Tablet Tensile Strength Research Articles

A Scale-Up, Phenomenological Model Incorporating the Effect of Both Feed Frame Lubrication and Tumble Blending-Driven Lubrication on Tablet Mechanical Strength.

In tablet manufacturing, mixing operations in tumble blending (TB) and in the feed frame (FF) of the rotary press can both increase lubricity, negatively influencing the tablet mechanical strength. While the TB-driven lubrication was systematically studied, no reliable bench-scale methods exist for the effect of FF lubrication. Because TB and FF mixing are usually two successive operations in tablet manufacturing, we developed a phenomenological model to incorporate the impact of TB-driven lubrication and the FF lubrication on the tablet tensile strength (TS). We noted that exponential decay functions can describe the evolution of the tablet TS as the function of the extent of TB, as well as the residence time in FF. Hence, the overall lubrication sensitivity can be modeled by incorporating two distinct exponential decay functions. The model can be calibrated through bench-scale experiments. Using an investigational powder blend, we showed that this approach accurately predicted the tablet TS in a scale-up tablet compression study, thereby verifying its utility. This model can serve as a scale-up diagnostic and risk-assessment tool, with the ability to adjust the overall effect of lubrication by changing the TB scale and the FF residence time commensurate with the large-scale operations.

Supercritical-CO2 Foam Extrusion of Hydroxypropyl Methyl Cellulose Acetate Succinate/Itraconazole Amorphous Solid Dispersions: Processing-Structure-Property Relations.

This study investigates the effects of supercritical CO2 as a foaming agent on structure and physical properties of hot melt extruded hydroxypropyl methylcellulose acetate succinate (HPMCAS)-itraconazole (ITZ) amorphous solid dispersions (ASDs) with the aim of improving the milling efficiency and tabletability of these ASDs. Two different grades of AFFINISOLTM HPMCAS, the standard grade (Std) and the High Productivity grade (HP) were used. The HP-grade has a lower molecular weight, melt viscosity and wider processing temperature range. Extrudates with different ITZ concentrations (0%, 20% and 40%) and CO2 injection pressure of 100 and 200 bar were prepared. The cellular microstructure of the foams showed that HP-grade HPMCAS had better affinity with the CO2 resulting in better distribution of CO2. The results of DSC and X-ray diffraction analysis revealed that the supercritical CO2 did not affect the amorphous state of the API in the extrudates. Milling efficiency of the ASDs was significantly improved up to around 90% increase in the mass recovery. The tabletability of the milled extrudates showed a considerable increase in tablet tensile strength. In addition, foaming considerably improved the supersaturation of HP-grade ASD while showing minimal improvement in dissolution behavior of the Std-grade material.

Ockham's Razor Applied on Pharmaceutical Powder Compaction Models

This investigation contains a critical survey of a collection of five well-known and often used standard models in pharmaceutical technology. The basic idea is to use the recognised Ockham's razor as a tool in search for simpler methods or explanations for these models. The study includes the indirect tensile strength of tablets, Pitt's equation for tensile strength of biconvex tablets, Adams' model for strength of agglomerates, Weibull's distribution for variability of strength measurements and Heckel's equation for compressibility. In all these cases simpler and equally valid solutions and explanations are presented and subsequently preferred rather than the original.

Improvement of Physico-mechanical and pharmacokinetic attributes of naproxen by cocrystallization with l-alanine

The current research investigates the improvement in key physico-mechanical and pharmacokinetic properties of naproxen by cocrystallizing it with L & β-alanine which were used as coformers. Naproxen belonging to BCS class II, suffers low oral bioavailability due to extremely low solubility. It also manifests poor mechanical properties due to its inability to undergo plastic deformation on applying stress. In this study, naproxen and coformers were ground together in three different ratios (1:1, 1:2 &2:1) by mechanochemical method and characterized by PXRD, DSC, intrinsic dissolution rate and tabletability analysis. Naproxen/l-alanine cocrystal in 1:1 ratio showed improved physicochemical and mechanical properties. Within the whole range of compaction pressure used, the tablet tensile strength of naproxen was low and lamination and sticking occurred in some tablets. On the contrary, cocrystal acquired a desirable tensile strength ~3 MPa making it a suitable candidate for tablet formulation. Cocrystal exhibited 4 and 2 fold higher intrinsic dissolution rate than naproxen in 0.1 M HCl and phosphate buffer pH 7.4. Furthermore cocrystal was easily formulated into tablets by direct compression with adequate hardness and showed better dissolution profiles (~38% and ~85%) in 0.1 M HCl and phosphate buffer pH 7.4 respectively when compared to a commercial formulation, Neoprox® (~25% and ~80%) after 60 min. In a single dose sheep model study cocrystal showed ~1.4 times enhanced total area under the curve and peak concentration. To conclude with, cocrystal of naproxen with l-alanine modified the physico-mechanical and pharmacokinetic profile of pure drug.

