Different Grades Of Microcrystalline Cellulose Research Articles

Effect of particle size on the dispersion behavior of magnesium stearate blended with microcrystalline cellulose

The majority of tablets manufactured contain lubricants to reduce friction during ejection. However, especially for plastically deforming materials, e.g., microcrystalline cellulose (MCC), the internal addition of lubricants is known to reduce tablet tensile strength. This reduction is caused by the surface coverage by lubricant particles, the extent of which depends on both process and formulation parameters. Previously published models to predict the lubrication effect on mechanical strength do not account for changes in the excipient particle size. In this study, the impact of both lubricant concentration and mixing time on the tensile strength of tablets consisting of three different grades of MCC and four grades of magnesium stearate (MgSt) was evaluated. By taking into account the particle size of the applied excipients, a unifying relationship between the theoretically estimated surface coverage and compactibility reduction was identified. Evaluating the dispersion kinetics of MgSt as a function of time reveals a substantial impact of the initial surface coverage on the dispersion rate, while the minimal tensile strength was found to be comparable for the majority of formulations. In summary, the presented work extends the knowledge of lubricant dispersion and facilitates the reduction of necessary experiments during the development of new tablet formulations.

A compactibility-based lubricant dispersion model describing the effect of formulation and paddle speed

In rotary tablet presses, the powder flow into the dies is typically facilitated by paddle feeder. For internally lubricated formulations, the shear forces exerted by the paddle rotation can result in a considerable decrease in tablet strength due to the dispersion of lubricant agglomerates. Available models to describe the lubricant dispersion in paddle feeder allow only a limited quantitative description and transferability of the process. This study introduces an empirical dispersion kinetic which is able to precisely describe the reduction of compactibility due to the shear stresses inside the paddle feeder, even for inhomogeneously flowing material. Additionally, by blending different grades of magnesium stearate at three levels of lubricant concentration with two different grades of microcrystalline cellulose, the impact of bulk properties on the lubrication dispersion in the feed frame was investigated. It was shown, that for a given formulation, the kinetics of compactibility reduction are comparable for different magnesium stearate concentrations. Additionally, the bulk properties of the applied magnesium stearate grade critically affect the dispersion kinetics as well as the maximum compactibility reduction inside the feed frame. In summary, the developed model represents a meaningful extension of the currently available process models for pharmaceutical tablet lubrication.

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing.

Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d=5mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.

Predictive modeling of die filling of the pharmaceutical granules using the flexible neural tree

In this work, a computational intelligence (CI) technique named flexible neural tree (FNT) was developed to predict die filling performance of pharmaceutical granules and to identify significant die filling process variables. FNT resembles feedforward neural network, which creates a tree-like structure by using genetic programming. To improve accuracy, FNT parameters were optimized by using differential evolution algorithm. The performance of the FNT-based CI model was evaluated and compared with other CI techniques: multilayer perceptron, Gaussian process regression, and reduced error pruning tree. The accuracy of the CI model was evaluated experimentally using die filling as a case study. The die filling experiments were performed using a model shoe system and three different grades of microcrystalline cellulose (MCC) powders (MCC PH 101, MCC PH 102, and MCC DG). The feed powders were roll-compacted and milled into granules. The granules were then sieved into samples of various size classes. The mass of granules deposited into the die at different shoe speeds was measured. From these experiments, a dataset consisting true density, mean diameter (d50), granule size, and shoe speed as the inputs and the deposited mass as the output was generated. Cross-validation (CV) methods such as 10FCV and 5x2FCV were applied to develop and to validate the predictive models. It was found that the FNT-based CI model (for both CV methods) performed much better than other CI models. Additionally, it was observed that process variables such as the granule size and the shoe speed had a higher impact on the predictability than that of the powder property such as d50. Furthermore, validation of model prediction with experimental data showed that the die filling behavior of coarse granules could be better predicted than that of fine granules.

