Expansion Of Tablets Research Articles

The effect of glidant on the tabletting behavior of common pharmaceutical excipients

Glidant used for the purpose of powder flowability enhancement is well known within the pharmaceutical industry to improve tablet manufacturing. Despite the widespread use of glidant for this purpose, the effect of glidant on the effect of tableting behavior is not well studied. To address this deficiency, the effect on glidant on the tabletting behavior of seven common excipients was investigated. Tabletability, compressibility, compactability, and tablet expansion were studied. It was shown that glidant increased the tabletability for excipients known to exhibit plastic behavior. Based on compressibility and compactability, it was inferred that an increase in total bonding strength due to the presence of glidant was responsible for the improvement in tabletability. Results suggest this may be due to an increase in inter-particle bonding area. Conversely, glidants did not affect the tabletability of brittle excipients. The effect of glidant on die-fill bulk density was also studied to examine the impact associated with air entrapment and tablet expansion. While glidant significantly increased the die-fill powder density, this did not have an observable effect on tablet expansion or any other tabletting behavior examined.

Effect of Hydrophobic Powders on the Tensile Strength of the Tablet

Zoe Chu1,2, Christopher Windows-Yule¹, Ian Gabbott², Gavin Reynolds², Rachael Shinebaum² and Andy Ingram¹1. School of Chemical Engineering, University of Birmingham, Edgbaston, B15 2TT2. Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UKEmail: zhc906@student.bham.ac.ukIntroductionA tablet consists of the active pharmaceutical ingredients (API), and the other components, excipients. A tablet needs to withstand coating, packing and shipping stresses whilst maintaining the dissolution time; therefore, the tensile strength is of great importance. Currently, there is a lack of understanding on why excipients improve the bulk powder properties and the bonding mechanisms of the powder during compression. This makes tablet formulation development an inefficient trial-and-error process that is required for every new API (1). Literature has shown that the surface energy of the powders contributes a significant amount towards the tablet tensile strength. Hydrophobic powders have a lower surface energy (2) and are seen to disrupt this tablet strength (3,4).Experimental Aim and MethodThe aim was to investigate the impact of the hydrophobicity of excipient powders on tabletability of microcrystalline cellulose. This was done by mixing powders of varying hydrophobicity with MCC at varying mass fractions. There was focus on a lower mass fraction (0.02-0.1 m/m) with increasing increments of 0.02 m/m of added additive as well as gaining a global picture (0.2-1 m/m) with increments of 0.2 m/m.ResultsIt was found that at low mass fractions (0.02-0.4 m/m) of additive added the hydrophobic powders disrupted the tablet strength more compared to hydrophilic powders which could be attributed to the levels of surface energy of the additive. In contrast, at higher mass fractions (0.6-0.8 m/m), the surface energy is not as important and it is hypothesised that the deformation mechanisms of the additives governs the tablet strength.1. Reynolds GK, Campbell JI, Roberts RJ. A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures. Int J Pharm [Internet]. 2017;531(1):215–24. Available from: http://dx.doi.org/10.1016/j.ijpharm.2017.08.0752. Sunkara D, Capece M. Influence of Material Properties on the Effectiveness of Glidants Used to Improve the Flowability of Cohesive Pharmaceutical Powders. AAPS PharmSciTech. 2018;19(4):1920–30. 3. Zuurman K, Maarschalk KVDV, Bolhuis GK. Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties. 1999;179:107–15. 4. Mishra SM, Rohera BD. Mechanics of tablet formation: a comparative evaluation of percolation theory with classical concepts. Pharm Dev Technol [Internet]. 2019;24(8):954–66. Available from: https://doi.org/10.1080/10837450.2019.1599913

Monitoring the weight and dimensional expansion of pyridostigmine bromide tablets under dynamic vapor sorption and impact of deliquescence on tablet strength and drug release

