Microcrystalline Cellulose (MCC) is made from wood pulp. It is used in pharmaceutical formulations as excipients. MCC can be pelletized as forms inert highly spherical starter beads (such as CELLETS®).

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nutritional table for CELLETS®

A nutritional table for CELLETS®

A nutritional table for CELLETS®, what is it about? CELLETS® are made of 100% microcrystalline cellulose (MCC), developed for state of the art oral dosage forms, such as MUPS, capsules, sachets, stick pack units. Anyway, some pharmaceutical applications move towards food products and vice versa. This field of nutraceutical applications are extending market share and we got more frequently asked about energy and nutritional levels of MCC. So, let’s shed some light on this.

MCC is a modified form of cellulose that is often used as a filler and stabilizer in the food and pharmaceutical industries. It consists of plant fibers and serves primarily as a dietary fiber, but contains practically no usable nutrients such as vitamins, minerals, proteins or fats. It is calorie-free as it is not digested in the human body.
As microcrystalline cellulose is not metabolized, it does not provide any usable macro- or micronutrients. A nutritional table for 100 g of microcrystalline cellulose would therefore look like this:

Substance quantity per 100 g
Energy 0 kcal
Protein 0 g
Fat 0 g
Carbohydrates 0 g
Dietary fiber 100 g
Sugar 0 g
Salt 0 g
Vitamins & minerals 0 mg

Microcrystalline cellulose is a pure dietary fiber with no nutritional value and is not broken down or absorbed in the human digestive tract [1]. It therefore has no calories and provides no nutrients to the body. This nutritional table also holds for CELLETS® but has rare importance in pharmaceutical formulations.

References

[1] N. Prabsangob, NFS Journal, 31 (2023) 39-49. doi:10.1016/j.nfs.2023.03.002

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fig-3_Plasticity of Microcrystalline Cellulose Spheres
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The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer

Abstract

Compaction pressure can induce an undesirable solid-state polymorphic transition in drugs, fragmentation, loss of coated pellet integrity, and the decreased viability and vitality of microorganisms. Thus, the excipients with increased plasticity can be considered as an option to decrease the undesirable effects of compaction pressure. This study aims to increase the plasticity (to reduce the mean yield pressure; Py) of dried microcrystalline cellulose (MCC) by loading it with a specially selected plasticizer. Diethyl citrate (DEC), water, and glycerol were the considered plasticizers. Computation of solubility parameters was used to predict the miscibility of MCC with plasticizers (possible plasticization effect). Plasticizer-loaded MCC spheres with 5.0 wt.% of water, 5.2 wt.% of DEC, and 4.2 wt.% glycerol were obtained via the solvent method, followed by solvent evaporation. Plasticizer-loaded formulations were characterised by TGA, DSC, pXRD, FTIR, pressure-displacement profiles, and in-die Heckel plots. Py was derived from the in-die Heckel analysis and was used as a plasticity parameter. In comparison with non-plasticized MCC (Py = 136.5 MPa), the plasticity of plasticizer-loaded formulations increased (and Py decreased) from DEC (124.7 MPa) to water (106.6 MPa) and glycerol (99.9 MPa), and that was in full accordance with the predicted miscibility likeliness order based on solubility parameters. Therefore, water and glycerol were able to decrease the Py of non-plasticized MCC spheres by 16.3 and 30.0%, respectively. This feasibility study showed the possibility of modifying the plasticity of MCC by loading it with a specially selected plasticizer.

References to “The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer”

Authors: Artūrs Paulausks, Tetiana Kolisnyk and Valentyn Mohylyuk

First published: Pharmaceutics 2024, 16(7), 945; https://doi.org/10.3390/pharmaceutics16070945

1. Introduction

Being non-invasive and, in most cases, not requiring medical assistance, tablets for oral administration are the most widespread and the most popular pharmaceutical and nutraceutical dosage forms. Despite the rising topic of individualised/personalised medicine, including individualised dosing, drug release, and customer properties, national healthcare systems worldwide are highly dependent on the mass-market production of tablets and their usage following treatment protocols.
In the vast majority of cases, pharmaceutical substances cannot be converted into tablets via tableting with high-speed rotary tablet presses [1]. To achieve the desirable mechanical and biopharmaceutical properties, specific excipients are required. Appropriate mechanical properties, such as tablet hardness (or tensile strength) and abrasion resistance (friability) should ensure tablet applicability to transportation, coating, and packaging processes without losing their appearance, dose, and biopharmaceutical properties. Moreover, the intrinsic properties of tablet excipients and the structural-mechanical properties of the tablets formed eventually affect the disintegration and drug release behaviour of the dosage form, and so, can be deliberately selected to achieve the desired release profile [2].
Upon tableting, the compaction pressure and tableting speed (dwell time) induce elastic and plastic deformation, or fragmentation, and affect the extent of these deformations [3]. The tableting cycle can be described with a force–displacement profile: the distance between punches, which is plotted against the compaction pressure or force. This can be determined with state-of-the-art equipment, such as compaction simulators containing hi-tech sensors and sophisticated user-friendly software [4,5].
fig-1_Plasticity of Microcrystalline Cellulose Spheres

Figure 1. An example of a force-displacement profile highlighting: the rearrangement energy (E1), plastic energy (E2 + E4), elastic energy (E3; or energy lost), plastic flow energy (E4), compaction energy (E1 + E2 + E3), and mean yield pressure (Py). The arrows on the curve are showing the direction of curve development.

