CELLETS® are pellets or spheres made of microcrystalline cellulose. The size ranges from 100 µm to 1400 µm. Being neutral starter cores, they can be used as carrier system for low-dosed APIs and allow diverse functional coating. See pellet technologies for a detailed description.
Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.
Available size classes are (click for more information):
- CELLETS® 100
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- CELLETS® 350
- CELLETS® 500
- CELLETS® 700
- CELLETS® 1000
Any size class of CELLETS® have same striking advantages:
- low friability and extreme hardness
- insolubility in water
- high spherictity
- smooth surface
- good monodispersity
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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].
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. 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. 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+ln1/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).
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. 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).
Figure 3. SEM of MCC spheres (D10% = 563 µm, D50% = 651 µm, and D90% = 696 µm).
Figure 4. FTIR spectrum of dried and loaded MCC spheres in the range of 4000–500 cm−1.
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).
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).
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.
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).
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.
Figure 9. Comparison of non-plasticized (dried) with plasticized MCC spheres (Cellets® 500) in terms of Py (a plasticity parameter).
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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Glatt
Selected Scientific literature
Please, find scientific literature on CELLETS®, MCC spheres. This list is constantly updated and does not claim to be complete. If you are author, scientist or R&D specialist, please submit your present publication to us for improving the visibility.
List – Publications with MCC spheres, 2024
Thesis
Characterization of dense granular flows using a continuous chute flow rheometer
Purdue University, School of Materials Engineering, West Lafayette, Indiana, posted on 2024-07-20, 03:12
Kayli Lynn Henry
Research article
The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer
Pharmaceutics (2024), 16(7), 945; doi:10.3390/pharmaceutics16070945
A. Paulausks, T. Kolisnyk, V. Mohylyuk
Research article
The development of an innovative method to improve the dissolution performance of rivaroxaban
Heliyon 10 (2024) e33162; doi:10.1016/j.heliyon.2024.e33162
E.A. Ozon, E. Mati, O. Karampelas, V. Anuta, I. Sarbu, A.M. Musuc, R.-A. Mitran, D.C. Culita, I. Atkinson, M. Anastasescu, D. Lupuliasa, M.A. Mitu
Thesis
Modelling the disintegration of pharmaceutical tablets: integrating a single particle swelling model with the discrete element method
University of Strathclyde, Strathclyde Institute of Pharmacy and Biomedical Sciences, CMAC National Facility, 2024, Thesis identifier T16863
M. Soundaranathan
List – Publications with MCC spheres, 2023
Research article
Paediatric solid oral dosage forms for combination products: Improving in vitro swallowability of minitablets using binary mixtures with pellets
European Journal of Pharmaceutical Sciences (2023), 187, 106471; doi:10.1016/j.ejps.2023.106471
A. Avila-Sierra, A. Lavoisier, C. Timpe, P. Kuehl, L. Wagner, C. Tournier, M. Ramaioli
Research article
Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating
Pharmaceuticals (2023), 16(8), 1064; doi:10.3390/ph16081064
A. Kara, D. Kumar 2, A.M. Healy, A. Lalatsa, and D.R. Serrano
Research article
High-Speed Tableting of High Drug-Loaded Tablets Prepared from Fluid-Bed Granulated Isoniazid
Pharmaceuticals (2023), 15(4), 1236; doi:10.3390/pharmaceutics15041236
V. Mohylyuk, and D. Bandere
Research article
The Effect of Design and Size of the Fluid‑Bed Equipment on the Particle Size‑Dependent Trend of Particle Coating Thickness and Drug Prolonged‑Release Profile
AAPS PharmSciTech (2023) 24, 93. doi:10.1208/s12249-023-02540-9
T. Brezovar, G. Hudovornik, M. Perpar, M. Luštrik, R. Dreu
Research article
Amorphous Solid Dispersions Layered onto Pellets—An Alternative to Spray Drying?
Pharmaceutics (2023) 15(3), 764. doi:10.3390/pharmaceutics15030764
M. Neuwirth, S.K. Kappes, M.U. Hartig, K.G. Wagner
Research article
Optimization of Fluidized-Bed Process Parameters for Coating Uniformity and Nutrient-Release Characteristics of Controlled-Release Urea Produced by Modified Lignocellulosic Coating Material
Agronomy (2023) 13(3), 725. doi:10.3390/agronomy13030725
A.M. Ali, B. Azeem, A.M. Alghamdi, K. Shahzad, A. Ahmad Al-Zahrani, M. Imtiaz Rashid, A. Binti Mahpudz, A. Jamil
Research article
Hydrodynamic behaviour of CELLETS® (Ph.Eur./USP) in a spouted bed using image processing method
Particuology (2023), 76, 101-112, doi:10.1016/j.partic.2022.07.009
J. Vanamu, A. Sahoo
List – Publications with MCC spheres, 2022
Research article
Product-Property Guided Scale-Up of a Fluidized Bed Spray Granulation Process Using the CFD-DEM Method
Processes (2022) 10(7), 1291. doi:10.3390/pr10071291
P. Kieckhefen, S. Pietsch-Braune, S. Heinrich
Research article
Influence of In Situ Calcium Pectinate Coating on Metoprolol Tartrate Pellets for Controlled Release and Colon-Specific Drug Delivery
Pharmaceutics (2022) 14(5), 1061. doi:10.3390/pharmaceutics14051061
P. Wanasawas, A. Mitrevej, N. Sinchaipanid
Research article
Delamination and wetting behavior of natural hot-melt coating materials
Powder Technology (2022) 404, 117443. doi:10.1016/j.powtec.2022.117443
B.M. Woerthmann, L. Totzauer, H. Briesen
Research article
A systematic approach for assessing the suitability of enteral feeding tubes for the administration of controlled-release pellet formulations
International Journal of Pharmaceutics (2022) 612, 121286. doi:10.1016/j.ijpharm.2021.121286
F. Karkossa, N. Lehmann, S. Klein
Research article
Spray-freeze-dried lyospheres: Solid content and the impact on flowability and mechanical stability
Powder Technology (2022) 411, 117905. doi:10.1016/j.powtec.2022.117905
A. Rautenberg, A. Lamprecht
Conference proceedings
Assessment of the effect of microcrystalline cellulose (MCC) spheres size on the flow via powder rheology
The FORGE, 2022 – pure.qub.ac.uk
V. Mohylyuk, R. Dattani
Research article
Solventless amorphization and pelletization using a high shear granulator. Part II; Preparation of co-amorphous mixture-layered pellets using indomethacin and arginine
European Journal of Pharmaceutics and Biopharmaceutics (2022) 181, 183-194. doi: 10.1016/j.ejpb.2022.11.011
K. Kondo, T. Rades
Research article
Solventless amorphization and pelletization using a high shear granulator. Part I; feasibility study using indomethacin
European Journal of Pharmaceutics and Biopharmaceutics (2022) 181, 147-158. doi: 10.1016/j.ejpb.2022.11.010
K. Kondo, T. Rades
Research article
