# Impact of Vertical Blender Unit Parameters on Subsequent Process Parameters and Tablet Properties in a Continuous Direct Compression Line

^{1}

^{2}

^{*}

## Abstract

**:**

_{L}), torque of lower impeller SD (T

_{L}SD), HUM SD and blend potency SD), material attributes of the blend (conditioned bulk density (CBD), flow rate index (FRI) and particle size (d

_{10}values)), tableting parameters (fill depth (FD), bottom main compression height (BCH) and ejection force (EF)) and tablet properties (tablet thickness (TT), tablet weight (TW) and tensile strength (TS)) could be found. Furthermore, relations between these process parameters were evaluated to define which process states were caused by which input variables. For example, the mixing parameters were mainly impacted by impeller speed, and material attributes, FD and TS were mainly influenced by variations in total blade passes (TBP). The current work presents a rational methodology to minimize process variability based on the main blender variables hold-up mass, impeller speed and throughput. Moreover, the results facilitated a knowledge-based optimization of the process parameters for optimum product properties.

## 1. Introduction

_{in}= mass

_{out}). Feed fluctuations of each feeder and the respective variability in the mass flow can be balanced that way. Smaller exit valve opening widths are recommended so that newly entering raw materials can be properly mixed together with the blend that is already present in the blender. Otherwise, unmixed or poorly mixed material can pass by and leave the CMT without being blended, causing content-uniformity variability [8].

## 2. Materials and Methods

#### 2.1. Materials

#### 2.2. DoE Settings

#### 2.3. Feeder Settings

#### 2.4. Bulk and Tapped Density

_{0}) after 750 and 1250 taps were noted. Each sample was analyzed in triplicate. Hausner Ratio and Carr’s Index were calculated as shown in Equations (3) and (4) and interpreted as shown in Table 4.

#### 2.5. Freeman Powder Rheometer FT4

#### 2.5.1. Stability and Variable Flow Rate

#### 2.5.2. Powder Compressibility

#### 2.5.3. Shear Cell

#### 2.6. Particle Size Distribution

_{10}, d

_{50}and d

_{90}values were obtained (see Supplementary Table S34).

#### 2.7. Tableting

#### Tensile Strength

_{s}= tablet core crushing strength, D = tablet core diameter, t = tablet core thickness and W = cylinder length. Tablet-crushing strength was measured by using the combi-tester, which is directly connected to the continuous manufacturing line.

#### 2.8. Blend Potency

#### 2.9. Software

#### 2.9.1. MODDE

#### 2.9.2. Osi Pi

#### 2.9.3. GraphPad Prism

## 3. Results and Discussion

#### 3.1. DoE Results

_{10}values), tablet press parameters (FD, BCH and EF) and tablet properties (TS, TW, TT and corresponding standard deviation) are presented. A visualization where responses are expected is shown in Figure 4. The data were fitted by using an MLR model, wherein significant model terms are identifiable when error bars (=95% confidence interval) do not cross the zero-line. Corresponding-fit statistics are shown in Supplementary Tables S2–S33. In this paper, models with Q

^{2}> 0.500 (=estimate of prediction precision) and R

^{2}≥ 0.800 (=model fit) are considered good models, indicating a significant correlation between input variables and responses.

#### 3.1.1. Mixing Parameters

#### 3.1.2. Material Attributes of the Blend

_{10}values of the blend were evaluated (Figure 6). THR, HUM and IMP show a similar impact on CBD and d

_{10}values of the powder. In contrast, the coefficients regarding FRI show a positive impact of THR and a negative influence by IMP and THR*THR.

_{10}can be considered good models. For further details, see Supplementary Section B, “Summary of Fit: Material Attributes of the Blend”.

#### 3.1.3. Tableting Parameters

^{2}and R

^{2}. For further information regarding fit statistics and model equations, see Supplementary Section C, “Summary of Fit: Tablet Press Parameters”.

