Successful Formulation Window for the design of pharmaceutical tablets with required mechanical properties.

Pharmaceutical tablet formulations combine the active ingredient with processing aids and functional components. This paper evaluates compressibility based predictive models for binary and ternary formulations to establish an acceptable range of tablet compression parameters that satisfy prescribed quality target criteria for tablets including minimum tablet strength and processing constraints such as maximum ejection stress and maximum compaction pressure. The concept of Successful Formulation Window (SFW) is introduced. A methodology is proposed to determine the SFW for a given formulation based on compaction simulator data collected for individual formulation components. The methodology is validated for binary and ternary mixtures and lubricated formulations. The SFW analysis was developed to support tablet formulation design to meet mechanical requirements.

Challenges in the transfer and scale-up of mini-tableting: Case study with losartan potassium.

Mini-tablets (MTs) with losartan potassium were developed to treat the rare disease Epidermolysis Bullosa. The focus was placed on transfer and scale-up of a direct compressible formulation from the compaction simulator STYL'One Evo (CS) to the rotary tablet press Korsch XM 12 (RP). Transfer of tabletability and compactibility profiles from CS to RP did not show good agreement, e.g. at a tableting pressure of 125 MPa mean tensile strengths (TS) of 4 MPa on CS and 1-1.5 MPa on RP were reached. These results highlight the impact of the feed frame on final product qualities depending on process and material factors. In the scale-up studies the critical quality attributes (CQAs) mass variation, content uniformity, TS and disintegration time were investigated. After an appropriate run-up time, most CQAs reached a plateau, after reaching a balance between influx, efflux and distribution of lubricant in the feed frame. TS values of 1-2 MPa, disintegration times of max. 50 s, mass variation of 0.9-2.2 % (CV) and acceptance values below 15.0 were reached depending on chosen process parameters.

Upscaling of external lubrication from a compaction simulator to a rotary tablet press.

External lubrication is a highly valuable alternative lubrication method as it minimizes the negative impact on tablet properties encountered when using internal lubrication. In current study, experiments were performed with automated external lubrication systems implemented in a compaction simulator and rotary tablet press using three lubricants (magnesium stearate (MgSt), sodium stearyl fumarate (SSF) and glyceryl dibehenate (DBHG)). The effect of process parameters related to the tableting process (main compaction pressure and tableting speed) and external lubrication systems (spraying time, atomizing pressure, dust extraction system and lubricant feed rate) on the responses was studied for a placebo formulation which is non-processable without lubrication. Low and comparable ejection forces were recorded for all lubricants on both tablet presses. No negative effect on tensile strength was observed for process parameters of both external lubrication systems, irrespective of lubricant type. Disintegration times were slightly higher for SSF compared to MgSt and DBHG for the tablets produced on the rotary tablet press, linked to higher lubricant concentrations on the tablets for SSF, while disintegration times were similar for all lubricant types on the compaction simulator. The potential of external lubrication for implementation on production scale tableting equipment and during scale-up was demonstrated for multiple lubricants.

Screening of lubricants towards their applicability for external lubrication.

Internal lubrication is associated with decreasing tensile strength and prolonged disintegration. These effects can be minimized using external lubrication. In current study, six lubricants (magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl dibehenate, poloxamer 188 and sucrose monopalmitate) were processed with an external lubrication system implemented in a compaction simulator. The effect of process parameters related to the tableting process (main compaction pressure and tableting speed) and external lubrication system (spraying time, atomizing pressure and dust extraction system) on the responses was studied for a placebo formulation (80% mannitol - 20% microcrystalline cellulose). Internally lubricated blends (0.75 - 4%) were processed as reference. All lubricants proved successful in reducing ejection forces through external lubrication while yielding substantially lower lubricant concentrations compared to internal lubrication. No negative effect of external lubrication on tensile strength and disintegration time was observed, irrespective of lubricant type. Similar tensile strengths and disintegration times were measured for the different lubricants. This was in contrast to internal lubrication where a decrease in tensile strength and prolonged disintegration was generally observed. Additionally, the lubricant types affected tensile strength and disintegration differently. This study demonstrates the versatility of external lubrication as an alternative lubrication method for production of pharmaceutical tablets.

Impact of alternative lubricants on process and tablet quality for direct compression.