Application of different models to evaluate the key factors of fluidized bed layering granulation and their influence on granule characteristics
Powder Technology (2022), 408:117737. doi: 10.1016/j.powtec.2022.117737
R. Maharjan, S. H. Jeong
Research article
Evaluation of gravitational consolidation of binary powder mixtures by modified Heckel equation
Powder Technology (2022), 408:117729. doi: 10.1016/j.powtec.2022.117729
P. Svačinová, O. Macho, Ž. Jarolímová, M. Kuentz, Ľ. Gabrišová and Z. Šklubalová
Research article
Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing
Pharmaceutics (2022), 14(5)1058. doi: 10.3390/pharmaceutics14051058
M. W. Stocker, M. J. Harding, V. Todaro, A. M. Healy and S. Ferguson
List – Publications with MCC spheres, 2021
Research article
Correlating Granule Surface Structure Morphology and Process Conditions in Fluidized Bed Layering Spray Granulation
KONA Powder and Particle Journal (2021), DOI:10.14356/kona.2022016
M. Orth, P. Kieckhefen, S. Pietsch and S. Heinrich
Research article
Relative bioavailability enhancement of simvastatin via dry emulsion systems: comparison of spray drying and fluid bed layering technology
Eur J Pharm Biopharm (2021), S0939-6411(21)00353-2. doi: 10.1016/j.ejpb.2021.12.004
M. Pohlen, J. Aguiar Zdovc, J. Trontelj, J. Mravljak, M. G. Matjaž, I. Grabnar, T. Snoj and R. Dreu
Research article
A novel method for assessing the coating uniformity of hot-melt coated particles using micro-computed tomography
Powder Technology, Volume 378, Part A, 22 January 2021, Pages 51-59
B.M. Woerthmann, J.A. Lindner, T. Kovacevic, P. Pergam, F. Schmid, H. Briesen
List – Publications with MCC spheres, 2020
Research article
Material specific drying kinetics in fluidized bed drying under mechanical vibration using the reaction engineering approach
Advanced Powder Technology, Volume 31, Issue 12, December 2020, Pages 4699-4713
Soeren E. Lehmann, Tobias Oesau, Alfred Jongsma, Fredrik Innings, Stefan Heinrich
Research article
Simulation of pellet coating in Wurster coaters
International Journal of Pharmaceutics, Volume 590, 30 November 2020, 119931
Hamid Reza Norouzi
Research article
Quantification of swelling characteristics of pharmaceutical particles
International Journal of Pharmaceutics, Volume 590, 30 November 2020, 119903
Mithushan Soundaranathan, Pattavet Vivattanaseth, Erin Walsh, Kendal Pitt, Blair Johnston, Daniel Markl
Short communication
Introduction of the energy to break an avalanche as a promising parameter for powder flowability prediction
Powder Technology, Volume 375, 20 September 2020, Pages 33-41
Žofie Trpělková, Hana Hurychová, Martin Kuentz, Barbora Vraníková, Zdenka Šklubalová
Research article
Easy to Swallow “Instant” Jelly Formulations for Sustained Release Gliclazide Delivery
Journal of Pharmaceutical Sciences, Volume 109, Issue 8, August 2020, Pages 2474-2484
Simmi Patel, Nathan Scott, Kavil Patel, Valentyn Mohylyuk, William J. McAuley, Fang Liu
Research article
Regulating the pH of bicarbonate solutions without purging gases: Application to dissolution testing of enteric coated tablets, pellets and microparticles
International Journal of Pharmaceutics, Volume 585, 30 July 2020, 119562
Nathan Scott, Kavil Patel, Tariro Sithole, Konstantina Xenofontos, Valentyn Mohylyuk, Fang Liu
Research article
Measuring segregation characteristics of industrially relevant granular mixtures: Part II – Experimental application and validation
Powder Technology, Volume 368, 15 May 2020, Pages 278-285
Alexander M. Fry, Vidya Vidyapati, John P. Hecht, Paul B. Umbanhowar, Julio M. Ottinoa, Richard M. Lueptow
Research article
Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility
International Journal of Pharmaceutics, Volume 581, 15 May 2020, 119217
Matteo Cerea, Anastasia Foppoli, Luca Palugan, Alic Melocchi, Lucia Zema, Alessandra Maroni, Andrea Gazzaniga
Research article
Effects of humidity on cellulose pellets loaded with potassium titanium oxide oxalate for detection of hydrogen peroxide vapor in powders
Powder Technology, Volume 366, 15 April 2020, Pages 348-357
Maria H. Kastvig, Cosima Hirschberg, Frans W.J. Van Den Berg, Jukka Rantanen, Mogens L. Andersen
Research article
In-line particle size measurement and process influences on rotary fluidized bed agglomeration
Powder Technology, Volume 364, 15 March 2020, Pages 673-679
Marcel Langner, Ivonne Kitzmann, Anna-Lena Ruppert, Inken Wittich, Bertram Wolf
Research article
Recent advance in delivery system and tissue engineering applications of chondroitin sulfate
Carbohydrate Polymers, Volume 230, 15 February 2020, 115650
Jun Yang, Mingyue Shen, Huiliang Wen, Yu Luo, Rong Huang, Liyuan Rong, Jianhua Xie
Research article
Fixed-bed-column studies for Methylene blue removal by Cellulose CELLETS
Environmental Engineering and Management Journal, Volume 19 (2), March 2020, 269-279
Iulia Nica, Gabriela Biliuta, Carmen Zaharia, Lacramioara Rusu, Sergiu Coseri, Daniela Suteu
Research article
Optimization and tracking of coating processes of pellets with polyvinylpyrrolidone solutions in an acoustic levitator
Powder Technology, Volume 360, 15 January 2020, Pages 1126-1133
Doris L. Wong, Anna-Lena Wirsching, Kai Betz, Andreas Reinbeck, Hans-Ulrich Moritz, Werner Pauer
List – Publications with MCC spheres, 2019
Research article
Measurement of hydrogen peroxide vapor in powders with potassium titanium oxide oxalate loaded cellulose pellets as probes
AAPS PharmSciTech, Volume 21(1):3, 11 Nov 2019
Maria H. Kastvig, Johan P. Bøtker, Ge Ge, Mogens L. Andersen
Research article
Wurster Fluidised Bed Coating of Microparticles: Towards Scalable Production of Oral Sustained-Release Liquid Medicines for Patients with Swallowing Difficulties
AAPS PharmSciTech, Volume 21(1):3, 11 Nov 2019
Valentyn Mohylyuk, Kavil Patel, Nathan Scott, Craig Richardson, Darragh Murnane, Fang Liu
Research article
Assessment of the effect of Cellets’ particle size on the flow in a Wurster fluid-bed coater via powder rheology
Journal of Drug Delivery Science and Technology, Volume 54, December 2019, 101320
Valentyn Mohylyuk, Ioanna Danai Styliari, Dmytryi Novykov, Reiss Pikett, Rajeev Dattani
Research article
Particle electrification in an apparatus with a draft tube operating in a fast circulating dilute spout-fluid bed regime
Particuology, Volume 42, February 2019, Pages 146-153
Wojciech Ludwig
Research article
Development and evaluation of budesonide-based modified-release liquid oral dosage forms
Journal of Drug Delivery Science and Technology, Volume 54, December 2019, 101273
Federica Ronchi, Antonio Sereno, Maxime Paide, Ismaël Hennia, Pierre Sacré, George Guillaume, Vincent Stéphenne, Jonathan Goole, Karim Amighi
Research article
Evaluation of in-line particle measurement with an SFT-probe as monitoring tool for process automation using a new time-based buffer approach
European Journal of Pharmaceutical Sciences, Volume 128, 1 February 2019, Pages 162-170
Theresa Reimers, Jochen Thies, Stefan Dietrich, Julian Quodbach, Miriam Pein-Hackelbusch
Research article
In vitro and sensory tests to design easy-to-swallow multi-particulate formulations
