Wax beads as cushioning agents during the compression of coated diltiazem pellets.

Placebo particles were mixed with film-coated diltiazem pellets to evaluate them as cushioning agents during tabletting in order to protect the film coat from damage. The cushioning properties of alpha-lactose monohydrate granules, microcrystalline cellulose pellets and wax/starch beads were evaluated by comparing the dissolution profile of the coated pellets before and after compression (compression force 10 kN). Only the tablet formulations containing wax/starch beads provided protection to the film coat. However, the dissolution rate of tablets formulated with waxy maltodextrin/paraffinic wax placebo beads was too slow as the tablets did not disintegrate. Adding 50% (w/w) drum-dried corn starch/Explotab/paraffinic wax beads to the formulation was the optimal amount of cushioning beads to provide sufficient protection for the film coat and yield disintegrating tablets. Using a compression simulator, the effect of precompression force and compression time on the dissolution rate was found to be insignificant. The diametral crushing strength of tablets containing 50% (w/w) drum-dried corn starch/Explotab/paraffinic wax beads was about 25.0 N (+/-0.3 N), with a friability of 0.4% (+/-0.04%). This study demonstrates that adding deformable wax pellets minimizes the damage to film-coated pellets during compression.     

Influence of disintegrant type and proportion on the properties of tablets produced from mixtures of pellets

The influence of the composition and properties of pellets on the properties of the tablets prepared from their mixtures has been evaluated. Three types of pellets were prepared, (a) those containing a model drug readily identifiable by colour, to evaluate tablet consistency; (b) those containing a deformable material, glyceryl monostearate, to provide pressure absorbing and binding properties, and (c) those containing an inorganic disintegrating agent. Tablets from various mixtures of these pellets, in a statistical designed manner, were prepared at a known compression force and their weight uniformity, friability, diametral breaking load and disintegration times were measured. The uniformity of composition of selected tablets was also determined. Analysis of variance established that the disintegrant type, the proportion of drug pellets and the proportion of disintegrant pellets influenced the breaking load and the disintegration time of the tablets. The proportion of drug and disintegrant pellets influenced the tablet friability whereas the type of disintegrant did not. Canonical analysis failed to establish an exact relationship between pellet properties and tablet properties. However some conclusions can be drawn from this analysis. First, an increase in either the amount of drug pellets or disintegrant pellets decreases the tablet breaking load, and the disintegration times are reduced. Secondly, disintegration times are increased with disintegrants of a high density. Thirdly, larger amounts of drug and disintegrant pellets increase the tablet friability.     

Development of a rapidly dispersing tablet of a poorly wettable compound: formulation DOE and mechanistic study of effect of formulation excipients on wetting of celecoxib

Celecoxib has extremely poor aqueous wettability and dispersibility. A dispersibility method was developed to study the effects of formulation excipients and processing methods on wetting of celecoxib. In this method, a tablet or powder was placed in water and the turbidity of the resulting "dynamic" suspension was measured. Higher turbidity values reflect better dispersibility. Results show that wet granulation facilitates better drug dispersion than does dry granulation or direct compression. Results from a screening formulation statistical design of experiments (DOE) show that sodium lauryl sulfate (SLS), an anionic surfactant, gives higher celecoxib dispersibility than polysorbate 80, a neutral surfactant. Polyplasdone XL as a disintegrant results in better celecoxib dispersibility than sodium starch glycolate. The binder Kollidon 30 leads to better dispersibility, but slower disintegration than Kollidon 12. Jet-milling celecoxib with excipients not only improves dispersibility of the drug but also the ease of material handling. The method of microcrystalline cellulose addition does not significantly impact tablet properties. The effect of critical formulation variables on the wettability of celecoxib was further examined in prototype formulations. It is found that ionic surfactant resulted in better dispersibility than a neutral surfactant, probably due to charge dispersion. Kollidon 30 gives better drug dispersion than hydroxypropylmethyl cellulose and hydroxypropyl cellulose. This may be explained through a surface energy calculation, where the spreading coefficients between Kollidon 30 and celecoxib indicate formation of open porous granules in which pores can facilitate water uptake. The mode of disintegrant addition also impacts dispersibility of the drug. Dense granules were formed when the disintegrant, Polyplasdone, was added intra-granularly. As the extra-granular portion of the disintegrant increases, the dispersibility of the drug increases as well. The drug initial dispersibility (turbidity at 5 min during the dispersibility test) increases as the tablet porosity increases. A 3-factor face-centered experimental design was conducted to optimize the levels of surfactant (SLS), binder (Kollidon 30) and disintegrant (Polyplasdone). Within the range that was studied, the dispersibility of micronized drug increases as the amount of SLS and Kollidon 30 increases. The level of Polyplasdone has no significant impact on the dispersibility of micronized drug; however, higher levels of Polyplasdone lead to significantly harder tablets.     

