3 1.2 1, John F. Gamble2, Mike Tobyn2, Phillip Robbins1, Richard ... · Jason Dawes1, John F. Gamble2, Mike Tobyn2, Phillip Robbins1, Richard Greenwood1 1School of Chemical Engineering,

Jason Dawes1, John F. Gamble2, Mike Tobyn2, Phillip Robbins1, Richard Greenwood1

1School of Chemical Engineering, University of Birmingham, Edgbaston B15 2TT 2Materials Science, DPST, Bristol-Myers Squibb R&D, Moreton, Merseyside, CH46 1QW, UK

1. IntroductionThe deleterious effects of magnesium stearate on the properties of roller compacted ribbons and hence tablets are well documented [1]. The extent of these effects can be

limited through the implementation of a two-step mixing operation [2], in which a formulation is blended to hom*ogeneity prior to the addition of magnesium stearate. The

secondary mixing step including magnesium stearate is limited, such that it is non-hom*ogenously distributed within the formulation. Consequently the formulation is sensitive to

further mixing that can occur during further downstream processes [3], such as within the feeding system of a roller compactor. The influence of mixing within the feed system is

likely to alter the „lubricity‟ of the formulation and hence have an unpredictable affect on the tablet properties.

The aim of the current study is to characterise the role of magnesium stearate during roller compaction and hence to determine the actual need

for its inclusion.

3. MethodsFormulation: Avicel Ph102, lactose anhydrous, croscarmellose sodium, magnesiumstearate

Mixing: Step 1 – formulation tumble blended for 10 minutes (15 rpm) (withoutmagnesium stearate), Step 2 – Further blended with magnesium stearate for either 7minutes (15 rpm) or 60 minutes (15 rpm)

Lubricant sensitivity – tensile strength of

tablets compacted from just mixed formulation (7

minutes mixing) was compared to the tensile

strength of formulation which had transitioned

through the roller compactor feeding system

Roller compaction – the initial experiment was

designed to produce unlubricated ribbons of

varying porosity by altering the process

parameters. This was achieved by finding the

minimum pressure required to maintain a roll gap

of 2.2 mm at a range of screw speed. Roll speed

was kept constant at 3.4 rpm. The process

parameters were repeated for lubricated ribbons

2. Roller Compactor Particle size enlargement step

Powder force fed via the action of ascrew feeder

Compaction zone split into threeregions

Slip region – low pressure,densification largely due toparticle rearrangement

Nip region – powder „grips at theroll surface, high pressure, ribboncompact formed

Release region – ribbon releasefrom roller surface, elasticrecovery

Formulation sticking to roll surface is acommon problem [4]

Pressure transducers located acrossroll width measure pressure profiles

Uneven pressure distribution [5]

Nip

Angle

Release

AngleFormulation on rolls

Higher density at centre

Auger Speed

(rpm)

Hydraulic

Pressure (bar)

25 45

30 60

32 80

34 110

7. Conclusion

Use of a two step mixing operation, in which magnesium stearate is non-

hom*ogenously distributed throughout a blend renders the formulation sensitive to any

further uncontrolled mixing within the feeding system of a roller compactor

Addition of magnesium stearate to a placebo formulation prior to roller compaction

has an unexpected advantage of improving mass throughput and increasing nip

angle, possibly due to the densification kinetics in the slip region

This increase in mass throughput with increasing magnesium stearate plateaus

above 0.25% w/w, additional magnesium stearate provides no further benefits

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0 20 40 60 80 100

lk D

sit

y (

g/c

m3)

Normal Pressure (MPa)

0.01% (w/w)

0.1% (w/w)

0.25% (w/w)

0.5% (w/w)

1.0% (w/w)

6. Instrumented Rollers

The nip angle was found to increase with increasing magnesium stearate at low levels

(< 0.25% w/w). Further magnesium stearate addition lead to a slight reduction in nip

angle. This observation contradicts previous investigations which suggest that nip

angle decreases with increasing magnesium stearate concentration [6]. This

disagreement is attributed to the configuration of the roller compactor used. The roller

compactor used utilizes a horizontal force feeding system. Presence of magnesium

stearate reduces the pressure required to increase the bulk density of the powder bed.

