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Scanning electron micrographs of the six types of excipients and two API grades used in this study: a) anhydrous lactose, b) milled lactose monohydrate, c) spray dried lactose, d) granular lactose, e) MCC 101, f) MCC 102, g) paracetamol standard powder, h) paracetamol dense powder. The scale bar represents 100 μm.

Scanning electron micrographs of the six types of excipients and two API grades used in this study: a) anhydrous lactose, b) milled lactose monohydrate, c) spray dried lactose, d) granular lactose, e) MCC 101, f) MCC 102, g) paracetamol standard powder, h) paracetamol dense powder. The scale bar represents 100 μm.

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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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... grades is also represented by a difference in the effective angle of internal friction (ϕ e ). The spray dried lactose shows a lower ϕ e , indicating lower friction between sliding layers of powder due to the more spherical morphology of the particles. The varying morphologies of the excipients used in this study are depicted by SEM images in Fig. ...
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... bulk density of both MCC grades is much lower than the density of the varying lactose grades. The morphology of the MCC particles is very different from lactose, showing a fibrous structure with a high aspect ratio (Fig. 1e,f). This different morphology results in a larger surface area for MCC. Paracetamol is used as a model API for blending with these excipients. The standard paracetamol grade used here has a relatively small particle size, similar to the milled lactose grade, and shows very poor flowability with ffc = 1.9 and a high effective angle of ...
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... The bulk density of this API grade is similar to MCC and much lower than the different lactose grades. The second grade of paracetamol used has a particle size that is three times larger than the standard grade and also shows a higher bulk density and improved flowability. The different morphologies of the two paracetamol grades are shown in Fig. 1g,h and the difference in morphology is also reflected by a large difference in ϕ e . Overall, these grades of excipients and API represent a broad spectrum of physical material properties that are relevant for powders used in pharmaceutical OSD ...
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... the continuous process shows improved blend homogeneity compared to the batch process. It should be noted for API contents below 2% 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 ...
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... cohesiveness and poor flow properties of the paracetamol used in this study. This makes a consistent mass flow rate of the API through the continuous process challenging, especially at low dosage where the API feed rate is low. Quite surprisingly, the feed rate variability of the API over time shows very little dependence on API dosage (Table S1, Fig. S1). Even at the lowest API dosage of 2% w/w, the feed rate as a function of time is very consistent. For the continuous blending of MCC with the lowest API dosage, however, a small increase in API feed rate at the start of the process (Fig. S1) could be responsible for the high label claim observed for the first data point in Fig. 3. The ...
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... the feed rate variability of the API over time shows very little dependence on API dosage (Table S1, Fig. S1). Even at the lowest API dosage of 2% w/w, the feed rate as a function of time is very consistent. For the continuous blending of MCC with the lowest API dosage, however, a small increase in API feed rate at the start of the process (Fig. S1) could be responsible for the high label claim observed for the first data point in Fig. 3. The type of excipient used has little effect on the consistency of the continuous blending process over ...

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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.