Lubrication empirical model to predict tensile strength of directly compressed powder blends.

A new approach is proposed to support prediction of tablet tensile strength as a function of both solid fraction (and/or compression pressure) and extent of lubrication by using empirical data to parameterise the model. This is a pre-requisite for simulation of the compaction unit operation where a linkage from tablet press operating parameters and formulation material properties to output tensile strength is required. The approach extends the previously published Kushner and Moore model to allow calculation across a range of solid fractions. The applicability of the approach is supported by testing using formulations with different commonly used pharmaceutical excipients.

Twin-screw granulation and high-shear granulation: The influence of mannitol grade on granule and tablet properties.

Granule structure has a key influence on tablet critical quality attributes. The ability to control this structure through excipient choice is an important part of formulation development. Mannitol is a popular diluent and the choice of input grade has been shown to impact granule properties. Allopurinol formulations containing two grades of mannitol (Pearlitol 160C and 200SD) were prepared by wet-granulation (twin-screw and high-shear) at different liquid/solid ratios (0.3 and 0.6g/g). The particle and bulk properties were characterised by a range of techniques and linked to flow performance and tablet tensile strength during compression on a rotary tablet press. During granulation, 200SD underwent a polymorphic transition from a mixture of α and β to predominantly β. This transition was accompanied by a morphology change. Mannitol needles were formed, giving more porous granules with a higher specific surface area, which led to poorer flow properties but higher tablet tensile strength. This study concludes that understanding the effect of mannitol grade is a crucial part of formulation selection.

Tabletability Flip – Role of Bonding Area and Bonding Strength Interplay

Predicting tableting performance of mixtures from that of individual components is of practical importance for achieving efficient and robust tablet design. It has been commonly assumed that a solid form exhibiting better tabletability will result in better tabletability when formulated. However, we show that the rank order of tabletability between two powders can flip when mixed with another powder, a phenomenon termed tabletability flip. Using three examples, we show that the tabletability flip upon mixing with microcrystalline cellulose is activated by the switch of the dominating factor in the bonding area (BA) and bonding strength (BS) interplay that determines tablet tensile strength. A mechanistic understanding of this phenomenon can significantly improve the accuracy of predicted tableting performance of mixtures from that of individual powders.

Effect of Hydroxypropyl Cellulose Level on Twin-Screw Melt Granulation of Acetaminophen.

This study investigated the effect of binder level on the physicochemical changes and tabletability of acetaminophen (APAP)-hydroxypropyl cellulose (HPC) granulated using twin-screw melt granulation. Even at 5% HPC level, the tablet tensile strength achieved up to 3.5MPa. A minimum of 10% HPC was required for the process robustness. However, 20% HPC led to tabletability loss, attributable to the high mechanical strength of APAP granules. The over-granulated APAP granules had thick connected HPC scaffold and low porosity. Consequently, these granules were so strong that they underwent a lower degree of fracture under compression and higher elastic recovery during decompression. HPC was enriched on the surface of APAP extrudates at all HPC levels. Amorphous APAP was also observed on the extrudate surface at 20% HPC level, and it recrystallized within 24h storage. To achieve a robust process and optimal improvement in APAP tabletability, the preferred HPC level was 10 to 15%.

Conversion of α-lactose monohydrate to anhydrous form with superior tabletability by twin-screw extrusion at elevated temperature.