Considering the true density of the material, an in-die Heckel plot can be built: ln(1/porosity) is plotted against the compaction pressure. The greater the slope of the linear region (K), the greater the degree of plasticity of the material [6]. The mean yield pressure (Py) of the solid is reciprocal to K [7] and describes the point after which the deformation is irreversible (pointed out in Figure 1). It should be stressed that the mean yield pressure from the in-die Heckel analysis can be used as a reliable plasticity parameter: the lower the Py, the greater the degree of plasticity of the material [8].
Possessing information about the Py of each ingredient in the blend allows predicting the sequence of the events of the material irreversible deformations upon tableting cycle. Consequently, the targeted composition of a tableting blend based on excipients’ Py can predetermine the deformation (the extent of deformation) of the specific ingredients in this blend upon tableting at a specific compaction pressure [9]. Considering the possibility of undesirable solid-state polymorphic transition of the drug [10,11], particle fragmentation, the loss of coated pellet integrity [12,13], and the decreased viability and vitality of microorganisms [14,15] as a function of compaction pressure, the above-mentioned circumstances are of particular interest.
Microcrystalline cellulose (MCC) is a partially depolymerised, naturally occurring polymer in the form of crystalline powder or spheroids composed of porous particles [16], and it is one of the most commonly used excipients in tablet formulations [17]. MCC is used for direct compression (up to 90 wt.%), dried granulation/roll-compaction, and wet granulation to achieve tablets with desirable mechanical and biopharmaceutical properties [3,10,16]. MCC is recognised as an excipient with relatively low Py that undergoes plastic deformation at relatively low compression forces [3].
The effect of water on the plasticization of the MCC as well as its effect on the compaction properties upon tableting has been previously reported [18,19,20]. To the best of our knowledge, the information regarding MCC plasticization with other solvents or excipients in order to influence the compaction properties upon tableting is lacking. Nevertheless, the practice of modulating cellulose derivatives plasticity for film forming [21,22], hot-melt extrusion, and/or fusion deposition modelling 3D-printing [23,24] is common practice. While solubility parameters were found to be a useful instrument for plasticizer pre-screening [24,25].
This study aims to increase the plasticity (to reduce the Py) of MCC by loading it with a specially selected (based on the solubility parameters) plasticizer. It was assumed that a lower Py of the MCC could enable tablets to be prepared at lower compaction pressure and decrease the undesirable effect of compaction pressure.

2. Materials and Methods

2.1. Materials

CELLETS® 500 MCC cores (lot# 21E1034; IPC Process-Center GmbH & Co KG, Grunaer Weg, Germany) were used as the starting cores. The rest of the chemicals used for the experiment, such as diethyl citrate (DEC), glycerol, and methanol were of Pharmacopeia grade and used as received.

2.2. Theoretical Solubility Parameter Computation

The drug–polymer miscibility was assessed theoretically via calculations of Hansen solubility parameters (HSPs) via the group contributions methodology. Thus, the energies of dispersion forces (Ed), polar forces (Ep), and hydrogen bonding (Eh) gave the dispersion (δd), polar (δp), and hydrogen bonding (δh) partial solubility parameters, respectively [26,27].
All calculations were performed using the Hansen Solubility Parameters in Practice (HSPiP) software (5th edition, version 5.1.03). In this study, we calculated HSPs for cellulose and DEC, while HSPs for water and glycerol were taken from the software database. It should be noted that the HSPiP database includes three sets of HSPs for water: one of them is derived from the energy of vaporisation of water at 25 °C and relates to a single molecule, whereas the other two relate to six-molecule associates which are more typical for water in a liquid state [28]. In this regard, the set of HSPs for water as associated units (based on a correlation of total miscibility with certain solvents) were used in this study.
HSPs for cellulose and DEC were calculated using the following HSPiP software DIY methods: the Yamamoto-molecular break (Y-MB), in which the components were input as simplified molecular input line entry syntax (SMILES) codes; the Van Krevelen method where the components were entered by accounting for chemical constituents and taking molar volumes from Y-MB calculations; and the Hoy method with similar input procedure as the latter one. Finally, the average HSP values within all three methods were determined.
The assessment of MCC–plasticizer miscibility was accomplished by comparing HSPs calculated according to three approaches that are based on the principle ‘like dissolves like’ [29].

The approach authored by Van Krevelen and Hoftyzer estimates a high likelihood of successful mixing of two substances if the parameter ΔδT (Equation (1)) is not more than 5 MPa0.5, while complete immiscibility occurs when ΔδT exceeds 10 MPa0.5 [30,31].

ΔδT = ((δd1 − δd2)2 + (δp1 − δp2)2 + (δh1 − δh2)2)0.5

By Bagley’s approach, the drug–polymer miscibility is evaluated using the combined solubility parameter δv (Equation (2)).

δv = (δd2 + δp2)0.5

The probability of miscibility is concluded if the distance between two points in the two-dimensional plot is D12 ≤ 5.0 (Equation (3)) [31].

D12 = ((δv1 − δv2)2 + (δh1 − δh2)2)0.5

The approach by Greenhalgh evaluates the miscibility as the absolute difference Δδt (Equation (4)) between the total solubility parameters δt which are calculated from Equation (5).

Δδt = |δt1 − δt2|
δt = (δd2 + δp2 + δh2)0.5
According to the latter approach, drug–polymer miscibility was assumed to be likely if Δδt ≤ 7, while Δδt ≥ 10 MPa0.5 indicated immiscibility [27].