This results in a powder bed with higher density in the slip region and hence increases

the pressure applied by the powder bed to the rollers forcing the roll gap to open wider

allowing more powder to pass through the system.

1.000.750.500.250.00

MgSt Concentration (% w/w)

Nip

gle

)

110

4. Lubricant Sensitivity

Tablet strength of the uncompacted

formulation (previously tumble blended

for 7 minutes) collected from the

region before the rollers was

compared to that of just blended

formulation. Mixing that occurs within

the feeding system has had a

significant affect on the tablet tensile

strength.

4.0

4.5

5.0

5.5

6.0

6.5

0 20 40 60

ble

t Te

ile

Str

gth

)

Feed Auger Rotation Speed (rpm)

5. Mass throughput

Addition of magnesium stearate has lead to a significant increase in mass

throughput. Increase in mass throughput was unexpected since addition of

magnesium stearate to the formulation would promote slip between the roll surface

and powder bed and hence theoretically reduce the mass of powder drawn through

the rollers. The extent of mass throughput improvement is largest at magnesium

stearate levels < 0.25% (w/w). Subsequent addition of magnesium stearate shows

little further improvement in the mass throughput. A corresponding increase in roll

gap was observed with increasing mass throughput. Since in-gap ribbon porosity

was found to be constant (for a given set of parameters) at each magnesium

stearate level, this increase in roll gap is directly related to the increase in mass

throughput.

1.000.750.500.250.00

400

350

300

250

200

150

1.000.750.500.250.00

MgSt Concentration (% w/w)

rou

t (g

/min

) 60

Screw Speed (rpm)

1.000.750.500.250.00

50403020100

1.000.750.500.250.00

5040302010

MgSt Concentration (% w/w)

cre

e (

32 34

Mixing Time (mins)

8. AcknowledgementsThe authors would like to thank Dr. John Grosso, Dr Nancy Barbour, Dr Peter Timmins, Dr. Enes Supuk, and Mr Martin

Vernon for their support during this study. The authors would also like to acknowledge the Engineering and Physical

Sciences Research Council and Bristol Myers Squibb for their financial support during this project.

9. Literature[1] X. He, P.J. Secreast, G.E. Amidon, “Mechanistic study of the effect of roller compaction and lubricant on tablet mechanical strength”. J. Pharm. Sci 96(5) (2007) 1342-1355.

[2] G. Ragnarsson, A.W. Holzer, J. Sjogren “The influence of mixing time and colloidal silica on the lubricating properties of magnesium stearate”. Int. J. Pharm (1979) 3 127-131.

[3] J. Kushner, F. Moore, “Scale-up model describing the impact of lubrication on tablet tensile strength”. Int. J. Pharm (2010) 399 19-30.

[4] A.M. Miguelez-Moran, C. Y. Wu, H. Dong, and J. P. K Seville. “Characterisation of density distributions in roller compacted ribbons using micro-indentation and X-ray micro-computed tomography”. Eur. J. Pharm. Biopharm 1 (2009) 173-182.

[5] A.M. Miguelez-Moran, C.-Y. Wu, and J.P.K Seville. “The effect of lubrication on desity distributions of roller compacted ribbons”. Int. J. Pharm 362 (2008) 52-59

[6] P. Kleinebudde. “Roll compaction/dry granulation: Pharmaceutical applications”. Eur. J. Pharm. Biopharm 58(2) (2004) 317-326.

Roll Pressure (bar)

3 1.2 1, John F. Gamble2, Mike Tobyn2, Phillip Robbins1, Richard ... · Jason Dawes1, John F. Gamble2, Mike Tobyn2, Phillip Robbins1, Richard Greenwood1 1School of Chemical Engineering, - [PDF Document] (2024)

References