Close-up SEM images of Cellets® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (bold).

Multidimensional Correlation of Surface Smoothness and Process Conditions

Abstract

Multidimensional Correlation of Surface Smoothness and Process Conditions is a necessary attempt to better understand, optimize and outperform process steps of drug formulations. Particle coating and layering in a fluidized bed process is a main attempt in pharmaceutical industry for drug production for modern oral dosage forms. The precise knowledge of control process parameters leads to high surface control of the drug-loaded particles and therefore is crucial for the quality and yield of production in a more general aspect. This application note presents a multidimensional attempt by Orth et al. [1] to correlate particle surface structure morphology and process conditions in a fluidized bed layering spray granulation. CELLETS® 500 are used as spherical, high-quality starter cores.

About fluidized bed process conditions

Fluidized bed processes are used in pharmaceutical, food and agro industries. Solid particles are transported in a defined gas stream inducing fluidized bed conditions. Solid-containing dispersions or liquids are sprayed onto the fluidized particles. Variable settings of process parameters allow particle layering, coating, coalescence and agglomeration. This point seems to make the fluidized bed becoming a universal process for particle processing, but also requests deeper knowledge about the desired process parameter settings: The goal is a stable, high-quality, high-output process.

Standard process parameters are:

  • liquid spray rate (m­1)
  • fluidization air flow rate (Vair)
  • fluidization air temperature (Tin)
  • spray air temperature (Tat)
  • spray atomization pressure (p­at)

Beside the spraying process, also the drying process plays an important role. By drying, moisture, sticky conditions and flowability are strongly influenced. Hampel [2] analyzed in her doctoral thesis the importance of the drying process using CELLETS® 200 as model particles.

Technology, Materials and Analysis

The coating experiments were carried out in a ProCell® 5 LabSystem with the fluidized bed process chamber GF3 (Glatt GmbH, Germany) as shown in Figure 1. The ProCell® 5 LabSystem is designed for testing of spouted bed and fluidized bed processes in the single kg-scale.

Sketch of the experimental fluidized bed setup (Procell® 5 LabSystem with GF3 chamber).

Fig.1: Sketch of the experimental fluidized bed setup (Procell® 5 LabSystem with GF3 chamber).

As Materials, pellets made of 100% microcrystalline cellulose (CELLETS® 500) are employed as perfect starter cores. These pellets provide smooth and defined surface properties, chemical inertness, robustness and a high degree of sphericity. Specific properties of CELLETS® 500 for this study are shown in Table 1. The roughness is at 1.5 µm and therefore delivers perfect initial conditions for controlled spray granulation.

Property Value
Sauter diameter 639 µm
Sphericity 0.96
Surface roughness 1.5 µm
Solid density 1.445 g/cm3

Table 1: Properties of CELLETS® 500.

As spray liquid, a 30 wt% sodium benzoate solution was injected into the process chamber. The mass ratio of spray liquid to starter cores was 1:2. Different coating conditions have statistically been driven. In turn, the spray-coated particles show different surface structures (Figure 2a-d).

SEM images of Cellets® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (bold).

Fig.2a: SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (bold).

Close-up SEM images of Cellets® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (bold).

Fig. 2b: Close-up SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (bold).

SEM images of Cellets® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (italic).

Fig. 2c: SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (italic).

Close-up SEM images of Cellets® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (italic).

Fig. 2d: Close-up SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (italic).

 

Parameter Controlled values
liquid spray rate (m­1) 10 | 15 | 20
fluidization air flow rate (Vair) 80 | 105 | 130
fluidization air temperature (Tin) 50 | 85 | 120
spray air temperature (Tat) 20 | 70 | 120
spray atomization pressure (p­at) 0.5 | 1.75 | 3.0

Table 2: Process parameters and values used in coating experiments.

The coated particles were analyzed regarding their surface roughness via laser scanning microscopy (VK-X160K, Keyence, Japan). Additional images were obtained with a scanning electron microscope (Supra VP55, Zeiss, Germany).

A 3D-profile of the particle surface was created and evaluated in a defined measurement area. Roughness analysis can be performed through several parameters as defined in DIN EN ISO 4287:2010-07 (2010) and DIN EN ISO 25178-2:2012 (2012). In this attempt, the arithmetical mean height was used as roughness quantifier. The roughness was correlated to the process parameters and the resulting linear correlation was rigorously analyzed using a principal component analysis.