2.3. Plasticizer Loading onto MCC Cores Using Solvent Evaporation Method

To obtain glycerol- and DEC-loaded MCC spheres, the initial MCC spheres were dried in a vacuum oven, and their water content after drying was confirmed by Karl-Fisher (V10S; Mettler-Toledo GmbH, Greifensee, Switzerland) titration at the level of 0.1 wt.%. Two batches of plasticizer-loaded MCC spheres were made, one with DEC, using methanol as a solvent, and another with glycerol, using water as a solvent (Table 1).
table-1

Table 1. Used amounts of plasticizer and solvent for the plasticizer loading procedure.

About 150 g of MCC was weighed in a 500 mL round-bottom flask. Afterwards, the amount of solvent was calculated using the MCC/solvent ratio obtained from the MCC solvent absorption test. The excess solvent amount (that which could be absorbed and adsorbed by the MCC sphere) was used. The appropriate amount of plasticizer to achieve 5% loading was dissolved in the solvent. The plasticizer solution was added to MCC in a round-bottom flask (total volume of about 250 mL) and shaken vigorously by hand. The solvent was removed by a rotary evaporator (RV3 eco, from IKA-Werke GmbH & Co. KG, Staufen, Germany) at 50 °C under a pressure of 100 mbar. After that, each sample was additionally dried with dry air (50 m3/h) in a fluid-bed drier (Mini-Glatt; Glatt GmbH, Binzen, Germany) at 50 °C until constant outlet air temperature.

2.4. Thermogravimetric Analysis (TGA)

The thermal behaviour of the samples was examined using Thermal Advantage Q50 TGA (TA Instruments, New Castle, DE, USA). The samples (5–10 mg) were heated in an open aluminium pan at a heating rate of 5 °C/min or 50 °C/min from room temperature to 350 °C. Nitrogen was used as a purge gas at a flow rate of 50 mL/min for all TGA experiments. The weight remaining (%) was plotted as a function of temperature (°C). The weight loss (dM) between starting/room temperature (RT) and 200 ℃ (RT-200 °C) and temperature onset of degradation (Td onset) were determined for each formulation. Data was processed with a Universal V4.5A software (TA Instruments, USA) [32].

2.5. Differential Scanning Calorimetry (DSC)

To investigate the thermal properties of the sample before and after processing, a heat-flux DSC (DSC Q20; TA Instruments, USA) was conducted to characterise thermal behaviour. For measurement, the samples were weighed (5–8 mg) into aluminium DSC pans and heated from −10 °C to 390 °C at 50 °C/min with a continuous purge of nitrogen gas at 50 mL/min. Melting temperature onset (Tm onset), melting peak temperature (Tm peak), and melting enthalpy were determined for each formulation. The data were processed with Universal V4.5A software (TA Instruments, USA) [10].

2.6. Powder X-ray Diffraction (pXRD) Analysis

The study was conducted on a diffractometer (RigakuTM Miniflex 600 C; Rigaku Co., Tokyo, Japan) in θ/2θ geometry at ambient temperature using CuKα X-radiation (λ = 1.54182 Å) at 40 kV and 15 mA power. X-ray diffraction patterns were collected over the 2θ range of 3–60° at a 5°/min scan rate. The ground sample was applied to the low-background silicone sample holder.

2.7. Fourier-Transform Infrared (FTIR) Attenuated Total Reflectance (ATR) Spectroscopy

FTIR-ATR study of the samples was performed on a FTIR Spectrometer (Nicolete IS20, Thermo Scientific, Karlsruhe, Germany) using a diamond prism by scanning from 4000 to 400 cm−1, with 2.0 cm−1 resolution and 100 scans per spectrum (the background was taken before each sample). Every graphically represented FTIR-profile was obtained by averaging 3 spectra.

2.8. Scanning Electron Microscopy (SEM) and Particle Size Distribution Analysis

SEM pictures were captured with a microscope (TM3030; Hitachi High-Tech Corp., Tokyo, Japan) in a vacuumed environment at 15 kV to obtain information about morphology on a microscopic level. The particle size distribution (D10%, D50%, and D90%) of the MCC spheres was determined using image analysis coupled with a VIBRI feeder and a RODOS disperser (series QICPIC/L02; Sympatec GmbH, Clausthal-Zellerfeld, Germany).

2.9. Preparation of Tablets

The samples (Table 2) were tableted with 11.28 mm flat punches to obtain a target mass of 500 mg using the compaction simulator STYL’One Nano (Medelpharm, Beynost, France/Korsch, Berlin, Germany). Compression cycles of a small rotary press with a turret diameter of 180 mm, a precompression roll diameter of 44 mm, an angle between rollers of 65 degrees, a compression roll diameter of 160 mm, an angle between main compression and the beginning of the compression ramp of 60 degrees, an angle of the ejection ramp of 20 degrees at a tableting speed of 70 rpm (maximum for STYL’One Nano), a precompression and compression forces of 5 and 30 kN (equivalent of 50 and 300 MPa) were used [9].
table-2

Table 2. Formulations for tableting.

