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!

Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique

Abstract

Pellets are one of multiparticulate pharmaceutical forms and can offer numerous technical and biopharmaceutical advantages compared with single dose unit formulations, e.g. tablets and capsules. This study aimed at formulation of controlled-release pellets of doxazosin mesylate (DM), a widely used treatment for antihypertensive and benign prostatic hyperplasia. DM was loaded onto microcrystalline cellulose CELLETS® pellets using hydroalcoholic solution and alcoholic suspension layering techniques to achieve a minimum drug load of 4 mg DM/g pellets. DM-layered CELLETS were coated by Aquacoat dispersion (ready-made ethylcellulose dispersion) using a coating pan technique as a simple and widely utilized technique in pharmaceutical industry. Controlled-release DM-layered pellets showed a release profile comparable to the controlled-release commercial product Cardura® XL Tablet. Also, the mechanism of DM release from Aquacoat CELLETS was mathematically modeled and imaged by scanning electron microscopy to elucidate drug release mechanisms from the prepared pellet formulations. Accelerated stability studies of the prepared pellets were performed under stress conditions of 40 °C, and 75 % RH for 3 months. In conclusion, preparation of controlled-release DM-layered CELLETS® is feasible using a simple and conventional coating pan technology. Read more about controlled-release doxazosin mesylate pellets.

References

Journal of Pharmaceutical Investigation (2013), 43:333–342. doi: 10.1007/s40005-013-0077-0
H. A. Hazzah, M. A. EL-Massik, O. Y. Abdallah & H. Abdelkader. https://doi.org/10.1007/s40005-013-0077-0

Additional information

CELLETS® are perfect starter beads for coating and layering of API, such as doxazosin mesylate. Multilayer formulation attempts enable defined release profiles and improved bioavailability. Check different pellet sizes from 100 µm to 1400 µm which fit to your formulation.

Need formulation services?

Contact our partner Glatt Pharmaceutical Services!

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Pore Former basic drugs

Design and Optimization of a Nanoparticulate Pore Former as a Multifunctional Coating Excipient for pH Transition-Independent Controlled Release of Weakly Basic Drugs for Oral Drug Delivery

Abstract

Bioavailability of weakly basic drugs may be disrupted by dramatic pH changes or unexpected pH alterations in the gastrointestinal tract. Conventional organic acids or enteric coating polymers cannot address this problem adequately because they leach out or dissolve prematurely, especially during controlled release applications. Thus, a non-leachable, multifunctional terpolymer nanoparticle (TPN) made of cross-linked poly(methacrylic acid) (PMAA)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) was proposed to provide pH transition-independent release of a weakly basic drug, verapamil HCl (VER), by a rationally designed bilayer-coated controlled release bead formulation. The pH-responsive PMAA and cross-linker content in the TPN was first optimized to achieve the largest possible increase in medium uptake alongside the smallest decrease in drug release rate at pH 6.8, relative to pH 1.2. Such TPNs maintained an acidic microenvironmental pH (pHm) when loaded in ethylcellulose (EC) films, as measured using pH-indicating dyes. Further studies of formulations revealed that with the 1:2 VER:TPN ratio and 19% coating weight gain, bilayer-coated beads maintained a constant release rate over the pH transition and exhibited extended release up to 18 h. These results demonstrated that the multifunctional TPN as a pHm modifier and pH-dependent pore former could overcome the severe pH-dependent solubility of weakly basic drugs.

Introduction

Many existing active pharmaceutical ingredients (APIs) (drug compounds) are either weak acids or weak bases; their water solubility can change significantly with the lumen pH changes along the gastrointestinal tract (GIT) as a result of variation in the ionization degree. Severe pH-dependent solubility could pose a great challenge to achieving consistent and predictable performance of oral dosage forms, as abrupt changes in release rate may result in unexpected dissolution, absorption, and bioavailability of the drug, leading to increased risks of adverse side effects or decreased therapeutic efficacy. This problem may be pronounced for weakly basic drugs with low solubility at high pH, especially those with a narrow therapeutic index, or requiring prolonged release, because in the lower GIT the pH is >6.8 [1]. Furthermore, food intake, disease state (e.g., inflammatory bowel disease, gastritis, colitis), concomitant medication (e.g., proton pump inhibitors), and inter- and intra-individual variations, among other factors, can alter the pH in the GIT, which deviates from the pH of simulated gastric and intestinal fluid for in vitro testing and prediction [2,3,4]. Hence, novel strategies to formulate weakly basic drugs with extreme pH-dependent solubility in controlled release forms could enhance the repertoire of advanced medications available to patients.
To compensate for the varying pH values in the GIT, several approaches have been employed. One approach is the addition of small-molecule pH modifiers to the immediate vicinity of the drug to change the microenvironmental pH (pHm), thus enhancing the drug solubility. For example, organic acids (e.g., adipic, fumaric, and succinic acids) have been introduced into formulations of weakly basic drugs, reducing the pHm sufficiently, thereby facilitating drug dissolution, irrespective of the pH of the bulk solvent [5,6,7,8,9,10,11]. Drug release will depend on the compatibility of the organic acid with the drug in terms of the buffering capacity of organic acids and the pKa of the drug. Nevertheless, the incorporation of organic acids remains challenging as they are prone to leach out from the formulation, leading to inefficient pH modulation over time [12]. Therefore, large amounts of organic acids are required in order to achieve prolonged pH-independent drug release [5,13], which often makes this approach inadequate for controlled release formulations.
Another approach to compensate for the reduction in drug solubility is the use of enteric coating polymers on tablets, pellets, or beads as permeability modifiers, which can increase drug permeability at higher pH. In such coatings, polymers with pH-dependent solubility or swellability are employed, either alone or incorporated in a hydrophobic polymer (e.g., ethylcellulose (EC)) that acts as a membrane barrier to drug diffusion, resulting in slowed drug release. For example, methacrylic acid–ethyl acrylate copolymer (Eudragit® L) and hydroxypropyl methylcellulose acetate succinate are frequently incorporated into these membranes as pore forming materials for pH-dependent release [13,14,15,16,17,18,19,20,21,22,23]. At a pH above their pKa’s, the pore formers dissolve and leach out of the membrane film to form channels that facilitate drug diffusion. However, as pore formers leach out, the film becomes more porous and weaker, increasing the risk of dose dumping due to weakened structure or ruptures of the coating [24].
Recent advances using biopolymer-based nanomaterials, molecular imprinted polymers, and mathematical and computational models have been used to address the various challenges of drug delivery systems [25,26,27,28,29]. Biopolymers such as starch, collagen, chitosan, etc., are useful for their biocompatibility, biodegradability, and ease of synthesis and modifications [25]. Controlled release dosage forms capable of being flexible, releasing drugs in a timely manner, with desired duration and dosage, are more important than ever, and mathematical and computational models also function as influential tools in addressing the potential mechanisms or impediments of drug delivery systems [26,27,28,29].
Previously, a crosslinked terpolymer nanoparticle (TPN), consisting of poly(methacrylic acid)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) [30,31,32,33], was incorporated into ethylcellulose films (TPN-EC) to respectively reduce or enhance the permeability of the film coating by a pH-dependent shrinking (at low pH) and swelling (at high pH) mechanism [34]. Unlike other soluble polymeric pore-formers, the TPN did not increase the viscosity of EC dispersions for coating, attributable to its crosslinking structure [31,32,33]. For the same reason, TPN did not leach out from cast TPN-EC films, maintaining good mechanical properties compared to conventional Eudragit® L-EC films. When used as a membrane coating over beads loaded with a water-soluble drug, diltiazem HCl, TPN-EC provided faster drug release at pH 6.8 than at pH 1.2 [34]. The biocompatibility of TPN was demonstrated previously in vitro using isolated rat hepatocytes [32].
Inspired by previous findings regarding the pH-dependent properties of TPN, in this work, we explore the application of TPN for the first time to develop an advanced, controlled release bilayer-coated bead formulation for weakly basic drugs that exhibits severe pH-dependent water solubility. Verapamil HCl (VER) was selected as a model drug because it undergoes extreme decrease in solubility by several orders of magnitude when the media pH is increased from acidic to neutral and weakly basic conditions [9,35]. By exploiting the pH-dependence of TPN, we proposed that an increase in permeability at high pH could help compensate for the low solubility of the drug in its unionized form, thereby permitting a constant release rate when transitioning from gastric to intestinal pH. Additionally, we explored the ability of TPN to serve as a pHm modifier, owing to the presence of its acidic functional groups in MAA. Because TPN is retained within EC, unlike traditional leachable pHm modifiers when formulated together with the drug in a matrix, the source of the acidifying agent could be sustained throughout dissolution, while preserving dosage form integrity.
To investigate the effectiveness of combining both the permeability and the pHm modulation strategies of TPN, experiments were performed using EC matrix free-films incorporated with VER and TPN (VER-TPN-EC) and a bilayer-coated bead design consisting of an inner VER-TPN-EC matrix, surrounded by an outer membrane composed of TPN-EC. As illustrated in Figure 1, the TPN composition was first adjusted by varying the amounts of the pH-responsive monomer, MAA, and cross-linker, N,N′-methylenebis(acrylamide) (MBA) for pH-dependent swelling (medium uptake) and drug release via experiments using composite free-films. The best-performing TPN-containing films were then tested for their ability to lower pHm. Subsequently, the TPN was incorporated into a bilayer-coated bead design, where it was expected to lower the pHm in the matrix layer and regulate permeability in the membrane layer by its pH-dependent swelling. The effects of formulation parameters such as VER:TPN ratio within the matrix layer and membrane coating level on the pH-independence of dissolution rate in various pH conditions were evaluated.
Pharmaceutics 15 00547 g001 550
Figure 1. A flow chart of the optimization strategy to achieve pH transition-independent controlled release of VER from a TPN-containing bilayer-coated beads. Formulation strategy for TPN bilayer-coated beads containing weakly basic VER Optimization of TPN composition to achieve pHm modification and pH-dependent swelling, followed by strategic placement of TPN in the bilayer bead matrix and membrane layers are proposed to overcome pH-dependent solubility of VER. Figure created with BioRender.com (accessed on 15 December 2022).
Our cumulative research investigating the various applications of TPN (e.g., nanoparticle drug carrier in injectables, enteric coating agent and pore former in film coatings, recrystallization inhibitor in amorphous solid dispersions) is helping us widen the breadth of its capabilities. Namely, in the present research, the ability of TPN for pHm modification, pH-responsive swelling, nanoscale pore formation, interaction with drugs, and non-leachability comprise a set of multi-faceted features that set it apart from traditional excipients, which could improve the efficacy and quality of controlled release dosage forms for weakly basic drugs. As the landscape of new drug molecules continues to shift towards greater challenges (e.g., poor solubility, pH-dependent solubility, narrow therapeutic index, etc.) the need for more advanced, multifunctional excipients can be expected to increase.

