is to probe a sample to acquire qualitative and/or quantitative information about the interaction between NIR electromagnetic waves and the sample’s constituents. NIR spectroscopy has been employed to investigate H-bonds and hydration of various molecules, such as alcohols, fatty acids, amides, polymers, and water [45,46]. In the NIR region, (1) bands arising from overtones and combinations of O-H, N-H and C-H vibrations appear strongly due to their larger anharmonicity, and (2) large band shifts are induced by the formation of hydrogen bonds and hydration. Within the NIR wavelength range, i.e., 700 to 2500 nm, prominent absorption bands of liquid water are found at 760, 970, 1190, 1450, and 1940 nm [47,48]. These absorption bands are due to the second overtone of the OH stretching band (3ν1,3), the combination of the first overtone of the O-H stretching band and OH-bending band (2ν1,3 + ν2), the first overtone of the OH-stretching band (2ν1,3), and the combination of the OH-stretching band and O-H bending band (2ν1,3 + ν2) [49]. Hence, NIR spectroscopy has been used to measure the moisture content of pharmaceutical tablets and powders during granulation, drying, and the tableting process [46,50,51]. The quantification of moisture content is often based on an experimental calibration model obtained with partial least squares (PLS) regression, multiple linear regression, or principal component regression. The calibration model thus established is then used to predict the inline or offline moisture content of powder or tablets during such pharmaceutical processes as wet granulation or tableting [52,53,54].

This study aimed to investigate phenomenologically the buildup of the sticking phenomenon during the compaction of pharmaceutical powder through the simulation of powder moisture behavior under compression. The AFEM method, based on the modified DPC model, was used to investigate moisture transport and thermomechanical behavior of powder during the tableting process, particularly during the compaction phase. The evolution and distribution of powder bed density, temperature, and moisture changes during the compaction process were studied. We hypothesized that the migration of powder moisture toward compression tools due to temperature and local humidity gradients contributes to the development of sticking. The results of this study show how thermomechanical phenomena can lead to moisture migration and potentially further induce sticking through capillary forces. To validate the simulation results, the temperature of the tablet surface and sides and the surface moisture content of the tablet a second after ejection were measured using PAT tools, such as a thermal infrared camera and NIR sensor. The results of this study provide new and original insights into the phenomenology of the sticking defect observed during the tableting process.

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Materials

Microcrystalline cellulose (MCC) grade VIVAPUR PH101 (JRS Pharma, LP., Patterson, New York, NY, USA) was used as the model powder material. The bulk density of the loose powder was measured with a 100 mL beaker and was found to be 279 ± 2.5 kg/m3. The true density of the dry, solid particles of MCC ranges between 1512 and 1668 kg/m3 [55], and hence a value of 1570 kg/m3 [20] was adopted in this study. The powder was stored at a controlled humidity level of 33.5 ± 0.1% and a temperature of 21.1 ± 0.5 °C. The water content of the powder was measured with an analytical transmitter (Mettler M100, Mettler-Toledo Ltd., Leicester, UK), which dries the powder with an infrared source and calculates the water content by mass difference.

Koumbogle, K.; Gosselin, R.; Gitzhofer, F.; Abatzoglou, N. Moisture Behavior of Pharmaceutical Powder during the Tableting Process. Pharmaceutics 2023, 15, 1652. https://doi.org/10.3390/pharmaceutics15061652