High-speed Tablet Research Articles

Investigating the effect of punch geometry on high speed tableting through radial die-wall pressure monitoring

Dwell time mainly depends on punch geometry, so some tableting problems such as capping and lamination could occur at high speed compaction. Robust tools are required to monitor the interaction of punch tip and powder bed at these high speeds. Our aim was to investigate the effect of punch geometry (flat and standard concave) on powder compaction at high speed using radial die-wall pressure (RDWP) as a monitoring tool. Instrumented die guided by compaction simulation was applied for five materials with different compaction behaviors. Flat-faced punch showed higher residual, maximum die-wall pressures, and axial stress transmission than concave punches, p < 0.003. Moreover, flat-faced punches showed less friction upon ejection, p < 0.003. Flat compacts showed higher elastic recovery, tensile strength, and required less work of compaction than convex compacts, p < 0.05. RDWP monitoring was a useful tool to prove that flat-faced punch induced higher radial stresses and particle/particle interactions in comparison to concave punch.

Reproducibility of flow properties of microcrystalline cellulose — Avicel PH102

Earlier work showed that a batch of microcrystalline cellulose (MCC, Avicel PH102) exhibited minimum acceptable flow properties required for successful high speed tableting. The aim of this work was to assess the suitability of using Avicel PH102 as a reference indicator of minimum powder flow by examining the reproducibility of flow properties of seven batches of Avicel PH102. Powder flow properties have been characterized in terms of flow function, flow factor, cohesion, bulk density, effective angle of internal friction, angle of linearized yield locus, and angle of internal friction at steady-state flow. Results show that the measured flow function is independent of operator. Batch-to-batch flow functions are not statistically different at 95% confidence level suggesting acceptable reproducibility. These results corroborate that Avicel PH102 may be used as a reference powder for predicting flow performance of a new formulation during high speed tableting.

Investigating the effect of particle size and shape on high speed tableting through radial die-wall pressure monitoring

Investigating particle properties such as shape and size is important in understanding the deformation behavior of powder under compression during tableting. Particle shape and size control the pattern of powder rearrangement and interaction in the die and so the final properties of the compact. The aim of this study was to examine the effect of particle size and shape on compactability. Particle friction and adhesion were investigated through radial die-wall (RDW) pressure monitoring. To fulfill this aim, powders and granules of different sizes and shapes of materials with different compaction behaviors were used. Compaction simulation using the Presster™ with an instrumented die was applied. Small particle size increased residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) ( p < 0.05) for plastic and viscoelastic materials, respectively, while big particle size had an opposite effect. No effect was found on brittle material, however big particle size showed higher friction for such materials. Regarding morphology, fibrous elongated particles of microcrystalline cellulose had less friction tendency to the die-wall in comparison to rugged surface mannitol particles. RDW pressure monitoring is a useful tool to understand the compactability of particles in respect to size and shape.

Radial die-wall pressure as a reliable tool for studying the effect of powder water activity on high speed tableting

The effect of moisture as a function of water activity (Aw) on the compaction process is important to understand particle/water interaction and deformation. Studying powder/moisture interaction under pressure with radial die-wall pressure (RDWP) tool was never done. The aim of our study was to use this tool to study this interaction at high compression pressure and speed. Moreover, the effect of changing ejection cam angle (EA) of the machine on ejection force (EF) was investigated. Also, a new tool for prediction of tablet sticking was proposed. Materials with different deformation behaviors stored at low and high moisture conditions were used. Compaction simulation guided by modeling was applied. High Aw resulted in a low residual die-wall pressure (RDP) for all materials, and a high maximum die-wall pressure (MDP) for plastic materials, p < 0.05. This was due to the lubricating and plasticizing effects of water, respectively. However, microcrystalline cellulose showed capping at high Aw and compaction pressure. By increasing compression pressure at high Aw for all materials, effective fall time (EFT) was increased, p < 0.05, showing tendency for sticking. Increasing EA caused an increase of friction and EF for powders, p < 0.05. RDWP was a useful tool to understand particle/moisture interaction under pressure.

Setting the bar for powder flow properties in successful high speed tableting

Abstract An inadequate powder flow leads to problems in tablet manufacturing. The knowledge of minimum flow properties required for successful tableting on a high speed press is critically important to the efficient development of pharmaceutical tablets. This may be achieved by identifying a powder that exhibits minimally acceptable flow properties on a high speed tablet press. A grade of a common tablet excipient, microcrystalline cellulose (Avicel PH102) lies near the borderline between acceptable and poor flow regions during high speed tableting. It can therefore serve as a reference material for judging adequacy of flow properties of prototype formulations by the way of comparison. A powder exhibiting poorer flow properties than Avicel PH102 likely exhibits flow problems and should be avoided. An implementation of this simple approach in formulation development can minimize potential flow problems during large scale tablet manufacture.