Materials and Methods

2.1. Materials

Soluble corn starch, methacrylic acid (MAA), N,N′-methylenebisacrylamide (MBA), sodium thiosulfate (STS), potassium persulfate (KPS), sodium dodecyl sulfate (SDS), and sodium phosphate tribasic were purchased from Sigma Aldrich (Oakville, ON, Canada). Verapamil HCl (VER) was purchased from Spectrum Chemicals, (New Brunswick, NJ, USA). Hydrochloric acid (HCl) was purchased from Caledon (Georgetown, ON, Canada). SNARF-4F (#S23920) was purchased from Fisher Scientific (Ottawa, ON, Canada). Bromocresol green was purchased from Sigma Aldrich (Oakville, ON, Canada). Ethylcellulose (Surelease® E-7-19040) was kindly donated by Colorcon (West Point, PA, USA). Polyvinylpyrrolidone (PVP) (Kollidon®/PVPK30) was kindly donated by BASF (Ludwigshaven, Germany). Polysorbate 80 (Tween 80-LQ-(CQ)) was kindly donated by Croda (Edison, NJ, USA). Microcrystalline cellulose (MCC) beads ([…] annotation from the publisher: for example: CELLETS® 700) were used as the coating substrate […].

Conclusions

In this work, the multifunctionality of a nanogel TPN was investigated as a non-leachable pHm modifier and pH-responsive pore former in a bilayer-coated bead formulation for the pH transition-independent controlled release of weakly basic drugs. The results demonstrated that incorporation of TPN, comprised of pH-sensitive MAA and cross-linker MBA, enables the inner matrix layer of VER-TPN-EC to maintain a pHm approximately 1.5 unit lower than the external buffer pH, which may be further enhanced by coating with a TPN-EC membrane. In a simulated gastric and intestinal pH transition condition (i.e., from pH 1.2 to 6.8), the bilayer-coated beads with 16% to 19% WG resulted in a constant release rate during the pH transition, followed by a sustained release of VER up to 18 h, beyond the extent achieved when tested in single pH media. This ability to overcome the poor solubility of VER at high pH can be ascribed to the combinatory effects of the pH-dependent swelling of TPN that increased permeability, preferred retention of protons in the TPN due to Donnan equilibrium, pH-dependent complexation between MAA and VER, and the barrier to diffusion of buffer ions by the outer coating. This work suggests that the multifunctionality and tunability of TPN-EC formulations and the formulation design strategy may be expanded to tackle the challenges faced by other drugs with severe pH-dependence of water solubility.

Disclaimer

Excerpt from: Pharmaceutics 2023, 15(2), 547; https://doi.org/10.3390/pharmaceutics15020547. by Hao Han R. Chang, Kuan Chen, Jamie Anne Lugtu-Pe, Nour AL-Mousawi, Xuning Zhang, Daniel Bar-Shalom, Anil Kane, and Xiao Yu Wu.

References

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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

We identified, that amorphous solid dispersions gain in importance as they increase the solubility and dissolution rate of poorly water-soluble drugs. There are severall attempts, in which each of them positive aspects and certain issues occur. It’s time, drawing amorphous solids dispersions in a more general context and sheding some more light on elementary aspects. We like to point on an excellent summary given by Thomas Rades and Keita Kondo [Rades_2022]. Before switching over, we like to emphasis and anticipate one message: The lastest attempts for amorphous solid dispersions is using CELLETS® 175 (MCC spheres) which do not only act as drug carrier, but – due to best friability – as milling balls. You might like follow this attempt with MCC starter beads, so please contact us for getting some materials. Let’s now read more from Rades et al.:

Draw-back on Amorphous solid dispersions

Amorphization is a promising approach to improve the solubility and dissolution rate of poorly water-soluble drugs as amorphous solids lack a crystal lattice with long-range order [1]. However, since amorphous forms are thermodynamically unstable due to a high chemical potential compared to crystalline forms, amorphous drugs exhibit low physical stability and finally recrystallizes [2], [3]. Thus, strategies to stabilize amorphous forms are essential in the development of amorphous products and include the design of amorphous solid dispersions (ASDs) [4], [5] and co-amorphous formulations [6], [7], [8]. ASDs are the most common approach for preparing amorphous products and involve glass formation by molecularly dispersing drug compounds into an amorphous polymer [4], [5]. However, ASD preparations may require a large quantity of polymer to stabilize amorphized drug due to their low miscibility with drug molecules [9], leading to a high bulk volume of the amorphous products. Co-amorphous systems have recently attracted attention as an alternative approach to amorphous formulations and include the formation of a single amorphous phase in which multiple low molecular weight initially crystalline materials (including drug compounds) are uniformly mixed at the molecular levels [6], [7], [8]. Co-amorphous mixtures typically exhibit high physical stability and dissolution characteristics [6], [7], [10].

