In-situ Study of Single Pharmaceutical Granule Drying using Synchrotron X-ray Imaging

The drying process of wetted granules using common methods such as fluidized bed drying is a key unit operation in the pharmaceutical tableting industry. To ensure homogeneity and product quality for a wide range of formulations in the final tableted product, the monitoring of changes to an individual granules structure, and therein its composition and the associated properties, is essential. Granule drying can occur very rapidly, and many pharmaceutical powders are opaque in nature. Lab-based methods are therefore unable to capture the drying process occurring internally within the individual granules. Comparatively, the use of in-situ synchrotron X-ray imaging techniques allows for fast processes such as single pharmaceutical granule drying to be visualized due to the higher photon flux, good stability, and higher spatial and temporal resolutions that lead to a much faster method than conventional lab-based X-ray imaging. \n This study employs the use of synchrotron X-ray imaging techniques to investigate the internal changes of single pharmaceutical granules and how the removal of moisture influences the thermal properties of the individual granules to better predict the drying process. A single granule drying method was implemented to obtain quantitative information of the granule drying process. The liquid binder of water was used with pure components and binary mixtures composed of one active pharmaceutical ingredient and one excipient to produce individual wetted granules for drying. The pharmaceutical powders include the active ingredients acetaminophen and carbamazepine, in addition to common excipients such as microcrystalline cellulose and lactose monohydrate. \n A lab-based analysis investigated the effects of moisture content and porosity on the thermal conductivity and specific heat capacity of the pharmaceutical materials. A transient line heat source method was used, with relationships established between thermal conductivity and the volumetric specific heat capacity with porosity and moisture content for the pharmaceutical ingredients. In general, all compositions were observed to have a decrease in porosity with an increase in moisture content, with the thermal properties increasing with an increase in moisture content that followed a three-parameter predictive model for both the thermal conductivity and volumetric specific heat capacity. For APAP, the thermal conductivity increased from 0.171 W/(m k) to 0.402 W/(m k) and the volumetric specific heat capacity increased from 1.300 MJ/(m3 K) to 2.265 MJ/(m3 K) with a change in moisture content from 4.98 % to 14.91 %; the thermal conductivity of MCC increased from 0.127 W/(m k) to 0.360 W/(m k) and the volumetric specific heat capacity increased from 0.701 MJ/(m3 k) to 1.739 MJ/(m3 K) with a moisture change from 4.55 % to 30.07 %; thermal conductivity of LMH increased from 0.181 W/(m k) to 0.692 W/(m k) and the volumetric specific heat capacity increased from 1.145 MJ/(m3 K) to 2.716 MJ/(m3 K) with a change in moisture content from 1.19 % to 22.75 %.\n In-situ synchrotron-based X-ray techniques were used to investigate the dynamic drying of single pharmaceutical granules, quantifying internal changes occurring over the drying time. For most samples, the drying time and granule composition were determined to significantly influence the evolution of the pore volume and the moisture content, with the initial air volume fraction being as low as 0.02 and increasing to as much as 0.38 with the moisture ratio decreasing from 1.00 to as low as 0.00 throughout the drying process. Granules containing MCC were observed to shrink during the drying process, decreasing by up to 25.2 % in volume, with all other materials not observing shrinkage effects. Drying gas velocity and temperature were found to have mixed significance on the rate of increasing pore connectivity and the removal of moisture, with sample composition influencing these changes. This is easily seen in examples such as 80LMH20APAP, where the increase in velocity from 0.02 m/s to 0.10 m/s allows for a larger decrease in the moisture ratio, with increasing temperature from 25 °C to 40 °C observed to further decrease the moisture ratio over the same drying time. The effects of hydrophobicity and hydrophilicity were also observed using carbamazepine and acetaminophen respectively, with the influences of carbamazepine’s material properties being minimal in both pure and binary mixtures, whereas acetaminophens hydrophilic nature was dominant in all granules that it is present, with acetaminophen loadings of 20 % to 50 % influencing the drying behaviour for both lactose monohydrate and microcrystalline cellulose. The changes in the moisture content were further analyzed for all materials and fit to nine thin-layer drying models, with the Henderson and Pabis model producing the best predictions for the single pharmaceutical granules used in this work, with R2 values ranging between 0.635 and 0.998, with 83.3% of the drying models possessing an R2 greater than 0.90. \nThe monitoring of the single pharmaceutical drying process using in-situ synchrotron X-ray imaging techniques was, for the first time, demonstrated with data collected on the pore volume evolution and changes to the moisture content obtained. This study revealed how individual pharmaceutical granules were affected by both the velocity and temperature of the drying gas. The information gained from this research includes a three-parameter model to predict the thermal properties of the pharmaceutical granules that can be used in conjunction with the thin-layer modelling of the drying process of the single pharmaceutical granules, that will benefit the selection of materials and process conditions for drying processes in the pharmaceutical industry.

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