Effects of powder flowability on die-fill properties in rotary compression

The flow behavior of a powder during high-speed tableting with a rotary press has been investigated using a mixed powder of microcrystalline cellulose (MCC) and spray-dried lactose as a model. Characteristics of the powder such as angle of repose, compressibility, dynamic flowability, expansion displacement and the morphology of particles were measured and are discussed in relation to the die-fill properties in a rotary press. This study revealed that the die-fill properties correlated with the static flowability properties such as the angle of repose and compressibility in the case of gravity feeding in a rotary press, but the dynamic flowability measured by a powder rheometer was the most important factor in the case of force feeding using a die feeder. The flowability of mixed powders containing 20-40% long, narrow MCC particles was statically low but dynamically high, and these powders had excellent die-fill properties. It is suggested that the use of long, narrow MCC particles is suitable for high-speed tableting, because they become entangled with other particles and hold air uniformly in a powder bed when agitated in a die feeder.

Preparation, Characterization, and Scale-up of Ketoconazole with Enhanced Dissolution and Bioavailability

ABSTRACTMany new molecular entities targeted for pharmaceutical applications face serious development challenges because of poor water solubility. Although particle engineering technologies such as controlled precipitation have been shown to enhance aqueous dissolution and bioavailability of poorly water soluble active pharmaceutical ingredients, the data available are the results of laboratory-scale experiments. These technologies must be evaluated at larger scale to ensure that the property enhancement is scalable and that the modified drugs can be processed on conventional equipment.In experiments using ketoconazole as the model drug, the controlled precipitation process was shown to produce kg-scale modified drug powder with enhanced dissolution comparable to that of lab-scale powder. Ketoconazole was demonstrated to be stable throughout the controlled precipitation process, with a residual methanol level below the ICH limit. The modified crystalline powder can be formulated, and then compressed using conventional high-speed tableting equipment, and the resulting tablets showed bioavailability more than double that of commercial tablets. When appropriately protected from moisture, both the modified powder and tablets prepared from the modified powder showed no change in dissolution performance for at least 6 months following storage at accelerated conditions and for at least 18 months following storage at room temperature.

Formulation, release characteristics and bioavailability of novel monolithic hydroxypropylmethylcellulose matrix tablets containing acetaminophen

Effect of incorporating pharmaceutical excipients on the in vitro release profiles and the release mechanism of monolithic hydroxypropylmethylcellulose (4000 cps) matrix tablets (m-HPMC tablets) in terms of mimicking the dual drug release character of bi-layered Tylenol® ER tablets was studied. We also compared the in vitro release profiles of optimized m-HPMC matrix tablet and Tylenol® ER tablet in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid, and in vivo drug bioavailabilities in healthy human volunteers. Acetaminophen was used as the model drug. The m-HPMC tablets were prepared using a wet granulation method followed by direct compression. Release profiles and swelling rates of m-HPMC tablets were found to be highly influenced by the types and amounts of pharmaceutical excipients incorporated. Starch 1500 (Prejel®) and sodium lauryl sulfate (SLS) played a key role in determining the dissolution rate of m-HPMC tablets. Additional excipients, i.e., microcrystalline cellulose (Avicel® PH101) and NaH2PO4 were used to tune the release profiles of m-HPMC tablets. The effect of pharmaceutical excipients on drug release from HPMC-based matrix tablets was found to be mainly due to a change in hydrophilic gel expansion and on physical interactions between the drug and HPMC. The optimized m-HPMC tablet with a balanced ratio of Prejel®, SLS, Avicel® PH101, and NaH2PO4 in the formulation showed dual release profiles in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid in vitro. Dual release was defined as immediate drug release within few minutes followed by extended release over 8 h. The similarity factors of m-HPMC tablets and bi-layered Tylenol® ER tablets were 79.8, 66.1, and 82.7 in water, gastric fluid and intestinal fluid, respectively, indicating the equivalence of the two release profiles. No significant in vivo bioavailability differences were observed in healthy human volunteers. The developed m-HPMC tablet with dual release characteristics can be easily prepared using a conventional high-speed tablet machine and could provide an alternative to commercially available bilayered Tylenol® ER tablets.

Impact of Solid-State Properties on Lubrication Efficacy of Magnesium Stearate

The advent of high-speed tableting and slug capsule-filling machines has ushered in an increasingly important role for the lubricants to enact during manufacturing of dosage forms. Although lubricants help in processing, they can also adversely affect the flow properties and dissolution profile of the drug. It is thus critical to maintain a balance between these two behaviors, by understanding the underlying mechanisms and using their optimum concentration in the formulation. The source and manufacturing process inculcate different solid-state properties to magnesium stearate, the most commonly used lubricant, leading to variations in its lubrication efficacy. However, there has been no complete study relating the lubrication efficacy of magnesium stearate to various levels of solid state. Hence, this study was aimed at comprehensively scrutinizing the role of molecular, particle, and bulk level properties of solid state on the lubrication efficacy of magnesium stearate. A method based on net work done during compression using texture analyzer, was developed and validated to analyze its performance. Particle and bulk-level properties were studied using microscopy, particle size analysis, and particle surface area determination, and molecular level was characterized using thermal, spectroscopic, and crystallographic methods. Interplay of solid-state characteristics such as particle size, degree of agglomeration, and crystal habit were found to markedly influence the lubrication potential of magnesium stearate.