Co-amorphous systems are typically classified as drug-drug combinations and drug-excipient mixtures. In the former combinations, amorphous phases comprise two drug compounds, which act as a stabilizer for each other by forming intermolecular interactions [11], [12], [13]. These formulations are expected to offer a combination of drugs to enhance the therapeutic effects but their applicability is limited as drug-drug combinations forming co-amorphous solids are not necessarily suitable for combination therapy, or require fixed doses, not necessarily suitable for co-amorphization. In the co-amorphous drug-excipient systems, low molecular-weight substances (including organic acids [14], sugars [15] and amino acids [16]) act as a co-former and their properties and mixing ratio with the drug affect dissolution characteristics and physical stability of the resulting co-amorphous mixtures [8], [10]. Recently, various combinations of drug compounds and amino acids were systematically investigated [17], [18], indicating that co-amorphous mixtures with high dissolution characteristics and physical stability can be produced by selecting amino acids that can form interactions with the target drug compounds (e.g. pairs of acidic drugs and basic amino acids). Therefore, amino acids are a promising co-former class for co-amorphous formulations.

Preparation of co-amorphous mixtures has been reported using melt quenching [13], [19], spray drying [20], [21], and ball milling [16], [22]. Since the resulting solids are in cake or powder forms (regardless of the preparation method), downstream processes including milling and granulation are usually essential to produce final dosage forms such as capsules and tablets for oral administration [23]. These processes can lead to increased risk of phase separations and crystallization due to moisture, thermal, and mechanical stresses. In ASD systems, to avoid the problems due to the downstream processes, one-step preparations of ASD granules by amorphizing drug compounds during the granulation process using fluidized bed processors [24], [25], [26], [27], [28], [29], [30] and high shear granulators [31], [32], [33], [34] have been investigated. However, to our knowledge, there are no reports on one-step preparation methods for co-amorphous granules. In the first part of the current study, we investigated the feasibility of solventless amorphization and pelletization using a high shear granulator and could obtain fully amorphized indomethacin-layered pellets by simply mixing indomethacin crystals and microcrystalline cellulose spheres without using solvent and heating. Indomethacin crystals were pulverized and amorphized due to collisions with the spheres and subsequently are deposited on the surface of the spheres. Therefore, we hypothesized that co-amorphous mixture-layered pellets can be produced through a one-step amorphization and pelletization process using this technique, as the preparation of co-amorphous mixtures has previously been performed by mechanical activation [16], [22]. Furthermore, this technique holds promise as an economical as well as sustainable approach to manufacture co-amorphous formulations as the need for solvent and/or heat is eliminated.

In previous research, various combinations of indomethacin and amino acids for co-amorphous preparations were systematically investigated. The findings suggest that arginine is an excellent co-former for indomethacin to prepare co-amorphous mixtures with fast dissolution characteristics and high physical stability [18], as an amorphous salt is formed due to strong interactions between the acidic drug indomethacin and the basic amino acid arginine [35], [36]. In the current study, to investigate whether co-amorphous layer pellets can be produced through a one-step amorphization and pelletization process, indomethacin and arginine were selected as the model drug and the co-former, respectively. In the first part of this study, indomethacin crystals were mixed with microcrystalline cellulose spheres (with various mean diameters of 140 μm, 195 μm, 275 μm, 414 μm, and 649 μm) at a weight ratio of 1:10 using a high shear granulator [added: TMG1/6, Glatt GmbH, Binzen, Germany]. Fully amorphized indomethacin-layered pellets were obtained using carriers of 414 μm in diameter, whereas partially amorphized indomethacin-layered pellets were obtained using carriers of 195 μm in diameter. This difference was likely due to the higher impact forces of larger carriers promoting mechanical activation of indomethacin crystals. In this part of the study, to clarify the effects of using arginine on the amorphization and pelletization of indomethacin, the smaller cellulose spheres of 195 μm in diameter were employed as carrier particles. Indomethacin crystals and arginine crystals were initially mixed at various molar ratios (1:1, 2:1, and 3:1), and then the resulting mixtures were high shear granulated with microcrystalline cellulose spheres at a weight ratio of 1:10. The resulting composite particles were characterized using solid-state and particle analytical techniques. To identify effective co-amorphization approaches, we examined high shear mixing under various jacket temperatures. Furthermore, physical stability and dissolution characteristics of 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,

  1. 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
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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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Scientific literature on MCC pellets (CELLETS)

Selected Scientific literature

Please, find scientific literature on CELLETS®, MCC spheres. This list is constantly updated and does not claim to be complete. If you are author, scientist or R&D specialist, please submit your present publication to us for improving the visibility.

List – Publications with MCC spheres, 2023

Research article
Amorphous Solid Dispersions Layered onto Pellets—An Alternative to Spray Drying?
Pharmaceutics (2023) 15(3), 764. doi:10.3390/pharmaceutics15030764
M. Neuwirth, S.K. Kappes, M.U. Hartig, K.G. Wagner

Research article
Optimization of Fluidized-Bed Process Parameters for Coating Uniformity and Nutrient-Release Characteristics of Controlled-Release Urea Produced by Modified Lignocellulosic Coating Material
Agronomy (2023) 13(3), 725. doi:10.3390/agronomy13030725
A. Mahmood, B. Azeem, A.M. Alghamdi, K. Shahzad, A. Ahmad Al-Zahrani, M. Imtiaz Rashid, A. Binti Mahpudz, A. Jamil

Research article
Hydrodynamic behaviour of CELLETS® (Ph.Eur./USP) in a spouted bed using image processing method
Particuology (2023), 76, 101-112, doi:10.1016/j.partic.2022.07.009
J. Vanamu, A. Sahoo

List – Publications with MCC spheres, 2022

Research article
Product-Property Guided Scale-Up of a Fluidized Bed Spray Granulation Process Using the CFD-DEM Method
Processes (2022) 10(7), 1291. doi:10.3390/pr10071291
P. Kieckhefen, S. Pietsch-Braune, S. Heinrich

Research article
Influence of In Situ Calcium Pectinate Coating on Metoprolol Tartrate Pellets for Controlled Release and Colon-Specific Drug Delivery
Pharmaceutics (2022) 14(5), 1061. doi:10.3390/pharmaceutics14051061
P. Wanasawas, A. Mitrevej, N. Sinchaipanid

Research article
Delamination and wetting behavior of natural hot-melt coating materials
Powder Technology (2022) 404, 117443. doi:10.1016/j.powtec.2022.117443
B.M. Woerthmann, L. Totzauer, H. Briesen

Research article
A systematic approach for assessing the suitability of enteral feeding tubes for the administration of controlled-release pellet formulations
International Journal of Pharmaceutics (2022) 612, 121286. doi:10.1016/j.ijpharm.2021.121286
F. Karkossa, N. Lehmann, S. Klein

Research article
Spray-freeze-dried lyospheres: Solid content and the impact on flowability and mechanical stability
Powder Technology (2022) 411, 117905. doi:10.1016/j.powtec.2022.117905
A. Rautenberg, A. Lamprecht

Conference proceedings
Assessment of the effect of microcrystalline cellulose (MCC) spheres size on the flow via powder rheolog
The FORGE, 2022 – pure.qub.ac.uk
V. Mohylyuk, R. Dattani