European Journal of Pharmaceutical Sciences, Volume 132, 30 April 2019, Pages 157-162
Marco Marconati, Felipe Lopez, Catherine Tuleu, Mine Orlu, Marco Ramaioli
Research article
Numerical study of the hydrodynamics of fluidized beds operated under sub-atmospheric pressure
Chemical Engineering Journal, Volume 372, 15 September 2019, Pages 1134-1153
Sayali Zarekar, Andreas Bück, Michael Jacob, Evangelos Tsotsas
Research article
Solidification of carvedilol loaded SMEDDS by swirling fluidized bed pellet coating
International Journal of Pharmaceutics, Volume 566, 20 July 2019, Pages 89-100
J. Mandić, M. Luštrik, F. Vrečer, M. Gašperlin, A. Zvonar Pobirk
Research article
Quantitative bin flow analysis of particle discharge using X-ray radiography
Powder Technology, Volume 344, 15 February 2019, Pages 693-705
Sanket Bacchuwar, Vidya Vidyapati, Ke-ming Quan, Chen-Luh Lin, Jan D. Miller
Research article
Adjustment of triple shellac coating for precise release of bioactive substances with different physico-chemical properties in the ileocolonic region
International Journal of Pharmaceutics, Volume 564, 10 June 2019, Pages 472-484>
Eva-Maria Theismann, Julia Katharina Keppler, Jörg-Rainer Knipp, Daniela Fangmann, Esther Appel, Stanislav N. Gorb, Georg H. Waetzig, Stefan Schreiber, Matthias Laudes, Karin Schwarz
Research article
The analysis of the influence of the normal restitution coefficient model on calculated particles velocities by means of Eulerian-Lagrangian approach
Powder Technology, Volume 344, 15 February 2019, Pages 140-151
Wojciech Ludwig, PaweƚPłuszka
Research article
Measurement of granule layer thickness in a spouted bed coating process via optical coherence tomography
Powder Technology, Volume 356, November 2019, Pages 139-147
Swantje Pietsch, Anna Peter, Patrick Wahl, Johannes Khinast, Stefan Heinrich
Research article
A novel method of quantifying the coating progress in a three-dimensional prismatic spouted bed
Particuology, Volume 42, February 2019, Pages 137-145
Swantje Pietsch, Finn Ole Poppinga, Stefan Heinrich, Michael Müller, Michael Schönherr, Frank Kleine Jäger
Research article
Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form
International Journal of Pharmaceutics, Volume 567, 15 August 2019, 118416
Federica Ronchi, Antonio, Sereno, Maxime Paide, Pierre Sacré, George Guillaume, Vincent Stéphenne, Jonathan Goole, Karim Amighi
Research article
Influence of separation properties and processing strategies on product characteristics in continuous fluidized bed spray granulation
Powder Technology, Volume 342, 15 January 2019, Pages 572-584
Daniel Müller, Andreas Bück, Evangelos Tsotsas
List – Publications with MCC spheres, 2018
Short communication
Novel production method of tracer particles for residence time measurements in gas-solid processes
Powder Technology, Volume 338, October 2018, Pages 1-6
Swantje Pietsch, Paul Kieckhefen, Michael Müller, Michael Schönherr, Frank Kleine Jäger, Stefan Heinrich
Research article
The effect of administration media on palatability and ease of swallowing of multiparticulate formulations
International Journal of Pharmaceutics, Volume 551, Issues 1–2, 15 November 2018, Pages 67-75
Felipe L. Lopez, Terry B. Ernest, Mine Orlu, CatherineTuleu
Research article
Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations
International Journal of Pharmaceutics, Volume 540, Issues 1–2, 5 April 2018, Pages 120-131
Josefina Nordström, Göran Alderborn, Göran Frenning
Research article
Effects of pharmaceutical processes on the quality of ethylcellulose coated pellets: Quality by design approach
Powder Technology, Volume 339, November 2018, Pages 25-38
Prakash Thapa, Ritu Thapa, Du Hyung Choi, Seong Hoon Jeong
Research article
Euler-Lagrange model of particles circulation in a spout-fluid bed apparatus for dry coating
Powder Technology, Volume 328, 1 April 2018, Pages 375-388
Wojciech Ludwig, Paweł Płuszka
Research article
Inline acoustic monitoring to determine fluidized bed performance during pharmaceutical coating
International Journal of Pharmaceutics, Volume 549, Issues 1–2, 5 October 2018, Pages 293-298
Allan Carter, Lauren Briens
Research article
Sifting segregation of ideal blends in a two-hopper tester: Segregation profiles and segregation magnitudes
Powder Technology, Volume 331, 15 May 2018, Pages 60-67
Mariagrazia Marucci, Banien Al-Saaigh, Catherine Boissier, Marie Wahlgren, Håkan Wikström
Conference abstract
Multiple unit mini-tablets: Content uniformity issues
International Journal of Pharmaceutics, Volume 536, Issue 2, 5 February 2018, Pages 506-507
Anna Kira Adam, Jörg Breitkreutz
Research article
Influence of gas inflow modelling on CFD-DEM simulations of three-dimensional prismatic spouted beds
Powder Technology, Volume 329, 15 April 2018, Pages 167-180
Paul Kieckhefen, Swantje Pietsch, Moritz Höfert, Michael Schönherr, Stefan Heinrich, Frank Kleine Jäger
Research article
A redispersible dry emulsion system with simvastatin prepared via fluid bed layering as a means of dissolution enhancement of a lipophilic drug
International Journal of Pharmaceutics, Volume 549, Issues 1–2, 5 October 2018, Pages 325-334
Mitja Pohlen, Luka Pirker, Matevž Luštrik, Rok Dreu
Review article
Overview of PAT process analysers applicable in monitoring of film coating unit operations for manufacturing of solid oral dosage forms
European Journal of Pharmaceutical Sciences, Volume 111, 1 January 2018, Pages 278-292
Klemen Korasa, Franc Vrečer
Research article
On the properties and application of beeswax, carnauba wax and palm fat mixtures for hot melt coating in fluidized beds
Advanced Powder Technology, Volume 29, Issue 3, March 2018, Pages 781-788
M.G. Müller, J.A. Lindner, H. Briesen, K. Sommer, P. Foerst
Research article
Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics
Journal of Controlled Release, Volume 287, 10 October 2018, Pages 247-256
Matteo Cerea, Alessandra Maroni, Luca Palugan, Marco Bellini, Anastasia Foppoli, Alice Melocchi, Lucia Zema, Andrea Gazzaniga
Research article
Role of plasticizer in membrane coated extended release oral drug delivery system
Journal of Drug Delivery Science and Technology, Volume 44, April 2018, Pages 231-243
Pinak Khatri, Dipen Desai, Namdev Shelke, Tamara Minko
Research article
Evaluation of pellet cycle times in a Wurster chamber using a photoluminescence method
Chemical Engineering Research and Design, Volume 132, April 2018, Pages 1170-1179
Domen Kitak, Rok Šibanc, Rok Dreu
Research article
Influence of perforated draft tube air intake on a pellet coating process
Powder Technology, Volume 330, 1 May 2018, Pages 114-124
Matevž Luštrik, Rok Dreu, Matjaž Perpar
Research article
Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating
European Journal of Pharmaceutics and Biopharmaceutics, Volume 124, March 2018, Pages 13-27
Dolores R. Serrano, David Walsh, Peter O’Connell, Naila A. Mugheirbi, Zelalem Ayenew Worku, Francisco Bolas-Fernandez, Carolina Galiana, Maria Auxiliadora Dea-Ayuela, Anne Marie Healy
Research article
Mechanics of Pharmaceutical Pellets—Constitutive Properties, Deformation, and Breakage Behavior
