# Compression Density as an Alternative to Identify an Optimal Moisture Content for High Shear Wet Granulation as an Initial Step for Spheronisation

^{1}

^{2}

^{*}

## Abstract

**:**

_{press}) as the said alternative, linking information from the powder material and the moisture content (R

^{2}= 0.995). We used ρ

_{press}to successfully predict liquid requirements for unknown formulation compositions. By means of this prediction, pellets with high quality, regarding shape and size distribution, were produced by carrying out a multi-step manufacturing process. Furthermore, the applicability of ρ

_{press}as an alternative quality parameter to other placebo formulations and to formulations containing active pharmaceutical ingredients (APIs) was demonstrated.

## 1. Introduction

## 2. Materials and Methods

#### 2.1. Granulation Equipment

^{®}TM6 (Vorwerk, Wuppertal, Germany) with a bowl size of 2.2 L. According to the manufacturer, the impeller’s speed can be adjusted from 40 rpm to 10,700 rpm [19]. In our study, we adjusted the impeller speed at 150 rpm. We replaced the original agitator by a custom-made mixing knife. The original Thermomix mixing knife was adapted by cutting off four mixing knives; then, stirring blades with dimensions of 4.5 cm × 1.5 cm × 0.2 cm were welded at an angle of 45°. This modification ensured proper material mixing and mimicked Diosna’s P 1–6 intensive mixer (DIOSNA Dierks & Söhne, Osnabrück, Germany). Water was added via a peristaltic pump (1B.1003-R/65, Petro Gas, Berlin, Germany). The inner diamater of the tube was 5 mm and equipped with a nozzle with an inner diameter of 1 mm. The amount of water added was controlled with a scale (PCE-BS 3000, PCE Instruments

^{™}, Meschede, Germany).

#### 2.2. Granulation in Lab-Scale

^{−1}, while keeping the impeller’s speed constant. The time for water addition was dependent on the amount of water. For example, with a dry mass of 150 g and a target water content on wet basis (ω

_{wet}) of 20%, the addition time was 2.5 min (37.5 g water). To ensure the preparation of homogeneous samples after all water was added, the mixing process stopped and material adhering to the mixing bowl was scraped off manually. Subsequently, larger agglomerates were crushed at a speed of 2000 rpm for 3 s. For each formulation, one batch was performed and samples were taken for the respective ω

_{wet}. The sample size was 38 g so that the compression density (ρ

_{press}) could be determined in triplicates (12 g each). The experimental procedure is summarized in Table 2. For details on the raw materials (abbreviated with A, B and API), we refer to Table 1.

#### 2.3. Measurement of ρ_{press}

_{press}. For each analysis, 12 g of granulate was weighed in and transferred to the body of the rig and compressed with 196 N for 20 s. The final height of the compressed material was registered. For data recording and evaluation, software Exponent (Stable Mirco Systems, Godalming, UK) was used.

#### 2.4. Proof of Concept: Pellet Production in Lab-Scale

#### 2.5. Statistical Analysis

_{press}measurements were performed in triplicates. Statistical analyses were performed by one-way ANOVA. A p-value smaller than 0.05 was considered statistically significant. Statistical analyses were performed using Minitab® 20.4. All experimental data are presented as mean ± standard deviation (n = 3).

## 3. Results and Discussion

#### 3.1. Identification of a Moisture Related Quality Parameter for Granules

_{press}. In a subsequent step of the test, a trap door underneath the powder cake opened. A piston then pushes (powder shear speed 0.5 mm s

^{−1}, distance 5 mm) a plug of the powder cake through this opening. During the entire process, the drag force is recorded (Figure 1, left part). Here, the area under the curve, the maximum force and the vertical shear strength are monitored. The area under the curve is provided by the integral of the curve section resulting from the shearing process (Figure 1, area highlighted in gray) and the maximum force corresponds to the local maximum of this curve section (Figure 1 right part). The vertical shear strength is the ratio of the max. force and the lateral surface area of the briquette (Equation (2)). Detailed information about the described measurement has been published in [20].

_{press}showed a clear dependence on both the formulation and moisture content.

