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.

CS_sphericity_image_4

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

Available size classes are (click for more information):

  • CELLETS® 100
  • CELLETS® 200
  • 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

See case studies to see these starter pellets in action!

Amorphous Solid Dispersions Layered onto Pellets - An Alternative to Spray Drying

Amorphous Solid Dispersions Layered onto Pellets – An Alternative to Spray Drying?

This article “Amorphous Solid Dispersions Layered onto Pellets – An Alternative to Spray Drying?” is an excerpt from the publication of Neuwirth et al., Pharmaceutics 2023, 15(3), 764; https://doi.org/10.3390/pharmaceutics15030764.

Abstract

Spray drying is one of the most frequently used solvent-based processes for manufacturing amorphous solid dispersions (ASDs). However, the resulting fine powders usually require further downstream processing when intended for solid oral dosage forms. In this study, we compare properties and performance of spray-dried ASDs with ASDs coated onto neutral starter pellets in mini-scale. We successfully prepared binary ASDs with a drug load of 20% Ketoconazole (KCZ) or Loratadine (LRD) as weakly basic model drugs and hydroxypropyl-methyl-cellulose acetate succinate or methacrylic acid ethacrylate copolymer as pH-dependent soluble polymers. All KCZ/ and LRD/polymer mixtures formed single-phased ASDs, as indicated by differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy. All ASDs showed physical stability for 6 months at 25 °C/65% rH and 40 °C/0% rH. Normalized to their initial surface area available to the dissolution medium, all ASDs showed a linear relationship of surface area and solubility enhancement, both in terms of supersaturation of solubility and initial dissolution rate, regardless of the manufacturing process. With similar performance and stability, processing of ASD pellets showed the advantages of a superior yield (>98%), ready to use for subsequent processing into multiple unit pellet systems. Therefore, ASD-layered pellets are an attractive alternative in ASD-formulation, especially in early formulation development at limited availability of drug substance.

Materials

The model drugs ketoconazole (KCZ) and loratadine (LRD) were purchased from Sris Pharmaceuticals (Hyderabad, India). HPMCAS LG (hydroxypropyl-methylcellulose acetate succinate, wt%: methoxyl 20–24%, hydroxypropyl 5–9%, succinyl 14–18%; Mw = 18,000, HPMC-AS) was donated from Shin-Etsu Chemical (Tokyo, Japan). Eudragit L100-55 (methacrylic acid ethylacrylate copolymer, ratio 1:1, Mw = 320,000, EL100-55) was donated by Evonik (Darmstadt, Germany). Cellets 1000 (microcrystalline cellulose starter pellets, 1000–1400 µm) were provided by Glatt Pharmaceutical Services (Binzen, Germany). A detailed list of the pellets’ characteristics is shown in Table 1. Ethanol 96% (v/v) (technical grade) used in the sample preparation, and methanol (analytical grade) used for the HPLC analytics as well as the buffer salts disodium mono-hydrogen phosphate dodecahydrate (Na2HPO4·12H2O) and monosodium dihydrogen phosphate dodecahydrate (NaH2PO4·12H2O) were obtained from VWR Chemicals GmbH (Darmstadt, Germany).
Pellet Properties
d50 (xc min) [µm] 1123.44
(±7.36)
SPAN 0.166
(±0.002)
b/l 0.893
(±0.000)
SPHT 0.956
(±0.001)
Particle density [g/cm3] 1.452
(±0.016)
Sm [cm2/g] 36.41
(±0.29)

Table 1. Pellet properties of Cellets 1000. d50: mean particle diameter determined by the particle width; SPAN: width of the particle distribution; b/l: aspect ratio; SPHT: sphericity; Sm: specific surface area.

Pellet Coating (PC)
For pellet coating (PC) a laboratory scale fluid bed system Mini Glatt equipped with a Micro-Kit (Glatt GmbH, Binzen, Germany) was used. The coating was applied with a 0.5 mm two-fluid nozzle in bottom spray using the special bottom plate of the Micro-Kit to emulate a three-fluid nozzle with micro-climate. In the beginning, the machine was filled with 25.0 g of Cellets® 1000. The following process parameters were maintained throughout the process: Process gas flow 30 m3/h, product temperature 30.0 ± 1.0 °C (resulting inlet temperature 32–35 °C), spray pressure 1.5 bar and spray rate 1.0 ± 0.2 g/min. The final pellets had a theoretical drug-load of 10% (w/w) due to the fact that ASD and core pellets were used in a 1:1-ratio. […] To prepare the spraying solutions, the API and polymer were dissolved in ethanol 96% (v/v) under continuous stirring (solid content of 10% (w/w)). Prior to spraying, each solution was sonicated for 15 min to ensure complete dissolution of the components.
Subsequently, the coated pellets were manually sieved with a 2 mm mesh to eliminate multicore pellets. The pellets were dried under vacuum for 24 h at the same conditions as the SD powder.