Internal lubrication with magnesium stearate (MgSt) is associated with a reduced tensile strength and prolonged disintegration and dissolution times. In the current study, alternative lubricants to MgSt were compared with regard to lubrication efficacy and their impact on tablet properties. The lubricants were combined in different concentrations (0.5-5% w/w) with three fillers (lactose, mannitol and microcrystalline cellulose (MCC)). The high lubrication efficiency of MgSt was associated with the highest reduction of tensile strength. The micronized stearic acid (SA) grades proved good alternatives as they showed a good lubrication efficiency in combination with a limited negative effect on tensile strength. The hydrophobic lubricants (e.g., MgSt and SA) did not prolong disintegration. In contrast, delayed disintegration was observed for sucrose monopalmitate combined with all three fillers and for several other hydrophilic lubricants (sodium lauryl sulfate, poloxamers 188 and P407) combined with MCC. These unexpected findings were explained by the competition-for-water hypothesis. The potential of alternative lubricants to MgSt was demonstrated in this study. Nevertheless, the impact of lubricant addition on process and tablet quality depended on lubricant (type and concentration) and formulation (lubrication need, deformation mechanism and disintegration behavior) properties. Therefore, lubricant selection should be carefully considered in formulation development.

Effect of feed frame on lubricant sensitivity during upscaling from a compaction simulator to a rotary tablet press.

Internal lubrication can be associated with reduced tabletability. Deformation mechanism, lubricant type, lubricant blending time and paddle speed (PS) of the forced feeder are known to be influenceable factors. This study investigated the effect of lubricant blending time and PS of forced feeders on the tensile strength of lubricated microcrystalline cellulose (MCC) and lactose tablets. Magnesium stearate (MgSt), sodium stearyl fumarate (SSF) and stearic acid (SA) were used as lubricants. Tablets were produced on a compaction simulator and a rotary tablet press to investigate lubricant sensitivity during upscaling. Lubricant sensitivity was found higher for MCC compared to lactose which was attributed to the higher plasticity of MCC. The reduction in tensile strength upon lubricant addition followed the order: MgSt > SSF > SA; which could be linked to particle size, specific surface area and particle shape of the lubricants. Although differences in tensile strength were observed between the lubricant types, comparable ejection forces were obtained. The impact of PS on tensile strength was higher compared to lubricant blending time for both tableting machines. A good correlation of tensile strength and lubricant sensitivity between the compaction simulator and rotary tablet press was observed based on the calculation of paddle passes (NPP).

Effect of binder type and lubrication method on the binder efficacy for direct compression.

The effect of different binders for direct compression on tablet critical quality attributes was investigated. Dicalcium phosphate, lactose and microcrystalline cellulose were used as fillers and combined with ten binders (10, 20 and 30% w/w). Binder properties were linked to tensile strength via partial least square analysis. Tablets containing VA64F and PH105 exhibited the highest tensile strength which was linked to their compaction properties (specific work of compaction, elasticity, cohesion index) and particle size. In contrast, S1500 and E15 exhibited the lowest tensile strength of all binders. Lubrication method influenced the tensile strength as lubricant sensitivity was observed to some extent for all binders. Tensile strength was significantly higher applying external compared to internal lubrication. Fast disintegration was observed for MCC (PH105 and PH200) and starch (S1500 and NMSt) grades, whereas HPC (KEXF and KEF) and E15 resulted in delayed disintegration. Wettability measurements, via determination of contact angle, correlated well with the disintegration behaviour of the binders and can therefore be used as an indicative measurement for tablet disintegration. This study revealed the effect of binder properties, filler type and lubrication method on tablet critical quality attributes. In addition, the potential of dry binder addition for direct compression was highlighted.

Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Transfer and scale-up of the manufacturing of orodispersible mini-tablets from a compaction simulator to an industrial rotary tablet press.

Orodispersible mini-tablets (ODMTs) are a promising dosage form for the pediatric use showing increasing interest from pharmaceutical industry. However, a scale-up process for ODMTs from a compaction simulator to a rotary tablet press following FDA and EMA guidelines has not been performed and investigated yet. Isomalt (galenIQ™721) and Ludiflash® both excipients with proven suitability for the development of ODMTs have been investigated in transfer and scale-up from a compaction simulator to a rotary tablet press. ODMTs with isomalt and Ludiflash® were produced on the rotary tablet press monitoring the product temperature over time and assessing the properties of the residual powder in the feed shoe. Critical quality attributes like tensile strength, mass and disintegration time were evaluated. The transfer from compaction simulator to rotary tablet press succeeded as for both excipients similar disintegration times, tabletability and compactibility profiles were obtained. However, during scale-up, disintegration time significantly increases over time for both excipients. Monitoring of the product temperature revealed that with increasing batch size the product temperature increases as well having a significant impact on disintegration time. The properties of ODMTs produced with the residual powder are comparable in tabletability and disintegration time compared with ODMTs produced from fresh powder.