2.10. The Theoretical True Density Calculation

The theoretical true density of tablet composition was calculated based on the pycnometric density (ρt) of MCC (1.586 g/cm3) [16,33], glycerol (1.262 g/cm3) [34], DEC (1.287 g/cm3) [35], and their shares (x, w/w) using the additive methodology and the following equation [1]:

𝜌𝑡=(𝜌𝑀𝐶𝐶×𝑥𝑀𝐶𝐶)+(𝜌𝑒𝑥𝑐×𝑥𝑒𝑥𝑐)ρt=ρMCC×xMCC+ρexc×xexc

2.11. In-Die Heckel Plot Construction

The relative density (ln(1/ε)) was calculated automatically with Alix software ver. 20220711 (Medelpharm, Beynost, France) [4]. The relative density and compaction pressure (P, MPa) data were plotted by the Heckel relationship [6]:

𝑙𝑛(1/𝜀)=𝐾×𝑃+𝑙𝑛(1/𝜀0)=𝐾×𝑃+𝐴ln⁡(1/ε)=K×P+ln⁡1/ε0=K×P+A

where: K is the slope of the linear region (the proportionality constant), and ln(1/ε0) is a constant, A, that represents the intercept/ degree of packing (at porosity ε0) achieved at low pressure because of the rearrangement process before an appreciable amount of interparticle bonding takes place. The mean yield pressure (Py, MPa) was calculated in accordance with Hersey and Rees by the equation [3,7,36]:

𝑃𝑦=1𝐾Py=1K
The mean yield pressure was measured (n = 10 for each formulation) in the pressure range between 70 and 210 MPa. A one-way ANOVA (analysis of variance) test was used to compare the means of two groups using the built-in possibilities of the current version of Excel (Microsoft 365; Redmond, Washington, DC, USA; Supplementary Materials).

3. Results and Discussion

MCC is manufactured by hydrolysis with dilute mineral acid solutions of α-cellulose sourced from raw plant material. After hydrolysis, the hydrocellulose is filtered, and the aqueous slurry is spray-dried. Thus, the MCC as an excipient contains up to 7 wt.% of moisture in accordance with pharmacopoeia (JP, PhEur, and USP) [16]. Theoretical solubility parameters were used to obtain three values (ΔδT, D12, and Δδt) to assess the possible miscibility of cellulose with water, glycerol, and DEC (Table 3, Figure 2).
fig-2_Plasticity of Microcrystalline Cellulose Spheres

Figure 2. Evaluation of MCC–plasticizer miscibility using averaged solubility parameters: 3D approach authored by Hoftyzer and Van Krevelen (a), 2D Bagley’s plot (b), and 1D bar graph according to Greenhalgh (c).

table-3

Table 3. Hansen solubility parameter calculations.

According to values averaged from the Y-MB, VK, and Hoy methods, the possible miscibility of all three plasticizers (below the proposed threshold; Table 2) was predicted only by Greenhalgh’s approach (based on Δδt calculation) which showed the following miscibility likeliness order: water > glycerol > DEC. At the same time, the other two approaches authored by Van Krevelen and Bagley, respectively, indicated that possible miscibility fell into an ambiguous region between 5 and 10 MPa0.5 for all studied plasticizers; however, the same likeliness order (glycerol > water > DEC) was established for both of them.
Therefore, the batch of dried non-plasticized (Figure 3) and three batches of glycerol-, water-, and DEC-loaded MCC spheres were used. Plasticizer-loaded MCC spheres contained 5.0 wt.% of water, 4.2 wt.% of glycerol, and 5.2 wt.% of DEC (Table 4, Figure 4).
fig-3_Plasticity of Microcrystalline Cellulose Spheres

Figure 3. SEM of MCC spheres (D10% = 563 µm, D50% = 651 µm, and D90% = 696 µm).

fig-4_Plasticity of Microcrystalline Cellulose Spheres

Figure 4. FTIR spectrum of dried and loaded MCC spheres in the range of 4000–500 cm−1.

table-4

Table 4. The summary of thermal properties determined by TGA and DSC.

The dried and plasticizer-loaded MCC-spheres were investigated with FTIR spectroscopy (Figure 4). All obtained FTIR spectra showed the characteristic vibration peaks of cellulose [37,38,39,40,41,42]:
  • The broad peak at 3333 cm−1 which is assigned to O–H stretching vibrations of the intermolecularly bonded hydroxyl group;
  • The peak at 2891 cm−1 that corresponds to C–H stretching vibrations;
  • The peak at 1645 cm−1 which is indicative of the O–H bending of bound water;
  • The multiple absorbance bands (peaks at 1428, 1368, 1334, and 1316 cm−1) assigned to the bending and stretching vibrations of C–H and C–O bonds;
  • The peaks at 1202, 1052, and 1021 cm−1 are assigned to the elongation of C-O bonds;
  • The peaks at 1158 and 897 cm−1 are due to the C–O–C stretching vibrations at the β-glycosidic linkage.
No evident differences were observed in the spectrum of water-plasticized MCC spheres compared to the dried non-plasticized sample. This could be explained by the remaining bound water in all samples even after drying (as evidenced by the persistence of the peak at 1645 cm−1 in all obtained spectra [37,41,42]. Nonetheless, some changes were established for MCC spheres treated with DEC and glycerol. Both these plasticizers led to the manifestation of the peak at ~1104 cm−1, which could be related to the stretching vibrations of the C–O bond in the ester group of DEC and the secondary alcohol group of glycerol [43,44,45]. In addition, the spectrum of DEC-loaded MCC spheres demonstrated the most explicit deviation from that of the dried MCC spheres that manifested as a peak at 1731 cm−1 which was absent in the spectra of all other three samples. This peak could be assigned to the C=O stretching of the ester functional group [43]. Therefore, it can be suggested that treatment of MCC spheres with DEC and glycerol resulted in intermolecular hydrogen bonding between hydroxyl groups of cellulose (hydrogen donor) and mentioned functional groups of these plasticizers (hydrogen acceptors), and thus, at the molecular level, the plasticization could be caused by a weakening of intermolecular hydrogen bonds between adjacent cellulose chains [46]. It is interesting to note that it was the secondary alcohol hydroxy group of glycerol (at 1103 cm−1), and not the primary ones (at ~1030 cm−1) [45], that appeared in the spectrum of the glycerol-loaded MCC. As a rule, glycerol primary hydroxy groups are more reactive, and because of that, they are more likely to be involved in homo-intermolecular hydrogen bonding (i.e., glycerol–glycerol). With loading into MCC spheres, hetero-intermolecular hydrogen bonding occurred, i.e., cellulose–glycerol, which apparently was mostly contributed by the secondary alcohol hydroxy group of glycerol, while the homo-glycerol hydrogen bonding network could be preserved. Analogue findings were demonstrated in the study of the glycerol–choline eutectic mixture, which was found to have homo-molecular glycerol hydrogen bonding network similar to that in pure glycerol, whereas choline bonds were at the interstitial voids of the glycerol network [47].
pXRD is a complementary technique to DSC and was used in assessing the presence of crystalline content in formulations. Thus, the pXRD profiles of dried and plasticizer-loaded MCC spheres were investigated. The diffraction patterns of all samples confirmed the crystalline nature of each sample with the same characteristic peaks (Figure 5). The characteristic MCC peaks were also shown to be similar to that reported in the literature [48]. Unfortunately, the pXRD method was reported to have relatively low sensitivity and a limit of detectability (LoD) of 5% [49,50]. Thus, considering the plasticizer load (approx. 5%), the pXRD profiles obtained can be considered similar (with approximately the same level of crystallinity).
fig-5_Plasticity of Microcrystalline Cellulose Spheres

