A systematic investigation of external lubrication of mini-tablets on a rotary tablet press with focus on the tensile strength.

External lubrication is an alternative to internal lubrication and its related detrimental effects on properties of tablets like tensile strength (TS). However, to date there are hardly any systematic investigations on external lubrication of mini-tablets on rotary tablet presses. Aim of this study was the systematic investigation of the impact of parameters tableting pressure, tableting speed, dosing rate and air pressure on the TS of mini-tablets. Both studies, the Central Composite Design (CCD) with SMCC 90 and the subsequently executed D-optimal design with SMCC 50, exhibited that tableting pressure had the highest positive effect on TS. Tableting speed and dosing rate in the CCD presumably did not seem to influence the TS, air pressure represented a positive coefficient. An additional temporal factor seemed to impact the results, deduced from the negative effect of the experimental order on TS in the CCD and from the negative correlation along the execution order in the residual plots. Additional long runs support findings of a non-linear decrease of TS over time. An interplay between dosing rate level and performance of the dust extraction collector is assumed, making more magnesium stearate available in the tablet press and potentially causing gradual contamination of the powder over time.

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.

A novel approach of external lubrication in a rotary tablet press using electrostatics.

PURPOSE: In powder compaction on rotary tablet presses, the addition of a lubricant is normally mandatory. However, the typical internal lubrication method tends toward overlubrication, resulting in an alteration of the critical quality attributes of the product. In this study, the feasibility of an external lubrication system only using electrostatics for the application was investigated. METHODS: Three well-established lubricants were analyzed regarding their ability to accumulate and retain charge. In subsequent tableting experiments, the impact of different lubrication methods on critical quality attributes and process parameters was investigated. RESULTS: Due to material characteristics, the charge on magnesium stearate particles was most stable over time. The application of this lubricant on the punches via external lubrication with electrostatic forces resulted in a significant reduction of the ejection forces. Furthermore, the tensile strength of the tablets produced in these trials was significantly higher compared to tablets that were produced with internal lubrication. CONCLUSION: The external lubrication method with an electrostatically charged lubricant is a promising method for reducing both the necessary amount of lubricant and the impact of the lubricant on the product.

Residence time and mixing capacity of a rotary tablet press feed frame.

PURPOSE: Most rotary tablet presses contain a feed frame to provide a continuous powder flow and to feed powder into the dies. The wide residence time distribution (RTD) of these feed frames is problematic, because it negatively affects material traceability in continuous manufacturing. In a rotary tablet press, different machine settings influence the RTD, which is characterized by the mean and the width of the distribution. This study focused on the effects of the rotational speed of the feed frame paddles and the rotary tablet press throughput on the RTD. METHODS: An in-line UV/Vis measurement method was developed for determining the RTD in the feed frame. A model based on a plug flow and a continuous stirred tank reactor was adapted to model the experimentally determined RTDs. Finally, the mixing capacity of a feed frame was evaluated and correlated with a model parameter of the RTD. RESULTS: Overall, the developed UV/Vis measurement method was suitable and could be used to obtain process information regarding content uniformity in real time. The experimentally-determined RTDs were described well by fitting an inverse mixing and a transport time. In addition, a correlation between the location and the shape of measured RTDs and tablet press throughput was found. In contrast, rotational feed frame paddle speed did not affect the RTDs. Split-feeding experiments indicated the mixing capacity of the rotary tablet press feed frame. CONCLUSION: The inverse mixing time can be used as an initial indicator for estimating the mixing capacity.

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.

The Challenge of Die Filling in Rotary Presses-A Systematic Study of Material Properties and Process Parameters.