Results

A linear regression model is fitted to the roughness data using the ordinary least squares method. This enables to create a linear model connecting the chosen process parameters to the surface roughness of the coated particles. It is mentionable, that in this attempt the fluidization air flow rate and the spray air temperature did not show a significant effect on the surface structure and were therefore removed from the model.

Process conditions: Influence of the liquid spray rate

Figure 3: Surface roughness versus liquid spray rate. The crosses mark the experimentally investigated spray rates; line represents a linear interpolation.

Figure 3: Surface roughness versus liquid spray rate. The crosses mark the experimentally investigated spray rates; line represents a linear interpolation.

The dependence of the surface roughness on the spray rate of the sodium benzoate solution is shown in Figure 3. A slight increase of surface roughness is identified for increasing spray rates. The main effect is considered to be influenced by the crystallization of sodium benzoate. Following, crystallization is higher at higher spray rates caused by lower evaporation due to higher liquid volumes in the process. The dependence of the crystallization of sodium benzoate on the drying conditions during fluidized bed coating was also observed by Rieck et al. [3] and Hoffmann et al. [4].

Process conditions: Influence of the fluidization air inlet temperature

Figure 4: Surface roughness versus fluidization air inlet temperature. The crosses mark the experimentally investigated temperatures; line represents a linear interpolation.

Figure 4: Surface roughness versus fluidization air inlet temperature. The crosses mark the experimentally investigated temperatures; line represents a linear interpolation.

An increase in the fluidization air inlet temperature results in a lower roughness of the coated particles and therefore in a smoother particle surface. The temperature of the fluidization air has a major impact on the drying conditions during the spray granulation process. As an increased temperature causes reduced relative humidity, the heated air can absorb a larger amount of water, which results in a high drying rate. Crystal growth of spray droplets is reduced by fast evaporation times and short drying times.

Process conditions: Influence of the atomization pressure

Figure 5: Surface roughness versus spray atomization pressure. The crosses mark the experimentally investigated pressures; line represents a linear interpolation.

Figure 5: Surface roughness versus spray atomization pressure. The crosses mark the experimentally investigated pressures; line represents a linear interpolation.

With increasing atomization pressure from 0.5 bar to 3.0 bar, the surface roughness is decreasing. The pressure of the spray air strongly influences the droplet size and velocity. With increasing atomization pressure, the droplet size and size distribution decreases while the droplet velocity increases which in causes a more homogeneous spreading and promotes smoother surface coatings.

Summary

CELLETS® 500 are used as model particles for analyzing the surface roughness of coated particles dependent on process conditions in a bottom-spray process. As the results suggest, a high surface roughness is achieved at low fluidization air temperatures, low atomization pressures and high spray rates of the coating solution. Conversely, at high air temperatures, high spray pressures and low liquid spray rates, particles with smooth and compact surfaces are produced.

Acknowledgement

Prof. Stefan Heinrich and his team are gratefully acknowledged for serving content for this note:

Hamburg University of Technology - Institute of Solids Process Engineering and Particle Technology
Hamburg University of Technology
Institute of Solids Process Engineering and Particle Technology
Contact: Prof. Dr. Stefan Heinrich
Denickestrasse 15, 21073 Hamburg, Germany
Tel: +49 40 42878 3750
E-mail: stefan.heinrich@tuhh.de
Website: https://www.tuhh.de/spe/

University Course Fluidization Technology

The authors got funding from the German Research Foundation within the DFG Graduate School GRK 2462 “Processes in natural and technical Particle-Fluid-Systems (PintPFS)” (Project No. 390794421) and funding from BASF SE.

CELLETS® 500 were sponsored by HARKE Pharma.

References

[1] M. Orth, P. Kieckhefen, S. Pietsch and S. Heinrich. KONA Powder and Particle Journal (2021). DOI: 10.14356/kona.2022016

[2] N.A. Hampel, Dissertation, Otto-von-Guericke-Universität Magdeburg, 2015. DOI:10.25673/4340

[3] Rieck C., Hoffmann T., Bück A., Peglow M., Tsotsas E., Powder Technology, 272 (2015) 120–131. DOI:10.1016/j.powtec.2014.11.019

[4] Hoffmann T., Rieck C., Bück A., Peglow M., Tsotsas E., Procedia Engineering, 102 (2015) 458–467. DOI: 10.1016/j.proeng.2015.01.189

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Figure 4: Images of a Jelly without (left) and with incorporation of sustained release micropellets (right).