Evaluation of tableting performance of Poly (ethylene oxide) in abuse-deterrent formulations using compaction simulation studies.

Poly (ethylene oxide) (PEO) has been widely used in abuse-deterrent formulations (ADFs) to increase tablet hardness. Previous studies have shown that formulation variables such as processing conditions and particle size of PEO can affect ADF performance in drug extraction efficiency. This work aims to understand the effect of PEO grades and sources on the compaction characteristics of model ADFs. PEOs from Dow Chemical and Sumitomo Chemical with different molecular weights were examined using a Styl'One compaction simulator at slow, medium, and fast tableting speeds. Particle-size distribution, thermal behavior, tabletability, compressibility using the Heckel model, compactibility, and elastic recovery were determined and compared between the neat PEOs and model ADFs. Multivariate linear regression was performed to understand the effect of compression conditions and PEO grades and sources. Our results show that neat PEOs with high molecular weight exhibit high tabletability. The source of neat PEOs contributes to the difference in tabletability, out-die compressibility, compactibility, and elastic recovery. However, the influence of the PEO source on tabletability and compactibility decreases after adding the model drug. In our model ADFs, tablets using PEOs with high molecular weight have high crushing strength, and tablets using PEOs from Dow Chemical display low elastic recovery.

Tableting of mini-tablets in comparison with conventionally sized tablets: A comparison of tableting properties and tablet dimensions.

Mini-tablets are solid dosage forms with increasing interest for pharmaceutical industry due to clinical and biopharmaceutical benefits. But technological aspects on mini-tableting are not fully investigated. Therefore, the impact of punch size and tableting pressure for industrially relevant excipients like microcrystalline cellulose, lactose, isomalt and Ludiflash® are investigated using 8 and 11.28 mm punches for conventionally sized tablets and 1,2 and 3 mm punches for mini-tablets. For evaluation of the effect of tablet size on deformation behaviour and mechanical properties, compressibility, compactibility and tabletability plots are created and evaluated. Deformation behaviour is analysed by In-Die Heckel plot and modified Weibull function. Further, specific plastic energy (SPE) profiles are generated out of force-displacement plots. The effect of the adjustment of the aspect ratio towards 1 as in conventionally sized tablets on deformation behaviour and tabletability is analysed. The effect of tablet size on deformation behaviour mainly showed lower yield pressures for conventionally sized tablets, whereas comparable SPEs were obtained with all tablet sizes. Furthermore, mini-tablets indicate better compactibility, as (depending on the excipient) higher tensile strengths were obtained at lower solid fractions. However, no superior tabletability properties are obtained for mini-tablets compared to conventionally sized tablets.

Evaluation of Lactose-Based Direct Tableting Agents' Compressibility Behavior Using a Compaction Simulator.

OBJECTIVES: A compaction simulator (CS) is a single-punch instrument that records data during the powder compaction process. The aim of the study was to determine the behavior of lactose-based direct tableting agents (DTAs) by CS. The data recorded were used to evaluate the flowability and compressibility of powders. The focus of the study was on comparing the compressibility of StarLac® [alpha lactose monohydrate (85%) and white maize starch (15%)] and FlowLac®100 (spray-dried alpha lactose monohydrate) in order to make tablets containing poorly flowable paracetamol. MATERIALS AND METHODS: Two lactose-based DTAs were used. Physical characterization of these powders was done by measuring bulk, tapped, and true densities alongside scanning electron microscopy analysis. Flow properties were then calculated by the angle of repose, Hausner ratio, and Carr's compressibility index. Force, in-die thickness, and punch displacement data produced by the CS were captured during in-die compression. Compressibility was calculated using the Heckel equation. RESULTS: The physical characterization test results showed no significant difference between the two DTAs. Hardness results revealed that tablet formulations containing FlowLac® had higher sensitivity to an increase in compression force in comparison with StarLac®. From the Heckel plots generated by the CS during the compression cycle, yield pressure (Py) values were calculated for FlowLac®100 and StarLac®. The Heckel parameter (Py) for FlowLac®100 and StarLac® was calculated as 87.5 MPa and 85.2 MPa, respectively, during the compaction cycle at 5 kN. These data indicated that both powders are compressible and have brittle behavior. CONCLUSION: StarLac® is less brittle, which was shown by its lower sensitivity to compression force. Py values obtained from the Heckel equation described the plasticity of particles, which gives distinct information on the compressibility of both DTAs in real time during the compaction cycle.