Changes of weight and axial expansion of tablets of the deliquescent drug pyridostigmine bromide with Kollidon SR were followed with relative humidity (RH) using dynamic vapor sorption and displacement transducer. The effects of RH on placebo and drug containing (API) tablets prepared at low and high compression were related to tablet strength and molecular changes. Tablet weight and expansion increased with RH, especially above RH 40%. Tablet rigidity and strength decreased linearly with moisture for placebo tablets whereas for API tablets there was decrease up to 50% followed by large drop at 60%. Raman spectra of tablets did not show chemical interactions due to moisture, but decreased intensity of drug peak at 2370 cm−1 indicating solid state changes. Decrease of polymer peak intensities at 805 and 1740 cm−1 occurred only in API tablets implicating drug deliquescence in polymer moisture sorption. X-ray diffraction and thermal analysis of tablets indicated complete drug liquefaction after exposure at 60% RH, which impacted great loss of strength but did not affect the sustained release profile. In conclusion, monitoring of the physical properties of tablets during production of deliquescent drugs is necessary to avoid pitfalls during downstream processes such as coating, packaging and storage.

Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets.

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

A Simple and Inexpensive Image Analysis Technique to Study the Effect of Disintegrants Concentration and Diluents Type on Disintegration

Tablets disintegration is often the result of a size expansion of the tablets. In this study, we quantified the extent and direction of size expansion of tablets during disintegration, using readily available techniques, that is, a digital camera and public domain image analysis software. After validating the method, the influence of disintegrants concentration and diluents type on kinetics and mechanisms of disintegration were studied. Tablets containing diluent, disintegrant (sodium starch glycolate, crospovidone, or croscarmellose sodium), and lubricant were prepared by direct compression. Projected area and aspect ratio of the tablets were monitored using image analysis techniques. The developed method could describe the kinetics and mechanisms of disintegration qualitatively and quantitatively. Sodium starch glycolate and crospovidone acted purely by swelling and shape recovery mechanisms. Instead, croscarmellose sodium worked by a combination of both mechanisms, the extent of which changed depending on its concentration and the diluent type. We anticipate that the method described here could provide a framework for the routine screening of tablets disintegration using readily available equipment.

Matrix tablets based on amino acid-derived polyesteramide containing release modifiers

The aim of this study was to develop controlled-release matrix tablets of ketoprofen (K) and dexketoprofen trometamol (DK-T), investigating a new application of the polymer poly (l-alanine-dodecanediol-l-alanine-sebacic) (PADAS). The influence on drug release of the type of filler (lactose, mannitol, microcrystalline cellulose or dibasic calcium phosphate) and of the polymer/filler proportion was also investigated.Evaluation of the flow properties of these materials (to facilitate a rational design of prolonged release formulation) showed this polymer to have good flowability. The compatibility between the formulation components was also investigated, by differential scanning calorimetry, and no drug-excipient interaction was detected.The dissolution study showed that PADAS is capable of forming inert matrix tablets with ketoprofen, and that drug retention within the matrix increases in line with the polymer proportion. Lactose and mannitol both promoted ketoprofen diffusion by forming channels in the matrix structure. Microcrystalline cellulose generated an axial expansion of tablets, which promoted drug release. Dibasic calcium phosphate retained ketoprofen, acting as an excipient for prolonged drug release. All tablets with ketoprofen behaved as inert matrix tablets, controlling drug release mainly by diffusion. However, the polymer did not retain dexketoprofen trometamol in the matrix, and so it presented a conventional dosage release form.

Tablet compression tooling – Impact of punch face edge modification

The influence of punch face edge geometry modification on tablet compression and the properties of the resultant tablets produced on a rotary press were investigated. The results revealed that tablets produced from the punches with radius edge face geometry consistently displayed better physical quality; higher tensile strength and lower capping tendency. Modification of the angled edge of the bevel face to the curved edge of the radius face, enabled deeper punch penetration in the die cavity during the compression cycle, bringing about greater compact densification. Improved die fill packing increased interparticulate bond formation and helped to dissipate destructive elasticity within the compact, consequently reduced tablet expansion during the decompression phase. The positive impact of punch face edge modification was also more noticeable at a higher turret speed. The application of the precompression force along with dwell time extension amplified the tableting performance of radius edge punch face design to a greater extent when compared to bevel edge punch face design. This could be attributed to the enhanced packing efficiency at both precompression and main compression stages.