Gliclazide formulations for Sustained Release Delivery

Abstract

Patients with dysphagia may have obstacles to swallow tablets or large multiparticulates. The former dosage form can even not be crushed in case that the tablet exhibits a modified release or taste-masking profile through outer layering. As a solution, so called jelly formulations may be a valuable attempt. Jellies are delivery vehicles incorporating sustained release microparticles for patients with dysphagia. This case study investigates a modified release formulation based on Gliclazide. Gliclazide is used to treat diabetes mellitus type 2. In combination with selected excipients, a jelly-like appearance is composed. Micropellets made of microcrystalline cellulose (Cellets®) are used as API carrier systems.

Goals and Formulation of a Gliclazide drug

The goal is to investigate a revolutionary method for geriatrics with dysphagia or potentially for paediatrics based on jelly-like formulations. The formulation should carry an API such as Gliclazide and show a modified release profile.

Free-standing jellies are formulated by mixing sodium alginate (0.5 % w/v with another polymer, and 1 % w/v w/o polymer), with an aqueous solution of dicalcium phosphate dihydrate (0.1-1 % w/v).

Soft granular jellies are formulated by preparing an aqueous sodium alginate (0.5-2 % w/v) solution with or without the presence of another polymer and by later adding an aqueous calcium chloride solution (0.1-0.3 % w/v).

Figure 1: Image of MCC micropellets (Cellets® 100).

Figure 1: Image of MCC micropellets (Cellets® 100).

MCC micropellets (Cellets® 100, Figure 1) are used as drug carriers. Gliclazide is layered onto the starter beads using a Wurster fluidized bed coater (Mini-Glatt, Glatt GmbH, Germany), so that a 50 % drug loading weight gain was reached. The overall final drug load including the functional layer is 21 % w/w. The composition of the layering suspension is given in Table 1.

Material QTY
Starter pellet: Cellets® 100 100 g
API: Gliclazide 10 % w/w
Aqueous vehicle for API:
  Hypromellose 1 % w/w
  Talc 1.9 % w/w
Coating of API layered pellets:
  Water
  Eudragit® NM 30 D
  Talc
Functional coating:
  Magnesium stearate
  Silicon dioxide

Table 1: Formulation for Gliclazide layered starter pellets: starter pellets, aqueous API layering, release profile coating, functional coating.

Although the formulation contains several coating and layering processes, the processed micropellets stay smooth in surface, show a high sphericity and narrow size distribution.

Size distribution and dissolution profiles of Gliclazide microparticles

Polymer coated micropellets with CL25 (coating level 25 %) are shown in  Figure 2. The yield of polymer coating and the final D50 values of the micropellets are displayed in Table 2.

Figure 2: SEM image of layered Gliclazide sustained release micropellets with a weight gain at 25 % (CL25).

Figure 2: SEM image of layered Gliclazide sustained release micropellets with a weight gain at 25 % (CL25).

Depending on the polymer coating, micropellets show a different Gliclazide release profile as shown in Figure 3: With increasing weight gain, the dynamics of Gliclazide release are slowed down. A comparison to Diamicron SR tablets in a pH 7.4 phosphate buffer, the CL25 formulation results in an adequate release profile.

Micropellet Size D50 [µm] Yield [%]
Starter pellet (Cellets® 100) 160 ± 2.1
Micropellet at CL16 173 ± 3.6 98.4
Micropellet at CL20 185 ± 2.4 99.3
Micropellet at CL25 198 ± 4.3 99.0
Micropellet at CL60 208 ± 6.7 98.7

Table 2: Particle size of the micropellets with and without layering. CL = coating level / weight gain in [%]. The yield for the polymer coatings at respective weight gains.

Figure 3: Gliclazide release from layered micropellets at coating levels 16 % (filled diamond), 20 % (open circles), 25 % (filled squares) and 60 % (filled circles) and the commercial Diamicron SR tablets (open squares) in phosphate buffer pH 7.4.