#### 3.1.4. Tablet Properties

^{2}and high THR*IMP resulted in higher TBP and higher densities. Since the FD adjustments only occurred occasionally when the displacement at the pre-compression exceeded internal limits at which the calculated weights are too high/low, higher powder density resulted in higher TW. Regarding variability in tablet properties, throughput has the highest impact on tablet weight and thickness standard deviations, whereas no significant model term regarding TS SD could be found.

#### 3.2. Response Factors

#### 3.2.1. Mixing Parameters

#### Exit-Valve-Opening Width

^{2}= 0.860 and R

^{2}= 0.905). The low model validity observed was due to the extremely low variability seen in the replicated center points, and, hence, it is not a cause for concern.

^{2}= 0.822 R

^{2}= 0.933). Furthermore, Figure 11c shows the EV standard deviation as a function of the EV opening width (0.785 p = 0.0002). This correlation leads to the conclusion that higher EV values increased the risk of a fluctuating opening width, impacting the variability of the blend potency values (0.952 p < 0.0001) and subsequently affecting content uniformity of the tablets. A correlation matrix with downstream parameters concerning the EV is shown in Figure 12.

^{−4}.

_{10}values, FD and TS.

#### HUM SD

_{in}= mass

_{out}. Therefore, if variability could be observed in the HUM, then it occurred in EV, as well. To avoid those fluctuations, we can rely on the previous section, where impeller speed is the recommended parameter to control the corresponding process parameters. A detailed example is given in Supplementary Section E, “Additional Demonstration of HUM SD”.

#### Torque of Lower Impeller

_{L}(Q

^{2}= 0.851 and R

^{2}= 0.916) and T

_{L}SD (Q

^{2}= 0.882 and R

^{2}= 0.949) could be considered good models. The low model validity for torque SD is, again, caused by low variability in the replicated center points, and, therefore, it is not a cause for concern. Basically, the torque represents the required energy to turn the impeller within the CMT and can be used to monitor the mixing process [43].

_{L}SD and EV SD (0.906 p < 0.0001). The correlation between these standard deviations is based on the impact of impeller speed (IMP—T

_{L}SD: 0.874 p < 0.0001), wherein the higher impeller rotation resulted in higher variabilities in both parameters (Figure 5 and Figure 14c).

#### Blend Potency SD

_{L}SD (0.965 p < 0.0001) and IMP (0.753 p = 0.0005) could be observed (Figure 12).

#### 3.2.2. Material Attributes of the Blend

#### Powder Density

^{2}= 0.735 and R

^{2}= 0.850).

#### Flow Rate Index

^{2}= 0.800 and R

^{2}= 0.896.

#### Particle Size

_{10}) (Figure 16c). At a high TBP, more magnesium stearate adhered to the particles, leading to a lower amount of the remaining free MgSt particles within the blend, and thus increasing the d

_{10}values (0.836 p < 0.0001). As a reference, a blend without magnesium stearate was mixed by using a Turbula blender (Willy A. Bachofen AG, Muttenz, Switzerland), where a d

_{10}value of 38.38 µm was obtained (Figure 16c).

_{10}value was similar to the blend without MgSt, implicating that the fine fraction of MgSt was almost completely attached to the remaining raw materials at the higher TBP. Moreover, particle-size changes due to destruction of particles could be ruled out. In this case, the d

_{10}values would have decreased with a higher shear.

_{10}values could be obtained (R

^{2}= 0.842 and Q

^{2}= 0.587). Particle sizes of raw materials and blends are shown in Supplementary Table S34.

#### 3.2.3. Tableting Parameters

#### Fill Depth

_{10}). In general, smaller particle sizes are considered to decrease essential flowability, impacting a complete fill of the dies [47].

#### Ejection Force

^{2}= 0.892 and R

^{2}= 0.944). For further explanation regarding TBP and ejection force, see Supplementary Section G, “Ejection Force”.

#### 3.2.4. Tablet Properties

#### Tensile Strength

#### Compression-Force Profile

## 4. Sweet Spot

## 5. Conclusions

_{10}values and flow-rate index), the fill depth and the tensile strength of the tablets.