Conclusions

In this study, we successfully prepared binary single phase ASDs of KCZ and LRD as weakly basic, slow crystallizing model APIs (drug load 20% (w/w)) using HPMC-AS or EL100-55 as pH-dependent soluble polymers via fluid bed pellet coating and spray drying. While the received ASD-pellets would not require further downstream processing other than capsule filling or tableting, the fine SD powder had to be transformed into dry granules. In combination with the slow crystallizers, KTZ and LOR, both manufacturing processes resulted in single-phased ASDs of high physical stability (up to 6 months) and similar dissolution performance when normalized to the total outer surface. The dissolution rate depends mainly on this total outer particle surface of the respective sample, independent of the manufacturing process, while the porosity of the sample had a minor impact on its dissolution behavior.
Especially for early formulation development, the high yield and ease of handling due to the pellet properties are strong advantages over the standard spray drying process. Nevertheless, the long process time in larger scale requires further process optimization in fluidized bed processing.
Amorphous solid dispersions Cellets 20230302

Figure: Amorphous solid dispersions.

[1] Neuwirth et al., Pharmaceutics 2023, 15(3), 764; https://doi.org/10.3390/pharmaceutics15030764

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Benefits of multilayer high drug-loaded amorphous solid dispersions

Benefits and challenges 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

 

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Amorphous solid dispersions at various aspects part 2ingredient pharm

Amorphous solid dispersions at various aspects

Amorphous solid dispersions play an essential role in modern pharmaceutical research. They improve the solubility and dissolution rate of poorly water-soluble drugs, and therefore they gain more importance in drug development. Although several approaches exist, each method shows clear benefits but also some challenges. As a result, it is necessary to examine amorphous solid dispersions in a broader scientific context. For a detailed overview, Thomas Rades and Keita Kondo [Rades_2022] present valuable insights into the fundamentals and latest findings. In addition, recent studies highlight CELLETS® 175, microcrystalline cellulose spheres, as a promising solution. These MCC spheres act as drug carriers and, due to their excellent friability, also function as milling balls. Consequently, they create new opportunities for drug formulation. Moreover, MCC starter beads expand these applications even further. Researchers who want to test this approach can request material samples before exploring the work of Rades and colleagues in more detail.

Draw-back on Amorphous solid dispersions

Amorphization is a promising way to improve solubility and dissolution of poorly water-soluble drugs. Amorphous solids lack a crystal lattice with long-range order [1]. However, amorphous forms remain thermodynamically unstable because their chemical potential is higher than in crystalline forms. As a result, amorphous drugs often show low physical stability and eventually recrystallize [2], [3]. Therefore, stabilizing strategies are crucial in the development of amorphous products. These strategies include amorphous solid dispersions (ASDs) [4], [5] and co-amorphous formulations [6], [7], [8].

ASDs are the most widely used method to prepare amorphous products. They involve glass formation by dispersing drug molecules into an amorphous polymer [4], [5]. Nevertheless, ASD systems often need a large amount of polymer to stabilize the drug, since miscibility between drug and polymer is low [9]. This requirement leads to a high bulk volume of the final product.

In contrast, co-amorphous systems have gained attention as an alternative. They create a single amorphous phase in which multiple low molecular weight compounds, including drugs, mix uniformly at the molecular level [6], [7], [8]. Moreover, co-amorphous mixtures usually provide both higher physical stability and improved dissolution [6], [7], [10].

drug-drug combinations and drug-excipient mixtures

Co-amorphous systems usually fall into two groups: drug-drug combinations and drug-excipient mixtures. In drug-drug combinations, two drug compounds form an amorphous phase. They stabilize each other through intermolecular interactions [11], [12], [13]. These systems can provide combined therapeutic effects. However, their use remains limited. Not all drug-drug pairs are suitable for combination therapy, and fixed dosing often restricts their application to co-amorphization.

In contrast, drug-excipient systems use low molecular-weight substances as co-formers. These include organic acids [14], sugars [15], and amino acids [16]. Their properties and the mixing ratio with the drug strongly influence both dissolution and physical stability [8], [10]. Recently, researchers systematically studied different combinations of drugs with amino acids [17], [18]. The results showed that well-chosen amino acids can improve dissolution and stability. For example, acidic drugs combined with basic amino acids often create strong interactions. Thus, amino acids emerge as a highly promising class of co-formers for co-amorphous formulations.

Amorphous solid dispersions: Co-amorphous mixtures

Co-amorphous mixtures have been prepared using melt quenching [13], [19], spray drying [20], [21], and ball milling [16], [22]. The resulting solids appear as cakes or powders regardless of the method. Therefore, downstream processes such as milling and granulation are usually necessary to obtain final dosage forms like capsules or tablets for oral use [23]. However, these additional steps often increase the risk of phase separation and crystallization because of moisture, thermal stress, and mechanical stress.

In amorphous solid dispersion (ASD) systems, researchers developed one-step preparation methods to avoid these issues. For example, ASD granules have been produced by amorphizing drug compounds during granulation with fluidized bed processors [24–30] or high shear granulators [31–34]. Yet, no reports exist on one-step methods for co-amorphous granules.