Compression behavior of formulations from Phyllanthus niruri spray dried extract

The aim of this study was to evaluate the compression behavior of Phyllanthus niruri spray dried extract as well as the influence of excipients on the properties of tablets containing a high dose (70% by weight) of this product. The effect of excipients was studied by a 22 factorial design. The factors investigated were the type of disintegrant (croscarmellose sodium and sodium starch glycolate) and the type of filler/binder (microcrystalline cellulose and dibasic dicalcium phosphate). The tablets were produced on a single punch tablet press using a constant compression force of 5000 N. The tablets formulated with microcrystalline cellulose presented a plastic behavior while the tablets containing dibasic dicalcium phosphate disclosed a fragmentary behavior. The disintegration time was significantly influenced by both factors, however, the tensile strength was only affected by the filler/binder. Additional experiments considering the influence of the compression force (2500 N and 5000 N) and the proportion of croscarmellose sodium (1.5%, 3.0% and 6.0%) on the mechanical properties of the tablets were performed by a 2 x 3 factorial design. Both factors significantly affected the tensile strength, friability and disintegration time of the tablets.     

An evaluation of starch obtained from plantain Musa paradisiaca as a binder and disintegrant for compressed tablets

The binding and disintegrant properties of plantain starch obtained from Musa paradisiaca, family Musaceae, have been evaluated. Its effect in tablets of paracetamol and chloroquine phosphate on their physical properties such as hardness, friability and disintegration time was compared with tablets prepared with maize starch. The results show that plantain starch can be used both as a tablet binder and disintegrant in the preparation of tablets and the indication is that plantain starch has about twice the binding efficiency and about half the disintegrant power of maize starch.     

Evaluation of starch obtained from Ensete ventricosum as a binder and disintegrant for compressed tablets

Abstract— The binding and disintegrant properties of starch obtained from Ensete ventricosum Musaceae have been evaluated. The effect of the starch on the physical properties such as crushing strength, friability and disintegration time of tablets of chloroquine phosphate, dipyrone and paracetamol was compared with tablets prepared with potato starch. The results show that enset starch can be used both as a tablet binder and disintegrant and the indication is that enset starch has a better binding ability and less disintegrating power than potato starch.     

Compression of controlled-release pellets produced by a hot-melt extrusion and spheronization process

The purpose of this study was to investigate the physicomechanical and dissolution properties of tablets containing controlled-release pellets prepared by a hot-melt extrusion and spheronization process. A powder blend of anhydrous theophylline, Eudragit Preparation 4135 F, and functional excipients was melt-extruded, pelletized, and then spheronized. The pellets were compressed into tablets using forces of 5, 10, 15, and 20 kN. Tablet diluents included microcrystalline cellulose, a mixture of spray-dried lactose and microcrystalline cellulose, modified food starch, and soy polysaccharides. The effective porosity of the compressed pellets was measured using mercury porosimetry and helium pycnometry, while the surface area was determined using Brunauer, Emmett, and Teller (BET) analysis. The disintegration time, hardness, and friability of compacts were determined. Drug release studies were performed according to USP 27 Apparatus 3 guidelines in 250 mL of medium (pH 1.0, 3.0, 5.0, 6.8, and 7.4) 37 degrees C and 20 dpm. Samples were analyzed by high pressure-liquid chromatography (HPLC). Effective porosity and surface area determinations of the melt-extruded pellets were not influenced by compression. The percent of theophylline released from rapidly disintegrating tablets was not affected by compression force or excipient selection, but tablets with prolonged disintegration times exhibited delayed drug release in acidic media. However, dissolution profiles of uncompressed pellets and all compacts were identical after transition from 0.1 N HCl to media increasing in pH from 3.0 to 7.4. Furthermore, pellet to filler excipient ratio and filler excipient selection did not influence the rate of drug release from compacts.     