_{lac}) positively correlates with $\rho $

_{press}. This observation is in good agreement to the tapped density of two raw materials. For Lac 200, the tapped density is 0.82 g cm

^{−3}[21] and the measured $\rho $

_{press}is 0.93 g cm

^{−3}(ratio

_{lac}100%). For MCC 101, the tapped density is 0.42 g cm

^{−3}[22] and the measured $\rho $

_{press}is 0.46 g cm

^{−3}(ratio

_{lac}0%). It could be assumed that the higher the tapped density of the raw material, the higher $\rho $

_{press}is. However, the tapped density is not exactly the same as $\rho $

_{press}. In both density measurements, particles are rearranged by externally applied forces (tapping or pressing). In the case of $\rho $

_{press}, the pressure can also lead to structural changes in particles due to breakage. Fractures due to applied pressure occur in brittle materials, such as lactose and mannitol. MCC, on the other hand, exhibits plastic deformation behavior and is not subject to fracture effects [23,24]. Thus, the differences between the tapped density and the measured $\rho $

_{press}of 11% for Lac 200 and 9% for MCC 101 exhibit the higher compressibility of Lac 200 to MCC 101, which is caused by breakage during compression whereby small fragments fill the inter-particulate pore’s space.

_{press}on $\omega $

_{wet}is shown in Figure 3. At a constant ratio

_{lac}, $\rho $

_{press}increases with increasing $\omega $

_{wet}, whereby a sigmoidal dependence can be recognized. After compressing the dry powder mixture, air-filled cavities are still present. These are filled with liquid when compressing moist granules, resulting in a higher $\rho $

_{press}. If all cavities are completely filled with liquid, $\rho $

_{press}cannot increase further but remains constant. Related to the states of the granules described in the introduction, the graph in Figure 3 represents the pendular state in the first exponential section up to 15% $\omega $

_{wet}. Here, intra-particulate pore spaces are initially filled with water, which only leads to minor changes in $\rho $

_{press}. At the transition from filling the intra-particulate pore spaces to filling inter-particulate pore spaces with liquid, the graph changes from the exponential section to the linear section. This section from 15% to 30% $\omega $

_{wet}represents the funicular state. The capillary state, where liquid saturation occurs, is described by the last section of the graph from 30% to 45% $\omega $

_{wet}. This sigmoidal progression of $\rho $

_{press}over $\omega $

_{wet}is similar to the change in power consumption with increasing moisture contents during granulation, as described by Leuenberger [7].

#### 3.2. Prediction for a Standard Placebo Formulation with Different Ratios of Lac 200 and MCC 101 and Various Moisture Contents

_{press}was found to show a correspondence with formulation compositions as well as with moisture content, the suitability of this alternative quality parameter should be verified by predicting the liquid requirement for further formulation compositions.

_{lac}, $\omega $

_{wet}and $\rho $

_{press}(p < 0.05).

^{2}, of 0.995 and a standard deviation of about 0.0178 g cm

^{−3}. The model is accurate, especially in the range of 0.95 g cm

^{−3}< $\rho $

_{press}< 1.35 g cm

^{−3}, corresponding to realistic values.

_{wet}), which shows good extrudability and spheronizability, a $\rho $

_{press}of 1.26 gcm

^{−3}was determined. Using Equation (3), we predicted the required ω

_{wet}for three different so-far untested formulations to obtain a ρ

_{press}of 1.26 g cm

^{−3}. Solving Equation (3) for ω

_{wet}yields three solutions, two of which are discarded because their values are outside the valid range of ω

_{wet}. For Lac:MCC ratios of 30:70, 55:45 and 72:28, the valid solutions for ω

_{wet}are 43.2%, 34.3% and 28.0%, respectively. The results of the experiments under predicted conditions are shown in Table 3.

_{press}of the three formulations resulting from the predicted water contents lie within the confidence interval of the prediction (Table 3). This indicates that the regression model is valid and that $\rho $

_{press}is suitable for predicting liquid requirements for binary formulations of Lac 200 and MCC 101.