Feasibility of solvent-free amorphization

In the first part of this study, we explored the feasibility of solvent-free amorphization and pelletization using a high shear granulator. We successfully produced fully amorphized indomethacin-layered pellets simply by mixing indomethacin crystals with microcrystalline cellulose spheres, without applying solvent or heat. Collisions with the spheres pulverized and amorphized the crystals, which then deposited on the surface of the spheres. Based on this, we hypothesized that co-amorphous mixture-layered pellets could also be prepared through one-step amorphization and pelletization. Since earlier studies have achieved co-amorphous mixtures by mechanical activation [16], [22], this approach seems highly promising. Moreover, it provides both economical and sustainable benefits by eliminating the need for solvent and heating.

Previous studies systematically investigated different combinations of indomethacin and amino acids for co-amorphous preparations. The results showed that arginine works as an excellent co-former for indomethacin [18]. This combination produces co-amorphous mixtures with fast dissolution and high physical stability. The reason is that an amorphous salt forms due to strong interactions between acidic indomethacin and basic arginine [35], [36].

Co-amorphous layer pellets

In this study, we aimed to test whether co-amorphous layer pellets can be produced through a one-step amorphization and pelletization process. Therefore, indomethacin was chosen as the model drug and arginine as the co-former. In the first stage, indomethacin crystals were mixed with microcrystalline cellulose spheres of various diameters (140 μm, 195 μm, 275 μm, 414 μm, and 649 μm) at a 1:10 weight ratio using a high shear granulator (TMG1/6, Glatt GmbH, Binzen, Germany). Fully amorphized indomethacin-layered pellets were obtained with 414 μm carriers, while 195 μm carriers resulted in partial amorphization. This difference was most likely caused by the higher impact forces of the larger carriers, which promoted stronger mechanical activation of indomethacin crystals.

To further clarify the role of arginine in amorphization and pelletization, we used smaller cellulose spheres of 195 μm as carriers. Indomethacin and arginine crystals were mixed at different molar ratios (1:1, 2:1, and 3:1). These mixtures were then granulated with cellulose spheres at a 1:10 weight ratio using high shear mixing. The resulting composite particles were analyzed with solid-state and particle characterization methods. In addition, we examined high shear mixing under different jacket temperatures to identify effective co-amorphization conditions. Finally, the physical stability and dissolution behavior of the co-amorphous layer pellets were investigated.

References

[Rades_2022] K. Kondo, T. Rades, 181 (2022) 183-194. doi:10.1016/j.ejpb.2022.11.011

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

[2] L. Yu, Adv. Drug Deliv. Rev. 48 (2001) 27-42.

[3] L.R. Hilden, K.R. Morris, J. Pharm. Sci. 93 (2004) 3-12.

[4] T. Vasconcelos, S. Marques, J. das Neves, B. Sarmento, Adv. Drug Deliv. Rev. 100 (2016) 85-101.

[5] S. Baghel, H. Cathcart, N.J. O’Reilly, J. Pharm. Sci. 105 (2016) 2527-2544.

[6] R. Laitinen, K. Lobmann, C.J. Strachan, H. Grohganz, T. Rades, Int. J. Pharm. 453 (2013) 65-79.

[7] R.B. Chavan, R. Thipparaboina, D. Kumar, N.R. Shastri, Int. J. Pharm. 515 (2016) 403-415.

[8] S.J. Dengale, H. Grohganz, T. Rades, K. Lobmann, Adv. Drug Deliv. Rev. 100 (2016) 116-125.

[9] S. Janssens, G. Van den Mooter, J. Pharm. Pharmacol. 61 (2009) 1571-1586.

[10] R. Laitinen, K. Lobmann, H. Grohganz, P. Priemel, C.J. Strachan, T. Rades, Int. J. Pharm. 532 (2017) 1-12.

[11] S. Yamamura, H. Gotoh, Y. Sakamoto, Y. Momose, Eur. J. Pharm. Biopharm. 49 (2000) 259-265.

[12] M. Allesø, N. Chieng, S. Rehder, J. Rantanen, T. Rades, J. Aaltonen, J. Control. Release 136 (2009) 45-53.

[13] K. Lobmann, R. Laitinen, H. Grohganz, K.C. Gordon, C. Strachan, T. Rades, Mol. Pharm. 8 (2011) 1919-1928.

[14] Q. Lu, G. Zografi, Pharm. Res. 15 (1998) 1202-1206.

[15] M. Descamps, J.F. Willart, E. Dudognon, V. Caron, J. Pharm. Sci. 96 (2007) 1398-1407.

[16] K. Lobmann, H. Grohganz, R. Laitinen, C. Strachan, T. Rades, Eur. J. Pharm. Biopharm. 85 (2013) 873-881.

[17] G. Kasten, H. Grohganz, T. Rades, K. Lobmann, Eur. J. Pharm. Sci. 95 (2016) 28-35.

[18] G. Kasten, K. Lobmann, H. Grohganz, T. Rades, Int. J. Pharm. 557 (2019) 366-373.

[19] A. Teja, P.B. Musmade, A.B. Khade, S.J. Dengale, Eur. J. Pharm. Sci. 78 (2015) 234-244.

[20] A. Beyer, L. Radi, H. Grohganz, K. Lobmann, T. Rades, C.S. Leopold, Eur. J. Pharm. Biopharm. 104 (2016) 72-81.

