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Blend uniformity represented by the RSD (n = 15) for binary powder blends of a coarser paracetamol grade with six different excipient types. Blends were prepared in a batch-wise and continuous blending process at an API loading of 10% w/w.

Blend uniformity represented by the RSD (n = 15) for binary powder blends of a coarser paracetamol grade with six different excipient types. Blends were prepared in a batch-wise and continuous blending process at an API loading of 10% w/w.

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The material properties of excipients and active pharmaceutical ingredients (API's) are important parameters that affect blend uniformity of pharmaceutical powder formulations. With the current shift from batch to continuous manufacturing in the pharmaceutical industry, blending of excipients and API is converted to a continuous process. The relati...

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... blends with 10% w/w of this coarser API grade were prepared with all six types of excipients depicted in Table 2. Similar to the experiments described previously, blending was performed in a batch and a continuous process using four different mixing times. Blend uniformity represented by the RSD of the paracetamol concentration is shown in Fig. ...
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... batch blending of lactose with the coarse API grade, lower RSD's indicating better blend uniformity are observed compared to the standard paracetamol grade (Fig. 4a). Especially for the spray dried and granular lactose grades, very good blend homogeneity is obtained in a batch process. For the anhydrous lactose and milled lactose monohydrate grade, higher RSD's are observed. These results again highlight the importance of powder flowability in a batch blending process, where the combination of a ...
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... of the coarse API grade is very similar to the density of the varying lactose grades. This minimizes the chance of segregation of lactose and API in a batch process, resulting in good blend homogeneity independent of mixing time. Batch-wise blending of MCC with the coarse API grade on the other hand shows very poor uniformity with RSD's up to 35% (Fig. 4c). These values are much higher than the RSD's observed for MCC with the finer API grade (Fig. 2e). A likely explanation for the poor blending of MCC with the coarser API grade is the large difference in bulk density between excipient and API. Previous work on powder blending has shown that large differences in density can results in ...
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... blending of the coarser API grade with varying excipients results in low RSD's in the range of 2-4% for most excipients (Fig. 4b,d). These values are similar to the values obtained for continuous blending of the standard API grade with varying excipients. The feed rate variability data for the continuous blending of the coarse API grade with varying excipients is given in the supplementary information (Fig. S2, Table S2). The coarser API grade shows a lower ...
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... blending methods is much smaller than for MCC. This is mainly due to the lower RSD's obtained in a batch process for lactose in combination with the coarser API grade. Although variations in blend uniformity between the different grades of lactose are small in a continuous process, the spray dried lactose stands out with a consistently higher RSD (Fig. 4b). This observation is in line with the results of the standard API grade, where spray dried lactose also shows relatively poor blend uniformity in the continuous process (Fig. 2b). As discussed in the previous section, possible explanations for the different performance of spray dried lactose could be found in the spherical morphology ...


The properties of pharmaceutical powders, and the liquid binder, directly influence the penetration behavior in the wet granulation process of the pharmaceutical industry. Conventional methods encounter challenges in understanding this fast process. In this work, an emerging synchrotron-based X-ray imaging technique (having fast imaging capability) was employed to investigate the internal process from 2D and 3D to real-time (in-situ with ms time intervals) 3D (also considered 4D) perspectives. Two commonly used excipients (lactose monohydrate (LMH) and microcrystalline cellulose (MCC)) were used to make binary mixtures with acetaminophen (APAP) as the active pharmaceutical ingredient (API). Isopropanol and water were employed as liquid binders in the single droplet impact method. Results showed that for most of the mixtures, the porosity increased at higher fractions of APAP. MCC mixtures experienced less agglomeration and more uniform pore distribution than LMH ones, resulting in a faster droplet penetration with isopropanol. Moreover, the imbibition-spreading studies showed that isopropanol penetration in MCC powders followed more unidirectional vertical movement than horizontal spreading. Our results also demonstrated that simultaneous granulation of LMH with water resulted in much slower penetration. This study revealed that synchrotron X-ray imaging can investigate 3D internal pore structures and how they affect the quantitively real-time internal penetration dynamics.