## Supplementary Materials

## Author Contributions

## Funding

## Acknowledgments

## Conflicts of Interest

## Abbreviations

API | active pharmaceutical ingredient |

BCH | bottom main compression height |

BFE | basic flow energy |

CBD | conditioned bulk density |

CMT | continuous mixing technology |

CP | compression pressure |

DC | direct compression |

DoE | design of experiment |

EF | ejection force |

EV | exit valve opening width |

EV SD | exit valve opening width standard deviation |

FD | fill depth |

FRI | flow rate index |

HUM | hold-up mass |

IMP | impeller speed |

LiW | loss in weight |

MBM | mass balance model |

MCC | microcrystalline cellulose |

MgSt | magnesium stearate |

MLR | multiple linear regression |

MRT | mean residence time |

NIR | near infrared |

PCMM | portable, continuous, modular, miniature |

PID | proportional–integral–derivative |

PLS | partial least square |

PV | process value |

RTD | residence-time distribution |

SE | specific energy |

SI | stability index |

SNV | standard normal variate |

SD | standard deviation |

TBP | total blade passes |

THR | throughput |

T_{L} | torque lower impeller |

T_{L} SD | torque lower impeller standard deviation |

TS | tensile strength |

TT | tablet thickness |

TW | tablet weight |

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**Figure 4.**Process overview of input factors (green,

**left**side) and observed responses (blue,

**right**side).

**Figure 5.**Coefficients plot of the impact of input variables on responses regarding the blending unit and uniformity of the blend. The 95% confidence interval is displayed as an error bar.

**Figure 6.**Coefficients plot of model terms regarding material attributes of the blends. The 95% confidence interval is displayed as an error bar.

**Figure 7.**Coefficients plot of model terms regarding tablet press parameters. The 95% confidence interval is displayed as an error bar.

**Figure 8.**Model terms regarding tensile strength (TS), tablet weight (TW), tablet thickness (TT) and corresponding standard deviation. The 95% confidence interval is displayed as an error bar.

**Figure 9.**Qualitative overview of process parameter connections and correlations. Input factors are marked in dark green (thick borders), confounding input parameters are marked in light green and the considered response parameters are shown in light orange. The color/shape of the borders classifies the responses into mixing parameters (orange line, rounded corners), material attributes of the blend (purple, striped background), tableting parameters (blue, dotted borders) and tablet properties (red, thin borders). Compression pressure (green) is considered an independent input factor of the tablet press.

**Figure 11.**(

**a**) Exit valve opening width vs. throughput (kg/h) in relation to varying impeller speeds. (

**b**) EV in dependence of impeller speed. (

**c**) EV SD vs. EV. (

**d**) EV as function of $\frac{\mathrm{HUM}\left[\mathrm{g}\right]}{{\mathrm{IMP}}^{2}[{\mathrm{rpm}}^{2}]\ast \mathrm{THR}\left[\frac{\mathrm{kg}}{\mathrm{h}}\right]}$ where x-values higher than 2 × 10

^{−4}result in EV below 5 mm.

**Figure 13.**(

**a**) HUM standard deviation as a function of impeller speed. (

**b**) Dependencies between SD in EV and HUM.

**Figure 14.**(

**a**) Torque of the lower impeller as a function of the sum of HUM and IMP. (

**b**) Correlation between variability in torque and exit valve opening width. (

**c**) Impact of impeller speed on the torque values.

**Figure 16.**(

**a**) Conditioned bulk density (CBD) (g/mL), (

**b**) flow rate index (FRI) and (

**c**) particle size (d

_{10}) (µm) as a function of total blade passes.

**Figure 17.**(

**a**) Fill depth as function of total blade passes compared to bulk density. (

**b**) Linearity between fill depth and d

_{10}values. (

**c**) Impact of compressibility on fill depth.

**Figure 19.**(

**a**) Overview of all phases (TBP) regarding compression pressure and tensile strength. (

**b**) Overview of all compression pressures and the corresponding tensile strength based on the lubrication (TBP).

**Figure 20.**Sweet spot (light green) reveals the combination of the DoE input variables in which the criteria are met. The color of the borders indicate which criterion is not met anymore. Black borders = TW SD, red borders = TS and orange boarders = EV.