Journal of Pharmaceutical Sciences, Volume 107, Issue 2, February 2018, Pages 571-586
Alexander Russell, Rok Šibanc, Rok Dreu, Peter Müller
List – Publications with MCC spheres, 2017
Research article
Production of composite particles using an innovative continuous dry coating process derived from extrusion
Advanced Powder Technology, Volume 28, Issue 11, November 2017, Pages 2875-2885
Fanny Cavaillès, Romain Sescousse, Alain Chamayou, Laurence Galet
Research article
Determination of the release mechanism of Theophylline from pellets coated with Surelease®—A water dispersion of ethyl cellulose
International Journal of Pharmaceutics, Volume 528, Issues 1–2, 7 August 2017, Pages 345-353
Jurgita Kazlauske, Maria Margherita Cafaro, Diego Caccavo, Mariagrazia Marucci, Gaetano Lamberti, Anna Angela Barba, Anette Larsson
Research article
In-line monitoring of multi-layered film-coating on pellets using Raman spectroscopy by MCR and PLS analyses
European Journal of Pharmaceutics and Biopharmaceutics, Volume 114, May 2017, Pages 194-201
Jin Hisazumi, Peter Kleinebudde
Research article
Analysis of pellet coating uniformity using a computer scanner
International Journal of Pharmaceutics, Volume 533, Issue 2, 30 November 2017, Pages 377-382
Rok Šibanc, Matevž Luštrik, Rok Dreu
Research article
Modeling of particle velocities in an apparatus with a draft tube operating in a fast circulating dilute spout-fluid bed regime
Powder Technology, Volume 319, September 2017, Pages 332-345
Wojciech Ludwig, Daniel Zając
Research article
UV imaging of multiple unit pellet system (MUPS) tablets: A case study of acetylsalicylic acid stability
European Journal of Pharmaceutics and Biopharmaceutics, Volume 119, October 2017, Pages 447-453
Anna Novikova, Jens M. Carstensen, Thomas Rades, Claudia S. Leopold
Research article
New hybrid CPU-GPU solver for CFD-DEM simulation of fluidized beds
Powder Technology, Volume 316, 1 July 2017, Pages 233-244
H.R. Norouzi, R. Zarghami, N. Mostoufi
Research article
A top coating strategy with highly bonding polymers to enable direct tableting of multiple unit pellet system (MUPS)
Powder Technology, Volume 305, January 2017, Pages 591-596
Frederick Osei-Yeboah, Yidan Lan, Changquan Calvin Sun
Research article
Synthesis and melt processing of cellulose esters for preparation of thermoforming materials and extended drug release tablets
Carbohydrate Polymers, Volume 177, 1 December 2017, Pages 105-115
Sanna Virtanen, Riku Talja, Sauli Vuoti
Research article
Downstream drug product processing of itraconazole nanosuspension: Factors influencing drug particle size and dissolution from nanosuspension-layered beads
International Journal of Pharmaceutics, Volume 524, Issues 1–2, 30 May 2017, Pages 443-453
Johannes Parmentier, En Hui Tan, Ariana Low, Jan Peter Möschwitzer
List – Publications with MCC spheres, 2016
Research article
In-line particle size measurement and agglomeration detection of pellet fluidized bed coating by Spatial Filter Velocimetry
Powder Technology, Volume 301, November 2016, Pages 261-267
Dimitri Wiegel, Günter Eckardt, Florian Priese, Bertram Wolf
Research article
Effect of formulation variables on oral grittiness and preferences of multiparticulate formulations in adult volunteers
European Journal of Pharmaceutical Sciences, Volume 92, 20 September 2016, Pages 156-162
Felipe L. Lopez, Alexandra Bowles, Mine Orlu Gul, David Clapham, Terry B. Ernest, Catherine Tuleu
Research article
Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen
International Journal of Pharmaceutics, Volume 499, Issues 1–2, 29 February 2016, Pages 271-279
Eva Julia Laukamp, Klaus Knop, Markus Thommes, Joerg Breitkreutz
Research article
Multivariate calibration of the degree of crystallinity in intact pellets by X-ray powder diffraction
International Journal of Pharmaceutics, Volume 502, Issues 1–2, 11 April 2016, Pages 107-116
Krisztina Nikowitz, Attila Domján, Klára Pintye-Hódi, Géza Regdon jr.
Research article
Towards improving quality of video-based vehicle counting method for traffic flow estimation
Signal Processing, Volume 120, March 2016, Pages 672-681
Yingjie Xia, Xingmin Shi, Guanghua Song, Qiaolei Geng, Yuncai Liu
Conference abstract
Multiple-unit orodispersible mini-tablets
International Journal of Pharmaceutics, Volume 511, Issue 2, 25 September 2016, Page 1128
Anna Kira Adam, Christian Zimmer, Stefan Rauscher, Jörg Breitkreutz
Research article
Asymmetric distribution in twin screw granulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 106, September 2016, Pages 50-58
Tim Chan Seem, Neil A. Rowson, Ian Gabbott, Marcelde Matas, Gavin K. Reynolds, AndyIngram
Research article
Measurement of particle concentration in a Wurster coater draft tube using light attenuation
Chemical Engineering Research and Design, Volume 110, June 2016, Pages 20-31
R. Šibanc, I. Žun, R. Dreu
List – Publications with MCC spheres, 2015
Research article
Two-dimensional particle shape analysis from chord measurements to increase accuracy of particle shape determination
Powder Technology, Volume 284, November 2015, Pages 25-31
D. Petrak, S. Dietrich, G. Eckardt, M. Köhler
Research article
Passive acoustic emission monitoring of pellet coat thickness in a fluidized bed
Powder Technology, Volume 286, December 2015, Pages 172-180
Taylor Sheahan, Lauren Briens
Research article
Tabletability Modulation Through Surface Engineering
Journal of Pharmaceutical Sciences, Volume 104, Issue 8, August 2015, Pages 2645-2648
Frederick Osei-Yeboah, Changquan Calvin Sun
Research article
Cellulose CELLETS as new type of adsorbent for the removal of dyes from aqueous media
Environmental Engineering and Management Journal, Volume 14, Issue 3, March 2015, Pages 525-532
Daniela Suteu, Gabriela Biliuta, Lacramioara Rusu, Sergiu Coseri, Gabriela Nacu
Research article
Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane
International Journal of Pharmaceutics, Volume 480, Issues 1–2, 1 March 2015, Pages 15-26
Sheng-Feng Hung, Chien-Ming Hsieh, Ying-Chen Chen, Cheng-Mao Lin, Hsiu-O Ho, Ming-Thau Sheu
Research article
Dry Coating Characterization of Coverage by Image Analysis: Methodology
Procedia Engineering, Volume 102, 2015, Pages 81-88
Olivier Lecoq, Fredj Kaouach, Alain Chamayou
Research article
Passive acoustic emissions monitoring of the coating of pellets in a fluidized bed—A feasibility analysis
Powder Technology, Volume 283, October 2015, Pages 373-379
Taylor Sheahan, Lauren Briens
List – Publications with MCC spheres, 2014
Research article
A New Apparatus for Real‐Time Assessment of the Particle Size Distribution of Disintegrating Tablets
Journal of Pharmaceutical Sciences, Volume 103, Issue 11, November 2014, Pages 3657-3665
Julian Quodbach, Peter Kleinebudde
Research article
In-line spatial filtering velocimetry for particle size and film thickness determination in fluidized-bed pellet coating processes
European Journal of Pharmaceutics and Biopharmaceutics, Volume 88, Issue 3, November 2014, Pages 931-938
Friederike Folttmann, Klaus Knop, Peter Kleinebudde, Miriam Pein