Figure 5. pXRD diffractograms of dried and loaded MCC spheres.

At a 5 °C/min heating rate, the onset of degradation temperature (Td onset) increased from water to DEC and glycerol (from 297.4 to 303.2 and 309.2 °C, respectively; Table 4, Figure 3). Melting of the MCC (DSC-curves) was observed upon its degradation (TGA-curve; Table 4, Figure 4). The increase in heating rate up to 50 °C/min made it possible to increase the Td onset for water-loaded MCC up to 345.7 °C and compare the melting onset temperatures (Tm onset) for MCC loaded with plasticizers. The part of the DSC curve that described melting demonstrated a two-step shape and was characterized by two Tm onsets. The increase in Tm onset 1 and Tm onset 2 was in the same sequence and increased from water to DEC and glycerol: 291.9, 305.7, 315.8 °C for Tm onset 1 and 325.6, 332.4, 335.6 °C for Tm onset 2, respectively (Table 4, Figure 6).
fig-6_Plasticity of Microcrystalline Cellulose Spheres

Figure 6. Weight loss as a function of temperature for loaded MCC spheres (TGA at 5 °C/min).

In this study, the Tm onset 1 and 2 (for water- and DEC-loaded samples) was associated with the thermal degradation of MCC [51]. That can be observed by comparing the first derivative of weight loss and respective Tm onset on the DSC profile of water-loaded MCC spheres (Figure 7). The increase in apparent melting peak temperature (Tm) and apparent melting enthalpy can be explained with the increase in Td from water to DEC and glycerol. Therefore, the thermal analysis did not provide us with insights regarding the plasticization of MCC with selected plasticizers.
fig-7_Plasticity of Microcrystalline Cellulose Spheres

Figure 7. Heat flow as function of temperature for loaded MCC spheres (DSC at 50 °C/min; left Y-axis); the first derivative of weight loss as a function of temperature for water-loaded MCC spheres (TGA at 50 °C/min; right Y-axis).

Tableting of plasticizer-loaded MCC spheres with a compaction simulator was illustrated with pressure-displacement profiles (Figure 8a; exemplified with glycerol-loaded MCC spheres), which were converted to in-die Heckel plots (Figure 8b).

fig-8_Plasticity of Microcrystalline Cellulose Spheres

Figure 8. In-die Heckel plot (a) and pressure-displacement profile (b) for MCC spheres (CELLETS® 500) loaded with glycerol.

The mean yield pressure (Py) of non-plasticized MCC was found at the level of 136.5 ± 6.9 MPa (Av. ± S.D.). Despite the sequence of Tm onsets, the mean yield pressure of plasticizer-loaded MCC spheres decreased from DEC (124.7 ± 9.2 MPa) to water (106.6 ± 10.0 MPa) and glycerol (99.9 ± 1.9 MPa; Figure 9, Table 5). That coincided with the miscibility likelihood order based on the HSP calculations. Therefore DEC, water, and glycerol were able to decrease the Py of non-plasticized MCC spheres by 4.7, 16.3, and 38.9%, respectively.

fig-9_Plasticity of Microcrystalline Cellulose Spheres

Figure 9. Comparison of non-plasticized (dried) with plasticized MCC spheres (Cellets® 500) in terms of Py (a plasticity parameter).

table-5

Table 5. Py data statistics.

Interestingly, despite FTIR revealing more hydrogen binding sites in the case of treatment with DEC (i.e., both C–O and C=O bonds of the ester functional group), glycerol with only one binding site (C–O bond of the alcohol group) was superior in its plasticizing ability, implying that MCC–glycerol hydrogen bonding was more efficient. This could be explained from the viewpoint of molecular weights of glycerol and DEC (92.09 and 248.23 g/mol, respectively). Considering an equal mass loading of both plasticizers (7.88 g), the loading of glycerol was 2.5 times higher in terms of molarity; therefore, more molecules of plasticizer were involved and, accordingly, more hydrogen bonds with cellulose could be formed in the case of glycerol. This follows the general logic that the smaller the molecule weight, the greater the plasticization effect of the plasticizer upon the polymer matrix [52]; however, the strength of intermolecular interactions should also be considered.
Water, as an MCC plasticizer, showed a relatively high ability to decrease Py (increase plasticity). The results obtained highlight the importance of water content in the raw MCC material. Changing the MCC plasticity by 16.3% (at 5 wt.%) significantly changed the mechanical properties. Thus, the fluctuation of moisture content in the MCC (even in the eligible pharmacopeial range) can be the reason for the variability of mechanical properties in complex tablet formulations [53]. Considering moisture as one of the most important factors in pharmaceutical tablets’ shelf-life, narrow specification of moisture content in MCC during the product development stage can be recommended.

