CELLETS® 700

(700-1000 µm)

CELLETS® 700 is a subtype of pellets made of microcrystalline cellulose. The size ranges from 700 µm to 1000 µm. Find more product information and technical specifications.

Benefits of multilayer high drug-loaded amorphous solid dispersions

Introduction on amorphous solid dispersions

What is the benefit of multilayer amorphous solid dispersions? Recently, several studies had been performed on amorphous solid dispersions working spheres or starter beads. Starter beads, such as MCC (Microcrystalline Cellulose) spheres are employed due to their high friability and chemical inertness. Some studies are even working on solventless pelletization and amorphization using high shear granulator techniques [1].

Amorphization of poorly water-soluble drugs is a promising approach to improve the solubility and dissolution rate as amorphous solids lack a crystal lattice with long-range order [2]. Unfortunately, a high chemical potential compared to crystalline forms makes amorphous forms thermodynamically unstable. Thus, amorphous drugs exhibit low physical stability and finally lack of recrystallization [3,4]. In turn, surface crystallization is to be minimized.

Multilayer amorphous solid dispersions

This is the key focus of a publication by Eline Boel and Guy Van den Mooter: They had been investigating a promising solution of multilayer high-drug load amorphous solid dispersions, as follows [5]:

Inhibiting surface crystallization is an interesting strategy to enhance the physical stability of amorphous solid dispersions (ASDs), still preserving high drug loads. The aim of this study was to investigate the potential surface crystallization inhibitory effect of an additional polymer coating onto ASDs, comprising high drug loads of a fast crystallizing drug, layered onto pellets. For this purpose, bilayer coated pellets were generated with fluid-bed coating, of which the first layer constitutes a solid dispersion of naproxen (NAP) in poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in a 40:60 or 35:65 (w/w) ratio, and ethyl cellulose (EC) composes the second layer. The physical stability of these double-layered pellets, in comparison to pellets with an ASD layer only, was assessed under accelerated conditions by monitoring with X-ray powder diffraction (XRPD) at regular time intervals. Bilayer coated pellets were however found to be physically less stable than pellets with an ASD layer only. Applying the supplementary EC coating layer induced crystallization and heterogeneity in the 40:60 and 35:65 (w/w) NAP-PVP-VA ASDs, respectively, attributed to the initial contact with the solvent. Caution is thus required when applying an additional coating layer on top of an ASD layer with fluid-bed coating, for instance for controlled release purposes, especially if the ASD consists of high loads of a fast crystallizing drug.

Read more on doi:10.1016/j.ijpharm.2022.122455.

How about following up studies on ASD formulation with starter beads? Simply, contact us für MCC spheres, such as CELLETS® 700 (700-1000 µm, US mesh 18/25).

Your technology and formulation partner for amorphous solid dispersions:

Glatt in amorphous solid dispersions

References

[1] K. Kondo, T. Rades, European Journal of Pharmaceutics and Biopharmaceutics 181 (2022) 183–194 doi:10.1016/j.ejpb.2022.11.011

[2] B.C. Hancock, M. Parks, Pharm. Res. 17 (2000) 397-404.

[3] L.I. Blaabjerg, E. Lindenberg, T. Rades, H. Grohganz, K. Lobmann, Int. J. Pharm. 521 (2017) 232-238.

[4] A. Singh, G. Van den Mooter, Adv. Drug Deliv. Rev. 100 (2016) 27-50.

[5] E. Boel, G. Van den Mooter, International Journal of Pharmaceutics (2022) 122455. doi:10.1016/j.ijpharm.2022.122455

 

Abstract

This case study is a short abstract on spouted bed characteristics, following closely findings in the publication by J. Vanamu and A. Sahoo [1].

Spouted bed systems are of highest importance for all powder processing industries, and more specific in pharmaceutical industry for coating and drying in pellet technologies [2]. These systems offer manufacturing particularly fine and temperature-sensitive particles from small to large scale: laboratory systems are capable of processing product volumes of very few grams, while production systems can handle capacities of several tons [3].

But how to control conditions in spouted beds for efficient process applications, like mixing, coating, or drying?