Compaction of Pharmaceuticals

It has been estimated that more than 80% of all medication doses are administered as tablets—that is, in unit dosage forms prepared by compacting powders in dies. For drugs with acceptable oral-absorption profiles, the compacted tablet is the first choice as a delivery system in drug development. Modern tablets range in size from 25 milligrams (veterinary implants) to several grams (veterinary “boluses”). The most common tablet shape is the double convex-faced disk. Shapes range from capsule to triangular forms, in many instances with bisects embossed or debossed with identification codes and company logos. Tablets may be either film- or sugar-coated, may be designed for immediate or extended release, or may be prepared as multilayer or laminated forms. In addition to oral administration, tablets may be predissolved or designed to be disintegrated in the mouth, or may be administered by injection or as suppositories. Production rates for over-the-counter products such as acetaminophen tablets can exceed three 1,000-kg batches per week, requiring high-speed multiple-station tablet presses for production. In contrast, implants—which have low-volume market requirements—must be made under aseptic conditions on special singlestation presses.

Occurrence of Capping Due to Insufficient Air Escape during Tablet Compression and a Method to Prevent It.

A study was made on the capping of tablets containing d-α-tocopheryl acid succinate. The study determined that capping occurs due to insufficient air escape from the granules during high-speed tablet compression. To prevent this, removal of air in the granules was necessary before tableting, and thus a degassing method by compaction was studied. In consideration of the long time required for the air to escape from the granules by compaction, a slow but continuous compacting force is thought to be more effective for degassing than an instantaneous high compression force. Consequently, a system to expel the air from the lubricated granules by compaction due to the weight of the upper punch itself was established before the pre-compression roller stage, and its effect was evaluated. This system achieved efficient degassing of the granules before tableting and completely prevented the capping of tablets containing d-α-tocopheryl acid succinate at a high concentration.

An evaluation of microcrystalline cellulose and lactose excipients using an instrumented single station tablet press

The objective of this study was to evaluate the effects of microcrystalline cellulose of two particle sizes from two suppliers at two concentration levels, in combination with anhydrous lactose or Fast-Flo lactose on various properties of hydrochlorothiazide tablets. The powder blends before compression were evaluated for flow, density and compressibility. Tablets were compressed at three hardnesses and evaluated for friability, disintegration and hydrochlorothiazide dissolution. Powder blends containing Fast-Flo lactose exhibited a flow rate predicted to be sufficient for high-speed tableting whereas only when anhydrous lactose was used with the larger particle size microcrystalline cellulose was the same degree of flowability obtained. Density was affected by the concentration of microcrystalline cellulose. Fast-Flo lactose markedly increased density at the lower level of microcrystalline cellulose concentration. No difference was found in blend compressibility as a result of microcrystalline cellulose particle size or supplier source at medium to high tablet hardness levels, however, anhydrous lactose blends were more compressible than Fast-Flo lactose blends. At all hardness levels, tablets from all blends exhibited excellent friability. In most instances, tablet disintegration seemed to be more rapid when Fast-Flo lactose was present. Hydrochlorothiazide dissolution from all tablets easily met USP specifications. The microcrystalline cellulose from the two sources are interchangeable within particle size classification. Anhydrous lactose is more compressible than Fast-Flo lactose but Fast-Flo lactose is more flowable and its use results in more rapid drug dissolution at the higher microcrystalline cellulose levels.

Process control and automatization of high-speed tablet presses

Process control and automatization of high-speed tablet presses

Flow rates of granular materials through moving orifices

An apparatus is described which will measure the flow of powder through a moving orifice (die). It is shown that this type of flow, denoted dynamic flow, differs in some respects from static flow, i.e. flow through a stationary orifice. In other respects, e.g. the relation of flow to orifice diameter, the relations found in dynamic flow are similar to the ones reported for static flow. The results are treated in such a fashion that extrapolations to speeds encountered in high speed tablet presses can be made.

Anhydrous Lactose in Direct Tablet Compression

The use of anhydrous lactose U.S.P. XVII, tablet grade, as a diluent in direct tablet compression was investigated. It was found that it possesses excellent tableting properties and can be run on a high-speed tablet machine. The placebo and active tablets produced were not affected by elevated temperatures, high humidity, and direct sunlight.