4. Conclusions

This study showed the possibility of increasing the plasticity of MCC by loading it with a deliberately chosen plasticizer. The computational approaches based on solubility parameters were found to be useful in predicting the plasticizing efficacy. Based on FTIR findings, it is suggested that plasticization resulted from intermolecular hydrogen bonding between the plasticizers and cellulose molecules that caused the weakening of hydrogen bonds between adjacent cellulose chains. At the plasticizer load used (approx. 5 wt.%), neither pXRD nor DSC gave any insights on the plasticization of MCC with selected plasticizers. Because of the relatively high plasticization ability of water towards cellulose and thus potential changes in MCC mechanical properties, narrow specification of moisture content in MCC during the product development stage can be recommended.

Additonal information on: Plasticity of Microcrystalline Cellulose Spheres

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pharmaceutics16070945/s1, Table S1. Raw values of Py; Statistical analysis: One-Way ANOVA (α = 0.05).

Author Contributions

Methodology, formal analysis, investigation, data curation: V.M. and A.P.; visualization, writing—original draft preparation, writing—review and editing: A.P., T.K. and V.M.; conceptualization and supervision: V.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

We would like to acknowledge the following people and their organisations for support of this project with pharmaceutical excipients. Business development manager Bastian Arlt (Glatt Pharmaceutical Services GmbH & Co. KG, Binzen, Germany) and head of business unit pharma Mandy Rehländer (HARKE Pharma GmbH, Mülheim an der Ruhr, Germany) for providing the CELLETS® 500-grade MCC spheres. We want to thank our colleagues Kirils Kukuls and Zoltán Márk Horváth for the data obtained with the compaction simulator and the improvement of the written English of this work, respectively. The author Tetiana Kolisnyk expresses a deep gratitude to the British Academy and Council for At-Risk Academics (UK) for the general and financial support in the frame of the Researchers-At-Risk program.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Lisence

The article “The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer” is published under Creative Common CC BY license. Any part of the article may be reused without permission provided that the original article is clearly cited. Reuse of an article does not imply endorsement by the authors or MDPI.

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CS_sphericity_image_1
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Sphericity and size distribution of µm-sized microcrystalline pellets

Abstract

Microcrystalline Cellulose (MCC) pellets represent a chemically inert class of active pharmaceutical ingredients (API) carriers. A narrow particle size distribution (PSD) maximizes control over content uniformity. In this case study, we will focus on measuring the particle size distribution and on sphericity.

Pellets for oral drug forms

MCC pellets are used as starter beads for API loading. Low or high drug dose loading is technically feasible. These pellets are made of pure MCC and provide a robust platform for delivery of one or multiple APIs. Certain processing technologies for pellet coating allow these starter beads to be compatible with soluble or insoluble APIs, e.g. by Wurster bottom spray [1,2] or Rotor dry powder layering technology [3]. Coated pellets can be filled into capsules, or compacted into multiple-unit pellet system (MUPS) tablets [4], where a tight PSD maximizes control over content uniformity.

Particle size distribution maximizes the control over content uniformity in applications of complex oral dosing forms. Speaking about uniform or monodisperse particles, these information always point to general information of the particular system, not of the individual particle itself. Therefore, PSD is a globular measure allowing simple, easy and fast analysis of the particulate matter. Major key information from a PSD measure are the so called D-values. A Dx value represents a dimension, where a ratio of X particles is smaller. For reasons of simplicity weighted functions, such as number, radius or volume, are not. Extending these metrics to D10 and D90 additionally informs about the width of the entire size distribution (Figure 1).

CS_sphericity_image_1

Particle size distribution of two different particle systems with identical median dimension D50. Blue: wide PSD, green: narrow PSD. Dotted lines are guides to the eyes.

Figure 1: Particle size distribution of two different particle systems with identical median dimension D50. Blue: wide PSD, green: narrow PSD. Dotted lines are guides to the eyes.

Dimensions of pellets

In this study, imaging technology (Horiba, Camsizer) was employed for the size analysis. Representatively, more than 50 charges of Cellets® 100 and Cellets® 500  (Figures 2-3) have been analyzed for the D10, D50 and D90 values.

CS_sphericity_image_2

D10 (red), D50 (green) and D90 (blue) value for several Cellets® 100 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 10 %.

Figure 2: D­10 (red), D50 (green) and D90 (blue) value for several Cellets® 100 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 10 %.

CS_sphericity_image_3

D10 (red), D50 (green) and D90 (blue) value for several Cellets® 500 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 4 %.

Figure 3: D10 (red), D50 (green) and D90 (blue) value for several Cellets® 500 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 4 %.

The results show only slight variations in the PSD between the charges. The standard deviation is smaller than 4 % (Cellets® 500) and smaller than 10 % (Cellets® 100) which confirms a high reproducibility in production (Table 1). Both values are remarkably good for technical spheres. Furthermore, none of the charges was out of specifications and fit into the desired size distribution between 500 µm and 710 µm easily. The close gap between D­10 and D90 clearly identify an excellent monodispersity.

