# Understanding the Effect of Granulation and Milling Process Parameters on the Quality Attributes of Milled Granules

^{*}

## Abstract

**:**

^{2}of 0.987, 0.953, 0.995 respectively) to enable their use in downstream process modeling.

## 1. Introduction

#### Motivation and Objectives

## 2. Materials and Methods

#### 2.1. Materials

^{®}PH101, FMC Biopolymer, Philadelphia, PA, USA) and α-lactose Monohydrate (46%, 310 NF, Foremost Farms USA, Baraboo, WI, USA). For the study of the effect of binder addition, polyvinylpyrrolidone (PVP K30, Fisher Scientific, Pittsburgh, PA, USA) was added to the formulation by replacing Avicel PH 101 and Lactose Monohydrate in equal parts (percentage wise). Distilled water was used as the binder liquid (for granulation) and was dripped into the granulator.

#### 2.2. Methods

#### 2.3. Particle Size Distribution

_{1}(<850 μm). The fine analysis consisted of sieve screen sizes ranging from 710 μm (#25), 500 μm (#35), 355 μm (#45), 250 μm (#60), 150 μm (#100), 90 μm (#170), 63 μm (#230), pan

_{2}(<63 μm). For the milled product, only one analysis was carried out using the sieve screen sizes starting from 850 μm (#20). This analysis was carried out for 20 min using an amplitude of 8 (2.72 mm). The granule mass collected on each mesh was recorded and used to develop a granule size distribution based on mass. This weighted distribution was used to identify d50, d90, d10, span and %fines of the powders. For the purpose of this study d10, d50 and d90 are calculated based on their weight.

#### 2.4. Bulk and Tapped Density

_{10}, V

_{500}, V

_{1250,}were noted down. The tapping was stopped if the difference between V

_{500}and V

_{1250}was less than or equal to 2 mL. If the difference was greater than 2 mL the tapping was continued in increments of 1250 taps until the difference between two successive volumes was less than or equal 2 mL [13].

#### 2.5. Friability

_{wt}) of sample is conditioned to remove the fines. For friability purposes, fines are defined as particles that have particle size lower than 150 μm screen size. The conditioned sample was then subjected to mechanical stress using a friabilator at 25 rpm for 10 min along with 200 glass beads (mean diameter 4 mm). Mechanical stress on the powder particles/granules is due to both the collisions with glass beads and collisions with the equipment (similar to a ball mill operation). After the glass beads were removed, the weight retained on the 150 μm screen was determined (F

_{wt}) [14]. Then, the friability of the sample was calculated as shown in Equation (1).

_{wt}− F

_{wt}) ÷ I

_{wt}) × 100%

#### 2.6. Porosity

_{t}) was measured using Accupyc II 1340 in a helium gas media using 10 cm

^{3}chamber. Envelope Density was measured using Geopyc 1360 using a 12.7 mm chamber-piston set. A dry solid medium (DryFlow

^{®}) consisting of small and rigid spheres with high flowability displaces the void space and closely envelops the particle surface, thereby giving the envelope density (ρ

_{e}) [15]. The porosity is calculated using the formula shown in Equation (2).

_{e}/ρ

_{t})) × 100%

## 3. Results and Discussion

#### 3.1. Effect of Impeller Speed and Batch Loading on Mass Throughput of the Mill

_{final}− m)

_{final}is the mass of the granules collected at the end of the milling cycle. Integrating Equation (3) with the initial condition of mass throughput of the mill at t = 0 is equal to 0 gives Equation (4)

_{final}(1 − e

^{−t/τ})

_{final}is throughput of the mill at t = 300 s, which was the run time for these experiments. τ = 1/K, which is the time required to collect 63% mass of m

_{final}. For the purposes of the equation all the masses were represented as a fraction of the batch loading.

_{final}and τ obtained for each of these experiments is shown in Table 3. The curve fit for each of these experiments showed good predictability.