Influence of loading volume of mefenamic acid on granules and tablet characteristics using a compaction simulator

Mefenamic acid (MA), a poorly water-soluble drug, was used as a model substance to investigate granules and tablet characteristics to be optimized for the loading volume of MA (0-74.1% v/v) in the formulation including lactose monohydrate/maize starch (7/3) as excipients. The compactibility of granules increased with loading volume of MA. This was related to the brittle behavior of MA during compression and the increase of intragranular pore volume of granules. The minimum disintegration time (266+/-8.3 s) was found in the tablet that was composed of 55.1% v/v MA and 13.6% v/v maize starch. The determination of the critical concentration of disintegrant (% v/v) required for a minimum disintegration time is suggested to be useful for solid dosage form design.     

Influence of loading volume of mefenamic acid on granules and tablet characteristics using a compaction simulator

Mefenamic acid (MA), a poorly water-soluble drug, was used as a model substance to investigate granules and tablet characteristics to be optimized for the loading volume of MA (0-74.1% v/v) in the formulation including lactose monohydrate/maize starch (7/3) as excipients. The compactibility of granules increased with loading volume of MA. This was related to the brittle behavior of MA during compression and the increase of intragranular pore volume of granules. The minimum disintegration time (266 +/- 8.3 s) was found in the tablet that was composed of 55.1% v/v MA and 13.6% v/v maize starch. The determination of the critical concentration of disintegrant (% v/v) required for a minimum disintegration time may be useful for solid dosage form design.     

Formulation and optimization of orodispersible tablets of flutamide

The present study aimed to formulate orodispersible tablets of flutamide (FTM) to increase its bioavailability. Orodispersible tablets were prepared by direct compression technique using three different approaches namely; super-disintegration, effervescence and sublimation. Different combined approaches were proposed and evaluated to optimize tablet characteristics. Sodium starch glycolate (SSG) was used as the superdisintegrant. The prepared powder mixtures were subjected to both pre and post compression evaluation parameters including; IR spectroscopy, micromeritics properties, tablet hardness, friability, wetting time, disintegration time and in-vitro drug release. IR studies indicated that there was no interaction between the drug and the excipients used except Ludipress. The results of micromeritics studies revealed that all formulations were of acceptable to good flowability. Tablet hardness and friability indicated good mechanical strength. Wetting and dispersion times decreased from 46 to 38 s by increasing the SSG concentration from 3.33 to 6.66% w/w in tablets prepared by superdisintegration method. The F8 formulation which was prepared by combined approaches of effervescence and superdisintegrant addition gave promising results for tablet disintegration and wetting times but failed to give faster dissolution rate. The incorporation of 1:5 solid dispersion of FTM: PEG 6000 instead of the pure drug in the same formulation increased the drug release rate from 73.12 to 96.99% after 15 min. This increase in the dissolution rate may be due to the amorphization of the drug during the solid dispersion preparation. The presence of the amorphous form of the drug was shown in the IR spectra.     

