Direct Compaction Research Articles

Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate

Intensive dry powder coating (mechanofusion) with tablet lubricants has previously been shown to give substantial powder flow improvement. This study explores whether the mechanofusion of magnesium stearate (MgSt), on a fine drug powder can substantially improve flow, without preventing the powder from being directly compacted into tablets. A fine ibuprofen powder, which is both cohesive and possesses a low-melting point, was dry coated via mechanofusion with between 0.1% and 5% (w/w) MgSt. Traditional low-shear blending was also employed as a comparison. No significant difference in particle size or shape was measured following mechanofusion. For the low-shear blended powders, only marginal improvement in flowability was obtained. However, after mechanofusion, substantial improvements in the flow properties were demonstrated. Both XPS and ToF-SIMS demonstrated high degrees of a nano-scale coating coverage of MgSt on the particle surfaces from optimized mechanofusion. The study showed that robust tablets were produced from the selected mechanofused powders, at high-dose concentration and tablet tensile strength was further optimized via addition of a Polyvinylpyrrolidone (PVP) binder (10% w/w). The tablets with the mechanofused powder (with or without PVP) also exhibited significantly lower ejection stress than those made of the raw powder, demonstrating good lubrication. Surprisingly, the release rate of drug from the tablets made with the mechanofused powder was not retarded. This is the first study to demonstrate such a single-step dry coating of model drug with MgSt, with promising flow improvement, flow-aid and lubrication effects, tabletability and also non-inhibited dissolution rate.

Tableting and Dissolution Characteristics of Mixed Fruit Powder

Abstract In this study four types fruit powder were mixed together in a 1:1 ratio and tableting was carried out by direct compaction method. Two types tablet were produced, normal mix fruit powder tablet and fruit powder effervescent tablet. Compressibility of the powder mixtures were observed by using Kawakita and Ludde equation. Normal fruit powder mixture was more compressible rather than fruit powder mixture with effervescent agent. Dissolution test was carried out in the dissolution medium of distilled water and simulated saliva fluid at room temperature and 37.5 °C temperature, respectively. Fruit powder effervescent tablet was dissolved faster in simulated saliva.

An Integrated Approach to Simulation of Pharmaceutical Processes for Solid Drug Manufacture

There are significant economic incentives to transition from batch to continuous processing of pharmaceutical products. However, several challenges must be overcome in order to implement continuous manufacturing systems for solids-based processes. Among these is the need to develop increased understanding of continuous processes and their sensitivity to variability in input materials, processing equipment, and operating conditions. In the current work, integrated flowsheet modeling is used to evaluate a continuous process for tablet production via direct compaction. Simulation of the flowsheet model is used to assess the impact of variability in input material properties as well as process design and operating parameters on product quality. Global sensitivity analysis is also used to identify gaps in the existing process model with the goal of determining specific areas where model improvement can be effected.

Impact of Alternative Solid State Forms and Specific Surface Area of High-Dose, Hydrophilic Active Pharmaceutical Ingredients on Tabletability

In order to investigate the effect of using different solid state forms and specific surface area (TBET) of active pharmaceutical ingredients on tabletability and dissolution performance, the mono- and dihydrated crystalline forms of chlorothiazide sodium and chlorothiazide potassium (CTZK) salts were compared to alternative anhydrous and amorphous forms, as well as to amorphous microparticles of chlorothiazide sodium and potassium which were produced by spray drying and had a large specific surface area. The tablet hardness and tensile strength, porosity, and specific surface area of single-component, convex tablets prepared at different compression pressures were characterized. Results confirmed the complexity of the compressibility mechanisms. In general it may be concluded that factors such as solid-state form (crystalline vs amorphous), type of hydration (presence of interstitial molecules of water, dehydrates), or specific surface area of the material have a direct impact on the tabletability of the powder. It was observed that, for powders of the same solid state form, those with a larger specific surface area compacted well, and better than powders of a lower surface area, even at relatively low compression pressures. Compacts prepared at lower compression pressures from high surface area porous microparticles presented the shortest times to dissolve, when compared with compacts made of equivalent materials, which had to be compressed at higher compression pressures in order to obtain satisfactory compacts. Therefore, materials composed of nanoparticulate microparticles (NPMPs) may be considered as suitable for direct compaction and possibly for inclusion in tablet formulations as bulking agents, APIs, carriers, or binders due to their good compactibility performance.

