The effect of spray drying on the compaction properties of hypromellose acetate succinate

Background: The aim of this study was to evaluate the compaction behavior of a model two-component amorphous spray-dried dispersion system compared with the unprocessed excipients, using simulated rotary tablet press production conditions. Method: In this study, the stabilizing polymer, hypromellose acetate succinate (HPMCAS), was solubilized and spray dried with and without sodium lauryl sulfate (SLS). The impact of compression force and speed on the tabletting process was quantified by means of tablet tensile strength, compaction energy, and Heckel analysis. Results: Addition of the surfactant SLS, spray dried or as a physical mix, reduced the tablet strength. However, a lesser impact on the unprocessed excipients was observed in comparison with the spray-dried excipients. In the presence of 1% (w/w) SLS, tablets displayed a tendency to cap when compressed at higher speeds, supported by high elastic energy values indicating high uniaxial stress upon decompression. In the presence of 3% (w/w) SLS, tablets could not be produced at high speeds. Heckel analysis revealed a greater strain rate sensitivity of HPMCAS when spray dried in the presence of surfactant. Exposure of samples to a range of relative humidities before compaction had no effect on tablet strength. Conclusion: This study has shown that spray drying of HPMCAS in the presence of a surfactant affects the compressibility of the material, resulting in decreased tablet strength, increased elastic deformation, and capping.     

Diametrical Elastic Relaxation During Ejection of Lactose-Cocoa Binary Tablets

This work investigates the diametrical elastic relaxation of a compacted binary powder mixture of lactose and cocoa. It has been observed that the addition of lactose improved the mechanical strength of the binary tablets at the higher compaction stresses used in this study. The tablets having the maximum tensile strengths have relatively low diametrical elastic relaxations, similar to the pure cocoa tablets. Meanwhile, pure lactose tablets displayed increasing diametrical elastic relaxations as the compaction stress increased.     

Effect of Particle Size on Direct Compaction of Urea Fertilizer

The effect of particle size on compaction properties and characteristics of urea tablets manufactured from available urea granules (TG tablets) and ground urea powders (TP tablets) was investigated. The compaction properties, namely, plastic work, elastic work, friction work, and maximum ejection pressure were analyzed from the force-displacement profile of the compaction process. Five applied pressures ranging between 37.67 MPa and 188.35 MPa were used to compact the materials using a universal testing machine. Characteristics of the tablets tested were mechanical strength and the release of ammonium ion through dissolution test. The results demonstrated that TG tablets underwent high plastic work and elastic work but low friction work compared to the TP tablets. TG tablets released lower amount of ammonium ion compared to the TP tablets at almost all applied pressures, except at 75.34 MPa. This study provides a valuable data for evaluating the behavior of urea in the form of granules and powders during the compaction process as well as the suitability in choosing the form of raw material for the production of urea tablets.     

Deformation and Mechanical Characteristics of Compacted Binary Mixtures of Plastic (Microcrystalline Cellulose), Elastic (Sodium Starch Glycolate), and Brittle (Lactose Monohydrate) Pharmaceutical Excipients

This work studies the tensile strength, coherence, elastic, and plastic energy of single and bi-component compacted tablets consisting of (i) microcrystalline cellulose (MCC) PH 102 as a plastic material, (ii) (SSG) as an elastic material, and (iii) alpha lactose monohydrate as a brittle material by direct compression. Compacted tablets were studied with various mass ratios formed at an ultimate compaction stress of 150 MPa. The loading and unloading stages of the compaction process for the single and binary tablets were evaluated based on the energies derived from the force-displacement data obtained. The resulting tablet quality was measured in terms of the tensile strength. Material that exhibit predominantly plastic deformation (MCC) shows a dominant property over elastically deforming sodium starch glycolate (SSG) and brittle (lactose) materials during the loading and unloading stages of the compaction process. In conclusion, the tensile strength of the formed tablets depends directly on the plastic energy and indirectly on the elastic energy and is negatively affected by the presence of a brittle material.     