Responses | |
---|---|

Mixing parameters | T_{L,} |

EV | |

Blend potency as predicted by the NIR model | |

Material attributes of the blend | FRI |

Particle size (d_{10}) | |

CBD | |

Tableting parameters | FD |

BCH | |

EF | |

Tablet properties | TS |

TT | |

TW |

Phase | Throughput (kg/h) | Hold-Up Mass (g) | Impeller Speed (rpm) | MRT (min) | TBP (rev) |
---|---|---|---|---|---|

1 | 10 | 400 | 200 | 2.4 | 480 |

2 | 10 | 400 | 650 | 2.4 | 1560 |

3 | 10 | 600 | 425 | 3.6 | 1530 |

4 | 10 | 800 | 200 | 4.8 | 960 |

5 | 10 | 800 | 650 | 4.8 | 3120 |

6 | 20 | 400 | 425 | 1.2 | 510 |

7 | 20 | 600 | 425 | 1.8 | 765 |

8 | 20 | 600 | 200 | 1.8 | 360 |

9 | 20 | 600 | 425 | 1.8 | 765 |

10 | 20 | 800 | 425 | 2.4 | 1020 |

11 | 20 | 600 | 425 | 1.8 | 765 |

12 | 20 | 600 | 650 | 1.8 | 1170 |

13 | 30 | 400 | 200 | 0.8 | 160 |

14 | 30 | 400 | 650 | 0.8 | 520 |

15 | 30 | 600 | 425 | 1.2 | 510 |

16 | 30 | 800 | 650 | 1.6 | 1040 |

17 | 30 | 800 | 200 | 1.6 | 320 |

Microcrystalline Cellulose | Saccharin Sodium Monohydrate | Calcium Di-Phosphate | Sodium Starch Glycolate | Magnesium Stearate | |
---|---|---|---|---|---|

Composition (%) | 49.104 | 21.844 | 24.552 | 3 | 1.5 |

Top-Up Volume (L) | 1.6 | 1.2 | 1.6 | 1.2 | 0.8 |

Gearbox Type | 1 (63:1) | 2 (235:1) | 2 (235:1) | 3 (455:1) | 3 (455:1) |

Screw Pitch (mm) | 20 | 10 | 20 | 10 | 20 |

Refill Level (dm^{3}) | 0.5 | 0.74 | 0.3 | 0.25 | 1.5 |

**Table 4.**Classification of Carr Index [30].

Flowability | Carr’s Index |
---|---|

Excellent | <15 |

Correct | 15–25 |

Poor | >25 |

**Table 5.**Interpretation of Pearson correlation coefficients [42].

Correlation Coefficient | Interpretation |
---|---|

0.9 to 1.0 (−0.9 to −1.0) | Very high correlation |

0.7 to 0.9 (−0.7 to −0.9) | High correlation |

0.5 to 0.7 (−0.5 to −0.7) | Moderate correlation |

0.3 to 0.5 (−0.3 to −0.5) | Low correlation |

0.0 to 0.3 (−0.0 to −0.3) | Negligible correlation |

**Table 6.**Overview of fit statistics regarding mixing parameters after removing non-significant model terms.

Response Factor | Data Transformation | Q^{2} | R^{2} | Adjusted R^{2} |
---|---|---|---|---|

Exit Valve Opening Width | Logarithmic | 0.860 | 0.905 | 0.883 |

Exit Valve Opening Width SD | Logarithmic | 0.822 | 0.933 | 0.893 |

Torque Lower Impeller | Logarithmic | 0.851 | 0.916 | 0.896 |

Torque Lower Impeller SD | Logarithmic | 0.882 | 0.949 | 0.933 |

Blend Potency SD | Logarithmic | 0.491 | 0.669 | 0.622 |

HUM SD | Logarithmic | 0.428 | 0.727 | 0.664 |

Response Factor | Data Transformation | Q^{2} | R^{2} | Adjusted R^{2} |
---|---|---|---|---|