Figure 3: Gliclazide release from layered micropellets at coating levels 16 % (filled diamond), 20 % (open circles), 25 % (filled squares) and 60 % (filled circles) and the commercial Diamicron SR tablets (open squares) in phosphate buffer pH 7.4.

Incorporation of the Gliclazide microparticles into jellies

The incorporation of sustained release Gliclazide microparticles into the Jellies is realized through mixing the required quantity of microparticles with polymers (sodium alginate or polymer mixture).

Sodium alginate is known to form gels in the presence of calcium ions at room temperature. Depending on the formulation, granular jellies (soft and easy to flow) or free-standing jellies (“ready-to-eat”) are formed. Formulations of jellies with and without API layered micropellets are shown in Figure 4. Incorporating the micropellets into the jellies did not cause a visual change in color or appearance. The API was kept inside the jellies. Also physical-chemical properties such as the gel strength, the texture, and the oral transit time in an in-vitro swallowing simulator are remained unchanged.

Figure 4: Images of a Jelly without (left) and with incorporation of sustained release micropellets (right).

Figure 4: Images of a Jelly without (left) and with incorporation of sustained release micropellets (right).

Figure 4: Images of a Jelly without (left) and with incorporation of sustained release micropellets (right).

A release profile of Gliclazide with a coating level of 25 % in a jelly formation is shown in Figure 5. In comparison to a reference release profile of a Diamicron 30 mg SR tablet, the coated micropellets show a competitive behavior as already discussed in Figure 3. After incorporating into the jelly formation, the release profile is decaying. Obviously, the intact and also the fragmented jelly formulation show comparable dynamics. In order to obtain a comparable release profile than with the non-formulated micropellets, a coating level of down to 20 % is required.

Figure 5: Gliclazide release from coated microparticles and in combination with Jellies in a pH 7.4 phosphate buffer. Diamicron 30 mg SR tablet (open triangle), no jelly at CL25 (closed triangle), jelly formulation (intact) incorporated with CL25 (closed circle), jelly formulation (fragmented) incorporated with CL25 (open circle), jelly formulation (intact) with CL20 (open square).

Figure 5: Gliclazide release from coated microparticles and in combination with Jellies in a pH 7.4 phosphate buffer. Diamicron 30 mg SR tablet (open triangle), no jelly at CL25 (closed triangle), jelly formulation (intact) incorporated with CL25 (closed circle), jelly formulation (fragmented) incorporated with CL25 (open circle), jelly formulation (intact) with CL20 (open square).

Summary

Sustained release Gliclazide micropellets with a final particle size D50 of less than 200 µm are successfully formulated with a 99 % production yield and adjustable drug release profiles.

The micropellets are based on Cellets® 100 and present an excellent surface smoothness, high sphericity and narrow size distribution. They were successfully incorporated in jelly formulations. This novel drug delivery platform is a suitable vehicle for the administration of sustained release microparticles. It is a valuable attempt to replace the commonly used thickened fluids for dysphagia patients.

Acknowledgement

Dr. Fang Liu and her team are gratefully acknowledged for serving content for this note.

Fluid Pharma logo

Fluid Pharma Ltd

Contact: Dr. Fang LIU

College Lane, Hatfield, AL10 9AB, UK

Tel: +44 1707 28 4273

+44 796 3230 628

www.fluidpharma.com

References

[1] S. Patel et al., Journal of Pharmaceutical 109 (2020) 2474-2484.

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Figure 2: SEM image of drug loaded and coated starter beads. Particles show a high level of homogeneity in size distribution.

Microparticle coating in Wurster Fluidized Bed – Scalable Production of Oral Sustained-Release Drugs

Abstract

Modified drug release formulations for suspensions are a perfect solution for children and patients with swallowing difficulties. In many cases, these formulations are based on pellets serving as starter beads. In this report, an attempt on microparticle coating by Mohylyuk et al. [1] is described. Herein, small scaled microcrystalline cellulose pellets (Cellets® 90 and Cellets® 100, Table 1) in the size range smaller than 150 µm are used. Through a modified Wurster fluidized bed process, a yield of 99 % was reached.

Starter materials PSD (> 85 %)
Cellets® 90 63-125 μm
Cellets® 100 100-200 µm

Table 1: Size distribution of Cellets® as starter beads in this formulation.