[21] E. Lenz, K.T. Jensen, L.I. Blaabjerg, K. Knop, H. Grohganz, K. Lobmann, T. Rades, P. Kleinebudde, Eur. J. Pharm. Biopharm. 96 (2015) 44-52.

[22] K.T. Jensen, F.H. Larsen, C. Cornett, K. Lobmann, H. Grohganz, T. Rades, Mol. Pharm. 12 (2015) 2484-2492.

[23] B. Demuth, Z.K. Nagy, A. Balogh, T. Vigh, G. Marosi, G. Verreck, I. Van Assche, M.E. Brewster, Int. J. Pharm. 486 (2015) 268-286.

[24] D.B. Beten, K. Amighi, A.J. Möes, Pharm. Res. 12 (1995) 1269-1272.

[25] H.-O. Ho, H.-L. Su, T. Tsai, M.-T. Sheu, Int. J. Pharm. 139 (1996) 223-229.

[26] N. Sun, X. Wei, B. Wu, J. Chen, Y. Lu, W. Wu, Powder Technol. 182 (2008) 72-80.

[27] A. Dereymaker, D.J. Scurr, E.D. Steer, C.J. Roberts, G. Van den Mooter, Mol. Pharm. 14 (2017) 959-973.

[28] A. Dereymaker, J. Pelgrims, F. Engelen, P. Adriaensens, G. Van den Mooter, Mol. Pharm. 14 (2017) 974-983.

[29] T. Oshima, R. Sonoda, M. Ohkuma, H. Sunada, Chem. Pharm. Bull. 55 (2007) 1557-1562.

[30] H.J. Kwon, E.J. Heo, Y.H. Kim, S. Kim, Y.H. Hwang, J.M. Byun, S.H. Cheon, S.Y. Park, D.Y. Kim, K.H. Cho, H.J. Maeng, D.J. Jang, Pharmaceutics 11(3) (2019) 136.

[31] N.S. Trasi, S. Bhujbal, Q.T. Zhou, L.S. Taylor, Int. J. Pharm. X 1 (2019) 100035.

[32] A. Seo, P. Holm, H.G. Kristensen, T. Schæfer, Int. J. Pharm. 259 (2003) 161-171.

[33] T. Vilhelmsen, H. Eliasen, T. Schaefer, Int. J. Pharm. 303 (2005) 132-142.

[34] Y.C. Chen, H.O. Ho, J.D. Chiou, M.T. Sheu, Int. J. Pharm. 473 (2014) 458-468.

[35] K.T. Jensen, L.I. Blaabjerg, E. Lenz, A. Bohr, H. Grohganz, P. Kleinebudde, T. Rades, K. Lobmann, J. Pharm. Pharmacol. 68 (2016) 615-624.

[36] K.T. Jensen, F.H. Larsen, K. Lobmann, T. Rades, H. Grohganz, Eur. J. Pharm. Biopharm. 107 (2016) 32-39.

More information on ASD

Read more about amorphous solid dispersions in our application notes.

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titelbild - Hydrodynamic behavior of MCC Spheres in a spouted bedingredientpharm
,

Hydrodynamic behavior of MCC Spheres in a spouted bed

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.

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muliparticulates-titleingredientpharm

Coating weight gain and API release in multiparticulates

Abstract

Multiparticulates made of pellets are ideal dosage forms to be used in pediatrics. Having the suitability of paediatric consumers in mind, formulations of small-sized pellets offer a valuable base for increased compliance and improved age-appropriately dosage form. Due to their round shape of pellets, smooth surface area and narrow particle size distribution they can easily be functionally coated [1] to achieve e. g. a taste masking, enteric protection or the controlled release of the active pharmaceutical ingredient (API) in defined parts of the gastro-intestinal (GI) tract. The release profile then often depends on the coating weight gain (thickness) and composition of the functional coating.

Coating weight gain, manufacture and analysis of pellets

A well soluble drug was used as model API.  In a first approach, pellets were produced applying the ProCell technology, a direct pelletization process allowing the production of highly drug loaded matrix pellets (here 95%) in a spouted bed. Two types of pellets were produced: A) with a poly amino saccharide-based binder, followed by a cellulose based seal coating and B) with a polyacrylic acid-based binder, followed by a pH-depending coating. In a second approach the API was layered onto inert starter cores (MCC, CELLETS® 200) by the aid of a cellulose based binder and antitacking agent applying the Wurster technology targeting a drug load of 50 %, followed by a pH-depending coating (C). All three pellets-based populations were functionally coated by a pH-independent sustained release polymer. Samples were taken at pre-defined coating levels for dissolution testing. For API layering and coating a GPCG 1.1 with a 6” Wurster insert was used. Direct pelletization was performed in a ProCell 5. Particle size distribution (PSD) analysis was performed by Eyecon2TM. The particle size is given as numeric or volumetric distribution (e.g. Dn50 or Dv50). The specific surface area is calculated by measuring the true density by gas pycnometry and the Sauter diameter by Laser diffraction. Dissolution was measured in the acid stage (0.1 M HCl), in buffer pH 5.5 and in buffer pH 7.2 over 300 min. The API should not be released in the first 180 min. Between 210 min and 240 min an increased drug release is expected. The dissolution rates at 225 min were compared for the coating levels at 10, 15 and 20 %.

