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Microcrystalline cellulose II (MCC II(1)) is a polymorph of commonly used MCC I; in 2010 it was introduced as new pelletization aid in wet-extrusion/spheronization leading to fast disintegrating pellets. Previous investigations suggested that the storage of the resulting pellets affect the disintegration behavior, the non-hygroscopic substance chloramphenicol that showed no polymorphism or hydrate formation due to relative humidity was used for the investigations. Therefore, theophylline-monohydrate that can dehydrate during storage, but also during manufacturing and drying was used for this study to confirm the results of the previous study and give a more detailed overview of the influence of recrystallization of theophylline monohydrate on disintegration. Storage recommendations should be derived. MCC II-based pellets were prepared of binary mixtures containing 10%, 20% or 50% MCCII as pelletization aid and theophylline-monohydrate as API. These pellets were stored at different relative humidity (0-97%rH; 20°C); the influence on their disintegration and drug release was investigated. The storage conditions had an impact on pellet disintegration. Low relative humidities (⩽ 40%rH) led to a conversion of the monohydrate to the anhydrous form. Newly grown crystals formed a kind of network around the pellet and inhibited the disintegration. High relative humidity (>80%rh) affected the disintegration caused by changes in the MCCII as already seen in the previous study. Due to the changed disintegration behavior also the drug release and release kinetic changed. Therefore, for theophylline containing pellets a storage humidity of 55%rH to 80%rH (20°C) is recommended. All in all, these investigations substantiate the knowledge of MCCII-based pellets providing a better basis for adequate storage conditions of MCCII based pellets., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Microcrystalline cellulose II (MCC II)--a polymorph of commonly used MCC I--was introduced as new pelletization aid in wet-extrusion/spheronization leading to fast disintegrating pellets. Previous investigations suggested that pellet properties were influenced by the fraction of MCC II. Furthermore, it is unknown whether the storage conditions can affect the disintegration behavior. Therefore, the effects of MCC II fraction and the storage conditions on several pellet properties were investigated. MCC II-based pellets were prepared of pure MCC II or binary mixtures containing 10-50% (steps of 10%) MCC II as pelletization aid and theophylline, chloramphenicol or lactose. The pellets were characterized by their aspect ratio, equivalent diameter, water content, tensile strength, porosity as well as shrinking, and disintegration behavior and drug release according to their MCC II fraction. Furthermore, the pellets were stored at different relative humidities (0-97%rh), and the influence on their disintegration and drug release was investigated. With increasing MCC II fraction, the pellets became lager in size, decreased their porosity, and required higher water contents for spheronization. Moreover, the disintegration time increased and the disintegration itself was incomplete. Furthermore, the storage conditions had an impact on the disintegration properties of MCC II-based pellets. The disintegrating was affected irreversibly after storage at high humidity (80-97%rh) resulting in a slow drug release. Therefore, MCC II-based pellets need to be stored below 80%rh to secure a fast disintegration. A better knowledge of the properties of MCC II-based pellets was obtained providing a basis for a successful manufacturing and adequate storage of MCC II-based pellets prepared by extrusion/spheronization., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Pellets are frequently used in pharmaceutical applications. The extrusion-spheronization process is a well-established technique used to produce pellets of a spherical shape and narrow size distribution. In this process, cylindrical extrudates are transformed into spherical pellets by spheronization. Most established mechanisms consider only breakage and deformation to explain pellet formation. An interaction between the rounding extrudates via adhesion of fine particles was not considered for many years. This study deals with the evolution of pellet properties over time during the spheronization process in order to quantify the influence of pellet interactions on their properties. Therefore the most important pelletization aids (MCCI, MCCII and κ-carrageenan) were investigated using acetaminophen as a model drug and lactose as a filler. In the first seconds of the spheronization process, a high fine fraction was seen which decreased during the process. Simultaneously, the material transferred between the pellets increased. However the fine fraction is not high enough to explain the mass transfer; therefore a direct transfer between the pellets was assumed. The pelletization aid has a huge influence on the amount of mass transferred. Whereas κ-carrageenan leads to a quite low mass transfer of 15%, MCCI and MCCII show higher values up to 25%., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Spherical granules (pellets) are quite useful in many pharmaceutical applications. The extrusion spheronisation technique is well established as a method of producing pellets of a spherical shape and narrow size distribution. After the extrusion, the cylindrical extrudates are transformed to spherical pellets by spheronisation. The frequently used models consider deformation and breakage during this process. However, the adhesion of fine particles has been neglected as a mechanism in spheronisation for many years. This study quantifies the mass transfer between pellets during spheronisation. During the investigation, the pelletisation aids (microcrystalline cellulose and kappa-carrageenan), the drug (acetaminophen and ibuprofen) and water content were varied systematically. A novel parameter, namely, the "mass transfer fraction" (MTF), was defined to quantify the mass transfer between the pellets. All four investigated formulations had an MTF between 0.10 and 0.52 that implies that up to 50 % of the final pellet weight was involved in mass transfer. Both pelletisation aids showed similar MTF, independent of the drug used. Furthermore, an increase of the MTF, with respect to an increase of the water content, was found for microcrystalline cellulose formulations. In conclusion, the mass transfer between the pellets has to be considered as a mechanism for spheronisation.