There might be certain reasons, that the hydrodynamic behavior of the spouted bed in the pharmaceutical industries is less investigated. The referred publication shed some light on the hydrodynamic characteristics of a spouted bed where the MCC Spheres (CELLETS®) are adopted as the bed material. These starter cores are ideal model systems due to their perfect sphericity and zero-level friability. At the same time, smooth and defined surface structure initiate perfect modelling conditions in the spouted bed dynamics.

Material

CELLETS®, made of 100% Microcrystalline Cellulose, have been used as bed material. The physical properties of the CELLETS® are shown in Table 1. The CELLETS® particle morphology is represented in Figure 1.

Parameter Value
CELLETS® 700 and CELLETS® 1000
Size distribution 700-1000 µm (CELLETS® 700)

1000-1400 µm (CELLETS® 1000)

Bulk density 800 kg/m3
Particle sphericity > 0.9
Void fraction 0.42
Geldart classification B

Table 1: Physical properties of the CELLETS®.

SEM micrographs of CELLETS® 700

Figure 1: SEM micrographs of CELLETS® 700, found in [1].

Spouted bed: experiment setup

There are some international players on the market of spouted bed technologies, such as Glatt which seems to be the major one (Figure 2). In this framework, a self-made setup is used for experiments. The experiments that have been carried out in a column, which is fabricated from a Perspex sheet. This column consists of a cylindrical section of height 0.53 m and a diameter of the cylinder of 0.135 m. The column further converged the diameter of the cylinder to 0.05 m as a conical bottom having a length of 0.47 m. The spouting air is supplied by a compressed air line is controlled by a gas regulator. The airflow is controlled by a gate valve and a mesh plate having a mesh size less than the size of the bed material is employed as a separator preventing the backflow of the bed material. Images are captured using a high-speed video camera to gain more details of the hydrodynamic characteristics of the flow pattern inside the spouted bed geometry.

Spouted bed

Figure 2: Scheme of a spouted bed (Glatt, Germany).

Experiments & spouted bed results

Experiments are carried out with three different static bed heights of shallow depth wherein the bed height is in the range of factor 2-3 of the Inlet diameter using two different particle distribution classes at 500-710 µm and 700-1000 µm, respectively. Analyzed parameters are the pressure drop across the bed, the bed expansion ratio, and the clusters concerning the superficial gas velocity are focused in the following.

J. Vanamu et al. found that the “bed expansion ratio increases with increasing superficial gas velocity until the onset of external spouting, further increase in the superficial gas velocity, the bed expansion ratio decreases. With increasing the volume of bed, the bed expansion ratio decreases. In a larger volume of bed, the particles tend to spout into the freeboard region rather than expanding with higher superficial gas velocity”. Initial spouting is symmetric, but with increasing superficial gas velocity spouting becomes asymmetric, and asymmetry is more pronounced or starts at lower superficial gas velocities for smaller particles. This agrees with existing theories of hydrodynamic behavior in a fluidized environment. Respecting the necessarity of a proper flow behavior for mixing, coating or drying applications in drug processing, symmetric spouting is essential. In turn, the superficial gas velocity may be kept low.

In case that high superficial gas velocity regimes are required for the operations a draft tube may be installed within the column to achieve the symmetric spout formation.

Summary

This case study highlights the Hydrodynamic behavior of MCC spheres in a spouted bed using image processing method. MCC spheres in the range between 500-710 µm and 700-1000 µm had been employed. All spheres showed a symmetric and asymmetric spouting in the spouted bed. With increasing superficial gas velocity, the fully suspended particles are limited to a certain height in the freeboard region due to the gas-solid crossflow. A change from symmetric to asymmetric spouting is observed with increasing superficial gas velocity.

Keeping the conditions efficient for the mixing, coating or drying applications requires finally to suppress high superficial gas velocities, or changing the setup in such way, that symmetric spouting conditions are kept upright even at higher superficial gas velocities.