Studies on Development of Controlled Release Matrix Tablets of Camptothecin-An Anticancer Drug

Abstract: Objectives: The present investigation was carried out with an objective of formulating prototype controlled release (CR) matrix tablets of Camptothecin (CPT), an anti-cancer drug. Experimental: pH solubility profile studies of CPT and solubility of CPT in different surfactants were carried out. Controlled release tablets were prepared by direct compression method using hydroxyl propylmethyl cellulose (HPMC LVCR and HPMC K4M) as release retardants. The effect of different grades of microcrystalline cellulose (MCC) like Avicel PH 101 and Avicel PH 105 and solubilizing agents like cyclodextrins were included in the formulations and their effect on CPT release from tablets were studied. Results and Discussion: Solubility studies were conducted in order to select suitable dissolution medium for CPT. Based on the solubility studies, 0.1N HCl with 3% w/v SLS (pH1.2) was selected as dissolution medium. The FTIR and DSC results indicated that there was no in situ interaction between CPT and the selected excipients in the formualtions. Formulations containing 20% w/w of hydroxypropyl-β-cyclodextrin with Avicel PH105 as filler and HPMC k4M as release retardant gave superior CPT release of 98.40 ± 1.02% at the end of 12 h and fulfilled the regulatory requirements. The Higuchi square root model showed higher correlation coefficient values (0.949-0.990) indicating diffusion was the release mechanism for CPT from tablets. Conclusion: CPT can be formulated in to CR matrix tablets using HPMC K4M as release retardant and MCC as filler for better therapeutic efficacy. Key Words: Camptothecin, CR matrix tablets, Cyclodextrins, Dissolution studies, Solubility studies.

In-line monitoring of particle size in a fluid bed granulator: Investigations concerning positioning and configuration of the sensor

According to the ICH Q8 guideline, analytic technologies (PAT) are important tools for characterization and optimization of pharmaceutical manufacturing processes. Particle size as a critical quality attribute for granules is therefore an important parameter that should be monitored during the fluid bed granulation process. This work focusses on optimizing position and configuration of an SFT-sensor for the in-line measurement of particle size distribution in a Glatt GPCG 3 fluid bed granulator. As model-substances, different grades of microcrystalline cellulose were used. The in-line measured particle size and particle rate in the sensor were evaluated. A sensor position in the deceleration zone of the granulator was found to be promising for in-line particle size measurement. Most reliable data were generated in this position when the probe was placed in a distance of 11cm from the chamber wall to avoid bias by the inlet air stream. No major influence of rotation angle of the probe was found in this position. Furthermore, an entire fluid bed granulation process was successfully monitored with the sensor installed in the optimized setting.

Evaluation of Ceolus™ microcrystalline cellulose grades for the direct compression of enteric-coated pellets

The preparation of multiparticulate tablets by direct compression of functionally coated pellets is technologically challenging. The objective was to investigate the influence of different grades of microcrystalline cellulose (Ceolus™ UF-711, PH-102, PH-200 and KG-802) as fillers on the properties of blends and tablets containing enteric pellets. Celphere™ spheres were drug-layered and then functionally coated with Eudragit® L 30 D-55/FS 30D dispersion. Tablets loaded with 50% pellets were prepared using pure or binary blends of microcrystalline cellulose fillers. The influence of the filler on the blend flow, segregation tendency, tablet hardness and enteric release properties were studied using a mixture design, and the optimum filler composition was determined. Rapidly disintegrating tablets, which yielded a drug release of less than 10% after 2 hours in acidic medium, could be successfully prepared. The blend composition had a significant effect on the flowability, but less on the tablet hardness which was influenced by the selection of lubricant. Blends containing celluloses with low bulk densities exhibited a reduced tendency to segregate. Pellet distribution uniformity was further improved when using Ceolus™ UF-711 blended with a high-density grade. As a conclusion, multiparticulate tablets containing enteric pellets with preserved delayed-release properties were successfully prepared using Ceolus™ microcrystalline celluloses as tableting excipients. The optimized filler blend for the direct compression of 50% enteric pellets into tablets contained Ceolus™ UF-711 as main component in combination with Ceolus™ PH-200.

The tensile strength of bilayered tablets made from different grades of microcrystalline cellulose

The aim of this work was to determine the tensile strength of bilayered tablets made from different grades of microcrystalline cellulose. While these grades are chemically identical, they differ significantly in their particle size distribution and in their mechanical properties such as Young's modulus of elasticity. Tablets were produced in the shape of beams of similar dimensions using uniaxial compression, and solid beams made from one material only were compared with bilayered beams made from various combinations of powders. It was found that in the production of layered tablets it is important for the purpose of quality assurance and control that the upper and lower layer of the compact can be identified. Otherwise, tensile strength measurements will result in large variability depending on which layer faces upwards during the test. Both particle size and Young's modulus of elasticity influenced the overall strength of layered tablets. If the material forming the lower layer was more elastic, then the beam strength was reduced due to tension introduced into the system, acting especially at the layer interface and potentially causing partial or complete delamination. Larger differences in the particle size of the materials forming the tablet layers resulted in an overall reduced compact tensile strength.