Conditioned Bulk Density | - | 0.735 | 0.850 | 0.816 |

Flow Rate Index | - | 0.800 | 0.896 | 0.848 |

Particle Size (d_{10}) | - | 0.587 | 0.842 | 0.747 |

Response Factor | Data Transformation | Q^{2} | R^{2} | Adjusted R^{2} |
---|---|---|---|---|

Fill Depth | - | 0.873 | 0.941 | 0.914 |

Bottom Main Compression Height | - | 0.774 | 0.928 | 0.885 |

Ejection Force | - | 0.892 | 0.944 | 0.931 |

Response Factor | Data Transformation | Q^{2} | R^{2} | Adjusted R^{2} |
---|---|---|---|---|

Tensile Strength | Logarithmic | 0.907 | 0.976 | 0.958 |

Tensile Strength SD | - | −0.090 | 0.283 | 0.117 |

Tablet Weight | Logarithmic | 0.641 | 0.904 | 0.847 |

Tablet Weight SD | - | 0.472 | 0.856 | 0.770 |

Tablet Thickness | Logarithmic | 0.718 | 0.953 | 0.917 |

Tablet Thickness SD | - | 0.395 | 0.694 | 0.592 |

**Table 10.**Overview of fit statistics regarding tensile strengths obtained during compression-force profiles.

Response Factor | Data Transformation | Q^{2} | R^{2} | Adjusted R^{2} |
---|---|---|---|---|

Tensile Strength at 118 MPa | Logarithmic | 0.905 | 0.958 | 0.942 |

Tensile Strength at 157 MPa | Logarithmic | 0.877 | 0.963 | 0.944 |

Tensile Strength at 169 MPa | Logarithmic | 0.870 | 0.940 | 0.918 |

Tensile Strength at 236 MPa | Logarithmic | 0.923 | 0.978 | 0.964 |

Tensile Strength at 275 MPa | Logarithmic | 0.927 | 0.975 | 0.963 |

Responses | Q^{2} | R^{2} | Adjusted R^{2} |
---|---|---|---|

Exit valve opening width | 0.860 | 0.905 | 0.883 |

Exit valve opening width SD | 0.822 | 0.933 | 0.893 |

Torque of lower impeller | 0.851 | 0.916 | 0.896 |

Torque of lower impeller SD | 0.882 | 0.949 | 0.933 |

Conditioned bulk density | 0.735 | 0.850 | 0.816 |

Flow rate index | 0.800 | 0.896 | 0.848 |

Fill depth | 0.873 | 0.941 | 0.914 |

Bottom main compression height | 0.774 | 0.928 | 0.885 |

Ejection force | 0.892 | 0.944 | 0.931 |

Tablet thickness | 0.718 | 0.953 | 0.917 |

Tablet weight | 0.642 | 0.904 | 0.847 |

Tensile strength | 0.907 | 0.976 | 0.958 |

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## Share and Cite

**MDPI and ACS Style**

Kreiser, M.J.; Wabel, C.; Wagner, K.G.
Impact of Vertical Blender Unit Parameters on Subsequent Process Parameters and Tablet Properties in a Continuous Direct Compression Line. *Pharmaceutics* **2022**, *14*, 278.
https://doi.org/10.3390/pharmaceutics14020278

**AMA Style**

Kreiser MJ, Wabel C, Wagner KG.
Impact of Vertical Blender Unit Parameters on Subsequent Process Parameters and Tablet Properties in a Continuous Direct Compression Line. *Pharmaceutics*. 2022; 14(2):278.
https://doi.org/10.3390/pharmaceutics14020278

**Chicago/Turabian Style**

Kreiser, Marius J., Christoph Wabel, and Karl G. Wagner.
2022. "Impact of Vertical Blender Unit Parameters on Subsequent Process Parameters and Tablet Properties in a Continuous Direct Compression Line" *Pharmaceutics* 14, no. 2: 278.
https://doi.org/10.3390/pharmaceutics14020278