Pellet manufacturing by extrusion/spheronization is quite common in the pharmaceutical field because the obtained product is characterized by a high sphericity as well as a narrow particle size distribution. The established mechanisms only consider deformation of the initially fractured particles but do not account for mass transfer between the particles as a factor in achieving spherical particles. This study dealt with the visualization of mass transfer during spheronization. Therefore, two common pelletization aids, microcrystalline cellulose and kappa-carrageenan, were used alone as well as in combination with lactose as a filler. This study proves that mass transfer between particles must be considered in addition to plastic deformation in order to capture the spheronization mechanism. Moreover, it is evident that there are regional distinctions in the amount of mass transfer at the particle surface. Therefore, the commonly espoused pelletization mechanisms need to be extended to account for material transfer between pellet particles, which has not been considered before.

The aim of this study was to produce pellet formulations containing a high drug load (80%) of the poorly soluble HIV-protease inhibitor darunavir, using wet extrusion/spheronization with kappa-carrageenan or microcrystalline cellulose (MCC) as pelletization aid. Drug release was assessed in vitro by a standardized paddle-dissolution test and in vivo by a single-dose pharmacokinetic study in dogs. Mean dissolution time (MDT) was 78.2+/-3.5 h from MCC pellets (1301+/-301 microm) and 6.1+/-0.7 min from kappa-carrageenan pellets (966+/-136 microm). In contrast to kappa-carrageenan pellets, MCC pellets did not disintegrate and showed a diffusion-controlled drug release. In line with the in vitro findings, the darunavir peak plasma levels and exposure after the administration of a 300 mg dose were more than 60-fold higher when formulated with kappa-carrageenan pellets when compared with MCC pellets, and 10-fold higher after co-administration with 10mg/kg of ritonavir. The relative bioavailability of darunavir versus the reference tablet (F(rel)) was 155% with kappa-carrageenan pellets and 2% with MCC pellets without ritonavir, while 78% and 9%, respectively, in presence of ritonavir. In conclusion, when compared with MCC pellets, the bioavailability of darunavir was substantially improved in kappa-carrageenan pellets, likely due to their better disintegration behavior.

Microcrystalline cellulose (MCC) is the golden standard to manufacture spherical particles (pellets) via extrusion-spheronisation since wetted microcrystalline cellulose has the proper rheological properties, cohesiveness and plasticity to yield strong and spherical particles. However, microcrystalline cellulose is not universally applicable due to a number of limitations: prolonged drug release of poorly soluble drugs, chemical incompatibility with specific drugs, drug adsorption onto MCC fibers. Hence, several products have been evaluated to explore their application as extrusion-spheronisation aid, aiming to avoid the disadvantages of MCC and to provide a broad application platform for extrusion-spheronisation: powdered cellulose, starch, chitosan, kappa-carrageenan, pectinic acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene oxide, cross-linked polyvinylpyrrolidone, glycerol monostearate. To determine the true potential of the proposed alternatives for MCC this review critically discusses the properties of the different materials and the quality of the resulting pellets in relation to the properties required for an ideal extrusion-spheronisation aid.

Microcrystalline cellulose (MCC) is commonly used as an excipient in extrusion/spheronisation process. However, MCC has several disadvantages as lack of disintegration and drug adsorption. Therefore, kappa-carrageenan was investigated to substitute MCC in pelletising processes. Formulations with 20% of pelletisation aid (kappa-carrageenan or MCC) and acetaminophen as a model drug have been produced. Different fillers (lactose, mannitol, maize starch and dicalciumphosphate dihydrate) at fractions of 0, 20, 40 and 80% were evaluated and the properties of the resulted pellets were determined (e.g. yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength and release profile). kappa-Carrageenan has proven to be a suitable substitute as pellets with sufficient quality were produced. The pellet batches of different formulations were characterised by high yield, spherical pellet shape and narrow pellet size distribution. The distinguished behaviour between kappa-carrageenan and MCC pellets was the lower tensile strength and the faster release of kappa-carrageenan pellets. For the various types and fractions of fillers only minor effects to the pelletisation process and pellet properties were noticed. From the practical view these effects are neglectable indicating a robust formulation and process.

The extrusion/spheronisation process is an established technique to produce pellets for pharmaceutical applications. Microcrystalline cellulose (MCC) is being usually used as a pelletisation excipient in the extrusion process. However, MCC has some disadvantages, e.g. lack of disintegration and prolonged drug dissolution. Therefore, kappa-carrageenan was investigated as a substitute for MCC to overcome such disadvantages. A fixed ratio of kappa-carrageenan (20%) was combined with different fillers (lactose, mannitol, maize starch and dicalciumphosphate dihydrate) and different drugs (acetaminophen, theophylline, mesalamine and hydrochlorothiazide) in several formulations. Some pellet properties (yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength and dissolution profile) were determined. Most formulations resulted in pellets of a sufficient quality with respect to size, size distribution and shape independent of the incorporated fillers and drugs. In contrast to MCC pellets, the release profile of kappa-carrageenan pellets was much less affected by the solubility of the drug. Generally, kappa-carrageenan pellets owned fast disintegration and fast drug release in contrast to MCC pellets.

κ-Carrageenan is a biopolymer extracted from red seaweeds which has been in the focus of pharmaceutical development for many years. Most applications make use of the large water binding capacity of κ-carrageenan. The primary limitation of κ-carrageenan is the variation in the substance quality. Therefore, the water binding capacity of different κ-carrageenan products was investigated by dynamic vapor adsorption, freezing and non-freezing bound water and water retention value. The κ-carrageenans were observed to have a higher water binding capacity than microcrystalline cellulose (MCC) in all three methods. The amount of adsorbed water is similar for all carrageenans. Differences between the carrageenan types (κ, ι, and λ) were remarkable for the freezing bound water and centrifugation bound water as well as between the κ-carrageenans of different suppliers. [ABSTRACT FROM AUTHOR]