Investigation of the Compressibility Characteristics of Paracetamol using "Compaction Simulator".

OBJECTIVES: This study was performed to understand the behavior of poorly compressible paracetamol powder using a compaction simulator (CS), equipment that records data during the compaction process. The aim was to investigate the compressibility of paracetamol tablets using a dry granulation (slugging) process, with different formulation compositions. MATERIALS AND METHODS: Formulations were prepared to observe the effect on compressibility with two different lactose-based fillers, Flowlac®100 and Granulac®70, and a binder, Kollidon® K90. In each combination, a total of four formulations were prepared with paracetamol to filler ratios of 1:1 and 0.8:1. Tablets were produced by single punch (11.28 mm) CS at six different pressures (152, 210, 263, 316, 400, and 452 MPa). During compression, upper punch displacement and force data were produced by the CS equipment. The compressed tablets were tested for hardness, thickness, and weight variation and compared with each other. RESULTS: All formulations reached maximum tensile strength at compaction pressures between 263 and 316 MPa. In the formulations without binder, those containing Granulac®70 had higher tensile strength than those containing Flowlac®100 at both filler ratios. The results obtained indicated that the addition of binder to the formulations (F-45-1, F-45-2, F-50-3, and F-50-4) improved the compressibility of paracetamol. Formulation F-45-2, containing Flowlac®100 and binder, showed better compressibility at 2.9 MPa tensile strength. Data from the CS were used to compare Young's modulus and work of compaction on selected formulations (F-45-1 and F-45-2). CONCLUSION: The proposed lactose-based filler, Flowlac®100, with low pressure can be successfully applied for improving the compressibility of paracetamol. An optimum formulation can be designed with smaller amounts of materials using a compaction simulator.

Evaluation of an external lubrication system implemented in a compaction simulator.

The internal blending of magnesium stearate is often associated with decreasing tensile strengths and longer disintegration and dissolution times. Therefore, external lubrication has gained interest in the pharmaceutical industry as these negative effects could be minimized using this method. In this study, an external lubrication system implemented in a compaction simulator was investigated. The influence of 2 process parameters related to the external lubrication system, spraying time and atomizing pressure, on the responses was studied using 4 common fillers and 2 model drugs. While the parameters of the external lubrication system had a significant impact on the ejection forces, no negative effect was observed on the tensile strength and disintegration time as similar values were obtained compared to non-lubricated experiments. Moreover, equal or lower ejection forces were obtained for external lubrication using a lower concentration of magnesium stearate compared to internal lubrication, where a decrease in tensile strength and prolonged disintegration was noticed for most formulations. The observed results could be correlated to the wall friction angle, compaction properties and tablet brittleness index of the raw materials and blends. This study showed the potential of external lubrication as an alternative lubrication method for lubricant-sensitive formulations.

Investigation of critical factors affecting mechanical characteristics of press-coated tablets using a compaction simulator.

Press-coated tablets have become an indispensable dosage form in chronotherapeutic drug delivery. Drug release from press-coated tablets has been extensively studied, yet there is little knowledge about their mechanical characteristics. This study aimed to systematically investigate the effects of critical factors on the structure, layer adhesion, and delamination tendency of the tablets. Material elasticity was found to play an important role in determining tablet structure in that excessive elastic mismatch between core and shell materials caused tablet defects during decompression and ejection. Unlike bilayer tablets, the overall strength of press-coated tablets was more affected by binding capacity of coating materials than by the core properties. Shell/core ratio was another factor affecting tablet integrity against external stresses. To mitigate the risk of delamination, poor layer adhesion must be compensated by increasing the coating thickness or enhanced by optimizing the formulation and process (e.g., core plasticity/brittleness, initial core solid fraction, and compression speed). X-ray micro-computed tomography revealed the presence of a shell-core gap and inhomogeneous density distribution within the tablet where the side coat appeared as the least dense and weakest region. These findings will enable the improvement of tablet quality and widen the application of press coating in industrial manufacturing.

Systematic approach to elucidate compaction behavior of acyclovir using a compaction simulator.