Effects of Tableting Pressure on Hydration Kinetics of Theophylline Anhydrate Tablets

The effects of tableting pressure on hydration kinetics of types I and II theophylline anhydrate tablets at 95% relative humidity, 35 degrees C, have been studied by using various kinetic equations. Relations between tablet expansion and hydration were studied. Samples of 2 cm diameter tablets (1 g) were compressed at 5, 10 and 20 MPa. The hydration of types I and II tablets decreased with increased tableting pressure. The time required for 50% hydration of 2 cm diameter tablets, compressed at various pressures suggests that the tablet hydration rate was affected by the tableting pressure. Types I and II tablets expanded 11.37-16.75% in volume during hydration to the monohydrate. The thickness expansion of the tablets exceeded the diameter expansion as the tablet structure was not uniform owing to the orientation of particles during the compression. The final expansion ratio of the tablets increased with increased tableting compression pressure. The Hancock Sharp constant (m) and fitting of the kinetic data to a suitable model suggested that the hydration of theophylline anhydrate tablets followed the two-dimensional phase boundary equation (type I tablets) or the three-dimensional phase boundary equation (type II tablets).

Pore formation in tablets compressed from binary mixtures as a result of deformation and relaxation of particles

This paper describes the internal structure of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch. The minimum particle diameter of pregelatinised starch inside tablets compressed from mixtures was calculated from the difference between the initial pore size distribution and the pore size distribution after removal of the starch particles by burning. Subsequently, the tablets were carefully crushed. These powders, consisting of almost only sodium chloride particles, were measured by laser diffraction. It was found that the diameter of the sodium chloride particles hardly changed, whereas the minimum diameter of starch particles strongly decreased during the compaction process. As an effect of the difference in yield pressure, the harder sodium chloride particles cause deformation of the softer starch particles, resulting in a change in particle shape. The pore size distribution of tablets compressed from mixtures of sodium chloride and starch is typically that of viscoelastic materials; the larger pores (>5 μm) change, while the small pores stay constant in number and size. The median pore diameter in tablets compressed from the mixtures is higher than the median pore diameter in tablets compressed from the pure materials. This paper shows that the formation of large pores was the result of the extra porosity expansion of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch.

Quantitative NMR imaging study of the mechanism of drug release from swelling hydroxypropylmethylcellulose tablets

NMR imaging has been used to study the release behavior of two model drugs, triflupromazine–HCl and 5-fluorouracil, from swelling hydroxypropylmethylcellulose (HPMC) tablets. Preliminary experiments were performed on equilibrium mixtures of drug, polymer and water to determine how properties such as NMR relaxation parameters and self-diffusion were affected by the drug and polymer concentrations. The tablet swelling was restricted to one dimension and distributions of the water and model drugs were obtained by 1H and 19F imaging, respectively. The HPMC distribution at each time in the swelling process was determined indirectly from its effect on the relaxation parameters of the water and the drugs. In the one-dimensional swelling tablet, distributions of drug and polymer were compared to determine what factors influenced the release of drug from the swelling tablet. The distributions for triflupromazine–HCl and HPMC paralleled each other and the drug was only released at the eroding edge of the tablet where the HPMC concentration dropped below 10%. In contrast, 5-fluorouracil was released much more rapidly from the tablet and appeared to escape by diffusion from regions as high as 30% HPMC. An empirical measure of the rate of tablet edge movement can be obtained from plots of the edge position as a function of the square root of time. For HPMC, the rate of tablet expansion was determined in this way to be (2.4±0.8)×10 −6 cm 2 s −1. The self-diffusion of triflupromazine–HCl in equilibrated mixtures of similar composition to the eroding tablet edge is ∼3×10 −6 cm 2 s −1 while the self-diffusion coefficient of 5-fluorouracil remained higher than this value until the HPMC concentration reached about 30%. This comparison of ‘diffusion’ properties may be useful in predicting the mechanism of drug release from other swelling hydrophilic matrix systems.

Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties

The negative effect of magnesium stearate on tablet strength is widely known. This strength reduction is always considered to be the result of reduction of interparticle bonding. It is also known that interparticle bonding affects relaxation of tablets. Relaxation increases with decreasing bonding. Microcrystalline cellulose is an example of a material with a high lubricant sensitivity, which effect is caused by its plastic deformation behavior during compression. This paper shows for microcrystalline cellulose that the porosity under pressure was equal for unlubricated tablets and for tablets containing 0.5% magnesium stearate. This points to equal densification properties. The lubricated tablets show, however, a much larger relaxation than the tablets without magnesium stearate. This difference can be ascribed to the reduction of interparticle bonding by the lubricant, because a strong interparticle bonding counteracts tablet relaxation. In contrast to microcrystalline cellulose, aggregated γ-sorbitol (Karion Instant) has a low lubricant sensitivity. Both porosity under pressure and tablet relaxation were found to be equal for lubricated and unlubricated sorbitol tablets. This phenomenon is caused by the particle structure of γ-sorbitol. During compression, a lubricant film will be destroyed by fragmentation of the sorbitol aggregates. For this reason, magnesium stearate will hardly affect the interparticle bonding between sorbitol particles and hence have only a small or no effect on tablet relaxation.

Polyethylene glycol and dicalcium phosphate mixtures: effect of tableting pressure

The effect of compression pressure on Polyethylene glycol 10 000 (PEG): Dicalcium phosphate (DCP) mixtures has been evaluated. The tensile strength increased with PEG content exhibiting a maxima between 40 and 80% w/w PEG depending on the compression pressure. Similar strengths could be obtained using lower pressures however higher amounts of PEG was required. PEG densified rapidly and increasing the pressure above 82 MPa has no effect on plastic energy whilst only a small increase in tensile strength was observed. Above 82 MPa, asperity melting probably occurred. DCP expended less energy in tablet expansion than PEG or their mixtures, whilst at higher pressures the plastic energy for DCP was the greatest. However the tensile strength of DCP was smaller than that of PEG and their mixtures at any compression pressure. At higher pressure, extensive fragmentation of DCP occurred and a large number of contact points were created. Although the area of contact was greater, the amount of energy involved for bonding on each contact point was smaller and consequently the bonds formed between particles were weak and the compact has low strength. The tablets containing 80% PEG:20% DCP produced the best tablets, consuming the smallest energy while producing tablets that were mechanically tough. This study showed that mixtures of a brittle material (DCP) and a plastic material (PEG) produced tablets with higher tensile strengths than those made from the pure materials alone.

Stress relaxation of compacts produced from viscoelastic materials

Stress relaxation of tablets is a phenomenon that is known to be related to elastic deformation of particles. Expressions of stress relaxation are tablet expansion and capping. It has been shown that there is a direct relation between the changes in volume of the tablet and the amount of stored energy, calculated from the elastic modulus and the yield strength of the material. The relations are, however, different for the different materials. On the basis of the assumption that the increase in tablet volume is an expression of stress relaxation and stored energy is the driving force for it, there should be a counteracting force that prevents a compact from expansion. This paper shows that the counteracting force is determined by particle bonding, quantified by the Ryshkewitch-Duckworth relation and friction of the tablet with the die wall, quantified by the ejection pressure. The data presented here suggest that the final tablet porosity is unequivocally determined by stored energy, particle attraction and friction of the tablet with the die wall. All tablets that were capped showed both high stored energies and large particle bonding. From this observation it is concluded that porous and capped tablets suffer from the same problem, but the expression stress relaxation is different for the different materials.

Development of a novel controlled-release system for gastric retention.

We report on the development of a novel controlled-release gastric retention system, which consists of a matrix tablet, coated with a permeable membrane. When immersed in simulated gastric fluid, the tablet expands. The tablet remains expanded for eighteen to twenty hours, during which time the drug is released. The tablet then either disintegrates into fragments or loses its integrity. Tablets containing a soluble drug (chlorpheniramine maleate, i.e., CPM) and a poorly soluble drug (riboflavin 5' phosphate, i.e., R5'P) were compressed. They were coated with a permeable and elastic polymer (Eudragit). Dissolution profiles of these tablets were studied. The changes in the pH, viscosity, and deformation characteristics as a function of time were measured. Carbopol provided a firm structure to the swollen tablet. Polyvinyl pyrrolidone XL (PVP XL) contributed to the swelling of the tablet. Carbonates provided the initial alkaline micro-environment for Carbopol to gel and conferred buoyancy to the tablet. Coating provided the support needed for the core to remain intact during drug release and, at the same time, it allowed drug release due to its permeable nature. During release, the gelling properties of Carbopol lessened, resulting in a decrease in the firmness of the core. This was evident from the decrease in the viscosity of the core. The energy required at 50% strain also decreased as the drug release progressed. When this tablet is ingested, the chances of its elimination through the pylorus should be greatly reduced due to tablet's expansion, and due to its disintegration or loss in integrity it should then be expelled out of the stomach at the end of the drug release.