Results

With increasing coating weight gains decreasing dissolution rates at 225 min were measured for the sustained release coating with a good linearity. Matrix PEL (A) show higher dissolution rates comparing the same coating levels than Matrix PEL (B), Wurster pellets showed the strongest decrease with increasing CWG, table 1, figure 1. This correlation was not observed for pH-depending coating (data not shown).

Dv 50 [µm] Dn 50 [µm] PSD mean [µm] Specific surface area [m2/g]
A Matrix PEL 496 475 481 0,00980
B Matrix PEL 461 427 425 0,01210
C Wurster PEL 414 396 401 0,01100

Table 1. PSD data and specific surface area of starter beads before functional coating.

coating weight gain

Figure 1. Dissolution at 225 min vs. coating weight gain (CWG)

Summary

Drug loaded pellets were prepared either as matrix pellets applying the ProCell technology, or by layering of starter cores applying the Wurster technology. Both populations were coated with different coating levels of a sustained release functional coating, resulting in decreasing dissolution rates with increasing coating weight gain. Due to the good correlation between coating weight gain and dissolution profile a prediction of the dissolution rate might be possible for pre-defined coating levels. These findings are a crucial step towards novel paediatric formulations with improved dissolution profiles and dosage safety.

References

[1] Palugan, L.; Cerea, M.; Zema, L.; Gazzaniga, A.; Maroni, A. Coated pellets for oral colon delivery, Journal of Drug Delivery Science and Technology 25, 1 – 15 (2015).

This study was presented on 14th annual EuPFI conference, Rome, Italy.

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Metoprolol pellets

Metoprolol Tartrate: controlled release drug layered pellets for colon-specific drug delivery

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

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Figure 3: SEM picture of cross section of a Taste masked pellets coated with 25 mg Eudragit EPO.
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Atomoxetine HCl Pellets in MUPS Formulations

Abstract

This case study on Atomoxetine HCl pellets is a short abstract of the publication by Y.D. Priya et al. [1].

Atomoxetine is a medication used to treat attention deficit hyperactivity disorder (ADHD) [2]. The API is marketed under the trade names Atomoxetine, Atomoxe, Agakalin, and Strattera (initially launched) [3]. Atomoxetine is an extremely bitter API. As being initially launched for children as capsules or tablets, the paediatric compliance by improved taste-masking and the simplified administration to paediatrics are in focus of this study.

A multi-unit particulate pellet coating (MUPS) was selected as oral dosage form. The fluidized bed technology (with Wurster column) was employed for coating and layering processes. This is a well-known technology, which Is for instance offered by Glatt. Starter cores were coated with the API, followed by layering with a polymeric coating for which realized the taste-masking.

Atomoxetine layering

Starter cores are made of Microcrystalline Cellulose (MCC) in sizes comparable to CELLETS® 200, while a fair efficiency of drug layering was observed with the combination of HPMC (Hydroxypropyl methyl cellulose) and HPC (Hydroxypropyl cellulose) as binders. The composition of API layering is presented in Table 1. The drug dispersion was sprayed onto the MCC pellets with an inlet temperature between 50 °C and 55 °C and a fluidized bed temperature between 35 °C and 40 °C.

API layering material Composition
Starter core
  MCC pellets 58.00
API layering
  Atomoxetine HCl 25.00
  Hydroxypropyl methylcellulose 3.50
  Hydroxypropyl Cellulose 3.50
  Low-Substituted Hydroxypropyl Cellulose 5.00
  Talc 5.00
  Purified Water Qs
Total weight (mg) 100.00

Table 1: Formulation of API layered pellets.

Taste-masking coating

The polymeric taste-masking layer is made of a methacrylate co-polymer (Eudragit EPO) providing an excellent coating with taste masking properties for fine particles and tablets. The composition of the taste-masking suspension is shown in Table 2. The inlet temperature is between 40 °C and 45 °C, and fluidized bed temperature is between 25 °C and 30 °C.

Polymeric coating material Composition
Drug Layered pellets 100.00
Eudragit EPO 25.00
Sodium Lauryl Sulfate 2.500
Stearic acid 3.750
Talc 6.25
FD&C Yellow No. 6 0.50
FD&C Red No. 3 0.05
Purified Water Qs
Total weight (mg) 138.050

Table 2: Formulation of polymeric coating suspension.

The efficiency of taste-masking was benchmarked by a bitterness rating on human volunteers. Figure 1 shows, that the taste sensitivity identifies a bitterness at 6 µg/ml API concentration and an extreme bitterness at 7 µg/ml API and higher concentration. Thus, the threshold bitterness of Atomoxetine HCl is 6 µg/ml.

Atomoxetine: bitternessFigure 1: Concentration of drug solution (µg/ ml). Bitter intensity ratings from no bitterness (green), bitterness (blue), extremely bitter (red).