Research article
Solventless amorphization and pelletization using a high shear granulator. Part II; Preparation of co-amorphous mixture-layered pellets using indomethacin and arginine
European Journal of Pharmaceutics and Biopharmaceutics (2022) 181, 183-194. doi: 10.1016/j.ejpb.2022.11.011
K. Kondo, T. Rades

Research article
Solventless amorphization and pelletization using a high shear granulator. Part I; feasibility study using indomethacin
European Journal of Pharmaceutics and Biopharmaceutics (2022) 181, 147-158. doi: 10.1016/j.ejpb.2022.11.010
K. Kondo, T. Rades

Research article
Application of different models to evaluate the key factors of fluidized bed layering granulation and their influence on granule characteristics
Powder Technology (2022), 408:117737. doi: 10.1016/j.powtec.2022.117737
R. Maharjan, S. H. Jeong

Research article
Evaluation of gravitational consolidation of binary powder mixtures by modified Heckel equation
Powder Technology (2022), 408:117729. doi: 10.1016/j.powtec.2022.117729
P. Svačinová, O. Macho, Ž. Jarolímová, M. Kuentz, Ľ. Gabrišová and Z. Šklubalová

Research article
Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing
Pharmaceutics (2022), 14(5)1058. doi: 10.3390/pharmaceutics14051058
M. W. Stocker, M. J. Harding, V. Todaro, A. M. Healy and S. Ferguson

List – Publications with MCC spheres, 2021

Research article
Correlating Granule Surface Structure Morphology and Process Conditions in Fluidized Bed Layering Spray Granulation
KONA Powder and Particle Journal (2021), DOI:10.14356/kona.2022016
M. Orth, P. Kieckhefen, S. Pietsch and S. Heinrich

Research article
Relative bioavailability enhancement of simvastatin via dry emulsion systems: comparison of spray drying and fluid bed layering technology
Eur J Pharm Biopharm (2021), S0939-6411(21)00353-2. doi: 10.1016/j.ejpb.2021.12.004
M. Pohlen, J. Aguiar Zdovc, J. Trontelj, J. Mravljak, M. G. Matjaž, I. Grabnar, T. Snoj and R. Dreu

Research article
A novel method for assessing the coating uniformity of hot-melt coated particles using micro-computed tomography
Powder Technology, Volume 378, Part A, 22 January 2021, Pages 51-59
B.M. Woerthmann, J.A. Lindner, T. Kovacevic, P. Pergam, F. Schmid, H. Briesen

List – Publications with MCC spheres, 2020

Research article
Measuring segregation characteristics of industrially relevant granular mixtures: Part II – Experimental application and validation
Powder Technology, Volume 368, 15 May 2020, Pages 278-285
Alexander M. Fry, Vidya Vidyapati, John P. Hecht, Paul B. Umbanhowar, Julio M. Ottinoa, Richard M. Lueptow

Short communication
Introduction of the energy to break an avalanche as a promising parameter for powder flowability prediction
Powder Technology, Volume 375, 20 September 2020, Pages 33-41
Žofie Trpělková, Hana Hurychová, Martin Kuentz, Barbora Vraníková, Zdenka Šklubalová

Research article
Material specific drying kinetics in fluidized bed drying under mechanical vibration using the reaction engineering approach
Advanced Powder Technology, Volume 31, Issue 12, December 2020, Pages 4699-4713
Soeren E. Lehmann, Tobias Oesau, Alfred Jongsma, Fredrik Innings, Stefan Heinrich

Research article
In-line particle size measurement and process influences on rotary fluidized bed agglomeration
Powder Technology, Volume 364, 15 March 2020, Pages 673-679
Marcel Langner, Ivonne Kitzmann, Anna-Lena Ruppert, Inken Wittich, Bertram Wolf

Research article
Regulating the pH of bicarbonate solutions without purging gases: Application to dissolution testing of enteric coated tablets, pellets and microparticles
International Journal of Pharmaceutics, Volume 585, 30 July 2020, 119562
Nathan Scott, Kavil Patel, Tariro Sithole, Konstantina Xenofontos, Valentyn Mohylyuk, Fang Liu

Research article
Easy to Swallow “Instant” Jelly Formulations for Sustained Release Gliclazide Delivery
Journal of Pharmaceutical Sciences, Volume 109, Issue 8, August 2020, Pages 2474-2484
Simmi Patel, Nathan Scott, Kavil Patel, Valentyn Mohylyuk, William J. McAuley, Fang Liu

Research article
Quantification of swelling characteristics of pharmaceutical particles
International Journal of Pharmaceutics, Volume 590, 30 November 2020, 119903
Mithushan Soundaranathan, Pattavet Vivattanaseth, Erin Walsh, Kendal Pitt, Blair Johnston, Daniel Markl

Research article
Effects of humidity on cellulose pellets loaded with potassium titanium oxide oxalate for detection of hydrogen peroxide vapor in powders
Powder Technology, Volume 366, 15 April 2020, Pages 348-357
Maria H. Kastvig, Cosima Hirschberg, Frans W.J. Van Den Berg, Jukka Rantanen, Mogens L. Andersen

Research article
Recent advance in delivery system and tissue engineering applications of chondroitin sulfate
Carbohydrate Polymers, Volume 230, 15 February 2020, 115650
Jun Yang, Mingyue Shen, Huiliang Wen, Yu Luo, Rong Huang, Liyuan Rong, Jianhua Xie

Research article
Simulation of pellet coating in Wurster coaters
International Journal of Pharmaceutics, Volume 590, 30 November 2020, 119931
Hamid Reza Norouzi

Research article
Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility
International Journal of Pharmaceutics, Volume 581, 15 May 2020, 119217
Matteo Cerea, Anastasia Foppoli, Luca Palugan, Alic Melocchi, Lucia Zema, Alessandra Maroni, Andrea Gazzaniga

Research article
Optimization and tracking of coating processes of pellets with polyvinylpyrrolidone solutions in an acoustic levitator
Powder Technology, Volume 360, 15 January 2020, Pages 1126-1133
Doris L. Wong, Anna-Lena Wirsching, Kai Betz, Andreas Reinbeck, Hans-Ulrich Moritz, Werner Pauer

List – Publications with MCC spheres, 2019

Research article
Measurement of hydrogen peroxide vapor in powders with potassium titanium oxide oxalate loaded cellulose pellets as probes
AAPS PharmSciTech, Volume 21(1):3, 11 Nov 2019
Maria H. Kastvig, Johan P. Bøtker, Ge Ge, Mogens L. Andersen

Research article
Wurster Fluidised Bed Coating of Microparticles: Towards Scalable Production of Oral Sustained-Release Liquid Medicines for Patients with Swallowing Difficulties
AAPS PharmSciTech, Volume 21(1):3, 11 Nov 2019
Valentyn Mohylyuk, Kavil Patel, Nathan Scott, Craig Richardson, Darragh Murnane, Fang Liu

Research article
Assessment of the effect of Cellets’ particle size on the flow in a Wurster fluid-bed coater via powder rheology
Journal of Drug Delivery Science and Technology, Volume 54, December 2019, 101320
Valentyn Mohylyuk, Ioanna Danai Styliari, Dmytryi Novykov, Reiss Pikett, Rajeev Dattani

Research article
Particle electrification in an apparatus with a draft tube operating in a fast circulating dilute spout-fluid bed regime
Particuology, Volume 42, February 2019, Pages 146-153
Wojciech Ludwig

Research article
Development and evaluation of budesonide-based modified-release liquid oral dosage forms
Journal of Drug Delivery Science and Technology, Volume 54, December 2019, 101273
Federica Ronchi, Antonio Sereno, Maxime Paide, Ismaël Hennia, Pierre Sacré, George Guillaume, Vincent Stéphenne, Jonathan Goole, Karim Amighi