Surrogate-Based Optimization of Expensive Flowsheet Modeling for Continuous Pharmaceutical Manufacturing

Simulation-based optimization is a research area that is currently attracting a lot of attention in many industrial applications, where expensive simulators are used to approximate, design, and optimize real systems. Pharmaceuticals are typical examples of high-cost products which involve expensive processes and raw materials while at the same time must satisfy strict quality regulatory specifications, leading to the formulation of challenging and expensive optimization problems. The main purpose of this work was to develop an efficient strategy for simulation-based design and optimization using surrogates for a pharmaceutical tablet manufacturing process. The proposed approach features surrogate-based optimization using kriging response surface modeling combined with black-box feasibility analysis in order to solve constrained and noisy optimization problems in less computational time. The proposed methodology is used to optimize a direct compaction tablet manufacturing process, where the objective is the minimization of the variability of the final product properties while the constraints ensure that process operation and product quality are within the predefined ranges set by the Food and Drug Administration.

Wear Behavior of Al-20Vol. %SiCp Composites Manufactured by Dynamic Consolidation

Dynamic consolidation is the route that can be used as a processing method to produce aluminum-matrix composite. This process offers several unique advantages over the static compaction methods in conventional powder metallurgy. Al-20vol.% SiCp composites were manufactured by direct explosive compaction with various explosive pad thicknesses that resulted in densities of compacts from 92% to 98.5% TD. The wear behavior of the various compacts was evaluated using a pin-on-disc wear tester. The microstructure characterization was performed using light microscopy. The dominant wear mechanisms were evaluated using scanning electron microscopy. The results showed that the sliding wear resistance increased with the increase in the density of the compact composites.

System-wide hybrid MPC–PID control of a continuous pharmaceutical tablet manufacturing process via direct compaction

The next generation of QbD based pharmaceutical products will be manufactured through continuous processing. This will allow the integration of online/inline monitoring tools, coupled with an efficient advanced model-based feedback control systems, to achieve precise control of process variables, so that the predefined product quality can be achieved consistently. The direct compaction process considered in this study is highly interactive and involves time delays for a number of process variables due to sensor placements, process equipment dimensions, and the flow characteristics of the solid material. A simple feedback regulatory control system (e.g., PI(D)) by itself may not be sufficient to achieve the tight process control that is mandated by regulatory authorities. The process presented herein comprises of coupled dynamics involving slow and fast responses, indicating the requirement of a hybrid control scheme such as a combined MPC–PID control scheme. In this manuscript, an efficient system-wide hybrid control strategy for an integrated continuous pharmaceutical tablet manufacturing process via direct compaction has been designed. The designed control system is a hybrid scheme of MPC–PID control. An effective controller parameter tuning strategy involving an ITAE method coupled with an optimization strategy has been used for tuning of both MPC and PID parameters. The designed hybrid control system has been implemented in a first-principles model-based flowsheet that was simulated in gPROMS (Process System Enterprise). Results demonstrate enhanced performance of critical quality attributes (CQAs) under the hybrid control scheme compared to only PID or MPC control schemes, illustrating the potential of a hybrid control scheme in improving pharmaceutical manufacturing operations.

Dry coating of micronized API powders for improved dissolution of directly compacted tablets with high drug loading

Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 μm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 μm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non-micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t(80) for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings.

Ti-6Al-4V Billet Produced by Compaction of BE Powders Using Equal-Channel Angular Pressing

In the present study, ECAP compaction was used to produce Ti-6Al-4V billet from CP Ti powder mixed with two different Al-V master alloys. It was demonstrated that ECAP at 400 °C with applied back-pressure of about 210 MPa permits consolidation of the powder mixtures to relative green densities as high as 99.3 %. A combination of temperature, high hydrostatic pressure and plastic shear deformation gave rise to excellent green densities and good compositional homogeneity due to enhanced self-diffusion. It was shown that the temperature of sintering required after direct compaction of BE powders can be reduced by 150-250°C if compaction is conducted by ECAP with back-pressure. This becomes possible due to high green density and the presence of a large number of fast diffusion paths associated with dislocations and grain boundaries. It is suggested that the ECAP-based processing route may offer a significant saving of production cost.