For the efficient and safe production of pharmaceutical tablets, a deep process understanding is of high importance. An essential process step during tableting is the die filling, as it is responsible for a consistent tablet weight and drug content. Furthermore, it affects the results of subsequent process steps, compaction and ejection, and thus critical quality attributes. This study focuses on understanding the influences of process parameters and material properties on die filling on a rotary tablet press. By the systematic variation in process parameters as the turret and paddle speeds as well as the fill and dosing depths, five formulations with differing properties are processed. Analysis of the normalized tablet weight, called filling yield, revealed different limitation mechanisms of the filling process, i.e., incomplete filled dies for certain parameter settings. Kinetic limitations occur due to a short residence time under the feed frame (filling time) caused by high turret speeds, which additionally induce high tablet weight variation coefficients. Characteristic maximum turret speeds at certain paddle speeds can be found to still achieve complete filling. At low turret speeds, densification of the powder inside the dies takes place, induced by two mechanisms: either high paddle speeds or high overfill ratios, or a combination of both. The challenge to fill the dies completely as well as avoid densification is dependent on material properties as the flowability. The mass discharge rate from an orifice was found to be in a linear correlation to the filling results of different formulations below complete filling.

Influence of the feed frame design on the powder behavior and the residence time distribution.

The feed frame system is one of the key elements of a rotary tablet press. The powder in the funnel flows through the feed frame system, which ensures a uniform powder flow to the die disc. The objective of the present study was to investigate the effect of different feed frame designs of a production-scale rotary tablet press on the residence time distribution of two microcrystalline cellulose blends, one of them serving as a tracer blend and the other serving as a filling material. With these powder blends, the effect of a reduction of the filling volume of a three chamber feed frame on the powder residence time was investigated. It was shown, that the volume reduction of the three chamber feed frame equipped with three modified large hub wheels led to a decrease of the powder residence time as well as to low intermixing of the powder particles. Furthermore, the residence time distribution within the three chamber feed frame was compared to that within a single chamber cone-shaped feed frame. Both feed frame designs had a similar filling volume but different powder paths through the respective feed frame chambers. The results showed that the single chamber feed frame led to a narrower distribution of the powder residence time and a lower intermixing than the three chamber feed frame. An interesting output of the study was that the variation of the feed frame design had a more pronounced effect on the powder behavior than the variation of the filling volume.

Comparison of two paddle wheel geometries within the filling chamber of a rotary tablet press feed frame with regard to the distribution behavior of a model powder and the influence on the resulting tablet mass.

Objective: The purpose of this study was to compare the influence of two different paddle wheel geometries on the distribution behavior of a model powder within the filling chamber of the modified feed frame of a rotary tablet press. Moreover, both paddle wheels were compared regarding their influence on the resulting tablet mass during the tableting process. Significance: Insights are provided regarding the influence of the paddle wheel geometry on the powder distribution to optimize the die filling process. Materials and methods: Avicel PH 102 served as model powder. A laser triangulator was used to scan the powder surface level within the feed frame and, combined with the determination of the angle position of the paddle wheel, an in-house written software was used to calculate the powder surface profiles and filling levels. Two experimental setups, one based on the filling chamber filled with a defined amount of powder (offline) and one using the filling chamber during tableting (inline) were applied. Results: Both paddle wheel geometries caused a significantly different distribution behavior of the powder within the filling chamber. The tablets obtained with the round rod filling wheel showed significantly higher tablet masses and significantly lower standard deviations. The inflow of powder into the filling chamber appeared to be improved with the round rod filling wheel. Conclusions: Under the applied experimental conditions, the round rod filling wheel showed obvious advantages compared to that with flat rods in terms of the uniformity of tablet masses and the extent of die filling.

The effect of different feed frame components on the powder behavior and the residence time distribution with regard to the continuous manufacturing of tablets.