Research article
Evaluation of in-line particle measurement with an SFT-probe as monitoring tool for process automation using a new time-based buffer approach
European Journal of Pharmaceutical Sciences, Volume 128, 1 February 2019, Pages 162-170
Theresa Reimers, Jochen Thies, Stefan Dietrich, Julian Quodbach, Miriam Pein-Hackelbusch

Research article
In vitro and sensory tests to design easy-to-swallow multi-particulate formulations
European Journal of Pharmaceutical Sciences, Volume 132, 30 April 2019, Pages 157-162
Marco Marconati, Felipe Lopez, Catherine Tuleu, Mine Orlu, Marco Ramaioli

Research article
Numerical study of the hydrodynamics of fluidized beds operated under sub-atmospheric pressure
Chemical Engineering Journal, Volume 372, 15 September 2019, Pages 1134-1153
Sayali Zarekar, Andreas Bück, Michael Jacob, Evangelos Tsotsas

Research article
Solidification of carvedilol loaded SMEDDS by swirling fluidized bed pellet coating
International Journal of Pharmaceutics, Volume 566, 20 July 2019, Pages 89-100
J. Mandić, M. Luštrik, F. Vrečer, M. Gašperlin, A. Zvonar Pobirk

Research article
Quantitative bin flow analysis of particle discharge using X-ray radiography
Powder Technology, Volume 344, 15 February 2019, Pages 693-705
Sanket Bacchuwar, Vidya Vidyapati, Ke-ming Quan, Chen-Luh Lin, Jan D. Miller

Research article
Adjustment of triple shellac coating for precise release of bioactive substances with different physico-chemical properties in the ileocolonic region
International Journal of Pharmaceutics, Volume 564, 10 June 2019, Pages 472-484>
Eva-Maria Theismann, Julia Katharina Keppler, Jörg-Rainer Knipp, Daniela Fangmann, Esther Appel, Stanislav N. Gorb, Georg H. Waetzig, Stefan Schreiber, Matthias Laudes, Karin Schwarz

Research article
The analysis of the influence of the normal restitution coefficient model on calculated particles velocities by means of Eulerian-Lagrangian approach
Powder Technology, Volume 344, 15 February 2019, Pages 140-151
Wojciech Ludwig, PaweƚPłuszka

Research article
Measurement of granule layer thickness in a spouted bed coating process via optical coherence tomography
Powder Technology, Volume 356, November 2019, Pages 139-147
Swantje Pietsch, Anna Peter, Patrick Wahl, Johannes Khinast, Stefan Heinrich

Research article
A novel method of quantifying the coating progress in a three-dimensional prismatic spouted bed
Particuology, Volume 42, February 2019, Pages 137-145
Swantje Pietsch, Finn Ole Poppinga, Stefan Heinrich, Michael Müller, Michael Schönherr, Frank Kleine Jäger

Research article
Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form
International Journal of Pharmaceutics, Volume 567, 15 August 2019, 118416
Federica Ronchi, Antonio, Sereno, Maxime Paide, Pierre Sacré, George Guillaume, Vincent Stéphenne, Jonathan Goole, Karim Amighi

Research article
Influence of separation properties and processing strategies on product characteristics in continuous fluidized bed spray granulation
Powder Technology, Volume 342, 15 January 2019, Pages 572-584
Daniel Müller, Andreas Bück, Evangelos Tsotsas

List – Publications with MCC spheres, 2018

Short communication
Novel production method of tracer particles for residence time measurements in gas-solid processes
Powder Technology, Volume 338, October 2018, Pages 1-6
Swantje Pietsch, Paul Kieckhefen, Michael Müller, Michael Schönherr, Frank Kleine Jäger, Stefan Heinrich

Research article
The effect of administration media on palatability and ease of swallowing of multiparticulate formulations
International Journal of Pharmaceutics, Volume 551, Issues 1–2, 15 November 2018, Pages 67-75
Felipe L. Lopez, Terry B. Ernest, Mine Orlu, CatherineTuleu

Research article
Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations
International Journal of Pharmaceutics, Volume 540, Issues 1–2, 5 April 2018, Pages 120-131
Josefina Nordström, Göran Alderborn, Göran Frenning

Research article
Effects of pharmaceutical processes on the quality of ethylcellulose coated pellets: Quality by design approach
Powder Technology, Volume 339, November 2018, Pages 25-38
Prakash Thapa, Ritu Thapa, Du Hyung Choi, Seong Hoon Jeong

Research article
Euler-Lagrange model of particles circulation in a spout-fluid bed apparatus for dry coating
Powder Technology, Volume 328, 1 April 2018, Pages 375-388
Wojciech Ludwig, Paweł Płuszka

Research article
Inline acoustic monitoring to determine fluidized bed performance during pharmaceutical coating
International Journal of Pharmaceutics, Volume 549, Issues 1–2, 5 October 2018, Pages 293-298
Allan Carter, Lauren Briens

Research article
Sifting segregation of ideal blends in a two-hopper tester: Segregation profiles and segregation magnitudes
Powder Technology, Volume 331, 15 May 2018, Pages 60-67
Mariagrazia Marucci, Banien Al-Saaigh, Catherine Boissier, Marie Wahlgren, Håkan Wikström

Conference abstract
Multiple unit mini-tablets: Content uniformity issues
International Journal of Pharmaceutics, Volume 536, Issue 2, 5 February 2018, Pages 506-507
Anna Kira Adam, Jörg Breitkreutz

Research article
Influence of gas inflow modelling on CFD-DEM simulations of three-dimensional prismatic spouted beds
Powder Technology, Volume 329, 15 April 2018, Pages 167-180
Paul Kieckhefen, Swantje Pietsch, Moritz Höfert, Michael Schönherr, Stefan Heinrich, Frank Kleine Jäger

Research article
A redispersible dry emulsion system with simvastatin prepared via fluid bed layering as a means of dissolution enhancement of a lipophilic drug
International Journal of Pharmaceutics, Volume 549, Issues 1–2, 5 October 2018, Pages 325-334
Mitja Pohlen, Luka Pirker, Matevž Luštrik, Rok Dreu

Review article
Overview of PAT process analysers applicable in monitoring of film coating unit operations for manufacturing of solid oral dosage forms
European Journal of Pharmaceutical Sciences, Volume 111, 1 January 2018, Pages 278-292
Klemen Korasa, Franc Vrečer

Research article
On the properties and application of beeswax, carnauba wax and palm fat mixtures for hot melt coating in fluidized beds
Advanced Powder Technology, Volume 29, Issue 3, March 2018, Pages 781-788
M.G. Müller, J.A. Lindner, H. Briesen, K. Sommer, P. Foerst

Research article
Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics
Journal of Controlled Release, Volume 287, 10 October 2018, Pages 247-256
Matteo Cerea, Alessandra Maroni, Luca Palugan, Marco Bellini, Anastasia Foppoli, Alice Melocchi, Lucia Zema, Andrea Gazzaniga

Research article
Role of plasticizer in membrane coated extended release oral drug delivery system
Journal of Drug Delivery Science and Technology, Volume 44, April 2018, Pages 231-243
Pinak Khatri, Dipen Desai, Namdev Shelke, Tamara Minko

Research article
Evaluation of pellet cycle times in a Wurster chamber using a photoluminescence method
Chemical Engineering Research and Design, Volume 132, April 2018, Pages 1170-1179
Domen Kitak, Rok Šibanc, Rok Dreu

Research article
Influence of perforated draft tube air intake on a pellet coating process
Powder Technology, Volume 330, 1 May 2018, Pages 114-124
Matevž Luštrik, Rok Dreu, Matjaž Perpar