The mechanical properties of model-compacted tablets

In this study, the compressive strength of tablets made with salt, starch and fat was investigated. The strength was found to increase with compaction pressure, up to a maximum value where further increase in the compaction pressure led to no increase in the strength. The maximum strength corresponded to the point where zero porosity was obtained during the compaction process. However, because of the elastic rebound of the tablets after ejection, the maximum strength corresponded to non-zero final tablet porosities which varied between the materials. For this reason, the use of the density occurring during the compaction process appeared to provide a more reliable comparison between the materials. A simple linear mixing rule did not hold in characterising the strength in the salt:starch:fat systems. However, two regimes were observed depending on the salt volume fraction. At low salt volume fractions, the effect of the salt was negligible. After a certain critical salt volume fraction, increasing the salt led to an increase in the strength. Finite element simulations based on X-ray microtomography images of the tablets suggested that in the first regime, the stresses due to the salt particles were localised but in the second regime, stress-bearing networks were formed between the salt particles.

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Compaction of and drug release from coated pellets of different mechanical properties

The aim of this work was to relate the mechanical properties of film-coated pellets to their damage received during compaction, and to establish the significance of this damage for the release of a model drug from the resulting tablets. The formulations contained paracetamol and various excipient combinations chosen to provide different mechanical properties of the pellets, which were film-coated with Surelease® at various film thicknesses, and then compacted into tablets using three different compaction pressures. The drug release from the tablets was determined and compared to that of the uncompacted pellets. The compressibility and compactability of the various types of pellets was significantly influenced by the nature of the excipient combinations and binder liquids used to prepare the pellet cores, which also affected the drug release from the tablets. This could be attributed to the different responses of the pellets to compressive and shear stress. The film thickness and the mechanical properties of the film coating were found to be less important for tablet formation, but the film thickness played an important role in controlling the drug release rate from the tablets.     

Effect of compression force, compression speed, and particle size on the compression properties of paracetamol.

The compression characteristics of two particle size fractions (< 90 microm, 105-210 microm) of paracetamol were examined. Each fraction produced extremely weak tablets and displayed a high tendency to cap. Low correlation coefficients of the initial parts of the Heckel plots, a low strain rate sensitivity, and an increase in mean yield pressure (from 34.2 to 45.5 MPa) with decrease in particle size all confirmed that the main mechanism during the compaction of paracetamol was fragmentation. The 105-210-microm particles underwent more fragmentation than the less than 90-microm powder. Heckel analysis confirmed that the larger size fraction of paracetamol produced denser compacts than the smaller fraction. The 105-210-microm fraction resulted in tablets with lower elastic recoveries and elastic energies. The elastic, plastic energy ratios indicated that the majority of energy involved during the compaction of paracetamol was utilized as elastic energy, indicative of massive elastic deformation of paracetamol particles under pressure.     

Surrogate functionality of celluloses as tablet excipients

Background: The variety of excipients from different sources and prices to which we have access gives rise to the necessity to evaluate their functional characteristics. The aim of this work is to determine some physical and technological characteristics of celluloses from different sources, India and United States, to ascertain their functionality as tablet excipients. Methods: The used surrogate functionality properties are particle morphology and particle size distribution, compactibility, ejection pressure, and the disintegration properties of pure excipients and their compressed tablets. Results: The innovators Avicel and Croscarmellose show advantages over the generic celluloses Alfacel and Carmacel. Avicel PH 101 and 102 show an average of 26% greater compactibility than both types of Alfacel, whereas the compactibility of Croscarmellose is greater than that of Carmacel in about 50%. Avicel tablets compacted at a compaction pressure of 47 MPa exhibit shorter disintegration times (3.7 minutes) than Alfacel tablets (28 minutes), whereas Carmacel show better disintegrant properties than Croscarmellose. This occurs regardless of the similar particle morphology, size, and size distribution. As expected, all celluloses show low ejection pressures. Conclusion: The surrogate functionality properties of the generic celluloses are still considered as satisfactory to be used as tablet excipients, although they are inferior in some aspects to innovator celluloses. Alfacel and Carmacel have the potential to be used as filler, binder, and disintegrant, in the design of tablets. Moreover, one should bear in mind that the differences reported here may be altered because of a possible inter-batch variability and variations in the moisture content.     