Research article
On-line monitoring of fluid bed granulation by photometric imaging
European Journal of Pharmaceutics and Biopharmaceutics, Volume 88, Issue 3, November 2014, Pages 879-885
Ira Soppela, Osmo Antikainen, Niklas Sandler, Jouko Yliruusi
Research article
Application properties of oral gels as media for administration of minitablets and pellets to paediatric patients
International Journal of Pharmaceutics
Volume 460, Issues 1–2, 2 January 2014, Pages 228-233
Anna Kluk, Malgorzata Sznitowska
Research article
In-line monitoring of pellet coating thickness growth by means of visual imaging
International Journal of Pharmaceutics, Volume 470, Issues 1–2, 15 August 2014, Pages 8-14
Nika Oman Kadunc, Rok Šibanc, Rok Dreu, Boštjan Likar, Dejan Tomaževič
Research article
Optical microscopy as a comparative analytical technique for single-particle dissolution studies
International Journal of Pharmaceutics, Volume 469, Issue 1, 20 July 2014, Pages 10-16
Sami Svanbäck, Henrik Ehlers, Jouko Yliruusi
Research article
Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs
European Journal of Pharmaceutics and Biopharmaceutics, Volume 87, Issue 1, May 2014, Pages 107-113
Lieselotte De Smet, Lien Saerens, Thomas De Beer, Robert Carleer, Peter Adriaensens, Jan Van Bocxlaer, Chris Vervaet, Jean PaulRemon
Research article
Global monitoring of fluidized-bed processes by means of microwave cavity resonances
Measurement, Volume 55, September 2014, Pages 520-535
Johan Nohlert, Livia Cerullo, Johan Winges, Thomas Rylander, Tomas McKelvey, Anders Holmgren, Lubomir Gradinarsky, Staffan Folestad, Mats Viberg, Anders Rasmuson
List – Publications with MCC spheres, 2013
Research article
Water-mediated solid-state transformation of a polymorphic drug during aqueous-based drug-layer coating of pellets
International Journal of Pharmaceutics, Volume 456, Issue 1, 1 November 2013, Pages 41-48
Andres Lust, Satu Lakio, Julia Vintsevits, Jekaterina Kozlova, Peep Veski, Jyrki Heinämäki, Karin Kogermann
Research article
Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique
Journal of Pharmaceutical Investigation (2013), 43:333–342. doi: 10.1007/s40005-013-0077-0
H. A. Hazzah, M. A. EL-Massik, O. Y. Abdallah & H. Abdelkader
Research article
Development of high drug loaded pellets by Design of Experiment and population balance model calculation
Powder Technology, Volume 241, June 2013, Pages 149-157
Florian Priese, Bertram Wolf
Research article
Particle sizing measurements in pharmaceutical applications: Comparison of in-process methods versus off-line methods
European Journal of Pharmaceutics and Biopharmaceutics, Volume 85, Issue 3, Part B, November 2013, Pages 1006-1018
Ana F.T. Silva, Anneleen Burggraeve, Quenten Denon, Paul Van der Meeren, Niklas Sandler, Tom Van Den Kerkhof, Mario Hellings, Chris Vervaet, Jean Paul Remon, João Almeida Lopes, Thomas De Beer
Research article
Physical properties of pharmaceutical pellets
Chemical Engineering Science, Volume 86, 4 February 2013, Pages 50-60
Rok Šibanc, Teja Kitak, Biljana Govedarica, StankoSrčič Rok Dreu
Research article
Continuous pellet coating in a Wurster fluidized bed process
Chemical Engineering Science, Volume 86, 4 February 2013, Pages 87-98
N. Hampel, A. Bück, M. Peglow, E. Tsotsas
Research article
Study of the recrystallization in coated pellets – Effect of coating on API crystallinity
European Journal of Pharmaceutical Sciences, Volume 48, Issue 3, 14 February 2013, Pages 563-571
Krisztina Nikowitz, Klára Pintye-Hódi, Géza Regdon Jr.
Research article
The influence of rolling friction on the shear behaviour of non-cohesive pharmaceutical granules – An experimental and numerical investigation
European Journal of Pharmaceutical Sciences, Volume 49, Issue 2, 13 May 2013, Pages 241-250
Ann-Sofie Persson, Göran Frenning
Research article
Characteristics of pellet flow in a Wurster coater draft tube utilizing piezoelectric probe
Powder Technology, Volume 235, February 2013, Pages 640-651
Matevž Luštrik, Rok Šibanc, Stanko Srčič, Matjaž Perpar, Iztok Žun, Rok Dreu
Research article
Estimating coating quality parameters on the basis of pressure drop measurements in a Wurster draft tube
Powder Technology, Volume 246, September 2013, Pages 41-50
Matjaž Perpar, Matevž Luštrik, Rok Dreu, Stanko Srčič, Iztok Žun
Research article
Influence of Non-Water-Soluble Placebo Pellets of Different Sizes on the Characteristics of Orally Disintegrating Tablets Manufactured by Freeze-Drying
Journal of Pharmaceutical Sciences, Volume 102, Issue 6, June 2013, Pages 1786-1799
Ulrike Stange, Christian Führling, Henning Gieseler
List – Publications with MCC spheres, 2012
Research article
A density-based segmentation for 3D images, an application for X-ray micro-tomography
Analytica Chimica Acta, Volume 725, 6 May 2012, Pages 14-21
Thanh N. Tran, Thanh T. Nguyen, Tofan A. Willemsz, Gijsvan Kessel, Henderik W. Frijlink, Kees van der Voort Maarschalk
Research article
Attrition and abrasion resistance of particles coated with pre-mixed polymer coating systems
Powder Technology, Volume 230, November 2012, Pages 1-13
G. Perfetti, F. Depypere, S. Zafari, P. van Hee, W.J. Wildeboer, G. M. H. Meesters
Research article
New spout-fluid bed apparatus for electrostatic coating of fine particles and encapsulation
Powder Technology, Volume 225, July 2012, Pages 52-57
Roman G. Szafran, Wojciech Ludwig, Andrzej Kmiec
Research article
Particle size and packing characterization by diffuse light transmission
Particuology Volume 10, Issue 5, October 2012, Pages 619-627
Henrik Ehlers, Jyrki Heinämäki, Jouko Yliruusi
Research article
Dry Powder Coating in a Modified Wurster Apparatus
Procedia Engineering, Volume 42, 2012, Pages 437-446
W. Ludwig, R.G. Szafran, A. Kmiec, J. Dziak
Research article
Attrition strength of water-soluble cellulose derivative coatings applied on different core materials
Powder Technology, Volume 222, May 2012, Pages 71-79
Katarzyna Nienaltowska, Frédéric Depypere, Giacomo Perfetti, Gabrie M.H. Meesters, Frederik Ronsse, Jan G. Pieters, Koen Dewettinck
Research article
An experimental evaluation of the accuracy to simulate granule bed compression using the discrete element method
Powder Technology, Volume 219, March 2012, Pages 249-256
Ann-Sofie Persson, Göran Frenning
List – Publications with MCC spheres, 2011
Research article
Dry particle high coating of biopowders: An energy approach
Powder Technology, Volume 208, Issue 2, 25 March 2011, Pages 378-382
S. Otles, O. Lecoq, J. A. Dodds
Research article
A density based segmentation method to determine the coordination number of a particulate system
Chemical Engineering Science, Volume 66, Issue 24, 15 December 2011, Pages 6385-6392
Thanh T. Nguyen, Thanh N. Tran, Tofan A. Willemsz, Henderik W. Frijlink, Tuomas Ervasti, Jarkko Ketolainen, Kees van der Voort Maarschalk
Research article
Study of the preparation of a multiparticulate drug delivery system with a layering technique
Powder Technology, Volume 205, Issues 1–3, 10 January 2011, Pages 155-159
Krisztina Nikowitz, Péter Kása Jr., Klára Pintye-Hódi, Géza Regdon Jr.