A novel approach to crystallisation of nanodispersible microparticles by spray drying for improved tabletability

High-dose API powders which are to be tableted by direct compression should have high compactibility and compressibility. This note reports on a novel approach to the manufacture of crystalline powders intended for direct compaction with improved compactibility and compressibility properties. The poorly compactable API, chlorothiazide, was spray dried from a water/acetone solvent mix producing additive-free nanocrystalline microparticles (NCMPs) of median particle size 3.5 μm. Tablets compacted from NCMPs had tensile strengths ranging from 0.5 to 4.6 MPa (compared to 0.6-0.9 MPa for tablets of micronised CTZ) at compression forces ranging from 6 kN to 13 kN. NCMP tablets also had high porosities (34-20%) and large specific surface areas (4.4-4.8m(2)/g). The time taken for tablets made of NCMPs to erode was not statistically longer (p>0.05) than for tablets made of micronised CTZ. Fragmentation of NCMPs on compression was observed. The volume fraction of particles below 1 μm present in the suspension recovered after erosion of NCMP tablets was 34.8±3.43%, while no nanosized particles were detected in the slurry after erosion of compacted micronised CTZ.

Production of Ti–6Al–4V billet through compaction of blended elemental powders by equal-channel angular pressing

Abstract In this work, compaction by warm equal-channel angular pressing (ECAP) with back pressure was used to produce Ti–6Al–4V billets from both commercially pure (CP) titanium and titanium hydride (TiH 2 ) powders, which were mixed with pulverised binary Al–V master alloys of two distinct Al/V ratios and with elemental aluminium powder to arrive at the nominal alloy composition. It was demonstrated that the right combination of temperature, high hydrostatic pressure and plastic shear deformation permits consolidation of the powder mixture to maximum green densities of 99.26%. Moreover, after direct compaction of blended elemental powders by equal-channel angular pressing (ECAP) with back pressure, the sintering temperature required for chemical and microstructural homogenisation of the compacts could be reduced by 150–250 °C. This was possible due to high green density, increased contact area between powder particles and the formation of fast diffusion paths associated with grain refinement by severe plastic deformation. The sintered Ti–6Al–4V billets exhibited a maximum density of 99.88%, Vickers hardness of 409–445 HV1 and ultimate tensile strength in the range of 1000–1080 MPa. In contrast to findings of other authors, the use of TiH 2 powders in conjunction with ECAP processing did not bring any benefits with regard to the production of the Ti–6Al–4V alloy.

An integrated approach for dynamic flowsheet modeling and sensitivity analysis of a continuous tablet manufacturing process

Manufacturing of powder-based products is a focus of increasing research in the recent years. The main reason is the lack of predictive process models connecting process parameters and material properties to product quality attributes. Moreover, the trend towards continuous manufacturing for the production of multiple pharmaceutical products increases the need for model-based process and product design. This work aims to identify the challenges in flowsheet model development and simulation for solid-based pharmaceutical processes and show its application and advantages for the integrated simulation and sensitivity analysis of two tablet manufacturing case studies: direct compaction and dry granulation. The developed flowsheet system involves a combination of hybrid, population balance and data-based models. Results show that feeder refill fluctuations propagate downstream and cause fluctuations in the mixing uniformity of the blend as well as the tablet composition. However, this effect can be mitigated through recycling. Dynamic sensitivity analysis performed on the developed flowsheet, classifies the most significant sources of variability, which are material properties such as mean particle size and bulk density of powders.