_{50}is the time taken to mill 50% of the batch loading. On regressing m

_{final}and τ we get the following equations:

_{final}= 3.351159 m + 0.145144 v − 1.43681 m

^{2}− 0.01826 mv

^{2}− 0.19605 m

^{2}v + 0.021326 m

^{2}v

^{2}− 1.15712

^{2}of 0.987, adjusted R

^{2}of 0.95 and significance F of 0.0383.

^{2}− 0.150

^{2}v

^{2}− 1.95513 mv

^{2}+ 3.047324 m

^{2}v

^{2}− 34.3714 m

^{2}v − 98.2929

^{2}of 0.9, adjusted R

^{2}of 0.922 and significance F of 0.2.

_{final}and τ obtained from Equation (5) and Equation (6), respectively, into Equation (4).

_{50}from Table 3 was regressed to get an equation in terms of batch loading fed and impeller speed.

_{50}= -556.582 m − 33.2253 v − 5.71665 m

^{2}v

^{2}+ 5.892524 mv

^{2}+ 92.89835 m

^{2}v −60.3054 mv + 596.8258

^{2}of 0.935 and adjusted R

^{2}of 0.75 and significance F of 0.183.

_{50}profiles, a minimum can be seen. This minimum falls between 0.8 and 0.9 kg of batch loading and between 10 to 11 m/s impeller speed. This corresponds to 1837 rpm to 2021 rpm. This minimum corresponds to the lowest time required to complete 50% of the mill cycle, and it also informs the conditions that should be employed to achieve that minimum time for 50% completion of mill cycle (i.e., the fastest rate at which this can be achieved).

#### 3.2. Effect of Impeller Speed and Batch Loading on PSD of the Milled Granule

#### 3.2.1. Fines

#### 3.2.2. D50

^{2}+ 24.2549 d50

^{2}− 4.7145 d10

^{2}

^{2}+ 23.2487 d50

^{2}− 4.0797 d10

^{2}

^{2}was found to be 0.9534, adjusted R

^{2}was found to be equal to 0.8370, and significance, F, was equal to 0.1124. Similarly, for the tapped density equation, R

^{2}was found to be 0.995, adjusted R

^{2}was found to be equal to 0.983 and significance, F, was equal to 0.0119. Both these equations were validated using one of the experimental values and the error was found to be approximately 10% in both cases.

#### 3.3. Effect of Mill Screen Type

#### 3.4. Effect of Granulation Parameters on Milling

#### 3.4.1. Liquid-to-Solid Ratio

#### 3.4.2. Impeller Speed

#### 3.4.3. Binder Addition

## 4. Conclusions

## Supplementary Materials

Supplementary File 1## Author Contributions

## Funding

## Conflicts of Interest

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**Figure 1.**Typical mass throughput profile of a Comil. The graph represents a 600 g batch loading and an impeller speed of 3000 rpm.

**Figure 3.**(

**a**) %fines obtained for each run, comparison between mill throughput and %fines at a batch loading of (

**b**) 300 g, (

**c**) 600 g and (

**d**) 1000 g.

**Figure 4.**(

**a**) d50 obtained for each run, comparison between mill throughput and d50 at a batch loading of (

**b**) 300 g, (

**c**) 600 g and (

**d**) 1000 g.

**Figure 6.**Plot showing the effect of batch loading on milled product d50 at different impeller speeds.

**Figure 8.**Comparison of particle movement between a normal screen (round shaped screen) and grated screen.

**Figure 9.**Plot showing the effect of batch loading on %fines (

**a**) and on d50 (

**b**) for grated and normal screen.

**Figure 10.**Plot showing the effect of L/S ratio on d50 and friability (

**a**), and the mass of milled granules and friability (

**b**).

**Figure 12.**Plot showing the log normal distribution of granules processed with 150 rpm, 170 rpm (CAF-3) and 190 rpm (CAF-5).