Research article
Effect of annealing time and addition of lactose on release of a model substance from Eudragit® RS coated pellets produced by a fluidized bed coater
Chemical Engineering Research and Design, Volume 89, Issue 6, June 2011, Pages 697-705
Ulrich M. Heckötter, Anette Larsson, Pornsak Sriamornsak, Mont Kumpugdee-Vollrath
Research article
Suspension pellet layering using PVA–PEG graft copolymer as a new binder
International Journal of Pharmaceutics, Volume 412, Issues 1–2, 30 June 2011, Pages 28-36
L. Suhrenbrock, G. Radtke, K. Knop, P. Kleinebudde
Research article
In-line particle sizing for real-time process control by fibre-optical spatial filtering technique (SFT)
Advanced Powder Technology, Volume 22, Issue 2, March 2011, Pages 203-208
Petrak Dieter, Dietrich Stefan, Eckardt Günter, Köhler Michael
Research article
Flowability of surface modified pharmaceutical granules: A comparative experimental and numerical study
European Journal of Pharmaceutical Sciences, Volume 42, Issue 3, 14 February 2011, Pages 199-209
Ann-Sofie Persson, Göran Alderborn, Göran Frenning
List – Publications with MCC spheres, 2010
Research article
Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices
Chemical Engineering Journal, Volume 164, Issues 2–3, 1 November 2010, Pages 268-274
Jari T. T. Leskinen, Matti-Antero H. Okkonen, Maunu M. Toiviainen, Sami Poutiainen, Mari Tenhunen, Pekka Teppola, Reijo Lappalainen, Jarkko Ketolainen, Kristiina Järvinen
Research article
X-ray micro tomography and image analysis as complementary methods for morphological characterization and coating thickness measurement of coated particles
Advanced Powder Technology, Volume 21, Issue 6, November 2010, Pages 663-675
Giacomo Perfetti, Elke Van de Casteele, Bernd Rieger, Willem J. Wildeboer, Gabrie M.H. Meesters
Research article
Granule size distribution of tablets
Journal of Pharmaceutical Sciences, Volume 99, Issue 4, April 2010, Pages 2061-2069
Satu Virtanen, Osmo Antikainen, Heikki Räikkönen, Jouko Yliruusi
Research article
New insights into segregation during tabletting
International Journal of Pharmaceutics, Volume 397, Issues 1–2, 15 September 2010, Pages 19-26
S. Lakio, S. Siiriä, H. Räikkönen, S. Airaksinen, T. Närvänen, O. Antikainen, J.Yliruusi
Short communication
Can encapsulation lengthen the shelf-life of probiotic bacteria in dry products?
International Journal of Food Microbiology, Volume 136, Issue 3, 1 January 2010, Pages 364-367
F. Weinbreck, I. Bodnár, M.L. Marco
Research article
Evaluation of in-line spatial filter velocimetry as PAT monitoring tool for particle growth during fluid bed granulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 76, Issue 1, September 2010, Pages 138-146
A. Burggraeve, T. Van Den Kerkhof, M. Hellings, J.P. Remon, C. Vervaet, T. De Beera
List – Publications with MCC spheres, 2009
Research article
Impact of polymers on dissolution performance of an amorphous gelleable drug from surface-coated beads
European Journal of Pharmaceutical Sciences, Volume 37, Issue 1, 11 April 2009, Pages 1-10
Chon gFan, Rashmi Pai-Thakur, Wantanee Phuapradit, Lin Zhang, Hung Tian, Waseem Malick, Navnit Shah, M. Serpil Kislalioglu
Short communication
Raman spectroscopic investigation of film thickness
Polymer Testing, Volume 28, Issue 7, October 2009, Pages 770-772
T. Sovány, K. Nikowitz, G. Regdon Jr., P. Kása Jr., K. Pintye-Hódi
Research article
In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 73, Issue 2, October 2009, Pages 280-284
Nele Poelvoorde, Hans Verstraelen, Rita Verhelst, Bart Saerens, Ellen De Backer, Guido Lopes dos Santos Santiago, Chris Vervaet, Mario Vaneechoutte, Fabienne De Boeck, Luc Van Borteld, Marleen Temmerman, Jean-Paul Remon
Research article
Modulating pH-independent release from coated pellets: Effect of coating composition on solubilization processes and drug release
European Journal of Pharmaceutics and Biopharmaceutics, Volume 72, Issue 1, May 2009, Pages 111-118
Simon Ensslin, Klaus Peter Moll, Hendrik Metz, Markus Otz, Karsten Mäder
Research article
Dry Particle High-Impact Coating of Biopowders: Coating Strength
Particulate Science and Technology, Volume 27(4), 2009
S. Ötles, O. Lecoq, J. A. Dodds
Book
Formulation and Analytical Development for Low-Dose Oral Drug Products
John Wiley & Sons , inc. (2009), ISBN 978-0-470-05609-7
Jack Zheng (Editor)
List – Publications with MCC spheres, 2008 and earlier
Research article
Attrition strength of different coated agglomerates
Chemical Engineering Science, Volume 63, Issue 5, March 2008, Pages 1361-1369
B. van Laarhoven, S.C.A. Wiers, S.H. Schaafsma, G.M.H. Meesters
Research article
Direct Drug Loading into Preformed Porous Solid Dosage Units by the Controlled Particle Deposition (CPD), a New Concept for Improved Dissolution Using SCF-Technology
Journal of Pharmaceutical Sciences, Volume 97, Issue 10, October 2008, Pages 4416-4424
Ragna S. Wischumerski, Michael Türk, Martin A. Wahl
Research article
Optimisation of an enteric coated, layered multi-particulate formulation for ileal delivery of viable recombinant Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 69, Issue 3, August 2008, Pages 969-976
Nele Poelvoorde, Nathalie Huyghebaert, Chris Vervaet, Jean-Paul Remon
Research article
Dynamic rearrangement of disulfide bridges influences solubility of whey protein coatings
International Dairy Journal, Volume 18, Issue 5, May 2008, Pages 566-573
René Floris, Igor Bodnár, Fanny Weinbreck, Arno C. Alting
Research article
New insight into modified release pellets – Internal structure and drug release mechanism
Journal of Controlled Release, Volume 128, Issue 2, 4 June 2008, Pages 149-156
Simon Ensslin, Klaus Peter Moll, Kurt Paulus, Karsten Mäder
Research article
Development of an enteric-coated, layered multi-particulate formulation for ileal delivery of viable recombinant Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 61, Issue 3, October 2005, Pages 134-141
Nathalie Huyghebaert, An Vermeire, Pieter Rottiers, Erik Remaut, Jean Paul Remon
Research article
Evaluation of extrusion/spheronisation, layering and compaction for the preparation of an oral, multi-particulate formulation of viable, hIL-10 producing Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 59, Issue 1, January 2005, Pages 9-15
Nathalie Huyghebaert, An Vermeire, Sabine Neirynck, Lothar Steidler, Eric Remaut, Jean Paul Remon
Research article
Liquid absorption capacity of carriers in the food technology
Powder Technology, Volume 134, Issue 3, 30 September 2003, Pages 201-209
Heidi Lankes, Karl Sommer, Bernd Weinreich
Abstract
The focus of the current work is to study and demonstrate the impact of the design, the scale, and settings of fluid-bed coating equipment on the differences in pellet coating thickness, which in case of prolonged-release pellets dictates the drug release. In the first set of coating experiments, the pellet cores were coated with the Tartrazine dye with the aim of estimating the coating equipment performance in terms of coating thickness distribution, assessed through color hue. In the second set, drug-layered pellets were film-coated with prolonged-release coating and dissolution profile tests were performed to estimate the thickness and uniformity of the coating thickness among differently sized pellets. In both study parts, film coating was performed at the laboratory and the pilot scale and essentially two types of distribution plate and different height adjustments of the draft tube were compared. The dye coating study proved to be extremely useful, as the results enable process correction and the optimal use of the process equipment in combination with the appropriate process parameters. Preferential film coating of larger drug-containing pellets was confirmed on the laboratory scale, while on the pilot scale, it was possible to achieve preferential coating of smaller pellets using rational alternatives of settings, which is desirable in terms of particle size-independent drug release profile of such prolonged-release dosage forms. […]
Materials
In the first part of the study, neutral MCC pellets (CELLETS 700, IPC Process Center GmbH, Germany) were coated with water solution composed of 8% w/w HPMC 6 mPas (Shin-Etsu Chemical, Japan), 1% w/w Macrogol 6000 (Clariant Produkte GmbH, Glendorf site, Germany), 1% w/w coloring agent Tartrazine (Sigma-Aldrich, USA), and purified water (90%, w/w).