#### 3.3. Proof of Concept for Standard Placebo Formulations

_{press}as an alternative measure of spheronizability, the processability of different formulations was assessed. For this purpose, the ω

_{wet}, required to obtain a ρ

_{press}of 1.26 g cm

^{−3}, was predicted (Equation (3)) for three further formulations. We also predicted the required ω

_{wet}for an over-wetted formulation at the upper limit of the valid range of Equation (3). Formulations and predicted ω

_{wet}for the desired ρ

_{press}are shown in Table 4.

_{press}of 1.26 g cm

^{−3}, the pellets are spherical and show a comparable average particle size (Figure 5). The slightly smaller size of the pellets with a higher MCC content is due to the behavior of the MCC, which tends to intrinsically round out [25]. In contrast, the pellets of the over-wetted formulation are spherical but show a much larger average particle size. This is due to coalescence, as over-wetted materials tend to uncontrolled agglomeration during spheronization, resulting in large pellets [3]. These results underscore that ρ

_{press}is suitable for assessing the quality of pellets.

#### 3.4. Applicability of ρ_{press} for Other Materials

_{press}is a suitable quality parameter for formulations as a function of ratio

_{lac}and ω

_{wet}, the applicability of the parameter to other placebo formulations should be investigated. It is noticeable that lactose monohydrate, lactose anhydrate and mannitol (raw materials A, Table 1) behave comparably with respect to the determined ρ

_{press}at the same proportion in the formulation and the same ω

_{wet}(Figure 6). This is in good agreement with the findings of Roberts and Rowe [26]. They stated that pure and water-free lactose, mannitol and also sucrose are materials with a medium yield pressure that are strain-rate dependent. This behaviour is indicative for moderately hard materials that plastically deform under loading. Only the ρ

_{press}of formulations with 60% material A at 30% ω

_{wet}show a differentiation between the material types. In detail, the anhydrous lactoses Lac H and Lac DCL 21 show the largest ρ

_{press}, and mannitol grades and lactose monohydrate grades have comparable ρ

_{press}. The similar compactibility behavior of formulations based on mannitol and lactose monohydrate is also visualized by the resulting surface of briquettes (Figure 7). However, as there is no significant difference between the ρ

_{press}of dry formulations with Lac 400 and Lac 70 (both for 60% and for 80% ratio

_{lac}), the former assumption that ρ

_{press}increases with an increasing tapped density of the raw materials must be put into perspective.

_{press}of dry formulations differ insofar as the ρ

_{press}for formulations with MCC 105 are distinctly lower than that of other formulations. This is caused by the very small particle size (the average particle size is 15 μm [27]) and the associated electrostatic effects, which decrease with water addition. However, this influence is minimized when water is added and the ρ

_{press}converge to the same value with increasing water content. For ω

_{wet}> 15%, the three VIVAPUR

^{®}products (MCC 101, MCC 102, and MCC 105) behave comparably with respect to the determined ρ

_{press}at the same proportion in the formulation. At contents of 20% and 40% and a ω

_{wet}≥ 22.5%, MCC MC-101 has a lower ρ

_{press}than the other celluloses tested. This difference could result from the different manufacturer. MCC MC-101 is spray-dried [28], whereas the other celluloses are air-stream-manufactured [22]. These oberservations agree with Kleinebudde [3], who summarized that the particle size of MCC has only a minor effect on the liquid requirement, whereas different manufacturers and material sources have a much greater influence. In addition, other studies already described that celluloses of the same grade exhibit differences in their physicochemical properties [22,29].

#### 3.5. Perspective for API Containing Formulations

_{press}could also be applied for API formulations. Again, we found that ρ

_{press}increases with increasing ω

_{wet}, independent of the evaluated API formulations (Figure 9). For the purpose of alignment, the area highlighted in gray shows the range between the measured values of the placebo formulation with Lac 200 and MCC 101 in a ratio of 60:40 (lower limit) and 80:20 (upper limit). The data of the ternary formulations lie in the highlighted area or slightly below. This shows that even with the use of APIs, the values of ρ

_{press}have a comparable order of magnitude. For a more accurate assessment, the API content in the formulation has to be increased in further trials and additional APIs have to be tested. This first insight nevertheless indicates the possibility of transferring the diagnostic ability of the ρ

_{press}measurement to ternary formulations with APIs.