Research article
Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating
European Journal of Pharmaceutics and Biopharmaceutics, Volume 124, March 2018, Pages 13-27
Dolores R. Serrano, David Walsh, Peter O’Connell, Naila A. Mugheirbi, Zelalem Ayenew Worku, Francisco Bolas-Fernandez, Carolina Galiana, Maria Auxiliadora Dea-Ayuela, Anne Marie Healy


Research article

Research article
Mechanics of Pharmaceutical Pellets—Constitutive Properties, Deformation, and Breakage Behavior
Journal of Pharmaceutical Sciences, Volume 107, Issue 2, February 2018, Pages 571-586
Alexander Russell, Rok Šibanc, Rok Dreu, Peter Müller

List – Publications with MCC spheres, 2017

Research article
Production of composite particles using an innovative continuous dry coating process derived from extrusion
Advanced Powder Technology, Volume 28, Issue 11, November 2017, Pages 2875-2885
Fanny Cavaillès, Romain Sescousse, Alain Chamayou, Laurence Galet

Research article
Determination of the release mechanism of Theophylline from pellets coated with Surelease®—A water dispersion of ethyl cellulose
International Journal of Pharmaceutics, Volume 528, Issues 1–2, 7 August 2017, Pages 345-353
Jurgita Kazlauske, Maria Margherita Cafaro, Diego Caccavo, Mariagrazia Marucci, Gaetano Lamberti, Anna Angela Barba, Anette Larsson

Research article
In-line monitoring of multi-layered film-coating on pellets using Raman spectroscopy by MCR and PLS analyses
European Journal of Pharmaceutics and Biopharmaceutics, Volume 114, May 2017, Pages 194-201
Jin Hisazumi, Peter Kleinebudde

Research article
Analysis of pellet coating uniformity using a computer scanner
International Journal of Pharmaceutics, Volume 533, Issue 2, 30 November 2017, Pages 377-382
Rok Šibanc, Matevž Luštrik, Rok Dreu

Research article
Modeling of particle velocities in an apparatus with a draft tube operating in a fast circulating dilute spout-fluid bed regime
Powder Technology, Volume 319, September 2017, Pages 332-345
Wojciech Ludwig, Daniel Zając

Research article
UV imaging of multiple unit pellet system (MUPS) tablets: A case study of acetylsalicylic acid stability
European Journal of Pharmaceutics and Biopharmaceutics, Volume 119, October 2017, Pages 447-453
Anna Novikova, Jens M. Carstensen, Thomas Rades, Claudia S. Leopold

Research article
New hybrid CPU-GPU solver for CFD-DEM simulation of fluidized beds
Powder Technology, Volume 316, 1 July 2017, Pages 233-244
H.R. Norouzi, R. Zarghami, N. Mostoufi

Research article
A top coating strategy with highly bonding polymers to enable direct tableting of multiple unit pellet system (MUPS)
Powder Technology, Volume 305, January 2017, Pages 591-596
Frederick Osei-Yeboah, Yidan Lan, Changquan Calvin Sun

Research article
Synthesis and melt processing of cellulose esters for preparation of thermoforming materials and extended drug release tablets
Carbohydrate Polymers, Volume 177, 1 December 2017, Pages 105-115
Sanna Virtanen, Riku Talja, Sauli Vuoti

Research article
Downstream drug product processing of itraconazole nanosuspension: Factors influencing drug particle size and dissolution from nanosuspension-layered beads
International Journal of Pharmaceutics, Volume 524, Issues 1–2, 30 May 2017, Pages 443-453
Johannes Parmentier, En Hui Tan, Ariana Low, Jan Peter Möschwitzer

List – Publications with MCC spheres, 2016

Research article
In-line particle size measurement and agglomeration detection of pellet fluidized bed coating by Spatial Filter Velocimetry
Powder Technology, Volume 301, November 2016, Pages 261-267
Dimitri Wiegel, Günter Eckardt, Florian Priese, Bertram Wolf

Research article
Effect of formulation variables on oral grittiness and preferences of multiparticulate formulations in adult volunteers
European Journal of Pharmaceutical Sciences, Volume 92, 20 September 2016, Pages 156-162
Felipe L. Lopez, Alexandra Bowles, Mine Orlu Gul, David Clapham, Terry B. Ernest, Catherine Tuleu

Research article
Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen
International Journal of Pharmaceutics, Volume 499, Issues 1–2, 29 February 2016, Pages 271-279
Eva Julia Laukamp, Klaus Knop, Markus Thommes, Joerg Breitkreutz

Research article
Multivariate calibration of the degree of crystallinity in intact pellets by X-ray powder diffraction
International Journal of Pharmaceutics, Volume 502, Issues 1–2, 11 April 2016, Pages 107-116
Krisztina Nikowitz, Attila Domján, Klára Pintye-Hódi, Géza Regdon jr.

Research article
Towards improving quality of video-based vehicle counting method for traffic flow estimation
Signal Processing, Volume 120, March 2016, Pages 672-681
Yingjie Xia, Xingmin Shi, Guanghua Song, Qiaolei Geng, Yuncai Liu

Conference abstract
Multiple-unit orodispersible mini-tablets
International Journal of Pharmaceutics, Volume 511, Issue 2, 25 September 2016, Page 1128
Anna Kira Adam, Christian Zimmer, Stefan Rauscher, Jörg Breitkreutz

Research article
Asymmetric distribution in twin screw granulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 106, September 2016, Pages 50-58
Tim Chan Seem, Neil A. Rowson, Ian Gabbott, Marcelde Matas, Gavin K. Reynolds, AndyIngram

Research article
Measurement of particle concentration in a Wurster coater draft tube using light attenuation
Chemical Engineering Research and Design, Volume 110, June 2016, Pages 20-31
R. Šibanc, I. Žun, R. Dreu

List – Publications with MCC spheres, 2015

Research article
Two-dimensional particle shape analysis from chord measurements to increase accuracy of particle shape determination
Powder Technology, Volume 284, November 2015, Pages 25-31
D. Petrak, S. Dietrich, G. Eckardt, M. Köhler

Research article
Passive acoustic emission monitoring of pellet coat thickness in a fluidized bed
Powder Technology, Volume 286, December 2015, Pages 172-180
Taylor Sheahan, Lauren Briens

Research article
Tabletability Modulation Through Surface Engineering
Journal of Pharmaceutical Sciences, Volume 104, Issue 8, August 2015, Pages 2645-2648
Frederick Osei-Yeboah, Changquan Calvin Sun

Research article
Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane
International Journal of Pharmaceutics, Volume 480, Issues 1–2, 1 March 2015, Pages 15-26
Sheng-Feng Hung, Chien-Ming Hsieh, Ying-Chen Chen, Cheng-Mao Lin, Hsiu-O Ho, Ming-Thau Sheu

Research article
Dry Coating Characterization of Coverage by Image Analysis: Methodology
Procedia Engineering, Volume 102, 2015, Pages 81-88
Olivier Lecoq, Fredj Kaouach, Alain Chamayou

Research article
Passive acoustic emissions monitoring of the coating of pellets in a fluidized bed—A feasibility analysis
Powder Technology, Volume 283, October 2015, Pages 373-379
Taylor Sheahan, Lauren Briens

List – Publications with MCC spheres, 2014

Research article
A New Apparatus for Real‐Time Assessment of the Particle Size Distribution of Disintegrating Tablets
Journal of Pharmaceutical Sciences, Volume 103, Issue 11, November 2014, Pages 3657-3665
Julian Quodbach, Peter Kleinebudde

Research article
In-line spatial filtering velocimetry for particle size and film thickness determination in fluidized-bed pellet coating processes
European Journal of Pharmaceutics and Biopharmaceutics, Volume 88, Issue 3, November 2014, Pages 931-938
Friederike Folttmann, Klaus Knop, Peter Kleinebudde, Miriam Pein