The present study focused on the effect of different feed frame components on the residence time distribution of a three-chamber feed frame system (Fill-O-Matic). A production-scale rotary tablet press was used to simulate the industrial manufacture of tablets. The powder residence time distribution was used to characterize the powder behavior in the Fill-O-Matic. Therefore, two powder blends based on microcrystalline cellulose, one of them serving as a plain powder blend (MCC blend) and the other blend (tracer blend) spray colored with an indigo carmine solution by a fluid bed granulator, were used. With these powder blends, the effect of the reduction of the Fill-O-Matic volume with a perspex disc on the residence time distribution was compared with the standard configuration of the Fill-O-Matic. Furthermore, the filling wheel design with regard to the rod shape and different gap size configurations between the feed frame and the die disc were investigated. Interestingly, the reduction of the feed frame volume led to a remarkable decrease of the mean residence time and the mean centered variance. Moreover, the results of the filling wheel design showed that the rod shape of the filling wheels had a high influence on the intermixing of the powder particles in the filling chamber, whereas the corresponding tablet weights and their relative standard deviation were not affected. The gap size between the feed frame and the die disc had low influence on the residence time distribution but an effect on the tablet weights and their standard deviation.

Analysis of the powder behavior and the residence time distribution within a production scale rotary tablet press.

This study focuses on the behavior of powder particles in a rotary tablet press with special focus on the feed frame system. To obtain a better knowledge of the continuous manufacturing of tablets, the experimental setup was carried out with a production scale rotary tablet press. The behavior of the powder particles at different flow rates through the tablet press, residual moisture contents, particle sizes, and amounts of tracer was investigated. The residence time distribution was evaluated using the tracer indigo carmine, which was sprayed onto microcrystalline cellulose particle as solution with fluidized bed spray granulator to obtain a tracer blend. The residence time distribution was increased by increasing the amount of tracer blend, and a transition from a plain MCC blend to the tracer blend with regard to continuous manufacturing was shown. Furthermore, it was found that an increase in the flow rates of the powder particles through the tablet press led to a decrease of the residence time distribution (Et). The variation of the flow rate had no influence on the mechanically applied strain at high throughputs, which was confirmed by a constant number of paddle passes (Npp). At the lowest flow rate, the Npp appears to be higher than the constant Npp values at higher flow rates. The residual moisture content did not shown any significant influence on the residence time distribution. The examination of the effect of different tracer blend particle sizes led to an interesting result: It was shown that the particle size segregation only had a low influence on Et. However, a comparably higher influence of the particle size segregation on the particle distribution in the produced tablets was demonstrated. Large particles were deposited at the top of the tablet surface whereas small particles were deposited at their bottom.

A novel method for determination of the filling level in the feed frame of a rotary tablet press.

AIM: The aim of this study was to investigate whether the filling level within the feed frame of a rotary tablet press can be quantified by laser triangulation combined with the angle recognition of one paddle wheel via rotary encoder. SIGNIFICANCE: Rotary tablet press feed frames are supposed to assure a uniform die filling and, thus, to guarantee the weight and content uniformity of the resulting tablets. Therefore, a constant bulk availability and flow within the feed frame is crucial and has to be ensured by the feed frame design and the operating conditions. So far, there is no instrument available to monitor the bulk filling level or the bulk distribution within feed frames. METHODS: Calcium phosphate dihydrate was used as model powder. The powder surface level was determined via laser triangulation and the angle position of the paddle wheel was monitored via incremental rotary encoder. The data of both parameters was acquired synchronously and evaluated by in-house written software. RESULTS: Different powder masses led to significantly different filling level signals. The experiments showed a high reproducibility of the determined filling levels. Furthermore, an influence of the rotational speed on the powder distribution was observed. CONCLUSIONS: The developed instrument may be used for quantification of the volumetric filling level within rotary tablet press feed frames. It may either be used to better understand the powder behavior within feed frames or for improvement of the die filling process by implementing the device into a feedback loop.

Influence of extended dwell time during pre- and main compression on the properties of ibuprofen tablets.