#### 3.6. Proof of Concept for Other Materials

_{press}at 22.5% and 30% water content (Figure 6 and Figure 9) to calculate ω

_{wet}required to achieve a ρ

_{press}of 1.26 g cm

^{−3}. Formulations and the estimated values for ω

_{wet}for the desired ρ

_{press}are shown in Table 5.

_{press}of 1.26 g cm

^{−3}is a suitable indicator for the extrudability of the granules. In summary, a ρ

_{press}of 1.26 g cm

^{−3}can be regarded as a type of anchor for good extrudability, from which the fine adjustment of the moisture content and/or the equippment can be made depending on the desired pellet size.

## 4. Conclusions

_{press}of the granule mass was identified as an alternative parameter. This parameter showed a relation with formulation compositions as well as with moisture content. A regression model, based on this relation, was successfully used to predict liquid requirements for unknown formulation compositions. In addition, uniform pellets were produced by carrying out the multi-step manufacturing process of granulation, extrusion and spheronization with the predicted liquid requirements for different formulations. Since these results could verify the suitability of ρ

_{press}as an alternative quality parameter, the applicability of the parameter to other placebo formulations was demonstrated. Moreover, first experiments with API formulations suggested the applicability to industrially relevant formulations. In conclusion, the results indicate that once a ρ

_{press}is defined for an optimal formulation, changes in material batches and even material types could be compensated with the right amount of water. However, one remaining question is which material properties, in addition to the tapped density and the brittleness, influence ρ

_{press}or correlate with it. If defined material properties could be determined, ρ

_{press}would not have to be defined for an optimal formulation but could be determined generally for corresponding material properties. One remaining disadvantage of the presented method is that the optimal ρ

_{press}for ideal further processing depends on the process parameters of the further processing itself (such as the extruder die). Therefore, no generally valid statement can be made about an optimal ρ

_{press}; this must be individually adapted to the multi-step manufacturing process’ parameters used.

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Acknowledgments

## Conflicts of Interest

## Abbreviations

API | active pharmaceutical ingredient |

$\rho $_{press} | compression density |

ratio_{lac} | lactose ratio in the dry formulation |

$\omega $_{wet} | water content on wet basis |

## Appendix A

Lac 200 (%) | MCC 101 (%) | ω_{wet} (%) |
---|---|---|

0 | 100 | 0 |

40 | ||

45 | ||

50 | ||

55 | ||

60 | ||

20 | 80 | 0 |

35 | ||

40 | ||

45 | ||

50 | ||

55 | ||

40 | 60 | 0 |

30 | ||

33.75 | ||

37.5 | ||

41.25 | ||

45 | ||

60 | 40 | 0 |

25 | ||

28.75 | ||

32.5 | ||

36.25 | ||

40 | ||

80 | 20 | 0 |

15 | ||

18.75 | ||

22.5 | ||

26.25 | ||

30 | ||

100 | 0 | 0 |

2.5 | ||

6.25 | ||

10 | ||

13.75 | ||

17.5 |

Formulation | $\mathit{\omega}$_{wet} (%) | Residual Moisture (%) |
---|---|---|

80% Lac 200, 20% MCC 101 | 25.0 | 0.39 |

70% Lac 200, 30% MCC 101 | 28.7 | 0.79 |

60% Lac 200, 40% MCC 101 | 32.4 | 0.40 |

60% Lac 200, 40% MCC 101 | 35.9 | 0.10 |

60% Lac 400, 40% MCC 101 | 31.9 | 0.31 |

60% Lac DCL 21, 40% MCC 101 | 28.8 | 0.16 |

60% Man 50 C, 40% MCC 101 | 31.5 | 0.22 |

40% Paracetamol, 40% Lac 200, 20% MCC 101 | 28.7 | 0.10 |

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**Figure 1.**Measurement curve of the Powder Vertical Shear Test (formulation with 80:20 Lac 200:MCC 101 ratio and $\omega $

_{wet}15%), performed with the Texture Analyser TA.XTplus with the Powder Vertical Shear Rig. (

**Left**): Entire curve. (

**Right**): Curve section, resulting from the shearing process. Highlighted in gray: Area under the curve.

**Figure 2.**Area under the curve, max. force, shear strength and compression density ($\rho $

_{press}) versus $\omega $

_{wet}for formulations with 0%, 20%, 40%, 60%, 80% and 100% lactose ratio in the dry formulation (ratio

_{lac}).