Effect of the mode of incorporation on the disintegrant properties of acid modified water and white yam starches

Acid modified starches obtained from two species of yam tubers namely white yam – Dioscorea rotundata L. and water yam – D. alata L. DIAL2 have been investigated as intra- and extra-granular disintegrants in paracetamol tablet formulations. The native starches were modified by acid hydrolysis and employed as disintegrant at concentrations of 5 and 10% w/w and their disintegrant properties compared with those of corn starch BP. The tensile strength and drug release properties of the tablets, assessed using the disintegration and dissolution (t₅₀ and t₈₀ – time required for 50% and 80% of paracetamol to be released) times, were evaluated. The results showed that the tensile strength and the disintegration and dissolution times of the tablets decreased with increase in the concentration of the starch disintegrants. The acid modified yam starches showed better disintegrant efficiency than corn starch in the tablet formulations. Acid modification appeared to improve the disintegrant efficiency of the yam starches. Furthermore, tablets containing starches incorporated extragranularly showed faster disintegration but lower tensile strength than those containing starches incorporated intragranularly. This emphasizes the importance of the mode of incorporation of starch disintegrant.     

The Influence of Granulation on Super Disintegrant Performance

The purpose of this study is to identify the causes of efficiency loss of super disintegrants following granulation or reworking. Two processes, precompression and prewetting, were proposed to simulate the processes during dry and wet granulation, respectively. The disintegration efficiency of the resulting disintegrant granules was tested in model formulations composed of dicalcium phosphate and lactose with the unprocessed disintegrants as controls. No significant difference was shown in the intrinsic swelling and the water uptake abilities of all super disintegrants following dry granulation. However, a significant decrease was observed for both Primojel and Polyplasdone XL10 in the rate of water being absorbed into the tablet matrix following wet granulation, but not for Ac-Di-Sol. United States Pharmacopeia (USP) disintegration testing without disc revealed a significant increase in disintegration time for tablets formulated with dry granulated Primojel and Polyplasdone XL10 and all wet granulated disintegrants. The increase in particle size following granulation appears to be the cause of the loss in disintegration efficiency. In conclusion, Ac-Di-Sol is less affected by both precompression and prewetting. The efficiency of Primojel and Polyplasdone XL10 is highly dependent on their particle size. Descreasing the particle size tends to increase their efficiency. Due to the size increase following granulation, a higher addition level of super disintegrant is required to ensure fast and uniform disintegration of tablets prepared by granulation.     

The influence of granulation on super disintegrant performance

The purpose of this study is to identify the causes of efficiency loss of super disintegrants following granulation or reworking. Two processes, precompression and prewetting, were proposed to simulate the processes during dry and wet granulation, respectively. The disintegration efficiency of the resulting disintegrant granules was tested in model formulations composed of dicalcium phosphate and lactose with the unprocessed disintegrants as controls. No significant difference was shown in the intrinsic swelling and the water uptake abilities of all super disintegrants following dry granulation. However, a significant decrease was observed for both Primojel and Polyplasdone XL10 in the rate of water being absorbed into the tablet matrix following wet granulation, but not for Ac-Di-Sol. United States Pharmacopeia (USP) disintegration testing without disc revealed a significant increase in disintegration time for tablets formulated with dry granulated Primojel and Polyplasdone XL10 and all wet granulated disintegrants. The increase in particle size following granulation appears to be the cause of the loss in disintegration efficiency. In conclusion, Ac-Di-Sol is less affected by both precompression and prewetting. The efficiency of Primojel and Polyplasdone XL10 is highly dependent on their particle size. Descreasing the particle size tends to increase their efficiency. Due to the size increase following granulation, a higher addition level of super disintegrant is required to ensure fast and uniform disintegration of tablets prepared by granulation.     

Design and study of ibuprofen disintegrating sustained-release tablets comprising coated pellets.