In the second part of coating experiments, API-coated pellets containing Diclofenac sodium were coated with water-based sustained release coating dispersion containing Eudragit RS 30D (9.6% w/w), Eudragit RL 30 D (19.2% w/w) (Evonic Nutrition Care GmbH, Germany), 1.7% w/w triethyl citrate (Vertellus LLC, USA), and 10.4% w/w talc.
Methods
Pellet Film-Coating Experiments with Tartrazin
Coating experiments using Tartrazine dye were performed on two laboratory-sized fluid-bed coaters (GPCG1, Glatt GmbH, Germany and BX FBD10, Brinox d.o.o., Slovenia) and on one pilot-sized (BX FBD30, Brinox d.o.o., Slovenia) fluid-bed coater. In case of both laboratory coaters, the type of distribution plate and the gap between the plate and the draft tube were varied. The pilot-scale setup with three swirl generators and draft tubes was used, while only the size of the gap was varied during coating experiments (Table I). All other process parameters were comparable within each coating process scale. […]
Size distributions of uncoated CELLETS® 700 used in Tartrazine coating experiments and of drug-layered pellets used in PR coating experiments
Conclusion
Considering the results of the coating process evaluation with the dye-coated pellet approach, based on previous research, it can be said that the obtained positive slopes of size preferential coating in the laboratory-scale CW process chamber are within the expected performance of this type of coater design. The values of the slope of the size preferential coating were always lower in the case of the SW distribution plate in comparison with the CW design of the distribution plate. However, within the laboratory-scale coater designs, different performances of swirl generator equipped flat and funnel-shaped distribution plates were identified, the latter exhibiting the least size dependent preferential coating performance. This was attributed to a less expressed dead zone effect enabling mixing and elimination of any segregation in the pellet bed region of the coater. On the pilot film-coating scale, coater equipped with flat SW distribution plates exhibited negative size preferential coating slope, meaning that smaller pellets obtained more coating than larger ones, which is unprecedented result. Moreover, the extent of the negative size preferential coating slope depended on the dynamics of the pressure drop fluctuations. This finding was effectively translated to the prolonged-release coating application, where the right extent of the negative size preferential coating ensures pellet size-independent drug release profiles, thus improving robustness of such multiple unit prolonged-release formulation. By lowering the air flow rate and using bimodal size distribution, rich in smaller drug-layered pellets, led to rather surprising results, where performance of prolonged drug release-coated pellets did not resemble size preferential coating results from the dye coating study part.
These results confirm the fact that we must have a good knowledge of the coater performance characteristics in combination with the process variables and even formulation properties, if we want to produce coated multiple-unit solid pharmaceutical products of the highest quality.
Disclaimer
Excerpt from: AAPS PharmSciTech, 24, 93 (2023), https://doi.org/10.1208/s12249-023-02540-9. by T. Brezovar, G. Hudovornik, M. Perpar, M. Luštrik, and R. Dreu.
Abstract on Continuous Manufacturing
Using cocrystals has emerged as a promising strategy to improve the physicochemical properties of active pharmaceutical ingredients (APIs) by forming a new crystalline phase from two or more components. Particle size and morphology control are key quality attributes for cocrystal medicinal products. The needle-shaped morphology is often considered high-risk and complex in the manufacture of solid dosage forms. Cocrystal particle engineering requires advanced methodologies to ensure high-purity cocrystals with improved solubility and bioavailability and with optimal crystal habit for industrial manufacturing. In this study, 3D-printed microfluidic chips were used to control the cocrystal habit and polymorphism of the sulfadimidine (SDM): 4-aminosalicylic acid (4ASA) cocrystal. The addition of PVP in the aqueous phase during mixing resulted in a high-purity cocrystal (with no traces of the individual components), while it also inhibited the growth of needle-shaped crystals. When mixtures were prepared at the macroscale, PVP was not able to control the crystal habit and impurities of individual mixture components remained, indicating that the microfluidic device allowed for a more homogenous and rapid mixing process controlled by the flow rate and the high surface-to-volume ratios of the microchannels. Continuous manufacturing of SDM:4ASA cocrystals coated on beads was successfully implemented when the microfluidic chip was connected in line to a fluidized bed, allowing cocrystal formulation generation by mixing, coating, and drying in a single step.
Conclusions
SDM:4ASA cocrystal particle engineering has been successfully achieved using 3D-printed microfluidic chips. The addition of PVP in the aqueous phase during mixing has allowed the inhibition of needle-shaped crystals and the generation instead of spherical crystal habits with higher purity compared to conventional mixing. A successful continuous manufacturing method for the fabrication of cocrystal-coated particles has been demonstrated by the combination of microfluidic chips with a fluidized bed, allowing the process intensification of mixing and drying in one step.
Authors:
Aytug Kara, Dinesh Kumar, Anne Marie Healy, Aikaterini Lalatsa, and Dolores R. Serrano.
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Read more on continuous manufacturing of cocrystals by Kara et al. here and find out the functionality of CELLETS® 500 (pellets made of microcrystalline cellulose, size: 500-710 µm).
ingredientpharmThe publication by G. Kumisbek, D. Vetchý, A. Kadyrbay describes gently the development and implementation of a new generic enteric form of CELLETS® 700 (MCC pellets, 700-1000 µm) loaded with omeprazole in capsules by Viva Pharm LLP, a pharmaceutical company based in Kazakhstan. The company’s solid-dosage-form production facility was utilized for this purpose. Detailed technological parameters for production were established and documented in production protocols for commercial batches. Stability testing confirmed the viability of the developed drug in two types of packaging. An analytical normative document containing comprehensive quality control test methods was created for both experimental purposes and the registration dossier.
