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Blend uniformity represented by the RSD (n = 15) for binary powder blends consisting of DC-grade excipients and paracetamol (2%, 5%, 10% or 30% w/w). The powder blends are prepared using both batch and continuous blending processes at varying mixing times.

Blend uniformity represented by the RSD (n = 15) for binary powder blends consisting of DC-grade excipients and paracetamol (2%, 5%, 10% or 30% w/w). The powder blends are prepared using both batch and continuous blending processes at varying mixing times.

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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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... blend homogeneity was less consistent and showed a dependence on blending time and type of excipient. To widen the knowledge space in terms of material properties, this section describes the batch and continuous blending of paracetamol with three DC-grade excipients. Blend uniformity is represented by the RSD of the API concentration, as shown in Fig. 2. For all three excipients, blends have been prepared at four different API concentrations. For the batch process, blends have been prepared using four different blending times. For the continuous process the blended material was collected at four distinct time points during the process, but the mean residence time of the material ...
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... the spray dried lactose grade, very good blend uniformity is obtained in a batch process. All batch blends show an RSD < 4%, except for the blend with the highest API dosage and shortest mixing time of 1 min ( Fig. 2a). At this high API dosage, longer mixing times improve blend uniformity as shown by a decrease in RSD. At lower API concentrations varying from 2% to 10% w/w, short mixing times are sufficient to obtain a homogeneous blend. At the lowest API concentration of 2%, no dependence of the RSD on blending time is observed and uniform blends ...
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... mixing. For the intermediate API concentrations of 5% and 10% w/w, a minor effect of varying blending time is observed, but all blends show acceptable homogeneity with RSD values below 4%. Continuous blending of spray dried lactose with paracetamol results in slightly higher RSD's compared to the batch process, both at low and high API dosage (Fig. 2b). This indicates that the batch process is more effective in making uniform blends of spray dried lactose and API than the continuous process used in the current study. These observations are remarkable, as previous blending trials showed a clear benefit of continuous blending for other excipients ( Jaspers et al., 2021). It should be ...
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... granular lactose grade does show a clear benefit for the continuous blending process (Fig. 2c,d). In batch-mode, several blends show poor uniformity with RSD's up to 10% whereas for the continuous process the RSD is consistently below 5%. Similar to what is observed for spray dried lactose, batch blending with the highest API content requires a longer blending time to obtain a uniform blend. For the batch blends with 30% w/w API ...
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... w/w, continuous processing may become more challenging due to issues with maintaining a consistent API feed rate. These issues are not observed, however, for the lowest API concentration of 2% w/w used in this study (Fig. S1). The microcrystalline cellulose DC-grade (Pharmacel® 102) shows similar blending performance as the granular lactose grade (Fig. 2e,f). Batch blending of MCC with paracetamol results in several blends with a high RSD up to 10%. Especially at the highest API content of 30% w/w, several individual samples with a high label claim are observed. This causes high RSD values for the blends with the highest API content and indicates inefficient API deagglomeration in the ...
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... 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 segregation of the components ( Oka et al., 2017;Shenoy et al., 2015;Yang, 2006). The fact that the ...
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... 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 variability in the feed rate over time compared to the finer grade, which is related to the difference in flowability between the two paracetamol grades. Compared to the batch process, much better blend uniformity is obtained in the continuous process for MCC in combination with the ...
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... 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 and low surface area of the spray dried ...

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Article
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.