One challenge in tableting of sustained-release multiparticulates is maintaining the desired drug release after compaction. The aim of this study was to design sustained-release ibuprofen tablets which upon oral ingestion rapidly disintegrate into sustained-release pellets in which the integrity of the pellet core and/or coat is preserved. First free films composed of Eudragit RS 30D and RL 30D in 4:1 ratio and containing different levels of triethyl citrate (TEC) were prepared and tested to optimize the plasticizer level. Cured Eudragit based pellets with 60% ibuprofen loading which in our previous study showed proper mechanical properties for compression were coated with Eudragit RS 30D/RL 30D (4:1) containing 20% triethyl citrate at different coating levels. The mechanical properties of the coated pellets were tested. Polymer coated pellets were compacted into tablets either alone or with a blend of excipients comprising Avicel, PEG 4000, cross-linked PVP. A 3(2) full factorial design was used to optimize the filler blend composition. Effects of pellet to filler ratio, compression force and granulation of filler on tablet characteristics were investigated. Results of mechanical test showed that the coating of cured pellets had no significant effect on yield point and elastic modulus of the pellets. In the case of 5% coating level sustained release of ibuprofen over a period of 24h was achieved. The results obtained from tableting procedure showed that by selecting suitable filler blend (60% Avicel, 10% cross-linked PVP and 30% PEG 4000), compression force, and granulation of filler it was possible to prepare sustained-release tablets containing high ratio of coated pellets (even 80%) with desirable strength, disintegration time, and drug release rate. It was observed that compression force, pellet to filler ratio, composition of filler blend and granulation of fillers had no effect on drug release rate from compacted pellets but had significant influence on tablet strength, friability, and disintegration time. SEM graphs and in vitro release profiles for compacted pellets showed no apparent damage to the coated pellets as a result of the compaction process.     

Performance of tablet disintegrants: impact of storage conditions and relative tablet density

Abstract

Tablet disintegration can be influenced by several parameters, such as storage conditions, type and amount of disintegrant, and relative tablet density. Even though these parameters have been mentioned in the literature, the understanding of the disintegration process is limited. In this study, water uptake and force development of disintegrating tablets are analyzed, as they reveal underlying processes and interactions. Measurements were performed on dibasic calcium phosphate tablets containing seven different disintegrants stored at different relative humidities (5–97%), and on tablets containing disintegrants with different mechanisms of action (swelling and shape recovery), compressed to different relative densities. Disintegration times of tablets containing sodium starch glycolate are affected most by storage conditions, which is displayed in decreased water uptake and force development kinetics. Disintegration times of tablets with a swelling disintegrant are only marginally affected by relative tablet density, whereas the shape recovery disintegrant requires high relative densities for quick disintegration. The influence of relative tablet density on the kinetics of water uptake and force development greatly depends on the mechanism of action. Acquired data allows a detailed analysis of the influence of storage conditions and mechanisms of action on disintegration behavior.     

Formulation and <Emphasis Type="Italic">in vivo</Emphasis> evaluation of ondansetron orally disintegrating tablets using different superdisintegrants

The aim of this study was to formulate cost effective taste-masked orally disintegrating tablets of ondansetron, a bitter drug using different superdisintegrants by a wet granulation technique. Microcrystalline cellulose (Avicel) as a diluent and disintegrant in addition to aspartame as a sweetener were used in all formulations. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. The tablets’ hardness was maintained in the range of 2–3 kg and friability was <1% for all batches. All tablet formulations disintegrated rapidly in vitro within 5.83 to 33.0 sec. The optimized formulation containing 15% Polyplasdone XL-10 released more than 90% of drug within 5 min and the release was comparable to that of a commercial product. In human volunteers, optimized formulation was found to have a pleasant taste and mouth feel and they disintegrated in the oral cavity within 12 sec. The stability results were also satisfactory. A pharmacokinetic study with the optimized formulation was performed in comparison with a reference (Zofer MD 8®) and they were found to be bioequivalent. In conclusion, a cost effective ondansetron orally disintegrating tablet was successfully prepared with acceptable hardness, desirable taste and rapid disintegration in the oral cavity.     

Influence of Loading Volume of Mefenamic Acid on Granules and Tablet Characteristics Using a Compaction Simulator

Mefenamic acid (MA), a poorly water-soluble drug, was used as a model substance to investigate granules and tablet characteristics to be optimized for the loading volume of MA (0–74.1% v/v) in the formulation including lactose monohydrate/maize starch (7/3) as excipients. The compactibility of granules increased with loading volume of MA. This was related to the brittle behavior of MA during compression and the increase of intragranular pore volume of granules. The minimum disintegration time (266 ± 8.3 s) was found in the tablet that was composed of 55.1% v/v MA and 13.6% v/v maize starch. The determination of the critical concentration of disintegrant (% v/v) required for a minimum disintegration time is suggested to be useful for solid dosage form design.     