Changes in the specific surface area of tablets composed of pharmaceutical materials with various deformation behaviors

Objective: The aim of this work is to study the effect of compaction on the specific surface area of tablets composed of various pharmaceutical materials (microcrystalline cellulose, lactose, and anhydrous calcium phosphate) compacted under seven degrees of compaction pressure. Methods: In a first part, the influence of the deformation behavior of the compacted materials on the evolution of the specific surface area is observed. In a second part, the brittle and ductile abilities of the materials are calculated using the specific surface area values. The experimental results are used to calculate the number and the force of interparticulate bonds inside the tablet.Results and Discussion: Tablets made of microcrystalline cellulose, which deform plastically, have specific surface areas that fall under pressure. In the case of lactose, the tablet specific surface area first increases to reach a maximum value at a pressure of 150 MPa. At higher pressure, however, the specific surface area decreases. The specific surface area of tablets composed of anhydrous calcium phosphate consistently increases, whatever the compaction pressure applied. Moreover, the evolution of the specific surface area is correlated with the tensile strength of the corresponding tablets. The number and the force of interparticulate bonds make it possible to classify the materials according to their deformation behavior and to quantify their ability to form cohesive tablets.     

Effect of repeated compaction of tablets on tablet properties and work of compaction using an instrumented laboratory tablet press

The repeated compaction of Avicel PH101, dicalcium phosphate dihydrate (DCP) powder, 50:50 DCP/Avicel PH101 and Starch 1500 was studied using an instrumented laboratory tablet press which measures upper punch force, punch displacement and ejection force and operates using a V-shaped compression profile. The measurement of work compaction was demonstrated, and the test materials were ranked in order of compaction behaviour Avicel PH101?>?DCP/Avicel PH101?>?Starch?>?DCP. The behaviour of the DCP/Avicel PH101 mixture was distinctly non-linear compared with the pure components. Repeated compaction and precompression had no effect on the tensile fracture strength of Avicel PH101 tablets, although small effects on friability and disintegration time were seen. Repeated compaction and precompression reduced the tensile strength and the increased disintegration time of the DCP tablets, but improved the strength and friability of Starch 1500 tablets. Based on the data reported, routine laboratory measurement of tablet work of compaction may have potential as a critical quality attribute of a powder blend for compression. The instrumented press was suitable for student use with minimal supervisor input.     

A study of the compaction process and the properties of tablets made of a new co-processed starch excipient

This article deals with the study of the energetic relationships during compaction and the properties of tablets produced from a co-processed excipient based on starch and called StarCap1500^®. This article compares it with the substance Starch1500^®. The study also includes the mixtures of StarCap 1500^® and the granulated directly compressible lactose Pharmatose DCL^®15. The tablet properties tested included tensile strength and disintegration time, examined in dependence on compression force, and also a 0.4% addition of magnesium stearate. The results show a better compressibility of StarCap 1500 in comparison with Starch 1500 and a lower elastic component of energy. The tablets were stronger and disintegrated more rapidly, but the substance possessed a higher sensitivity to an addition of a lubricant than Starch 1500. Increasing portions of StarCap 1500 in the mixtures with Pharmatose DCL 15 increased the tensile strength of tablets, disintegration period as well as the sensitivity to an addition of a lubricant. From the energetic viewpoint, energy for friction was decreasing, while the energy accumulated by the tablet during compaction and the elastic component of energy were increased.     

The Strength and Compaction of Millispheres: The design of a controlled-release drug delivery system for ibuprofen in the form of a tablet comprising compacted polymer-coated millispheres

Abstract

This paper reviews a case study of the design of a controlled-release drug delivery system for ibuprofen in the form of a tablet comprising compacted polymer-coated millispheres (multiparticulate pellets). The particular challenge was to prepare coated millispheres of ibuprofen (a high-dose drug) with the addition of minimal excipients so that the drug-release retarding polymeric membrane surrounding the millispheres remains intact during and after tablet compression, disintegration and release of the millispheres. The study included (a) the design of the uncoated core and its manufacture by wet massing, extrusion, spheronization and drying; (b) the coating of these millispheres with a range of possibly suitable polymers; (c) an assessment of the drug release profiles from these pellets; (d) the quantification by indentation rheology of the mechanical properties of the polymer films used to coat the spheres; (e) the measurement of the mechanical properties of individual uncoated and coated millispheres and f. the design, manufacture and evaluation of compressed tablets containing coated millispheres