Comparison study of single direction and friction assisted compaction of multiple alloy powders by finite element simulation

A comparative study is conducted by compaction experiments and finite element simulations on the compaction behavior of multiple alloy powders in the traditional single direction compaction and in the friction-assisted-compaction processes. The results suggest that, in the single direction compaction, stress, strain, and density of the green compacts along the vertical direction are not uniform due to the effects of the friction between the side die wall and powder particles; the density on the top of the green compacts is higher than that in the bottom. However, in the friction assisted compaction process, the density distribution along the vertical direction is more uniform and the density near the middle part of the green compacts is only slightly lower than that at the top and bottom parts of the green compact.

Model-Based Control-Loop Performance of a Continuous Direct Compaction Process

This study is concerned with enhanced model-based control of a continuous direct compression pharmaceutical process. The control-loop performance is assessed in silico and results obtained will be incorporated into the pilot plant facility of the continuous direct compaction process at the NSF Engineering Research Center of Rutgers University. The models used in the study are obtained via system identification from a combination of first principles-based dynamic models, experimental data, and/or literature data. The main objective of the paper is to formulate an effective control strategy at the basic/regulatory level, for the integrated continuous operation of the direct compaction process, and to maintain the process at the desired set-points, taking into account the multivariable process interactions and disturbances. Simulations show that that at very mild interactions, the proposed regulatory control strategy is able to maintain set-points at desired values. However, at moderate to high process interactions, oscillatory behavior of controlled variables is seen. The presence of disturbances also resulted in poor control-loop performance. Results also lend credence to the development of advanced control strategies in such scenarios and will be addressed in future work. Optimal control tuning parameters are obtained from a derivative-free optimization algorithm.

Investigation of compressibility and compactibility parameters of roller compacted Theophylline and its binary mixtures

Roller compaction is a dry granulation method which results in tablets with inferior tensile strength comparing to direct compaction. The effect of roller compaction on compressibility and compactibility of tablets prepared from Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate was investigated by measuring tensile strength of tablets as well as calculating compressibility and compactibility parameters by Leuenberger equation. The tablets under the same conditions were prepared by direct compaction and roller compaction. The binary mixtures of Theophylline anhydrate powder, Theophylline anhydrate fine powder, Theophylline monohydrate and microcrystalline cellulose were prepared in order to determine the optimal ratio of active material and excipients which delivers a sufficient mechanical strength of tablets. Tensile strength of MCC tablets and compactibility parameters calculated by Leuenberger equation after roller compaction was significantly decreased, while THAP, THAFP and THMO tablets showed only a minor reduction in compactibility and compressibility. Adding MCC to a mixture with Theophylline showed that the right choice and ratio of excipients can enable a sufficient mechanical strength of the tablets after roller compaction.

Properties of Nd-Fe-B Powder Explosively Compacted

Nd-Fe-B magnets are used in wide range of industrial applications. In this research we studied the possibility of producing bulk Nd-Fe-B magnetic compact by using the direct cylinder explosive compaction. After compaction the density of compact was measured by the Archimedes method. Highly dense compact (> 98% relative density) without cracks was obtained by this technique. A concentric hole was observed at center of some compacts. The magnetic properties of the compact are Br=7.95KG, iHc=10.5kOe, (BH)max= 14MOe, and these values are same as those before explosive compaction.

Roller compaction of different pseudopolymorphic forms of Theophylline: Effect on compressibility and tablet properties

The effect of roller compaction on disintegration time, dissolution rate and compressibility of tablets prepared from Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate was studied. In addition, the influence of adding microcrystalline cellulose, a commonly used excipient, in mixtures with these materials was investigated. Theophylline anhydrate powder was used as a model drug to investigate the influence of different compaction pressures on the tablet properties. Tablets with same porosity were prepared by direct compaction and by roller compaction/re-compaction. Compressibility was characterized by Heckel and modified Heckel equations. Due to the property of polymorphic materials to change their form during milling and compression, X-ray diffraction analysis of Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate powders and granules was carried out. After roller compaction the disintegration time and the dissolution rate of the tablets were significantly improved. Compressibility of Theophylline anhydrate powder and Theophylline anhydrate fine powder was decreased, while Theophylline monohydrate showed higher compressibility after roller compaction. Microcrystalline cellulose affected compressibility of Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate whereby the binary mixtures showed higher compressibility than the individual materials. X-ray diffraction analyses confirmed that there were no polymorphic/pseudopolymorphic changes after roller compaction.