Standard deviation Cellets 100 Cellets 500
of D­10 8.28 % 3.97 %
of D50 7.12 % 3.52 %
of D90 4.68 % 3.11 %

Table 1: Standard deviation for D­10, D­50 and D­90 values Cellets® 100 and Cellets® 500 charges.

CS_sphericity_image_4

Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.

Figure 4: Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.

Perfect sphericity? – Yes!

For a more detailed shape analysis, electron microscopy yield perfect imaging data of the MCC pellets’ surfaces (Figure 4). Additionally, MCC pellets have a distinguishing friability.

Summary

Microcrystalline Cellulose (MCC) pellets show excellent chemically inertness, high degree of sphericity, narrow size distribution and high reproducibility in production. These properties make Cellets® becoming one of the first choice for inert API carriers. We have proven these excellent properties for Cellets® 100 and Cellets® 500. The obtained results are representative for other size classes ranging from 100 µm to 1400 µm.

Acknowledgement

We acknowledge IPC Process-Center (Dresden, Germany) for the analytics, and Fraunhofer IFAM (Dresden, Germany) for recording the electron microscopic pictures.

References

[1] H. R. Norouzi, International Journal of Pharmaceutics, Volume 590 (2020) 119931

[2] D. Jones, Developing Solid Oral Dosage Forms, Pharmaceutical Theory And Practice (2009) 807-825

[3] M. Ahtola, Dry powder layering of high viscosity polymers using a fluidized bed rotor granulator, Master thesis, U of Helsinki (2014)

[4] S. Abdul, A. Chandewar, S. Jaiswal, Journal of Controlled Release, Volume 147(1) (2010) 2-16

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CS_taste_image_1

Taste-masked cellulose based pellets for compaction

Abstract

Several drug substances are known to be extremely bitter. In special for paediatric and geriatric applications, costumer compliance by means of taste acceptance is a highly sensitive topic. Taste masking is therefore an important issue in pharmaceutical industry of oral dosage forms not only to improve the compliance, but it is also used to define a unique taste identification by the costumer (competition advantages). This case study will focus on taste-masking of an API and on the optimization of release in the absorption window of the API.

Modifying the taste

Several methods are available to actively influence, hide or modify taste, such as the initial activation of the active pharmaceutical ingredient (API) by biotransformation [1], the complexation into the cavity of a complexing agent [2] or layering with coating substances [3] and other methods.

Among all these solutions, coating seems to be one of the best understood and most flexible methods. In terms of the API bitterness, mild and extreme bitter APIs are applicable. Additionally, coating [4] is well suited for high dosed API formulations. There are two main approaches: (1) direct coating of the bitter API particles in multiple unit pellet system (MUPS) tablets, or (2) global coating of the tablet which contains the bitter API.

In this case study, we focus on the direct coating of API in a formulation based on starter cores as the unit pellet system. CELLETS® 200 are used as starter cores. They are pellets made of microcrystalline cellulose in size ranges from 100 µm to 1400 µm. In this specific case study, the core size ranges between 100 µm and 200 µm with a defined size distribution. The main advantages of CELLETS® are high sphericity, low friability and optimum in hardness. An API is coated onto the starter cores with a drug load of 5-20 %. The taste-masking coating is performed with Eudragit EPO® so that the resulting particle size remains below 500 µm (Figure 1). Eudragit is the polymer of choice as it ideally prevents API release in oral cavity and allows its release in the absorption window of the API. The final dosage form is a MUPS tablet (Figure 2).

CS_taste_image_1

Sketch of a coated pellet starter core (green) with API (blue) and taste masking Eudragit EPO® (yellow) coating. The API drug load is between 5 % to 20 %. The resulting particle size remains below 500 µm.

Compaction is an issue during production, which requires mechanically stable pellets. Coated CELLETS® 200 after compaction still represent as “hard” core pellets. The coated pellets show only little deformation, a reversible compaction behavior and an intact coating.

CS_taste_image_2

Sketch of a MUPS tablet. Coated starter cores (yellow) and filling excipient formulation (white).

Here, the MUPS formulation defines a content uniformity with an excellent taste masking at pH 7 (as a measure for the oral cavity) and fast dissolution at pH 1 (representing conditions in the stomach). Figure 3 shows the evaluation of taste masking and dissolution efficiency tests, where the dissolution at pH 7 remains less than 10 % after 10 minutes, and a desired dissolution at pH 1 with a drug release better than 85 % after 30 minutes.

CS_taste_image_3

Drug release versus time for coated CELLETS® 200 starter cores. Blue line: in vitro dissolution testing at pH 1 (stomach). Red line: taste masking evaluation at pH 7 (oral cavity).

Summary

Taste masking and modification is crucial for costumer compliance in paediatric and geriatric applications. Several methods are available, such as direct API coating. CELLETS® are perfect starter cores for a successful formulation and simplify taste masking of extreme bitter APIs. CELLETS® properties allow perfect coating abilities due to a high degree of sphericity. CELLETS® of small sizes and narrow size distribution are applicable in MUPS tablets thanks to their low friability and excellent hardness.

References

[1] K. Rafik. Computationally Designed Prodrugs for Masking the Bitter Taste of Drugs. Drug Des. Open Access (2012).

[2] V. Vummaneni and D. Nagpal. Recent, taste masking technologies: an overview and updates. Int. J. Res. Pharm. Biomed. Sci. (2012) 3, 510-524.