Porosity expansion of tablets as a result of bonding and deformation of particulate solids

This paper describes the tabletting process of y-sorbitol on the basis of the stress-deformation curve. This curve distinguishes between small, elastic deformation and large, viscous deformation. Small deformations can be quantified by the dynamic Young's modulus. The results demonstrated an effect of both rate of strain and initial particle size on the Young's modulus. The yield strength of compacts is a quantification of large deformations. There appeared to be an effect of strain rate on yield strength, but no clear relation between initial particle size and yield strength. The study relates elastic deformation with storage of elastic energy. The amount of stored energy was found to increase with compaction speed, and is postulated to be the driving force for changes of tablet porosities after compression. The attraction between particles causes resistance against porosity expansion, and is defined as expansion capacity. The expansion capacity showed no relation to compaction speed. It is therefore concluded that the effect of compaction speed on tablet properties is purely an effect of the amount of stored energy. The reciprocal value of expansion capacity demonstrated a direct relation with the constant that fits the relation between tablet strength and porosity. The expansion capacity is hence a quantification of bonding.

Disintegrant properties of an agglomerated cellulose powder

The disintegrant efficiency and the mechanism of disintegrant action of an agglomerated cellulose powder were evaluated and compared to those of microcrystalline celluloses, Avicel PH 101 and Emcocel, and cross-linked sodium carboxymethylcellulose AcDiSol. Water penetration and tablet expansion rates of dicalcium phosphate tablets containing agglomerated cellulose were similar to those of tablets containing microcrystalline celluloses. The total water uptake and maximum tablet expansion were, however, greater for tablets containing agglomerated cellulose, although not as much as those of tablets containing cross-linked sodium carboxymethylcellulose. Possible explanations for greater expansion of tablets containing agglomerated cellulose compared to tablets containing microcrystalline celluloses are a more pronounced disrupting effect of water on the hydrogen bonds between cellulose particles and an expansion of deformed agglomerated cellulose particles. The maximum expansion of tablets, related to the development of the maximum disintegration force inside a tablet, correlated well with the disintegration time of tablets. The agglomerated cellulose powder was clearly more effective as a disintegrant in an insoluble tablet base than microcrystalline celluloses; however it was not as effective as strongly swelling sodium carboxymethylcellulose.

Moisture sorption and volume expansion of amorphous lactose tablets.

Measurements of the moisture sorption and the volume expansion of amorphous lactose tablets, as well as measurements of the formation of crystalline lactose, were carried out under controlled relative humidities. At high relative humidity, it was suggested that the supersaturated solution of lactose was formed on some parts of the surface of amorphous lactose particles and the crystallization occured in an autocatalytic manner, which led to a rapid expansion of tablets. On the other hand, at low relative humidity, it appeared that the hygroscopic swelling owing to the physical adsorption of moisture on the inner surface of tablets occured without crystallization.

Moisture sorption and volume expansion of lactose anhydrate tablets (author's transl)

The moisture sorption and volume expansion of anhydrous α- and β-lactose tablets were examined under various conditions of relative humidity. In the case of anhydrous α-lactose tablets, the moisture sorption and expansion of tablets occurred even at a relatively low humidity, leading to the formation of the α-monohydrate. The rate of moisture sorption and expansion increased with an increase in water vapor pressure and with a lowering in temperature. The effect of tablet thickness and of compaction pressure in tablet making were also examined using anhydrous α-lactose tablets. β-Lactose was less hygroscopic at below 90% relative humidity (R.H.). Moisture uptake was small and the expansion of tablets was not observed. When the water vapor pressure rose to almost saturation, β-lactose absorbed a large amount of moisture to form the α-monohydrate gradually.