**Figure 3.**$\rho $

_{press}versus $\omega $

_{wet}for a formulation with Lac 200 and MCC 101 in a ratio of 80:20. Granulation states are color annotated.

**Figure 4.**Pellets of the multi-step manufacturing process under predicted conditions. (

**a**) Lac:MCC ratio 80:20, $\omega $

_{wet}25.0%. (

**b**) Lac:MCC ratio 70:30, $\omega $

_{wet}28.7%. (

**c**) Lac:MCC ratio 60:40, $\omega $

_{wet}32.4%. (

**d**) Lac:MCC ratio 60:40, $\omega $

_{wet}35.9%.

**Figure 5.**Particle size of the pellets of the different formulations. (

**a**) Lac:MCC ratio 80:20, $\omega $

_{wet}25.0%. (

**b**) Lac:MCC ratio 70:30, $\omega $

_{wet}28.7%. (

**c**) Lac:MCC ratio 60:40, $\omega $

_{wet}32.4%. (

**d**) Lac:MCC ratio 60:40, $\omega $

_{wet}35.9%.

**Figure 6.**$\rho $

_{press}versus $\omega $

_{wet}for formulations with different raw material A according to 60% (

**left**) and 80% (

**right**) content.

**Figure 7.**Surfaces of the briquettes with 60% ratio

_{alac}and 30% ω

_{wet}. Left to right: (

**I**) Lac H and Lac DCL 21. (

**II**) Man and Man 50 C. (

**III**) Lac 70, Lac 200, Lac 200M and Lac 400.

**Figure 8.**$\rho $

_{press}versus $\omega $

_{wet}for formulations with different raw materials B according to 40% (

**left**) and 20% (

**right**) content.

**Figure 9.**$\rho $

_{press}versus $\omega $

_{wet}for ternary formulations with 40% API, 40% Lac 200 and 20% MCC 101. Highlighted in gray: range between the measured values of the binary formulation with Lac 200 and MCC 101 in a ratio of 60:40 (lower limit) and 80:20 (upper limit).

**Figure 10.**Pellets of the multi-step manufacturing process. (

**a**) Lac 400:MCC 101 ratio 60:40, $\omega $

_{wet}31.9%. (

**b**) Lac DCL 21:MCC 101 ratio 60:40, $\omega $

_{wet}28.8%. (

**c**) Man 50 C:MCC 101 ratio 60:40, $\omega $

_{wet}31.5%. (

**d**) Paracetamol:Lac 200:MCC 101 ratio 40:40:20, $\omega $

_{wet}28.7%.

Material | Type | Abbreviation | Company | |
---|---|---|---|---|

A | Lactose anhydrate | DuraLac^{®} H | Lac H | Meggle, Wasserburg, Germany |

Pharmatose^{®} DCL 21 | Lac DCL 21 | DMV International, Veghel, The Netherlands | ||

Lactose monohydrate | GranuLac^{®} 70 | Lac 70 | Meggle, Wasserburg, Germany | |

GranuLac^{®} 200 | Lac 200 | Meggle, Wasserburg, Germany | ||

Pharmatose^{®} 200M | Lac 200M | DFE Pharma, Goch, Germany | ||

SorboLac^{®} 400 | Lac 400 | Meggle, Wasserburg, Germany | ||

Mannitol | D(-)-Mannit | Man | Merck, Darmstadt, Germany | |

PEARLITOL^{®} 50 C | Man 50 C | Roquette Frères, Lestrem, France | ||

B | Microcrystalline cellulose | Microcel^{®} MC-101 | MCC MC-101 | Roquette Frères, Lestrem, France |