[3] D. Sharma, D. Kumar, M. Singh, G. Singh and M. Rathore. Taste masking technologies: a novel approach for the improvement of the organoleptic property of pharmaceutical active substance. Int. Res. J. Pharm. (2012) 3, 108-116.

[4] Hazzah, H.A., EL-Massik, M.A., Abdallah, O.Y. et al. Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique. Journal of Pharmaceutical Investigation 43 (2013) 333–342. https://doi.org/10.1007/s40005-013-0077-0

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MUPS_image_4
,

Better MUPS tablets: Aspects of MCC starter beads

Abstract

Starter beads such as pellets made of microcrystalline cellulose (MCC) are frequently used in the formulation of oral drug delivery systems, e.g. multiparticulates [1] or multi-unit pellet system (MUPS) tablets [2]. Certain properties are requested to MCC pellets. We shed some light on sphericity size and friability in this note.

Starter beads for MUPS tablets

MUPS tablets consist of pellets which are compressed – assisted by excipients such as disintegrants and fillers. The pellets used are usually functional coated to achieve desired drug release profiles.

CS_MUPS_image_1

Top: Inert Cellets® 100 (100-200 µm, left) in comparison with another MCC sphere (75-212 µm, right). Bottom: Inert Cellets® 200 (200-350 µm, left) in comparison with another MCC sphere (150-300 µm).

Figure 1: Top: Inert Cellets® 100 (100-200 µm, left) in comparison with another MCC sphere (75-212 µm, right). Bottom: Inert Cellets® 200 (200-350 µm, left) in comparison with another MCC sphere (150-300 µm).

The characteristics of the starter bead as a neutral carrier should therefore include high sphericity (Figure 1), constant particle size distribution and smooth surface. These aspects count especially for the formulation of low dosed highly active APIs.

For the application in MUPS tablets small size and high mechanical stability (low friability) are of interest to achieve desired drug loading and avoid film damage during compression.

Size

Any question relating to optimized drug load and coating layers of pellets is a question of size and sphericity of the starter beads.

So, what is the main influence of size? Size needs to be considered for achieving desired drug load in relation to a total dimension of the pellet. While the total dimension of the pellet is mainly defined by the application – e.g. processing as a capsule, tablet or sachet –, the initial pellet size defines the maximum thickness of coating levels (Figure 2). Size might also be a matter of content uniformity with low dosed API and also needs to be mentioned by means of processability, which is in particular electrostatic loading or sticking. Particle size distribution influences the dissolution profile.

CS_MUPS_image_2

Figure 2: Sketch of a functionally coated pellet. The size of the initial pellet (green) defines the maximum thickness of all coating layers (blue) which may contain API and excipients, as well.

Figure 2: Sketch of a functionally coated pellet. The size of the initial pellet (green) defines the maximum thickness of all coating layers (blue) which may contain API and excipients, as well.

Sphericity

Sphericity is a strong parameter which influence depends on drug loading and coating levels. Also for the control of dissolution profile where specific surface area and content uniformity play important roles, the influence of sphericity needs to be understood (Figure 3). Please do not forget, that with decreasing sphericity, the flow probabilities of powders are decreasing (powder rheology), which might affect process properties such as powder transport.

CS_MUPS_image_3

Figure 3: Sketch of non-spherical starter beads (green) with coating layers (blue). Coating layer thickness and dissolution profiles are hard to control in this case.

Figure 3: Sketch of non-spherical starter beads (green) with coating layers (blue). Coating layer thickness and dissolution profiles are hard to control in this case.

Thus, starter beads of uniform size (distribution) and sphericity are the better solution for overcoming these issues by simplifying drug formulation and processing. Such starter beads can be pellets of MCC, sugar or tartaric acid. MCC pellets surely show perfect initial conditions as they exhibit chemical inertness and therefore can be combined with several APIs. In case of weakly basic APIs, tartaric acid pellets are advantageous.

MUPS_image_4

Figure 4: A pellet inside a compressed MUPS tablet. The starter bead is surrounded by a coating layer of exemplarily excipient or API. A powdery excipients matrix surrounds the coated pellet. Friability is absolutely low.

Figure 4: A pellet inside a compressed MUPS tablet. The starter bead is surrounded by a coating layer of exemplarily excipient or API. A powdery excipients matrix surrounds the coated pellet. Friability is absolutely low.

Figure 4 shows a cross-section of a pellet in the matrix of a compressed MUPS tablet. It is mentionable, that due to low friability a high degree of sphericity as well as surface smoothness are kept after compression and film damage of coating layers is not identified.

Summary

Cellets® offer a perfect combination of chemical inertness towards the selection of the API and physical properties that allow optimized and stable processing in a fluid bed process for layering and coating of the starter beads. Main advantages are the low friability, smooth surface, sphericity and narrow size distributions.

Cellets® starter beads therefore provide excellent conditions for controlled drug dissolution profiles.

Acknowledgement

We acknowledge Fraunhofer IFAM (Dresden, Germany) for providing electron microscopic images.

References

[1] Pöllinger N, Drug Product Development for Older Adults—Multiparticulate Formulations. In: Stegemann S. (eds) Developing Drug Products in an Aging Society. AAPS Advances in the Pharmaceutical Sciences Series, vol 26 (2016). Springer, Cham. https://doi.org/10.1007/978-3-319-43099-7_16

[2] Bhad ME, Abdul S, Jaiswal SB, Chandewar AV, Jain JM, Sakarkar DM. MUPS tablets—a brief review. Int J Pharm Tech Res. 2010;2:847–55

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