The purpose of this study was to improve tabletability (tensile strength versus compaction pressure) of α-lactose monohydrate by twin screw extrusion (TSE) near its dehydration temperature but below its melting point. When extruded at 150 and 160°C, α-lactose monohydrate converted completely to α-lactose anhydrous that was mostly crystalline and only partially amorphous; the latter was indicated by glass transition observed in DSC scans. Tabletability of the material thus obtained by TSE was superior to anhydrous lactose available commercially or produced by hot air oven drying at 160°C. The superior tabletability was attributed to the partial conversion to amorphous lactose. When samples of anhydrous lactose powders obtained by TSE or oven drying were exposed to 25°C/60% RH and 40°C/75% RH, they reverted to the monohydrate with decreased tabletability. However, when anhydrous lactose powders produced by TSE were first compressed into tablets with high tensile strength and then exposed to similar stability testing conditions, there was no decrease in the tensile strength of tablets. Rather, it further increased, possibly due to the interaction of the amorphous fraction of lactose with moisture. Thus, TSE not only increased tabletability of α-lactose monohydrate, the compressed tablets remained intact and hard during shelf-life. These results demonstrate that a new modified anhydrous lactose may be produced by TSE that has better tabletability and superior physical stability than α-lactose monohydrate and the commercially available anhydrous lactose.

Comparison between twin-screw and high-shear granulation - The effect of filler and active pharmaceutical ingredient on the granule and tablet properties

The aim of the study was to compare continuous twin-screw granulation (TSG) with batch-wise high-shear granulation (HSG). Two different formulations containing either microcrystalline cellulose (MCC) and mannitol or MCC and dibasic calcium phosphate (DCP) as fillers were used. Three different active pharmaceutical ingredients (APIs) (allopurinol, paracetamol and metformin HCl) were used as model substances. To find the suitable liquid-to-solid (L/S) ratio for the granulations, preliminary trials were carried out using a mixer torque rheometry (MTR). Both granule and tablet properties were studied. Granules were characterized with respect to particle size distribution and flowability, while tablets were analysed for tensile strength. Both granulation techniques produced granules with unimodal particle size distribution after milling with the selected L/S ratios. Continuous TSG was less sensitive for liquid amount than HSG when comparing the granule size and tensile strength of tablets. The tabletability of the MCC-DCP formulation was decreased after the wet granulation, whereas the tabletability of MCC-mannitol was increased after wet granulation. Tablets made of TSG granules had a higher tensile strength than HSG tablets for all formulations. Even the APIs with poor compaction properties produced tablets with sufficient tensile strength. All the model substances behaved in a same way independently of the particle size and solubility of the pure API. These findings confirmed that continuous twin-screw granulation is a good alternative to batch-wise high-shear granulation.

Fine grade engineered microcrystalline cellulose excipients for direct compaction: Assessing suitability of different dry coating processes

Recent work showed that contrary to conventional wisdom, fine surface engineered excipients outperform their larger counterparts in blends of highly loaded blends of cohesive drug powders in terms of their packing, flowability and tablet tensile strength. Here, two continuous devices, fluid-energy mill (FEM) and conical mill (Comil), are compared with LabRAM, a batch device used in previous work, for nano-silica dry coating of microcrystalline cellulose (MCC) excipients, 20 and 30 μm. Coated MCCs from all three devices had higher bulk densities and flow function coefficients (FFCs) compared with Avicel PH-102. Silica coating quality was best with LabRAM, but also good with FEM and Comil, although Comil was less effective for the finer MCC. However, the better coating quality of LabRAM had a downside of having poorer compaction properties. The most surprising outcome was that multi-component blends of 17 wt% coated MCC with 60 wt % Ibuprofen 50 had higher bulk density, higher or similar flowability, higher tablet tensile strength, and comparable Ibuprofen dissolution from tablets, compared to those with Prosolv 50, a silicified excipient. The FEM dry coated MCC blends, having only 0.17 wt% silica, performed the best, having desirable bulk density, FFC, and tensile strength that could facilitate high-speed direct compression tableting. In summary, considering that achieving best coating quality need not be the primary objective, FEM may be the best option for producing desired sized dry coated fine excipients.

Modification of a scale-up model to improve prediction of the effect of lubrication on tablet tensile strength

Kushner et al. proposed a scale-up model to describe the effect of lubrication on tablet tensile strength. In our study, a lubricant cohesiveness term, (1 + α/V), was added to the lubrication scale-up model reported by Kushner et al. to address the cohesiveness of magnesium stearate. The modified model proposed is as follows: TSSF=0.85 = TSSF=0.85,0[β(1 + α/V)exp(−ϒ × 1.5 V1/3 × Fheadspace × r) + (1 − β)], where TSSF=0.85 is tablet tensile strength at solid fraction 0.85, V is blender size, Fheadspace is fraction of headspace, r is revolution number, TSSF=0.85,0 is theoretical initial tensile strength, α is the sensitivity constant of magnesium stearate powder cohesiveness, β is the sensitivity constant of the blend to lubrication, and γ is the lubrication rate constant. Using a high shear placebo granule, lubrication scale-up models were built using both equations, with and without the cohesiveness term, and tested by a 16-fold scale-up. The equation with the cohesiveness term demonstrated superior prediction of tablet tensile strength for scale-up within the selected granular system and the scale-up range studied in this work, indicating the usefulness of including magnesium stearate powder cohesiveness in building a scale-up predictive lubrication model using an active pharmaceutical ingredient (API) sparing approach with small quantity of materials.