The matching of millisphere and polymer mechanical properties was found to be essential in order to ensure minimal damage to the millispheres and the release of virtually intact coated spheres without destruction of their retarded drug-release characteristics. Aqueous polymeric dispersions which formed a film with similar elastic and tensile properties to the uncoated millisphere formulation resulted in the most satisfactory film coating for application to spherical particles which must withstand compaction. Those polymeric films exhibiting significantly greater resilience than the uncoated cores were inappropriate for the film coating of millispheres for compaction into tablets     

Correlating bilayer tablet delamination tendencies to micro-environmental thermodynamic conditions during pan coating

Objective: The objective of this study was to determine the impact that the micro-environment, as measured by PyroButton data loggers, experienced by tablets during the pan coating unit operation had on the layer adhesion of bilayer tablets in open storage conditions.

Materials and methods: A full factorial design of experiments (DOE) with three center points was conducted to study the impact of final tablet hardness, film coating spray rate and film coating exhaust temperature on the delamination tendencies of bilayer tablets. PyroButton data loggers were placed (fixed) at various locations in a pan coater and were also allowed to freely move with the tablet bed to measure the micro-environmental temperature and humidity conditions of the tablet bed.

Results: The variance in the measured micro-environment via PyroButton data loggers accounted for 75% of the variance in the delamination tendencies of bilayer tablets on storage (R^2?=?0.75). A survival analysis suggested that tablet hardness and coating spray rate significantly impacted the delamination tendencies of the bilayer tablets under open storage conditions. The coating exhaust temperature did not show good correlation with the tablets’ propensity to crack indicating that it was not representative of the coating micro-environment. Models created using data obtained from the PyroButton data loggers outperformed models created using primary DOE factors in the prediction of bilayer tablet strength, especially upon equipment or scale transfers.

Conclusion: The coating micro-environment experienced by tablets during the pan coating unit operation significantly impacts the strength of the bilayer interface of tablets on storage.     

Compressional Behaviour of an Agglomerated Cellulose Powder

Abstract

The ability of an agglomerated cellulose powder to total and plastic deformation was evaluated and compared with those of Avicel PH 101, Emcocel and an experimental depolymerized cellulose powder. The elastic recovely of compressed cellulose tablets was also measured. The effects of deformation of the material during the tableting process and recovery of tablet after maximum compression on the mechanical strength of tablets were also discussed.

The apparent net work done into tablets during compression as well as the yield pressures to total and plastic deformation, determined from the Heckel treatment, showed no great differences between the agglomerated cellulose powder and the other cellulose powders. Thus all the cellulose materials studied had rather similar ability to total, i.e. elastic and plastic, deformation and to permanent, i.e. pure plastic, deformation. The obvious fragmentation of the agglomerated cellulose powder already at low compressional pressure, however, seemed to be advantageous for the formation of strong compacts.     

Non-invasive and rapid analysis for observation of internal structure of press-coated tablet using X-ray computed tomography

Background: Since the internal structure of a tablet can be measured without destruction of the sample by X‐ray computed tomography (CT), it could be applied to quality control of tablets during the manufacturing process. Aim: A novel, fast, noninvasive tablet observation method was developed to evaluate the internal structure of commercial press-coated tablets by using X-ray CT. Method: Thirty-two CT image slices of four kinds of commercial press-coated tablets (tablets A, B, C, and D) were measured 300 m interval between edges of the tablet by using an X-ray CT. The thinnest layer thickness of the tablets and distance between centers of gravity (DCG) of tables were calculated. Results: The order of the TLT of the tablets was tablet B > tablet C > tablet D > tablet A. The result indicated that the order of DCG was tablet A > tablet D > tablet C > tablet B. Noninvasive observation of the internal structure of commercial, press-coated tablets by X-ray CT has been demonstrated to be useful in quality control of production. Conclusion: The internal structure of press-coated tablets could be observed without pretreatment, without destruction, and very rapidly by X‐ray CT.     