Dissolution enhancement of drugs. part i: technologies and effect of carriers

For complete absorption and good bioavailability of orally administered drug, the drug must be dissolved in gastric fluids. Dissolution of drug is the rate-controlling step which determines the rate and degree of absorption. Drugs with slow dissolution rates generally show erratic and incomplete absorption leading to low bioavailability when administered orally. Since aqueous solubility and slow dissolution rate of BCS class II and class IV drugs is a major challenge in the drug development and delivery processes, improving aqueous solubility and slow dissolution of BCS Class II and Class IV drugs have been investigated extensively. Various techniques have been used in attempt to improve solubility and dissolution rates of poorly water soluble drugs which include solid dispersion, micronization, lipid based formulations, melt granulation, direct compaction, solvent evaporation, coprecipitation, adsorption, ordered mixing, liquisolid compacts, solvent deposition inclusion complexation and steam aided granulation. In these techniques carrier plays an important role in improving solubility and dissolution rate. Polymers, superdisintegrants, surfactants are extensively studied in recent years for dissolution enhancement in drugs. This part of this review discusses technological overview and effect of polymers, superdisintegrants and surfactants on dissolution enhancement of drugs while Part II [Int J Health Res, Sept 2009; 2(3)] describes the role and applications of cyclodextrins, carbohydrates, hydrotropes, polyglocolized glycerides, dendrimers, acids and miscellaneous carriers in enhancing dissolution of drugs. Keywords: Dissolution enhancement; aqueous solubility, water soluble carriers; BCS class II, excipients.

Sucrose esters with various hydrophilic–lipophilic properties: Novel controlled release agents for oral drug delivery matrix tablets prepared by direct compaction

Sucrose esters (SE) are esters of sucrose and fatty acids with various hydrophilic–lipophilic properties which have attracted interest from being used in pharmaceutical applications. This study aimed to gain insight into the use of SE as controlled release agents for direct compacted matrix tablets. The study focused on the effect of hydrophilic–lipophilic properties on tableting properties and drug release. Sucrose stearate with hydrophilic–lipophilic balance (HLB) values ranging from 0 to 16 was systematically tested. Tablet formulations contained SE, metoprolol tartrate as a highly soluble model drug and dibasic calcium phosphate dihydrate as a tablet formulation filler in the ratio 1:1:2. The compaction behaviour of matrix tablets was compared with the compacts of individual starting materials as reference. SE incorporation improved the plasticity, compressibility and lubricating property of powder mixtures. The hydrophilic–lipophilic properties of SE affected tableting properties, drug release rate and release mechanism. Increasing hydrophilicity corresponding to the increased monoesters in SE composition increased the relative porosity, elastic recovery and tensile strength of the tablets due to the increased hydrogen bonding between the monoesters. This also facilitated the swelling behaviour of SE, which sustained the drug release rate. A sustained release effect prevailed in tablets containing SE with HLB values of 3–16. The ability to improve the tableting properties as well as sustain the drug release rate of the highly soluble model drug via gelation of SE highlights SE as promising controlled release regulators for direct compacted matrix tablets comprising drugs with various solubilities according to the Biopharmaceutics Classification System.

Dry granulation and tableting of St. John’s wort dry extract: effect of roll compaction variables, excipients, and tableting speed on granule and tablet properties

The aim of this study was to investigate the effect of roll compaction variables, various excipients, and tableting speed on the granule and tablet properties made of St. John’s wort dry extract. Three key process variables, such as roll pressure, roll speed, and milling speed were selected and their influences were studied using a factorial design. Bulk and tap density, particle size, tablet hardness and the disintegration time of tablets were significantly affected by these variables. The tablet properties such as hardness and disintegration time were considerably modified using different excipients. The effect of tableting speed on the final tablet hardness was reduced or eliminated by the application of roll compaction compared to direct compaction in the case of plastic material. Roll compaction could be successfully applied as a dry granulation method for St. John’s wort dry extract and it is suggested as a novel choice also for other herbal dry extracts to improve their undesirable properties.