A study on the impact of HPMC viscosity grade and proportion on the functional properties of co-freeze-dried mannitol-HPMC cushioning excipients for compacted MUPS

The co-processing of multiple excipients is driven by the potential of diversifying the properties and functionality of excipients when they are combined. Bulk freeze-drying-milling is a novel secondary processing approach to develop co-processed excipients. It offers a significant advantage of formulation flexibility. This study was designed to systematically investigate the impact of 3 factors, hydroxylpropyl methyl cellulose (HPMC) viscosity grade, mannitol to HPMC ratio and particle size fraction on the functional properties of freeze-dried (FD) mannitol-HPMC cushioning excipients produced for multi-unit pellet system tableting. Based on the results, the investigated formulation variables were significant in determining the functional properties of the FD-mannitol-HPMC cushioning excipients. Among the formulations, FD-mannitol-HPMC F4M (3:1 ratio) excipients exhibited the best cushioning performance. It was postulated that the protective effects of the cushioning excipient were brought about by its propensity for rearrangement around the coated pellets to reduce detrimental pellet-pellet contact and ability to absorb damaging compressive forces. Conversely, FD-mannitol-HPMC vLV (3:1 ratio) had cushioning effects but showed short disintegration time while maintaining adequate tablet tensile strength. Overall, the results of this study highlighted the impact of formulation variables on the functional properties of the cushioning excipients, arising from an interplay of the freeze-dried particle properties.

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.

Effect of particle size on powder compaction and tablet strength using limestone

Processability of powders in high load compaction constitutes a challenge due to particle rearrangement, compression and breakage occurring simultaneously. Although tableting is a central operation in pharmaceutical technology, a better understanding of the link between the macroscopic powder behaviour and its micro-mechanical properties is still required. In the present study, a dual focus on the powder compaction behaviour and the quality properties of final tablets using a compaction simulator is presented. Tableting has been performed for a wide size range of limestone powders from 10 to 400 MPa, in order to understand and compare the powder compaction behaviour at both low and high confining stresses.Compactibility of limestone, the relation between porosity and stress, has been assessed with both the classical (logarithmic) Heckel model and the newly proposed (double logarithmic) Wünsch model, confirming the improvement of the latter to enhance the description of the porosity change during compaction, as well as the model robustness towards non-pharmaceutical powders. The qualitative effect of particle size and thus cohesion on the bulk density at high pressure compaction is found to be very similar to the low pressure regime. However, the geometrical interlocking influence of large size powders found in a previous study becomes irrelevant at such high pressures. For d50<10 μm, the tablet tensile strength remains almost insensitive to the size variation. However, for the coarsest grades, the tensile strength decreases with increasing d50 at all compaction stresses. In addition, the tablet tensile strength is found to follow a non-monotonic trend with median particle size.

Material properties and tensile strength prediction model of traditional Chinese medicine tablets based on PCA-RBF neural network

This paper constructs a prediction model of material attribute-tensile strength based on principal component analysis-radial basis neural network( PCA-RBF),in order to predict the formability of traditional Chinese medicine tablets. Firstly,design Expert8. 0 software was used to design the dosage of different types of extracts,the mixture of traditional Chinese medicine with different physical properties was obtained,the powder properties of each extract and the tensile strength of tablets were determined,the correlation of the original input layer data was eliminated by PCA,the new variables unrelated to each other were trained as the input data of RBF neural network,and the tensile strength of the tablets was predicted. The experimental results showed that the PCA-RBF model had a good predictive effect on the tensile strength of the tablet,the minimum relative error was 0. 25%,the maximum relative error was2. 21%,and the average error was 1. 35%,which had a high fitting degree and better network prediction accuracy. This study initially constructed a prediction model of material properties-tensile strength of Chinese herbal tablets based on PCA-RBF,which provided a reference for the establishment of effective quality control methods for traditional Chinese medicine preparations.