Figure 1: Concentration of drug solution (µg/ ml). Bitter intensity ratings from no bitterness (green), bitterness (blue), extremely bitter (red).

All the volunteers felt bitter taste when the drug layered pellets were coated with 6.25 mg of Eudragit EPO. Whereas in the pellets coated with 12.5 mg and 18.75 mg of Eudragit EPO, bitter taste was masked up to 15 seconds after keeping the tablet in the mouth, and later all the human volunteers felt bitter taste. When the concentration of Eudragit EPO was increased to 25 mg, the bitter taste of Atomoxetine HCl was completely taste-masked and no volunteer was felt bitter taste.

Figure 2: In-Vivo Taste evaluation in healthy human volunteers.

Figure 2: In-Vivo Taste evaluation in healthy human volunteers.

Figure 3 depicts the entire particle size of a taste-masked MCC pellet coated with the Atomoxetine drug layer and 25 mg of Eudragit EPO. The average particle size of the taste-masked pellets is between 180 µm and 250 µm, assuming, that no gritty feeling of particles in patient’s mouth will appear. It should be said, that a micronization of Atomoxetine HCl was deemed to be necessary for the drug layering process. Micronization minimized the surface roughness of the API layered pellet so that an efficient taste-masking coating can be applied.

Figure 3: SEM picture of cross section of a Taste masked pellets coated with 25 mg Eudragit EPO.

Figure 3: SEM picture of cross section of a Taste masked pellets coated with 25 mg Eudragit EPO.

Summary

MCC pellets in the size of about 200 µm were layered with Atomoxetine. HPMC and HPC were used as binders, realizing a precise surface definition for a subsequent taste-masking coating. The taste-masking was most efficient at a polymeric concentration of 25 mg. Keeping the size of the coated pellets below 300 µm avoids a gritty feeling and thus increase the patient’s compliance.

This study by Priya et al. indicated that the fluidized bed process produced the most appropriate taste masked pellets of Atomoxetine HCl for oral disintegrating tablets.

References

[1] Y.D. Priya et al., Int J Pharm Pharm Sci, (6) 7, (2014) 110-115

[2] “Atomoxetine Hydrochloride Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 4 April 2019. Retrieved 22 March 2019.

[3] ROTE LISTE 2017, Verlag Rote Liste Service GmbH, Frankfurt am Main, ISBN 978-3-946057-10-9, (2017) 162.

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Taste masked coated micropellets
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Tamoxifen citrate was spray layered micropellets for Cre recombination research

Abstract on Tamoxifen

Tamoxifen is widely used in transgenic research in mice to induce Cre recombinase activity and achieve conditional gene knockouts [1]. However administrating tamoxifen to mice is challenging The commonly used dosing methods are oral gavage or intraperitoneal injection [2] which require specialist staff training and can cause pain, distress and adverse effects to the animal. Tamoxifen containing rodent chow is commercially available however, the poor palatability of the diet leads to reduced food intake and weight loss of the mice. The addition of sweeteners improves palatability, but this can affect the metabolic balance of the mice.

In this application a study is described in which a palatable tamoxifen containing rodent chow is developed by mixing taste masking coated micropellets with powdered rodent food. This attempt shell improve:

  • Reduction of potential welfare concerns,
  • Reduction of dose variability,

and induce

  • a more consistent recombinase activity,
  • a decrease in the variability of phenotyping data from these experiments,
  • a reduction in the number of animals used

Methods

The API was spray layered onto microcrystalline cellulose substrates CELLETS® 100 and subsequently coated using Surelease®, both as aqueous formulations in a bench top fluidized bed coater (Mini Glatt®). Two taste masking coated tamoxifen citrate micropellet formulations were prepared and analyzed. One formulation has a coating levels of 5 % (F1) and the second formulation contains mannitol in the drug layer with a coating level of 10 % (F2). Sieve analysis of taste masking coated micropellets (Figure 2) shows that both formulations achieved yields of at least 99 % (proportion of pellets with size < 250 µm), see Fig. 1.

Tamoxifen sieve analysis

Figure 1: Tamoxifen sieve analysis. Graphs: F1 (light green); F2 (light blue).

In USP II dissolution test the uncoated tamoxifen citrate (micronized and un-micronized particles) showed a fast dissolution at >80 % release within 45 minutes (Figure 3). The micronized particles dissolved slower than the un-micronized due to particle agglomeration during dissolution.

Drug release slowed down after applying the taste masking coating; with decreasing pore former concentration or increasing coating thickness, the drug release rate decreases. After 45 min, both formulations F1 and F2 showed >75 % drug release, successful as immediate release formulations (Fig. 2).

Drug release of Tamoxifen Citrate in USP II test

Figure 2: Drug release of Tamoxifen Citrate in USP II test. Graphs: F1 with coating Level 5 % and polymer ratio 75:25 (light green); F2 Mannitol with coating level 10 % polymer ratio 85:15 (light blue); Tamoxifen Citrate micronized (blue); Tamoxifen Citrate un-micronized (grey).