**Figure 13.**(

**a**) Plot showing the effect of %PVP on d50 & mass of milled granules, (

**b**) effect of %PVP on d50 and %fines, (

**c**) effect of impeller speed on d50 and %fines, (

**d**) effect of L/S ratio on d50 and %fines.

Granulation Parameters | Mill Parameters | |||
---|---|---|---|---|

Impeller Speed (rpm) | L/S Ratio (%) | %PVP in Formulation | Impeller Speed (rpm) | Batch Loading (g) |

150 | 55 | 0 | 2250 | 600 |

150 | 55 | 0 | 1500 | 1000 |

150 | 55 | 0 | 2250 | 300 |

150 | 55 | 0 | 3000 | 600 |

150 | 55 | 0 | 1500 | 300 |

150 | 55 | 0 | 3000 | 1000 |

150 | 55 | 0 | 1500 | 600 |

150 | 55 | 0 | 2250 | 1000 |

150 | 55 | 0 | 3000 | 300 |

Impeller Speed (rpm) | L/S Ratio (%) | %PVP | d10 (μm) | d50 (μm) | d90 (μm) |
---|---|---|---|---|---|

170 | 45 | 0 | 190 | 600 | 1900 |

170 | 50 | 0 | 280 | 1060 | 2070 |

170 | 55 | 0 | 470 | 1400 | 2150 |

150 | 55 | 0 | 215 | 840 | 1930 |

190 | 55 | 0 | 450 | 750 | 1700 |

150 | 55 | 2 | 480 | 1020 | 2010 |

150 | 55 | 4 | 1075 | 1900 | 3200 |

m (kg) | v (m/s) | RPM | m_{final} | τ | t_{50} |
---|---|---|---|---|---|

0.6 | 12,246 | 2250 | 0.780 | 56.85 | 58,195 |

1 | 8164 | 1500 | 0.553 | 20.67 | 48,660 |

0.3 | 12,246 | 2250 | 0.758 | 70.12 | 75,664 |

0.6 | 16,328 | 3000 | 0.675 | 46.26 | 62,486 |

0.3 | 8164 | 1500 | 0.522 | 53.93 | 170,761 |

1 | 16,328 | 3000 | 0.745 | 70.72 | 78,633 |

0.6 | 8164 | 1500 | 0.708 | 49.46 | 60,602 |

1 | 12,246 | 2250 | 0.584 | 28.45 | 55,197 |

0.3 | 16,328 | 3000 | 0.841 | 78.26 | 70,620 |

d50 | d90 | d10 | |
---|---|---|---|

Input batch | 840 | 1930 | 215 |

Output batch, after 30 s | 290 | 500 | 110 |

Output batch, after 5 min | 515 | 710 | 190 |

CQA | p-Value |
---|---|

span | 9.11 × 10^{−9} |

friability | 0.044 |

porosity | 0.006 |

bulk density | 0.00049 |

tap density | 2.91 × 10^{−7} |

**Table 6.**Table describing the mass of granules below 1000 μm for different input granulation batches.

Granulation Batch | Mass Below 1000 μm (g) |
---|---|

CAF-3 (170 rpm) | 201.18 |

CAF-4 (150 rpm) | 311.13 |

CAF-5 (190 rpm) | 422.14 |

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**MDPI and ACS Style**

Kotamarthy, L.; Metta, N.; Ramachandran, R.
Understanding the Effect of Granulation and Milling Process Parameters on the Quality Attributes of Milled Granules. *Processes* **2020**, *8*, 683.
https://doi.org/10.3390/pr8060683

**AMA Style**

Kotamarthy L, Metta N, Ramachandran R.
Understanding the Effect of Granulation and Milling Process Parameters on the Quality Attributes of Milled Granules. *Processes*. 2020; 8(6):683.
https://doi.org/10.3390/pr8060683

**Chicago/Turabian Style**

Kotamarthy, Lalith, Nirupaplava Metta, and Rohit Ramachandran.
2020. "Understanding the Effect of Granulation and Milling Process Parameters on the Quality Attributes of Milled Granules" *Processes* 8, no. 6: 683.
https://doi.org/10.3390/pr8060683