Investigation on the effect of roller compaction on paracetamol

Roller compaction is a popular dry granulation method that has been associated with loss of tabletability. In this study, the effect of roller compaction on a model brittle elastic material, paracetamol, was examined. Roller compaction of paracetamol was carried out at three roll force to examine the effects of roll force on the tablet compaction properties. Paracetamol granules consisting of small fragmented crystals were created through the process of roller compaction. A compaction simulator was used to produce tablets from a sieved fraction of roller compacted paracetamol and non-roller compacted paracetamol. Despite the higher elastic energy to plastic energy ratio observed with tablets produced from roller compacted granules of higher forces, the table tensile strength obtained was higher with a lower capping coefficient. At the same time, tablet elastic recovery was found to be lower for tablets produced using roller compacted paracetamol granules. Prefragmentation during roller compaction process helped to reduce the energy required for fragmentation during tablet compaction, increasing the energy available for bond formation. Roller compaction of brittle elastic materials may be a viable option for improving tablet tensile strength and reducing tablet capping.

A compression behavior classification system of pharmaceutical powders for accelerating direct compression tablet formulation design.

In this paper, a compression behavior classification system (CBCS) for direct compression (DC) pharmaceutical powders is presented. Seven descriptors from a series of compression models for powder compressibility, compactibility and tabletability analysis were included in the CBCS. A new tabletability index d was proposed to differentiate three categories of tensile strength (TS) vs. pressure relationships, and its physical meaning was explained thoroughly. 130 materials containing diverse pharmaceutical excipients and natural product powders (NPPs) were fully characterized and were compiled into an in-house developed material library, in which 70 materials with potential DC applications were used to justify the effectiveness of the CBCS. Principle component analysis (PCA) was used to uncover the latent structure of compression variables. Moreover, partial least squares (PLS) regression models are established in prediction of both tablet TS and solid fraction (SF) based on the raw materials' physical characteristics, the compression behavior indices and the compression force. The obtained scores and loadings are used to group the materials and the compression variables, respectively. Different categories of tabletability for DC powders were clearly clustered along two orthogonal directions pointing to the index d and the compression force. Finally, a multi-objective design space was identified under the latent variable space, summarizing the operationally possible region for both material properties and compression pressure required in DC tablet formulation design.

The Role of Particle Surface Area and Adhesion Force in the Sticking Behavior of Pharmaceutical Powders

The effect of particle surface area and adhesion force on sticking behavior for a model pharmaceutical blend was studied. Various lots of an active pharmaceutical ingredient (API) differing in particle size distribution and surface area were blended with commercial grades of microcrystalline cellulose ranging in size from 20 to 110 μm. A dry-coating technique was also used to modify the surface of microcrystalline cellulose to reduce its adhesion force. This allowed study of sticking behavior due to effects associated with particle adhesion force independently from effects associated with surface area. Using a removable-tip experiment to quantify the mass of adhered material to a tablet punch, this study concludes that both particle surface area and adhesion force significantly affect sticking behavior. Tablets with higher tensile strength comprised of API with lower surface area relative to the excipient surface area resulted in less sticking. This study found that the difference between the tablet tensile strength of the blend and that of the API normalized by the surface area fraction of API in the blend correlates well with the rate of mass adhered to the punch. This quantity, referred to as the sticking index, can be used to assess sticking propensity for a pharmaceutical blend.

Importance of free water in controlling granule and tablet properties in a novel granulation method, green fluidized bed granulation (GFBG).

In the pharmaceutical field, green fluidized bed granulation (GFBG) is a novel and eco-friendly manufacturing technology used to produce desired granules via simple blending and spraying steps at ambient temperature using a standard fluidized bed granulator. However, the relations between water content and granule and tablet qualities have not yet been elucidated for GFBG. The purpose of this study was to elucidate the influence of different water quantities used in the GFBG process on granule and tablet qualities. In addition, results from the GFBG process were compared with those from the moisture-activated dry granulation (MADG) process. In terms of tablet tensile strength and disintegration time, GFBG had a wider acceptable range for added water quantity (2.0-5.0%) than did MADG. For all added water quantities, the GFBG granules were within the upper limit of water activity (a surrogate of free water amount), which was 0.61 for tensile strength and 0.55 for disintegration time. The air flow in the GFBG process may have reduced the excess free water on the granules during the absorption process. It was concluded that as compared with MADG, GFBG may be a more robust process for manufacturing granules and tablets with superior properties.