Research article
On-line monitoring of fluid bed granulation by photometric imaging
European Journal of Pharmaceutics and Biopharmaceutics, Volume 88, Issue 3, November 2014, Pages 879-885
Ira Soppela, Osmo Antikainen, Niklas Sandler, Jouko Yliruusi

Research article
Application properties of oral gels as media for administration of minitablets and pellets to paediatric patients
International Journal of Pharmaceutics
Volume 460, Issues 1–2, 2 January 2014, Pages 228-233
Anna Kluk, Malgorzata Sznitowska

Research article
In-line monitoring of pellet coating thickness growth by means of visual imaging
International Journal of Pharmaceutics, Volume 470, Issues 1–2, 15 August 2014, Pages 8-14
Nika Oman Kadunc, Rok Šibanc, Rok Dreu, Boštjan Likar, Dejan Tomaževič

Research article
Optical microscopy as a comparative analytical technique for single-particle dissolution studies
International Journal of Pharmaceutics, Volume 469, Issue 1, 20 July 2014, Pages 10-16
Sami Svanbäck, Henrik Ehlers, Jouko Yliruusi

Research article
Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs
European Journal of Pharmaceutics and Biopharmaceutics, Volume 87, Issue 1, May 2014, Pages 107-113
Lieselotte De Smet, Lien Saerens, Thomas De Beer, Robert Carleer, Peter Adriaensens, Jan Van Bocxlaer, Chris Vervaet, Jean PaulRemon

Research article
Global monitoring of fluidized-bed processes by means of microwave cavity resonances
Measurement, Volume 55, September 2014, Pages 520-535
Johan Nohlert, Livia Cerullo, Johan Winges, Thomas Rylander, Tomas McKelvey, Anders Holmgren, Lubomir Gradinarsky, Staffan Folestad, Mats Viberg, Anders Rasmuson

List – Publications with MCC spheres, 2013

Research article
Water-mediated solid-state transformation of a polymorphic drug during aqueous-based drug-layer coating of pellets
International Journal of Pharmaceutics, Volume 456, Issue 1, 1 November 2013, Pages 41-48
Andres Lust, Satu Lakio, Julia Vintsevits, Jekaterina Kozlova, Peep Veski, Jyrki Heinämäki, Karin Kogermann

Research article
Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique
Journal of Pharmaceutical Investigation (2013), 43:333–342. doi: 10.1007/s40005-013-0077-0
H. A. Hazzah, M. A. EL-Massik, O. Y. Abdallah & H. Abdelkader

Research article
Development of high drug loaded pellets by Design of Experiment and population balance model calculation
Powder Technology, Volume 241, June 2013, Pages 149-157
Florian Priese, Bertram Wolf

Research article
Particle sizing measurements in pharmaceutical applications: Comparison of in-process methods versus off-line methods
European Journal of Pharmaceutics and Biopharmaceutics, Volume 85, Issue 3, Part B, November 2013, Pages 1006-1018
Ana F.T. Silva, Anneleen Burggraeve, Quenten Denon, Paul Van der Meeren, Niklas Sandler, Tom Van Den Kerkhof, Mario Hellings, Chris Vervaet, Jean Paul Remon, João Almeida Lopes, Thomas De Beer

Research article
Physical properties of pharmaceutical pellets
Chemical Engineering Science, Volume 86, 4 February 2013, Pages 50-60
Rok Šibanc, Teja Kitak, Biljana Govedarica, StankoSrčič Rok Dreu

Research article
Continuous pellet coating in a Wurster fluidized bed process
Chemical Engineering Science, Volume 86, 4 February 2013, Pages 87-98
N. Hampel, A. Bück, M. Peglow, E. Tsotsas

Research article
Study of the recrystallization in coated pellets – Effect of coating on API crystallinity
European Journal of Pharmaceutical Sciences, Volume 48, Issue 3, 14 February 2013, Pages 563-571
Krisztina Nikowitz, Klára Pintye-Hódi, Géza Regdon Jr.

Research article
The influence of rolling friction on the shear behaviour of non-cohesive pharmaceutical granules – An experimental and numerical investigation
European Journal of Pharmaceutical Sciences, Volume 49, Issue 2, 13 May 2013, Pages 241-250
Ann-Sofie Persson, Göran Frenning

Research article
Characteristics of pellet flow in a Wurster coater draft tube utilizing piezoelectric probe
Powder Technology, Volume 235, February 2013, Pages 640-651
Matevž Luštrik, Rok Šibanc, Stanko Srčič, Matjaž Perpar, Iztok Žun, Rok Dreu

Research article
Estimating coating quality parameters on the basis of pressure drop measurements in a Wurster draft tube
Powder Technology, Volume 246, September 2013, Pages 41-50
Matjaž Perpar, Matevž Luštrik, Rok Dreu, Stanko Srčič, Iztok Žun

Research article
Influence of Non-Water-Soluble Placebo Pellets of Different Sizes on the Characteristics of Orally Disintegrating Tablets Manufactured by Freeze-Drying
Journal of Pharmaceutical Sciences, Volume 102, Issue 6, June 2013, Pages 1786-1799
Ulrike Stange, Christian Führling, Henning Gieseler

List – Publications with MCC spheres, 2012

Research article
A density-based segmentation for 3D images, an application for X-ray micro-tomography
Analytica Chimica Acta, Volume 725, 6 May 2012, Pages 14-21
Thanh N. Tran, Thanh T. Nguyen, Tofan A. Willemsz, Gijsvan Kessel, Henderik W. Frijlink, Kees van der Voort Maarschalk

Research article
Attrition and abrasion resistance of particles coated with pre-mixed polymer coating systems
Powder Technology, Volume 230, November 2012, Pages 1-13
G. Perfetti, F. Depypere, S. Zafari, P. van Hee, W.J. Wildeboer, G. M. H. Meesters

Research article
New spout-fluid bed apparatus for electrostatic coating of fine particles and encapsulation
Powder Technology, Volume 225, July 2012, Pages 52-57
Roman G. Szafran, Wojciech Ludwig, Andrzej Kmiec

Research article
Particle size and packing characterization by diffuse light transmission
Particuology Volume 10, Issue 5, October 2012, Pages 619-627
Henrik Ehlers, Jyrki Heinämäki, Jouko Yliruusi

Research article
Dry Powder Coating in a Modified Wurster Apparatus
Procedia Engineering, Volume 42, 2012, Pages 437-446
W. Ludwig, R.G. Szafran, A. Kmiec, J. Dziak

Research article
Attrition strength of water-soluble cellulose derivative coatings applied on different core materials
Powder Technology, Volume 222, May 2012, Pages 71-79
Katarzyna Nienaltowska, Frédéric Depypere, Giacomo Perfetti, Gabrie M.H. Meesters, Frederik Ronsse, Jan G. Pieters, Koen Dewettinck

Research article
An experimental evaluation of the accuracy to simulate granule bed compression using the discrete element method
Powder Technology, Volume 219, March 2012, Pages 249-256
Ann-Sofie Persson, Göran Frenning

List – Publications with MCC spheres, 2011

Research article
Dry particle high coating of biopowders: An energy approach
Powder Technology, Volume 208, Issue 2, 25 March 2011, Pages 378-382
S. Otles, O. Lecoq, J. A. Dodds

Research article
A density based segmentation method to determine the coordination number of a particulate system
Chemical Engineering Science, Volume 66, Issue 24, 15 December 2011, Pages 6385-6392
Thanh T. Nguyen, Thanh N. Tran, Tofan A. Willemsz, Henderik W. Frijlink, Tuomas Ervasti, Jarkko Ketolainen, Kees van der Voort Maarschalk

Research article
Study of the preparation of a multiparticulate drug delivery system with a layering technique
Powder Technology, Volume 205, Issues 1–3, 10 January 2011, Pages 155-159
Krisztina Nikowitz, Péter Kása Jr., Klára Pintye-Hódi, Géza Regdon Jr.