Taste masking effectiveness of Tamoxifen micropellets

The in vitro tests for evaluating the taste masking effectiveness of the formulations showed that after 30s, micropellets with both coating formulations are effective in providing a taste masking barrier with a tamoxifen citrate release of less than 0.5% (Fig. 3).

 

Inverted Vial test for taste masking effect evaluation

Figure 3: Inverted Vial test for taste masking effect evaluation. Graphs: F1 (green), F2 (blue) with % Release after 30s (light color) and Concentration (mg/ml) after 30s (dark color).

Summary

Taste masking of coated tamoxifen citrate micropellets were successfully manufactured in a fluidized bed applying the MicroCoat™ technology with > 99% yield and particle size < 250 µm. The coating provided effective protection to prevent tamoxifen citrate release in the mouth but immediate drug release in the stomach pH conditions of the mice. Additionally, the small particle size of the coated micropellets ensured effective mixing with the powder rodent feed with excellent recovery and uniformity. The product is flexible in dose adjustment and improves API handling safety in animal units, offering an innovative approach of doing tamoxifen to mice for Cre recombination research via voluntary food intake. The method has the potential to reduce suffering
and improve welfare of the mice, promoting 3Rs (replacement, reduction and refinement) in animal research.

Taste masked coated micropellets

Taste masked coated micropellets

Acknowledgement

The project is funded by the United Kingdom National Centre for the Replacement, Refinement and Reduction of Animals in Research (the NC3Rs) through the CRACK IT challenge Tat Fit  project number NC/C020S02/1).

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

 

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Advantages of technological methods compared to a pure API usage.Ingredient Pharm
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Technologies for enhancing bioavailability of Simvastatin

Abstract

This application note is based on content from Pohlen et al. [1]. Simvastatin (CAS number 79902-63-9) is a cholesterol-lowering agent with a low bioavailability of 5% [2,3]. This API is formulated as a lipid based drug delivery system for oral uptake. Two technologies, which are spray drying and fluidized bed layering technologies were compared with respect to the process and product characteristics of otherwise similar Simvastatin loaded dry emulsion systems. Investigated parameters are the process yield, encapsulation efficiency, relative product stability, particle morphology, drug content, and the relative increase in bioavailability.

Enhancing bioavailability

Some of the recently discovered new chemical entities (NCE) show a low solubility and high permeability (BCS class II), or even low permeability in the case of very high lipophilicity (BCS class IV).

Material Company
Simvastatin Krka, SI
1-oleoyl-rac-glycerol,

Magnesium stearate,

Tween® 20

 Merck, D
Pharmacoat 603 ShinEtsu, JAP
Miglyol® 812 Sasol, D
Pearlitol SD 200 Roquette, F
CELLETS® 200 HARKE Pharma, D
Avicel® PH 101,

Lactose mesh 200

 Lek, d.d., SI

Table 1: Used Material and origin.

This means a major challenge for formulation development in terms of assuring drug bioavailability [4,5]. A strategy for increasing the solubility are lipid based drug delivery systems (LBDDS). As main advantage, they are likely to solubilize the API and make it available for the absorption into the bloodstream [6]. Additionally, converting the liquid or semi-solid LBDDS into solid dosage forms eliminates undesired characteristics such as a lack of chemical stability and product portability, susceptibility for drug recrystallization and costly manufacturing [7]. Furthermore, solid dosage form solutions allow benefits, such as easy powder processing, flow and compression behavior, controlled drug release, improved patient safety. Among others, dry emulsions are a type of solidified LBDDS and allow carrying and releasing the encapsulated lipophilic API. In the following, some solidification process technologies are introduced. The required parameter for Wurster fluidized bed and spray drying are displayed in Table 2 and Table 3, respectively.

Opposite to the spray drying process, the fluidized bed process employs CELLETS® 200 as starter beads for layering. Several formulations are composed by Pohlen et al., the materials are listed in Table 1.

Parameter Value
Setup Glatt Fluidized bed Dryer Model GPCG-1 (Glatt, D)
Two-fluid

Schlick nozzle

 0.8 mm
cap opening diameter 2.50 mm
Inlet airflow rate 130 m3/h
Inlet air temperature 47 °C to 56 °C
outlet air / product temperature 34 °C
spraying rate 5 g/min to 9 g/min
atomizing air pressure 2 bar
Gap to Wurster insert bottom edge 17.5 mm
Drying time 180 s @ 42 °C
Starter pellets 200 g
starting

emulsion

 1000 g

Table 2: Parameters and values for Fluidized bed layering.

Parameter Value
Setup Mini Spray Dryer B-290 (Büchi, CH)
Two-fluid

nozzle

 1.4 mm
cap opening diameter 2.20 mm
Inlet airflow rate 28 m3/h
Inlet air temperature 145°C to 175 °C
outlet air / product temperature 75 °C to 80 °C
spraying rate 6 g/min
Drying time 180 s @ 80 °C
Starter pellets 200 g
starting

emulsion

 1000 g

Table 3: Parameters and values for spray drying.

Process yield

Spray drying results on average in lower process yield than the fluidized bed results. The process yield for spray drying experiments is in average value of 71.5 %, and of 83.3 % for fluidized bed layering experiments. It is assumed, that in spray drying process adhesion of the smallest particles to the cyclone walls or outtake through the air stream occur.