References

[1] J. Vanamu and A. Sahoo, Particuology 76 (2023) 101

[2] L. A. P. de Freitas, Particuology 42 (2019) 126

[3] Glatt GmbH, Binzen, Germany. Online on Nov 8, 2022: Spouted bed systems – Glatt – Integrated Process Solutions

Great thanks to Arihant Innochem Pvt. Ltd. who supplied and donated CELLETS® for this study.

Metoprolol pellets

Abstract on Metoprolol pellets

Metoprolol Tartrate is a salt of Metoprolol, a selective β1-receptor blocker medication. The application is the treatment of high blood pressure, chest pain due to poor blood flow to the heart, and several conditions involving an abnormally fast heart rate [2]. In the following, an attempt is shown, wherein MCC spheres are used as starter cores for a multi-layer pellet formulation.

This case study is a short abstract of the publication by P. Wanasawas et al. [1] and presents controlled release Metoprolol Tartrate layered pellets achieving colon-specific drug delivery.

Pellet technology attempt

In the following, in-situ calcium pectinate-coated MCC pellets (CELLETS® 700) were proposed by applying an alternate coating method to drug-layered pellets to achieve colon-specific drug delivery. Using a centrifugal granulator, inert MCC pellets were layered by a Metoprolol Tartrate water-soluble model drug. A protective HPMC layer helps to strengthen cracks or delamination from the core in the later stage of the coating processes. Then, alternate coatings of pectin and calcium chloride layers were spray coated by fluidized bed bottom spray technology (GPCG-1, Glatt®, Germany). This technology allows achieving uniform coating layers. The subcoating with pectin and calcium pectinate polymers allow site-specific drug delivery targeting the colon due to their low water solubility. Both excipients additionally degraded completely by gut microflora [3].

By testing different composition in multilayer coatings with calcium and pectin, some interesting phenomena are stated:

  • the release behavior follows the Higuchi model
  • the drug release can be described by a diffusion control mechanism
  • the coating of the outermost layer defines the success in controlled drug release

The latter point issues the importance of the outermost layer which is whether composed by pectin or calcium. In case of calcium, the drug release was accelerated independently of the number of Ca/P layers, such that a 4-layer system (P/Ca/P/Ca) yield a faster drug release that a 3-alyer system (P/Ca/P), see Figure 1. This is explained by the effect of the calcium ions in the outermost layer, leading to a weakening in the calcium pectinate coating layer.

Metoprolol pellets

Figure 1: Metoprolol pellets. From left to right: Ca/P, P/Ca/P, Ca/P/Ca/P layered pellets. Colors: Cellets as MCC pellet (green), Metoprolol Tartrate (orange), Talcum (blue), Calcium (white), Pectin (grey).

Once, pectin is the component in the outermost layer, this led to a difference in drug release at neutral and slightly acidic conditions of the dissolution media. While in a neutral pH 7.4 buffer, the dissolution kinetics were comparable for a P/Ca/P-system and Ca/P-system, the situation changes in a slightly acidic buffer at pH 6.0. In a phosphate buffer at pH 6.0 the dissolution of a P/Ca/P-system was faster than of a Ca/P-system due to the almost complete ionization of pectin at pH 6.0.

Summary

This case study highlights the controlled release profile of Metoprolol Tartrate as a water-soluble model drug. The formulation is based on CELLETS® 700, which serve as inert MCC spheres. By a variation in the multi-layer composition of calcium and pectin, the dissolution kinetics and controlled release profiles were examined.

Acknowledgement

This research was funded by Thailand Research Fund through Royal Golden Jubilee Ph.D. Program, grant number PHD/00005/2541.

References

[1] P. Wanasawas, A. Mitrevej, N. Sinchaipanid, Pharmaceutics 14 (2022) 1061, https://doi.org/10.3390/pharmaceutics14051061

[2] The American Society of Health-System Pharmacists. Archived from the original on 12 March 2014. Retrieved 21 April 2014. https://web.archive.org/web/20140312062359/http://www.drugs.com/monograph/metoprolol-succinate.html

[3] M. Khotimchenko, Int. J. Biol. Macromol. 158 (2020) 1110-1124. https://doi.org/10.1016/j.ijbiomac.2020.05.002