Validity of a Power Law Approach to Model Tablet Strength as a Function of Compaction Pressure

Designing quality into dosage forms should not be only based on qualitative or purely heuristic relations. A knowledge space must be generated, in which at least some mechanistic understanding is included. This is of particular interest for critical dosage form parameters like the strength of tablets. In line with this consideration, the scope of the work is to explore the validity range of a theoretically derived power law for the tensile strength of tablets. Different grades of microcrystalline cellulose and lactose, as well as mixtures thereof, were used to compress model tablets. The power law was found to hold true in a low pressure range, which agreed with theoretical expectation. This low pressure range depended on the individual material characteristics, but as a rule of thumb, the tablets having a porosity of more than about 30% or being compressed below 100 MPa were generally well explained by the tensile strength relationship. Tablets at higher densities were less adequately described by the theory that is based on large-scale heterogeneity of the relevant contact points in the compact. Tablets close to the unity density therefore require other theoretical approaches. More research is needed to understand tablet strength in a wider range of compaction pressures.

Effect of Some Commercial Grades of Microcrystalline Cellulose on Flowability, Compressibility, and Dissolution Profile of Piroxicam Liquisolid Compacts

The technique of liquisolid compacts is a promising method toward enhancing the dissolution of poorly soluble drugs. Lower flowability and compressibility is one of the limitations of this technique. The evaluation of effects of different grades of microcrystalline cellulose (MCC) on flowability, compressibility, and dissolution of liquisolid systems were the aims of this study. For this means, several formulations were prepared using various grades of MCC as carrier. Propylene glycol (PG), silica, and sodium starch glycolate were used as nonvolatile solvent, coating material, and disintegrant, respectively. Then flowability, friability hardness, and dissolution rate of prepared formulations were studied. The effect of tablet aging on mentioned properties was also investigated. The results showed that among the evaluated different grades of MCC, compacts containing MCC PH 101 and 102 showed better dissolution profiles. Harder compacts were obtained using MCC PH 101 and 200 as carriers. Better flowability was observed in compacts containing MCC PH 101. Also, these compacts demonstrated acceptable friability. Aging had no effect on hardness and dissolution profile of liquisolid tablets. It could be concluded that MCC PH 101 is a suitable carrier for preparing liquisolid systems for having acceptable flowability, friability, hardness, and dissolution profile.

Chargeability measurements of selected pharmaceutical dry powders to assess their electrostatic charge control capabilities

The purpose of this study was to develop an instrument (the Purdue instrument) and the corresponding methodologies to measure the electrostatic charge development (chargeability) of dry powders when they are in dynamic contact with stainless steel surfaces. The system used an inductive noncontact sensor located inside an aluminum Faraday cage and was optimized to measure the charging capabilities of a fixed volume of powder (0.5 cc). The chargeability of 5,5-diphenyl-hydantoin, calcium sulfate dihydrate, cimetidine, 3 grades of colloidal silicon dioxide, magnesium stearate, 4 grades of microcrystalline cellulose, salicylic acid, sodium carbonate, sodium salicylate, spray-dried lactose, and sulfinpyrazone were tested at 4 linear velocities, and the particle size distribution effect was assessed for 3 different grades of colloidal silicon dioxide and 4 different grades of microcrystalline cellulose. The chargeability values exhibited a linear relationship for the range of velocities studied, with colloidal silicon dioxide exhibiting the maximum negative chargeability and with spray-dried lactose being the only compound to exhibit positive chargeability. The instrument sensitivity was improved by a factor of 2 over the first generation version, and the electrostatic charge measurements were reproducible with relative standard deviations ranging from nondetectable to 33.7% (minimum of 3 replicates). These results demonstrate the feasibility of using the Purdue instrument to measure the electrostatic charge control capabilities of pharmaceutical dry powders with a reasonable level of precision.

Direct pelletization in a rotary processor controlled by torque measurements. III. Investigation of microcrystalline cellulose and lactose grade

The aim of the present study was to investigate the use of different grades of microcrystalline cellulose (MCC) and lactose in a direct pelletization process in a rotary processor. For this purpose, a mixed 2- and 3-level factorial study was performed to determine the influence of the particle size of microcrystalline cellulose (MCC) (approximately 60 and 105 microm) and lactose (approximately 30, 40, and 55 microm), as well as MCC type (Avicel and Emcocel) on the pelletization process and the physical properties of the prepared pellets. A 1:4 mixture of MCC and lactose was applied, and granulation liquid was added until a 0.45 Nm increase in the torque of the friction plate was reached. All combinations of the 3 factors resulted in spherical pellets of a high physical strength. The particle size of MCC was found to have no marked effect on the amount of water required for agglomerate growth or on the size of the resulting pellets. An increasing particle size of lactose gave rise to more spherical pellets of a more narrow size distribution as well as higher yields. The MCC type was found to affect both the release of the model drug from the prepared pellets and the size distribution. Generally, the determined influence of the investigated factors was small, and direct pelletization in a rotary processor was found to be a robust process, insensitive to variations in the particle size and type of MCC and the particle size of lactose.