Research article
Effect of annealing time and addition of lactose on release of a model substance from Eudragit® RS coated pellets produced by a fluidized bed coater
Chemical Engineering Research and Design, Volume 89, Issue 6, June 2011, Pages 697-705
Ulrich M. Heckötter, Anette Larsson, Pornsak Sriamornsak, Mont Kumpugdee-Vollrath

Research article
Suspension pellet layering using PVA–PEG graft copolymer as a new binder
International Journal of Pharmaceutics, Volume 412, Issues 1–2, 30 June 2011, Pages 28-36
L. Suhrenbrock, G. Radtke, K. Knop, P. Kleinebudde

Research article
In-line particle sizing for real-time process control by fibre-optical spatial filtering technique (SFT)
Advanced Powder Technology, Volume 22, Issue 2, March 2011, Pages 203-208
Petrak Dieter, Dietrich Stefan, Eckardt Günter, Köhler Michael

Research article
Flowability of surface modified pharmaceutical granules: A comparative experimental and numerical study
European Journal of Pharmaceutical Sciences, Volume 42, Issue 3, 14 February 2011, Pages 199-209
Ann-Sofie Persson, Göran Alderborn, Göran Frenning

List – Publications with MCC spheres, 2010

Research article
Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices
Chemical Engineering Journal, Volume 164, Issues 2–3, 1 November 2010, Pages 268-274
Jari T. T. Leskinen, Matti-Antero H. Okkonen, Maunu M. Toiviainen, Sami Poutiainen, Mari Tenhunen, Pekka Teppola, Reijo Lappalainen, Jarkko Ketolainen, Kristiina Järvinen

Research article
X-ray micro tomography and image analysis as complementary methods for morphological characterization and coating thickness measurement of coated particles
Advanced Powder Technology, Volume 21, Issue 6, November 2010, Pages 663-675
Giacomo Perfetti, Elke Van de Casteele, Bernd Rieger, Willem J. Wildeboer, Gabrie M.H. Meesters

Research article
Granule size distribution of tablets
Journal of Pharmaceutical Sciences, Volume 99, Issue 4, April 2010, Pages 2061-2069
Satu Virtanen, Osmo Antikainen, Heikki Räikkönen, Jouko Yliruusi

Research article
New insights into segregation during tabletting
International Journal of Pharmaceutics, Volume 397, Issues 1–2, 15 September 2010, Pages 19-26
S. Lakio, S. Siiriä, H. Räikkönen, S. Airaksinen, T. Närvänen, O. Antikainen, J.Yliruusi

Short communication
Can encapsulation lengthen the shelf-life of probiotic bacteria in dry products?
International Journal of Food Microbiology, Volume 136, Issue 3, 1 January 2010, Pages 364-367
F. Weinbreck, I. Bodnár, M.L. Marco

Research article
Evaluation of in-line spatial filter velocimetry as PAT monitoring tool for particle growth during fluid bed granulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 76, Issue 1, September 2010, Pages 138-146
A. Burggraeve, T. Van Den Kerkhof, M. Hellings, J.P. Remon, C. Vervaet, T. De Beera

List – Publications with MCC spheres, 2009

Research article
Impact of polymers on dissolution performance of an amorphous gelleable drug from surface-coated beads
European Journal of Pharmaceutical Sciences, Volume 37, Issue 1, 11 April 2009, Pages 1-10
Chon gFan, Rashmi Pai-Thakur, Wantanee Phuapradit, Lin Zhang, Hung Tian, Waseem Malick, Navnit Shah, M. Serpil Kislalioglu

Short communication
Raman spectroscopic investigation of film thickness
Polymer Testing, Volume 28, Issue 7, October 2009, Pages 770-772
T. Sovány, K. Nikowitz, G. Regdon Jr., P. Kása Jr., K. Pintye-Hódi

Research article
In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation
European Journal of Pharmaceutics and Biopharmaceutics, Volume 73, Issue 2, October 2009, Pages 280-284
Nele Poelvoorde, Hans Verstraelen, Rita Verhelst, Bart Saerens, Ellen De Backer, Guido Lopes dos Santos Santiago, Chris Vervaet, Mario Vaneechoutte, Fabienne De Boeck, Luc Van Borteld, Marleen Temmerman, Jean-Paul Remon

Research article
Modulating pH-independent release from coated pellets: Effect of coating composition on solubilization processes and drug release
European Journal of Pharmaceutics and Biopharmaceutics, Volume 72, Issue 1, May 2009, Pages 111-118
Simon Ensslin, Klaus Peter Moll, Hendrik Metz, Markus Otz, Karsten Mäder

Research article
Dry Particle High-Impact Coating of Biopowders: Coating Strength
Particulate Science and Technology, Volume 27(4), 2009
S. Ötles, O. Lecoq, J. A. Dodds


Research article

Book
Formulation and Analytical Development for Low-Dose Oral Drug Products
John Wiley & Sons , inc. (2009), ISBN 978-0-470-05609-7
Jack Zheng (Editor)

List – Publications with MCC spheres, 2008 and earlier

Research article
Attrition strength of different coated agglomerates
Chemical Engineering Science, Volume 63, Issue 5, March 2008, Pages 1361-1369
B. van Laarhoven, S.C.A. Wiers, S.H. Schaafsma, G.M.H. Meesters

Research article
Direct Drug Loading into Preformed Porous Solid Dosage Units by the Controlled Particle Deposition (CPD), a New Concept for Improved Dissolution Using SCF-Technology
Journal of Pharmaceutical Sciences, Volume 97, Issue 10, October 2008, Pages 4416-4424
Ragna S. Wischumerski, Michael Türk, Martin A. Wahl

Research article
Optimisation of an enteric coated, layered multi-particulate formulation for ileal delivery of viable recombinant Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 69, Issue 3, August 2008, Pages 969-976
Nele Poelvoorde, Nathalie Huyghebaert, Chris Vervaet, Jean-Paul Remon

Research article
Dynamic rearrangement of disulfide bridges influences solubility of whey protein coatings
International Dairy Journal, Volume 18, Issue 5, May 2008, Pages 566-573
René Floris, Igor Bodnár, Fanny Weinbreck, Arno C. Alting

Research article
New insight into modified release pellets – Internal structure and drug release mechanism
Journal of Controlled Release, Volume 128, Issue 2, 4 June 2008, Pages 149-156
Simon Ensslin, Klaus Peter Moll, Kurt Paulus, Karsten Mäder

Research article
Development of an enteric-coated, layered multi-particulate formulation for ileal delivery of viable recombinant Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 61, Issue 3, October 2005, Pages 134-141
Nathalie Huyghebaert, An Vermeire, Pieter Rottiers, Erik Remaut, Jean Paul Remon

Research article
Evaluation of extrusion/spheronisation, layering and compaction for the preparation of an oral, multi-particulate formulation of viable, hIL-10 producing Lactococcus lactis
European Journal of Pharmaceutics and Biopharmaceutics, Volume 59, Issue 1, January 2005, Pages 9-15
Nathalie Huyghebaert, An Vermeire, Sabine Neirynck, Lothar Steidler, Eric Remaut, Jean Paul Remon

Research article
Liquid absorption capacity of carriers in the food technology
Powder Technology, Volume 134, Issue 3, 30 September 2003, Pages 201-209
Heidi Lankes, Karl Sommer, Bernd Weinreich

 

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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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