Stability and repeatability of a continuous twin screw granulation and drying system

The aim of this study was to investigate the process transfer of a commercially available product from the current batch fluid bed granulation and drying production method to an innovative continuously operating “from powder to tablet” production line using twin screw granulation as an intermediate granulation step. By monitoring process outcomes (torque, water temperature at the granulator jacket inlet, differential pressure over the dryer filters, and temperature mill screen) and granule and tablet quality in function of process time, the stability and repeatability during long production runs were determined.Three consecutive 5 h “from powder to tablet” production runs were performed using the ConsiGma™-25 system (GEA Pharma Systems, Collette™, Wommelgem, Belgium). A premix of two active ingredients, powdered cellulose, maize starch, pregelatinized starch, and sodium starch glycolate was granulated with distilled water. After drying and milling (1000 μm and 800 rpm), granules were in-line blended with magnesium stearate and directly compressed using a Modul™ P tablet press (tablet weight: 430 mg, main compression force: 12 kN). Granule (loss on drying, particle size distribution, friability, flow) and tablet (weight uniformity, hardness, thickness, friability, content uniformity, disintegration time, and dissolution) quality was evaluated in function of process time.For each of the logged process outcomes, a stabilization period was needed to reach steady-state conditions. Slightly deviating particle size distribution and friability results for milled granules were observed during start-up due to initial layering of the mill screen. However, no deviating tablet quality was detected in function of process time.For multiple hours, granule and tablet quality was constant in function of process time. Furthermore, process data trends were highly repeatable. Consequently, the ConsiGma™-25 system can be considered as a stable and repeatable system for the continuous production of tablets via wet granulation.     

Influence of Loading Volume of Mefenamic Acid on Granules and Tablet Characteristics Using a Compaction Simulator

Mefenamic acid (MA), a poorly water-soluble drug, was used as a model substance to investigate granules and tablet characteristics to be optimized for the loading volume of MA (0–74.1% v/v) in the formulation including lactose monohydrate/maize starch (7/3) as excipients. The compactibility of granules increased with loading volume of MA. This was related to the brittle behavior of MA during compression and the increase of intragranular pore volume of granules. The minimum disintegration time (266 ± 8.3 s) was found in the tablet that was composed of 55.1% v/v MA and 13.6% v/v maize starch. The determination of the critical concentration of disintegrant (% v/v) required for a minimum disintegration time may be useful for solid dosage form design.     

Disintegrant Selection in Hydrophobic Tablet Formulations

The hydrophobicity of poorly soluble drugs can delay tablets disintegration. We probed here the influence of different disintegrants on the disintegration of challenging hydrophobic formulations. Tablets containing diluents, hydrogenated vegetable oil and either sodium starch glycolate (SSG), croscarmellose sodium (CCS) or crospovidone (XPVP) were prepared. The disintegration time of tablets was tested immediately and after storage at 40 °C and 75% RH in sealed bags. Results show that storage and compression force had a negative effect on disintegration, particularly with 1% disintegrant. The performance of the three disintegrants was in the following order: CCS (best) > SSG > XPVP. For example, tablets containing 1% CCS, SSG and XPVP, compressed at 20 kN, disintegrated in ≈3, ≈12 and ≈69 min, respectively, after two months storage. Settling volume, liquid uptake and effect of storage on physical properties of the pure disintegrants were also studied and revealed that the reduced performance of XPVP is related to: 1) its rapid, yet short-range expansion upon liquid exposure and 2) its change of behaviour on storage. In conclusion, CCS ensured rapid disintegration at low concentration across various compression forces and storage times. Thus, the use of CCS in hydrophobic tablet formulations is recommended.