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Convert the pre-formulated Ibuprofen DC 85 into a ready-to-use product.

Evaluating the performance of external lubrication to convert the pre-formulated Ibuprofen DC 85 into a ready-to-use product

Introduction

Recently, Continuous Manufacturing is a heavily investigated and discussed trend in the pharmaceutical industry. Key in this approach: the constant supply of a tableting blend to a fast running, pilot or production scale rotary tablet press. This approach either requires an incessant incorporation of small quantities of a lubricant into a powder blend, or the employment of external lubrication, respectively. The latter approach provides various advantages, e.g. the minimization of lubricant content, which is an inherent risk for potential incompatibilities.
In this investigation, pre-formulated, directly compressible Ibuprofen was used as model formulation. The tableting characteristics of this product have been well described allowing to focus on the efficiency of lubrication.
The aim of this study was the evaluation of the performance of external lubrication in comparison to internal lubrication, as well as the scaling up from a lab scale to a production scale rotary press. Three lubricants (magnesium stearate, stearic acid, and sodium stearyl fumarate) were evaluated in this study.

 

Materials and methods

Ibuprofen DC 85 (BASF) is a pre-formulated (granulated), directly compressible material. It contains 85% Ibuprofen, a binder (microcrystalline cellulose), a disintegrant (croscarmellose sodium) and merely requires the customized incorporation of some standard lubricant (e.g. magnesium stearate) to be ready for tableting. Three lubricants were evaluated in this study: magnesium stearate (Baerlocher), stearic acid (Kolliwax® S Fine, BASF), and sodium stearyl fumarate (Pruv®, JRS). Due to differences in lubrication efficiency, the lubricants were added in different concentrations, requiring slightly different tablet masses to deliver 200 mg Ibuprofen (Table 1). The lubricant concentrations (internal lubrication) were determined in a pre-test, adjusting the concentration as such in lab scale, that the same ejection force was achieved for all lubricants. The first set of experiments were conducted on a lab scale rotary press (Prexima 80, IMA), equipped with a turret that can either be assembled with four Euro-D, or four Euro-B tools. The current study was performed with Euro-D punches.
The second set of experiments (up-scaling) were conducted in a production scale rotary press (Prexima 300, IMA), equipped with an Euro-D turret holding 27 stations.
On both machines the same external lubrication unit (Lums, IMA) was employed. All parameters were set with the aim to minimize the lubricant quantity provided. This optimization was done for both scales. Two different screw types were required to address the different volumes/flow characteristics of the different lubricants.
All tests were conducted by either using round-shaped, bi-convex Euro-D punches, diameter 9 mm, or oblong-shaped, bi-convex Euro-D punches, 17×7 mm.
The experiments were performed at 2 kN pre-compression force and four different main-compression forces (6, 8, 10 and 12 kN).
All tablets were characterized regarding weight, thickness, crushing strength, friability and lubricant concentration.

 

Lubricant

Content
lubricant (%)

Content Ibuprofen
DC 85 (%)
Tablet mass (mg)
(providing 200 Ibuprofen)
Magnesium stearate 0,5 99.5 236.7
Stearic acid 4.0 96.0 244.7
Sodium stearyl fumarate 3.5 96.5 243.3

Table 1: Tablet formulations and resulting tablet mass.

 

Result and discussion

Tableting parameters could be scaled-up from lab to production scale rotary press by keeping the feeding time of the dies constant. Exemplarily, parameters applied for internal and external lubrication with magnesium stearate at 10 kN main-compression force (Prexima 300), as reported in Table 2 and 3.

 

Lubrication Int Ext

External
Lubrication
parameters

Air pressure bar 0,5
Mixer speed rpm 20
Screw type mm 10
Quantity sprayed g/h 347
Screw speed rpm 80
Equipment
parameters
Feeder speed rpm 90
Pre-compression force kN 1.8
Compression force kN 10
Ejection force N 500 520
Turret speed rpm 37
Production speed tab/h 59940

Table 2: Prexima 300 internal vs external lubrication using magnesium stearate and 9 mm tablets.

 

Lubrication Int Ext

External
Lubrication
parameters

Air pressure bar 0,5
Mixer speed rpm 20
Screw type mm 10
Quantity sprayed g/h 420
Screw speed rpm 108
Equipment
parameters
Feeder speed rpm 90
Pre-compression force kN 1.6
Compression force kN 10.5
Ejection force N 450 500
Turret speed rpm 37
Production speed tab/h 59940

Table 3: Prexima 300 internal vs external lubrication using magnesium stearate and 17×7 mm tablets.

 

To compare both approaches: internal and external lubrication, the results of the tablet characterization and analysis are reported in Table 4.

 

Parameters 9 mm 117,7mm
Int Ext Int Ext
Weight Average 236.9 234.6 475.2 471.7
RSD% 0.98 0.89 0.90 1.00
Thickness Average 4.10 4.07 5.16 5.14
RSD% 0.54 0.35 0.27 0.30
Hardness Average 113.6 118.5 99.4 103.5
RSD% 14.9 14.4 14.5 13
Friability % < 1 %
Lubricant quantity % 0.54 0.15 0.55 0.05

Table 4: Tablets characterization and analysis for 9 and 17×7 mm.

 

Ejection force and lubricant concentration were the most interesting information provided by the experiments.
In sum, external lubrication led to similar ejection forces compared to internal lubrication, and consequently, allowed for a similar processing performance.
This provided the advantage to employ lower lubricant contents and to eliminate a blending process reducing efforts in product handling.
Furthermore, it is worth noticing that external lubrication generally provided the advantage of increasing average crushing strength comparing the same tableting process parameters.

 

Conclusion

The successful introduction of external lubrication converts the directly compressible Ibuprofen DC 85 into a ready-to-use product, allowing the continuous production of tablets without requiring an up-stream blending step.
External lubrication demonstrated the possibility to reduce lubricant quantity used maintaining same tablet press performance and the easy transfer of the process from pilot lab rotary press to industrial equipment.

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