VIVAPUR^{®} 101 | MCC 101 | JRS Pharma, Rosenberg, Germany | ||

VIVAPUR^{®} 102 | MCC 102 | JRS Pharma, Rosenberg, Germany | ||

VIVAPUR^{®} 105 | MCC 105 | JRS Pharma, Rosenberg, Germany | ||

API | Active pharm. ingredient | Caffeine (pure) | Merck, Darmstadt, Germany | |

(2.0 μm ± 0.4 μm; n = 17) * | ||||

Ibuprofen 25 | BASF, Ludwigshafen, Germany | |||

(52.4 μm ± 25.9 μm; n = 17) | ||||

Ketoprofen | Hubei Xunda Pharmaceutical, Wuxue, China | |||

(2.8 μm ± 0.6 μm; n = 17) | ||||

Paracetamol | Merck, Darmstadt, Germany | |||

(19.5 μm ± 15.6 μm; n = 48) |

**Table 2.**Experimental procedure. Abbreviations and labeling can be found in Table 1.

Combination of Raw Materials | Raw Material Ratio | $\mathit{\omega}$_{wet} * |
---|---|---|

Lac 200:MC 101 ^{1} | 0:100–100:0 | see Table A1 |

Lac 200:MC 101 ^{2} | 80:20 | 0–45% |

A:MCC 101 | 80:20 and 60:40 | 0%, 15%, 22.5%, 30% |

Lac 200:B | 80:20 and 60:40 | 0%, 15%, 22.5%, 30% |

API:Lac 200:MCC 101 | 40:40:20 | 0%, 15%, 22.5%, 30% |

_{wet}is the water content on wet basis.

^{1}Formulation with 100% Lac 200: use of 180 g dry mass instead of 150 g.

^{2}Three batches; each batch n = 1.

**Table 3.**Obtained $\rho $

_{press}as means with corresponding standard deviations (SD) and confidence intervals of the experiments under predicted conditions.

Lac:MCC Ratio | $\mathit{\rho}$_{press} (g cm^{−3}) | ||
---|---|---|---|

Mean ($\mathit{n}=3$) | SD | 95%-Confidence Interval | |

30:70 | 1.262 | ±0.00393 | [1.252; 1.268] |

55:45 | 1.264 | ±0.00318 | [1.254; 1.266] |

72:28 | 1.253 | ±0.00130 | [1.253; 1.267] |

Formulation | Lac:MCC Ratio | Desired ρ_{press} (g cm^{−3}) | Predicted ω_{wet} (%) |
---|---|---|---|

(a) | 80:20 | 1.26 | 25.0 |

(b) | 70:30 | 1.26 | 28.7 |

(c) | 60:40 | 1.26 | 32.4 |

(d) | 60:40 | 1.34 | 35.9 |

**Table 5.**Estimated $\omega $

_{wet}to obtain a $\rho $

_{press}of 1.26 g cm

^{−3}for different formulations.

Formulation | Estimated $\mathit{\omega}$_{wet} (%) |
---|---|

(a) 60% Lac 400, 40% MCC 101 | 31.9 |

(b) 60% Lac DCL 21, 40% MCC 101 | 28.8 |

(c) 60% Man 50 C, 40% MCC 101 | 31.5 |

(d) 40% Paracetamol, 40% Lac 200, 20% MCC 101 | 28.7 |

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**MDPI and ACS Style**

Ramm, S.; Fulek, R.; Eberle, V.A.; Kiera, C.; Odefey, U.; Pein-Hackelbusch, M.
Compression Density as an Alternative to Identify an Optimal Moisture Content for High Shear Wet Granulation as an Initial Step for Spheronisation. *Pharmaceutics* **2022**, *14*, 2303.
https://doi.org/10.3390/pharmaceutics14112303

**AMA Style**

Ramm S, Fulek R, Eberle VA, Kiera C, Odefey U, Pein-Hackelbusch M.
Compression Density as an Alternative to Identify an Optimal Moisture Content for High Shear Wet Granulation as an Initial Step for Spheronisation. *Pharmaceutics*. 2022; 14(11):2303.
https://doi.org/10.3390/pharmaceutics14112303

**Chicago/Turabian Style**

Ramm, Selina, Ruwen Fulek, Veronika Anna Eberle, Christian Kiera, Ulrich Odefey, and Miriam Pein-Hackelbusch.
2022. "Compression Density as an Alternative to Identify an Optimal Moisture Content for High Shear Wet Granulation as an Initial Step for Spheronisation" *Pharmaceutics* 14, no. 11: 2303.
https://doi.org/10.3390/pharmaceutics14112303