Drug content

An averaged API content at 9.34 mg/g in fluidized bed experiments, and at 22.2 mg/g for spray dried dry emulsions is reached. Although spray drying offers a much higher drug content and more flexible formulations, the content variation between replicates is increased. The use a swirl air generator in the fluidized bed equipment increases process stability and allows an even larger amount of oil to be incorporated. It is possible increase the maximum amount of API to 22 mg/g onto the starter pellets. Anyhow, the fluidized bed technology suffers from sticky effects of oil phases which is not a big deal in spray drying processes.

Encapsulation efficiency

A low encapsulation efficiency shall be avoided as it causes drug losses during processing and increased production costs. The encapsulation efficiency in fluidized bed experiments is at 80.0 %, compared to spray drying experiments being at 68.4 %. A main issue of the spray drying technology might be higher process temperature leading to a higher risk of API degradation. Spray drying also suffers from a larger surface-to-volume area which might induce an increased risk of oxidation during the drying process.

Morphology and particle size

The main advantage of fluidized bed technology is the use of starter pellets, which are perfectly spherical starter beads. Following, API coating results in highly spherical coated particles with a high level of monodispersity and an average particle size around 336 µm (D50 value). Not mentionable, that spray drying technology results in smaller average particle sizes at 56 µm (D50 value), but the morphology shows a coarse, rough and undefined surface. In turn, dry emulsion layered pellets have better flow properties [8].

Redispersibility and oil droplet size

All re-dispersed oil droplets have a size of a few micrometers between less than 1 µm and less than 7 µm. Fluidized bed layering technology generally leads to larger droplets. Considering also the probable bimodal nature of the droplet size distribution, fluidized bed layering provides a narrower size distribution and thus better results. In turn, the fluidized bed technology might provide slightly better bioavailability.

Product stability

Stability is measured by means of the one-month relative drug content stability. The particles produced in the fluidized bed technology show a better one-month relative drug content stability than particles produced by spray drying. This might be caused by the higher monodispersity, larger particles and smoother surfaces. All properties minimize the risk of API gradation, treatment failure, or toxicity.

Dissolution

Both technologies show a superior dissolution behavior compared to the dissolution of pure crystalline API (less than 3 %) or a generic API tablet (less than 10 %). It has to be stated, that both technologies allow dissolution rates of more than 80 % within the first 30 minutes, wherein the Spray drying products show a slightly better and faster dissolution rate.

Bioavailability

Bioavailability of formulations from fluidized bed layered dry emulsion pellets provide the highest increase in relative bioavailability within the examined formulations, confirming that fluidized bed technology is superior to spray drying technology for potent or low dose APIs.

Summary

Fluidized bed layering and spray drying technology have been selected for analyzing the properties of dry emulsions. Simvastatin was selected as API, encapsulated in the dry emulsion.

Fluidized bed layering technology uses starter cores, such as CELLETS® as a dry emulsion carrier system, while spray drying does not.

The main advantage of the fluidized bed technology is the higher process yield, the better encapsulation efficiency and redispersibility, the defined morphology of the product causing better process handling and product stability.

Spray drying technology allows a higher drug content with better chances of formulation variation, and an even faster and more complete dissolution (Figure 1).

Advantages of technological methods compared to a pure API usage.

Figure 1: Advantages of technological methods compared to a pure API usage.

References

[1] M. Pohlen, J. Aguiar Zdovc, J. Trontelj, J. Mravljak, M. G. Matjaž, I. Grabnar, T. Snoj and R. Dreu, Eur J Pharm Biopharm (2021), S0939-6411(21)00353-2, doi:10.1016/j.ejpb.2021.12.004

[2] S. Geboers, J. Stappaerts, J. Tack, P. Annaert and P. Augustijns, Int. J. Pharm. 510 (2016) 296-303, doi:10.1016/j.ijpharm.2016.06.048

[3] T. Taupitz, J.B. Dressman and S. Klein, Eur J Pharm Biopharm. 84 (2013) 208-218, doi:10.1016/j.ejpb.2012.11.027.

[4] T. Das, C.H. Mehta and U.Y. Nayak, Drug Discov. Today 25(7) (2020) 1206-1212,  doi:10.1016/j.drudis.2020.04.016

[5] G.L. Amidon, H. Lennernäs, V.P. Shah and J.R. Crison, Pharm. Res. 12 (1995) 413-420,  doi:10.1023/a:1016212804288.

[6] H. Mu, R. Holm and A. Müllertz, Int. J. Pharm. 453 (2013) 215-224, doi:10.1016/j.ijpharm.2013.03.054.

[7] P. Joyce, T.J. Dening, T.R. Meola, H.B. Schultz, R. Holm, N. Thomas and C.A. Prestidge, Adv. Drug Deliv. (2018), doi:10.1016/j.addr.2018.11.006.

[8] X. Fu, D. Huck, L. Makein, B. Armstrong, U. Willen and T. Freeman, Particuology. 10 (2012) 203-208, doi:10.1016/j.partic.2011.11.003

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