Influence of substance properties on scaling up of tablet formulations

Abstract

The influence of water content of furosemide in a direct compressible tablet formulation was studied in pilot plant production. Small variations in the water content of furosemide as determined by thermogravimetry was found to have a substantial influence on the compaction properties of the direct compressible formulation.

A study of furosemide per se revealed that an increase in water content from 0.06% to 0.24% resulted in an increased elastic recovery and decreased net work at compaction. By adjusting the water content of furosemide in the direct compressible formulation it was possible to avoid the capping tendency at tablets.     

Investigation of the physical–mechanical properties of Eudragit® RS PO/RL PO and their mixtures with common pharmaceutical excipients

Ammonio methacrylate copolymers Eudragit^® RS PO and Eudragit® RL PO have found widespread use as key components in various types of extended release solid dosage forms. The deformation behavior of neat polymers and binary mixes was evaluated using Heckel Analysis, strain rate sensitivity, work of compaction and elastic recovery index. Additionally, the compact forming ability of neat materials and binary mixes were evaluated by analyzing their tabletability, compressibility and compactibility profiles. The Heckel analysis of both polymers exhibited a speed-sensitive deformation behavior typical to plastic materials. The yield values of the binary mixes of the polymers with microcrystalline cellulose revealed a linear relationship with the weight fractions of individual components. The yield values of binary mixes of both the polymers with dibasic calcium phosphate exhibited slight negative deviations from linearity. Both polymers exhibited axial relaxation after ejection typical of viscoelastic materials, as measured by the elastic recovery index values. The work of compaction and the elastic recovery index values of the binary mixtures were found to be linearly related to the weight fractions of the individual components thus, confirming ideal mixing behavior based on the composition. Addition of microcrystalline cellulose to both polymers significantly improved their tabletability and compactibility. The tensile strengths of the compacts prepared with neat materials and binary mixes with microcrystalline cellulose, dibasic calcium phosphate and lactose were the function of their solid fraction and independent of the tableting speeds tested; thus, validating compactibility as a reliable parameter in predicting acceptable tablet properties.     

Mechanical properties and drug release of venlafaxine HCl solid mini matrices prepared by hot-melt extrusion and hot or ambient compression

Objective/significance: To elucidate the role of plasticizers in different mini matrices and correlate mechanical properties with drug release.

Methods: Cylindrical pellets were prepared by hot-melt extrusion (HME) and mini tablets by hot (HC) and ambient compression (AC). Venlafaxine HCl was the model drug, Eudragit^® RSPO the matrix former and citric acid or Lutrol^® F127 the plasticizers. The matrices were characterized for morphology, crystallinity, and mechanical properties. The influence of plasticizer’s type and content on the extrusion pressure (P_e) during HME and ejection during tableting was examined and the mechanical properties were correlated with drug release parameters.

Results: Resistance to extrusion and tablet ejection force were reduced by Lutrol^® F127 which also produced softer and weaker pellets with faster release, but harder and stronger HC tablets with slower release. HME pellets showed greater tensile strength (T) and 100 times slower release than tablets. P_e correlated with T and resistance to deformation of the corresponding pellets (r²?=?0.963 and 0.945). For both HME and HC matrices the decrease of drug release with T followed a single straight line (r²?=?0.990) and for HME the diffusion coefficient (D_e) and retreat rate constant (k_b) decreased linearly with T (r²?=?0.934 and 0.972).

Conclusions: Lutrol^® F127 and citric acid are efficient plasticizers and Lutrol^® F127 is a thermal binder/lubricant in HC compression. The different bonding mechanisms of the matrices were reflected in the mechanical strength and drug release. Relationships established between T and drug release parameters for HME and HC matrices may be useful during formulation work.     

High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties

Context: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation.

Objective: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer.

Methods: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the ‘out-of-die’ Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4?L, 300?L, and 600?L.

Results and conclusion: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.