The low melting point, poor flow, physico-mechanical properties (particle size distribution, shape, particle surface roughness) and deformation mechanism of ibuprofen in combination with its high dose in tablets all contribute to the problems observed during the compaction of ibuprofen-based formulations. Since ibuprofen is plastically and elastically deforming, the rate of compaction plays an important role in both the final tablet properties and the risk of capping, laminating and sticking to the punches. While the compaction rate in most tableting machines is only determined by the tableting speed, the high speed rotary tableting machine used in this research project (MODUL™ P, GEA Process Engineering, Halle, Belgium) can adjust and control the dwell time independently from the tableting speed, using an air compensator which allows displacement of the upper (pre-) compression roller. The effect of this machine design on process parameters and tablet properties was investigated. Granules containing 80% ibuprofen were compressed into tablets at 250, 500 and 1000 tablets per minute via double compression (pre- and main compression) with or without extended dwell time. Prior to tableting, granule properties were determined. Process parameters and tablet properties were analyzed using Multivariate Data Analysis. Principal Component Analysis provided an overview of the main phenomena determining the tableting process and Partial Least Squares Analysis unveiled the main variables contributing to the observed differences in the tablet properties.

Development and validation of an in-line NIR spectroscopic method for continuous blend potency determination in the feed frame of a tablet press.

A calibration model for in-line API quantification based on near infrared (NIR) spectra collection during tableting in the tablet press feed frame was developed and validated. First, the measurement set-up was optimised and the effect of filling degree of the feed frame on the NIR spectra was investigated. Secondly, a predictive API quantification model was developed and validated by calculating the accuracy profile based on the analysis results of validation experiments. Furthermore, based on the data of the accuracy profile, the measurement uncertainty was determined. Finally, the robustness of the API quantification model was evaluated. An NIR probe (SentroPAT FO) was implemented into the feed frame of a rotary tablet press (Modul™ P) to monitor physical mixtures of a model API (sodium saccharine) and excipients with two different API target concentrations: 5 and 20% (w/w). Cutting notches into the paddle wheel fingers did avoid disturbances of the NIR signal caused by the rotating paddle wheel fingers and hence allowed better and more complete feed frame monitoring. The effect of the design of the notched paddle wheel fingers was also investigated and elucidated that straight paddle wheel fingers did cause less variation in NIR signal compared to curved paddle wheel fingers. The filling degree of the feed frame was reflected in the raw NIR spectra. Several different calibration models for the prediction of the API content were developed, based on the use of single spectra or averaged spectra, and using partial least squares (PLS) regression or ratio models. These predictive models were then evaluated and validated by processing physical mixtures with different API concentrations not used in the calibration models (validation set). The ß-expectation tolerance intervals were calculated for each model and for each of the validated API concentration levels (ß was set at 95%). PLS models showed the best predictive performance. For each examined saccharine concentration range (i.e., between 4.5 and 6.5% and between 15 and 25%), at least 95% of future measurements will not deviate more than 15% from the true value.

In-line monitoring of compaction properties on a rotary tablet press during tablet manufacturing of hot-melt extruded amorphous solid dispersions.

As the number of applications for polymers in pharmaceutical development is increasing, there is need for fundamental understanding on how such compounds behave during tableting. This research is focussed on the tableting behaviour of amorphous polymers, their solid dispersions and the impact of hot-melt extrusion on the compaction properties of these materials. Soluplus, Kollidon VA 64 and Eudragit EPO were selected as amorphous polymers since these are widely studied carriers for solid dispersions, while Celecoxib was chosen as BCS class II model drug. Neat polymers and physical mixtures (up to 35% drug load) were processed by hot-melt extrusion (HME), milled and sieved to obtain powders with comparable particle sizes as the neat polymer. A novel approach was used for in-line analysis of the compaction properties on a rotary tablet press (Modul P, GEA) using complementary sensors and software (CDAAS, GEA). By combining 'in-die' and 'out-of-die' techniques, it was possible to investigate in a comprehensive way the impact of HME on the tableting behaviour of amorphous polymers and their formulations. The formation of stable glassy solutions altered the formulations towards more fragmentary behaviour under compression which was beneficial for the tabletability. Principal component analysis (PCA) was applied to summarize the behaviour during compaction of the formulations, enabling the selection of Soluplus and Kollidon VA 64 as the most favourable polymers for compaction of glassy solutions.