A staining technique for evaluating the pore structure variations of microcrystalline cellulose powders

A staining technique was developed for evaluating the pore structure of microcrystalline cellulose powders. This technique used two direct dyes as molecular probes and was based on the differences between the two dyes' molecular size and affinity for microcrystalline cellulose. Direct Blue 1 has a smaller molecular size and weaker affinity for microcrystalline cellulose compared to Direct Orange 15, which has a larger molecular size and stronger affinity. We used the ratio of adsorbed Direct Orange 15 to adsorbed Direct Blue 1 after 48 h staining [designated as ( O B) 48 ] as the parameter for evaluating the pore structure variations between different microcrystalline cellulose powders. Seven microcrystalline cellulose samples of three different grades—Avicel PH-101, Avicel PH-102 and Avicel PH-103—were analyzed for their ( O B) 48 ratios, and significant differences were found. These differences are present primarily among different grades and seco among different batches of the same grade. Among the three grades tested, it was found the their ( O B) 48 ratios have the following sequence: Avicel PH-103 > Avicel PH-101 > Avicel PH-102. This suggested that structure variations are significant among different microcrystalline celluloses of both different grades and batches, but the degree of variation between different batches is less than that between different grades of microcrystalline cellulose.

The influence of particle size and shape of components of binary powder mixtures on the maximum volume reduction due to packing

The influence of particle size and shape of components of binary powder mixtures on the maximum volume reduction due to packing has been investigated in a systematic manner using the Kawakita-equation. Different grades of microcrystalline cellulose were mixed with defined size fractions of angular particles (lactose monohydrate), spherical particles (Elcema G250) and needle-shaped particles (acetylsalicylic acid). The particle shape of the mixture components clearly influenced the maximum volume reduction due to packing, represented by the Kawakita constant a. While angular particles improved the packing properties of the microcrystalline celluloses, the addition of spherical and needle-shaped particles generally resulted in lower values for a at equivalent concentrations. The addition of both spherical or needle-shaped particles in concentrations between 25% and 75% to fine grade microcrystalline cellulose led to a steady decrease in volume reduction ability, whereas for medium or coarse grade microcrystalline cellulose the graphical presentation of a as a function of concentration of the second mixture component always showed a maximum value. The particle size of both powders contained in the binary mixtures influenced the values of the Kawakita constant a with the exception of angular particles. The finer the particle size of each component, the larger became the value of a.

Dilution potential: a new perspective.

The objective of this work was to develop a method to assess the dilution capacity of direct compression excipients based on a technique previously proposed by Minchom and Armstrong (MA). The technique involves the addition of increasing quantities of a poorly compactible (compressible) material to the excipient and measuring the resultant decrease in the AUC of the tensile strength versus compaction force profiles. The AUC of each mixture is divided by the AUC of the "0% mixture" to obtain MA's "work potential," called "area ratios" in the present study. The applicability of this approach was tested using three excipients differing in their deformation mechanisms: microcrystalline cellulose (Avicel PH 101, 102, 200, 301, 302) representing a plastic material; dibasic calcium phosphate (Cal-Star) representing a brittle material, and anhydrous lactose, which exhibits both brittle and plastic properties. Ascorbic acid or acetaminophen was the poorly compactible challenge material. In the first study, the MA method was found to apply only to Avicel PH 101, since the area ratios for mixtures containing different compositions of acetaminophen with either Cal-Star or anhydrous lactose remain constant until a certain percentage of drug is exceeded, after which a decline starts to be observed. Further work carried out on mixtures of different grades of Avicel with ascorbic acid revealed that MA's approach reflects only the ability of the excipient to handle internal stress induced by the drug and does not take into account the intrinsic ability of the drug-free excipient to form strong compacts. A new index was thus proposed, called the dilution capacity index (DCI), which weights the MA index by the AUC of the drug-free excipient. The results suggest that DCI can be used to compare different grades of microcrystalline cellulose and provide in-house quality control for microcrystalline cellulose suppliers.