Goals and Formulation

The goal is to investigate a revolutionary platform for sustained-release microencapsulation using the industrial fluidized bed coating technology. Significant challenges of particle cohesion in the process shall be avoided by applying a small quantity of dry powder glidant periodically during the coating process. A highly water-soluble drug, which is metoprolol succinate, is reproducibly microencapsulated on pellet technologies with total pellet sizes of less than 200 µm and a drug release time of 20 hours.

Excipients for extended release profiles

For obtaining a sustained release profile, polymethacrylate-based copolymers, Eudragit RS/RL® 30 D and Eudragit® NM 30 D, were used in combination with a range of anti-tacking agents. The coating onto placebo Cellets® 100 starter beads was performed in a fluidized bed coater with a Wurster insert (Mini-Glatt, Glatt GmbH, Germany) in order to analyze the release profile. Process parameters are shown in Table 2. A small quantity of dry powder glidant was periodically added during processing, so that particle cohesion was eliminated. The optimized excipient composition for the desired release profile is achieved by testing 10 different compositions.

Parameter Value
Inlet air temperature
 Eudragit RS/RL® 30 D 35-40 °C
 Eudragit® NM 30 D 30-35 °C
Product temperature
 Eudragit RS/RL® 30 D 25-30 °C
 Eudragit® NM 30 D 18-20 °C
air flow rate 18 m3/h
Atomization pressure 1.5 bar
Spray rate 1.1-2.4 g/min

Table 2: Process parameter for a fluidized bed coater with a Wurster insert. A sustained release drug layer is coated onto placebo Cellets® 100 starter beads.

Drug coating

For drug coating, Cellets® 90 were layered with a suspension of metoprolol succinate in a composition as shown in Table 3.

Material Concentration (w/w)
Metoprolol succinate 22.8 %
Hypromellose 0.6 %
talc (Pharma M) 4.0 %
Deionized water 72.6 %

Table 3: Composition of metoprolol succinate suspension for drug layering onto Cellets® 90.

The metoprolol succinate-loaded Cellets® 90 microparticles were successfully coated with the Eudragit® NM 30 D based aqueous dispersion, achieving a high product yield of 99 % and a final particle size of less than 200 µm (D50 value).

Figure 1: Size distribution of Cellets® 90 as uncoated (empty squares), drug loaded (filled diamonds) and drug loaded and coated (filled circles) particles.

Figure 1: Size distribution of Cellets® 90 as uncoated (empty squares), drug loaded (filled diamonds) and drug loaded and coated (filled circles) particles.

The API loaded and coated starter beads are of high sphericity and show a homogeneous and narrow size distribution, which is shown as a SEM (scanning electron microscope) image in Figure 2.

In dissolution tests, an extended release time of up to 20 hours is obtained and can still be varied by the composition of excipients (Figure 3).

Figure 2: SEM image of drug loaded and coated starter beads. Microparticles show a high level of homogeneity in size distribution.

Figure 2: SEM image of drug loaded and coated starter beads. Microparticles show a high level of homogeneity in size distribution.

Figure 3: Drug release profiles of three batches of metoprolol succinate loaded and coated Cellets. An extended release of 20 hours is obtained.

Figure 3: Drug release profiles of three batches of metoprolol succinate loaded and coated Cellets. An extended release of 20 hours is obtained.

Summary

This case study is a short abstract of the publication on microparticle coating by Mohylyuk et al. [1], highlighting the proof of concept for reproducible microencapsulation of a highly water-soluble drug by applying a small quantity of dry powder glidant periodically during Wurster fluidized bed coating. The challenge of particle cohesion in the “down flow” zone was eliminated and a high product yields up to 99% was achieved.

Coated microparticles are in size of less than 200 μm and show a 20 hours sustained drug release profile. These conditions allow the usage in liquid suspensions. Furthermore, the applied technology is scalable. In conclusion, this displays a sustained-release dosage solution, which is suitable for paediatrics and geriatrics with swallowing difficulties.

Acknowledgement

Dr. Fang Liu and her team are gratefully acknowledged for serving content and data for this note.

Fluid Pharma logo

Fluid Pharma Ltd

Contact: Dr. Fang LIU

College Lane, Hatfield, AL10 9AB, UK

Tel: +44 1707 28 4273

+44 796 3230 628

www.fluidpharma.com

References

[1] V. Mohylyuk et al., AAPS PharmSciTech (2020) 21:3

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