In this research, various approaches were attempted with a compaction simulator to investigate the unidentified compaction behavior of acyclovir, a model compound. Various indicators for the compaction behavior of acyclovir were obtained and compared with those of three commonly used excipients with relatively well-known compaction behavior. From two frequently used powder compaction models, the Heckel and Walker models, curvature of plot, yield stress, D0, SRS value, and W value were acquired. In addition, compression and elastic energies were obtained during the loading and unloading phases, respectively. The ratio of the two energies was also utilized. To characterize the mechanical properties of materials during bond formation, the radial tensile strength of powder compacts was measured. For all evaluations, the effects of compaction rate and lubrication were studied simultaneously. We found that primary particles of acyclovir were compacted mainly by plastic flow, with high viscoelasticity and low particle interactions. Their bond formation was highly sensitive to strain rate and lubrication. This study showed the potential application of a compaction simulator to elucidate the compaction behavior of a material of interest.

Influence of the unloading conditions on capping and lamination: Study on a compaction simulator.

Capping and lamination are classical industrial issues that can be challenging during the scale up of solid dosage forms. Previous publications showed that changing the unloading conditions (triaxial decompression, loaded ejection) made it possible to mitigate capping. In the present study, a systematic study of the effect of the unloading conditions on capping and lamination was performed using a compaction simulator. One model formulation for capping and one for lamination were studied. When symmetrical decompression was performed, as on a rotary press, capping (on both side of the tablet) and lamination were obtained. Asymmetrical unloading (fixed lower punch during unloading) made it possible to suppress lamination and to limit capping to the upper face of the tablet. This unloading condition is similar to the unloading on an eccentric press with a stationary lower punch. Finally, loaded ejection (small pressure on both sides until the end of ejection) made it possible to eliminate both capping and lamination. By changing the unloading condition, it is possible to obtain defect free tablets even for formulations with a high capping or lamination tendency. Moreover, experiments performed on an eccentric press showed results similar to those obtained for asymmetrical unloading on a compaction simulator. Anticipation of tablets defects during the development on eccentric presses might thus be complicated especially in the case of lamination.

Use of roller compaction and fines recycling process in the preparation of erlotinib hydrochloride tablets.

This study focuses on improving the manufacturing process for a generic immediate-release tablet containing erlotinib hydrochloride by adding a fines recycling process during roller compaction. Due to the large fraction of small-sized API particles, the starting powder mixture was inconsistently fed into the roller compactor. Consequently, poorly flowing granules with a high ratio of fines were produced. A fines recycling step was, therefore, added to the existing roller compaction process to minimize the risks caused by the poor granule flow. A laboratory scale roller compactor and a tablet simulator were used to prepare granules at various process conditions. The effect of dry granulation parameters on size distribution, API distribution, powder flow, compaction properties, and dissolution profile was evaluated. The granule batch after fines recycling had markedly improved size distribution and flowability while maintaining acceptable tablet tensile strength and rapid dissolution profile. The application of the fines recycling process at commercial scale resulted in reliable dissolution performance and batch-to-batch consistency, which were further confirmed by bioequivalence to the reference product. Understanding how granule properties are impacted by the fines recycling process may enable fine-tuning of the dry granulation process for optimal product quality.

Co-Processed Excipients for Dispersible Tablets-Part 1: Manufacturability.

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr's index ˂ 20), excellent tabletability (tensile strength > 3.0 MPa at 0.85 solid fraction), very low friability (< 1% after 15 min), rapid disintegration times (27-49 s) and produced dispersions of ideal fineness (< 250 µm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients.

Understanding the Impact of Chemical Variability and Calibration Algorithms on Prediction of Solid Fraction of Roller Compacted Ribbons Using Near-Infrared (NIR) Spectroscopy.

The study is aimed at developing a near-infrared (NIR) method for predicting solid fraction (SF) of dry granulated ribbons manufactured with formulation variability. The study investigated the impact of unmodeled chemical variability and regression approaches on method performance. The study utilized an excipient-only formulation system. Calibration compacts were created with chemical and processing variability; followed by collection of NIR spectra. Partial least squares (PLS) and spectral slope algorithms were utilized to model compact SF. Later, the models were deployed to predict SF of test ribbons and compacts containing an API at various concentrations. The risk associated with unmodeled chemical variation manifested itself through generation of new peaks and decreased baseline absorbance in the NIR spectra. The spectral slope was able to better manage this risk, as demonstrated by relatively higher robustness to the increasing load of the active pharmaceutical ingredient (API). The reduced robustness of the PLS approach was attributed to the impact of chemical variability on both spectral baseline and peak absorbance. A prediction error of approximately 5% was observed at 10% drug load using the spectral slope approach. An understanding of the risk associated with unmodeled variability will enable NIR method development as an API sparing technique for low-dose product development.