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

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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
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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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