Equivalence to the innovative drug, Losec®, was demonstrated through dissolution profile testing and Bioequivalence Study (BES). The aim is to commercialize the new generic drug in the pharmaceutical market of Kazakhstan upon obtaining marketing authorization. This initiative aligns with Kazakhstan’s strategy to localize pharmaceutical production, mirroring similar practices in Europe, to ensure affordable and high-quality medicines for its population. The successful development and localization of this generic omeprazole formulation signify a step towards enhancing access to essential medications within Kazakhstan.
Abstract
Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.
Materials
The following materials were used in the study: omeprazole (Hetero Labs, Hyderabad, India) Active Pharmaceutical Ingredient (API), lactose monohydrate Supertab 22AN (Glentnam Life Sciences Ltd., Corsham, UK), sodium lauryl sulfate (RNDr Kulich Pharma s.r.o., Hradec Králové, Czech Republic), disodium hydrogen phosphate dodecahydrate cryst. EMPROVE® (Merck KGaA, Darmstadt, Germany), hydroxypropylmethylcellulose (Tailopur 603), hydroxypropyl cellulose Klucel EF Pharm (Ashland Industries Europe GmbH, Schaffhausen, Switzerland), pellets from microcrystalline cellulose (MCC) Cellets®700 (International Process center GmbH & Co. KG, Dresden, Germany), polyethylene glycol 400 (Applichem GmbH, Darmstadt, Germany), methacrylic acid–ethyl acrylate copolymer Eudragit® L30-D55 (Evonic Nutrition and Care GmbH, Darmstadt, Germany), hard gelatin capsules size 0 (Capsugel, Bornem, Belgium), PlasAcryl® HTP20 (Emerson Resources Ink., Norristown, PA, USA), titanium dioxide (Venator Germany GmbH, Krefeld, Germany), talc (Imerys Talc Italy S.p.A, Porte, Italy). All ingredients were of pharmaceutical production grade as described in the European Pharmacopoeia, and are widely used in preparations for oral use at concentrations not exceeding the recommended limits. Losec®, enteric capsules, 20 mg, AstraZeneca AB, Sweden, was used as the reference drug.
Conclusion
The quantitative and qualitative composition and technology for producing a new generic enteric form of omeprazole in capsules were developed and implemented at the solid-dosage-form production facility of the company Viva Pharm LLP, located in Kazakhstan. The technological parameters of the production process were established and specified in production protocols for commercialized product batches. The developed drug in two types of packaging has passed the stability test. An analytical normative document consisting of full quality control test methods was created for the experimental part and the registration dossier. The equivalence of the generic formulation omeprazole Viva Pharm, enteric capsules, to the innovative drug Losec®, enteric capsules, was proved by the dissolution profile test and BES. The new generic drug is aimed to be commercialized in the pharmaceutical market of the Republic of Kazakhstan after obtaining marketing authorization. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and high-quality medicines.
Source: Medicina 2024, 60(3), 427
Abstract on paediatric solid oral dosage forms
There is a growing interest in enhancing the acceptability of paediatric pharmaceutical formulations. Solid oral dosage forms (SODF), especially multiparticulates, are being considered as an alternative to liquid formulations, but they may compromise palatability when large volumes are required for dosing. We hypothesised that a binary mixture of multiparticulates for paediatric use, designed to increase the formulation maximum packing fraction, could reduce the viscosity of the mixture in soft food and facilitate swallowing.
Using the Paediatric Soft Robotic Tongue (PSRT) – an in vitro device inspired by the anatomy and physiology of 2-year-old children – we investigated the oral phase of swallowing for multi-particulate formulations, i.e., pellets (350 and 700 µm particles), minitablets (MTs, 1.8 mm), and their binary mixtures (BM), by evaluating oral swallowing time, the percentage of particles swallowed, and post-swallow residues. We also conducted a systematic analysis of the effect of the administration method, bolus volume, carrier type, particle size, and particle volume fraction on pellets swallowability.
The results demonstrated that the introduction of pellets affected the flowing ability of the carriers, increasing shear viscosity. The size of the pellets did not appear to influence particle swallowability but raising the particle volume fraction (v.f.) above 10% resulted in a decrease in the percentage of particles swallowed. At v.f. 0.4, pellets were easier to swallow (+ 13.1%) than MTs, being the administration method used highly dependent on the characteristics of the multi-particulate formulation under consideration. Finally, mixing MTs with only 24% of pellets improved particle swallowability, achieving swallowing levels similar to those of pellets alone. Thus, combining SODF, i.e., MTs and pellets, improves MT swallowability, and offers new possibilities for adjusting product palatability, being particularly attractive for combination products.
Authors: Alejandro Avila-Sierra, Anais Lavoisier, Carsten Timpe, Peter Kuehl, Leonie Wagner, Carole Tournier, Marco Ramaioli
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Get the full publication on paediatric solid oral dosage forms by Alejandro Avila-Sierra et al. here. Used MCC pellet: Cellets 350 and Cellets 700.
Abstract
Mini-tablets made into hard capsules or administered using special dosing units, as well as pellets in hard capsules or compressed into tablets, offer the advantages of multiparticulate drug delivery systems and are suitable for controlled drug release using polymer coatings. Four different kinds of solid drug preparations were manufactured and investigated concerning drug release. Inert pellets were coated with the model drug sodium benzoate and, in a second step, with the insoluble polymer ethylcellulose. The coated pellets were compressed into mini-tablets and into normal tablets. Another kind of mini-tablet was compressed from a sodium benzoate compression mixture and finally coated with ethylcellulose. The coating of the tablets was performed using fluidized bed technology. The sodium benzoate release plots of the coated pellets show a lag time and retarded release according first-order kinetics. The mini-tablets and normal tablets compressed from pellets release sodium benzoate according to first-order kinetics as well, but without the lag time due to distinct ethylcellulose layer destruction during tableting. The release is retarded with increasing ethylcellulose layer thickness on directly compressed mini-tablets. The different formulations of coated pellets, mini-tablets, and normal tablets offer a broad choice for variable drug release kinetics depending on the biopharmaceutical and pharmacological requirements.
Conclusion
Drug- and polymer-coated pellets may be compressed into mini-tablets as well as into normal tablets. Pellets and mini-tablets compressed into tablets as a multiparticulate drug delivery system offer the advantage of being widely spread in the small intestine for improved drug absorption and increased bioavailability compared to normal tablets. With both tablet types (normal and mini), the sodium benzoate release is delayed depending on the thickness and properties of the ethylcellulose film on the pellets.
Ethylcellulose-coated mini-tablets obtained through the direct compression of sodium benzoate and excipients are an alternative method for multiparticulate drug delivery system preparation. The product is characterized by a slow release rate depending on the ethylcellulose film thickness that may be suitable when prolonged release is required. The variation in release is increased compared to pellets and normal multiple-unit tablets with pellets. Sodium benzoate layering on pellets in the fluidized bed and the subsequent tableting process are feasible for both mini-tablets and normal tablets, representing an interesting option when a variation in the final pharmaceutical form is required for marketing/patenting reasons.
Authors
F. Priese, D. Wiegel, C. Funaro, G. Mondelli, and B. Wolf
Coatings 2023, 13(11), 1891; https://doi.org/10.3390/coatings13111891
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Read more about how CELLETS 200 are employed in mini-tablets and pellets as multiparticulate drug delivery systems by F. Priese et al. here.