Poster Reprint American Association of Pharmaceutical Scientists October, 2000

Optimizing Lubricant Usage in a Direct Compression Hydrochlorothiazide Formulation Containing a Plastically Deforming Excipient
Charles R. Cunningham and Laura K. Scattergood Colorcon, West Point, PA

OBJECTIVES
Examine the effect of magnesium stearate on the properties of a direct compression hydrochlorothiazide formulation. To develop a robust formulation which benefits from the addition of a plastically deforming excipient while avoiding potentially detrimental lubricant effects. Assess the effects of the lubricants on powder flowability, tablet ejection forces, tablet hardness, dissolution, and coated tablet film adhesion. Investigate the use of stearic acid as a potential alternative to magnesium stearate in this formulation. Starch 1500 (partially pregelatinized corn starch), used in this formulation as a flow aid and disintegrant, is an example of a plastically deforming

Formulations Tested
INGREDIENTS HCTZ Dicalcium phosphate Lactose MCC Starch 1500 Stearic acid Mg stearate Total 0.25 100.0 0.50 100.0 0.75 100.0 1.00 100.0 0.25 100.0 1.00 100.0 100.0 8.00 8.00 8.00 8.00 25.000 33.375 33.375 25.000 33.250 33.250 PERCENTAGES 25.000 33.125 33.125 25.000 33.000 33.000 25.000 33.375 33.375 8.00 25.000 33.000 33.000 8.00 8.00 1.00 25.000 33.000 33.000

All ingredients except magnesium stearate were blended together in a V-blender for 15 minutes. The magnesium stearate was then added and blended for an additional 5 minutes.

excipient which may exhibit sensitivity to high lubricant levels. Microcrystalline cellulose, another plastically deforming excipient, was also included in the study. METHODOLOGY Materials
Hydrochlorothiazide USP (HCTZ) Abbott Laboratories Partially pregelatinized corn starch Starch 1500, Colorcon Dicalcium phosphate dihydrate, unmilled Di-Tab, Rhodia Lactose monohydrate spray dried Fast Flo, Foremost Microcrystalline cellulose Emcocel 50M, Penwest Magnesium stearate N.F. HyQual , Mallinckro Stearic acid N.F. Purified vegetable grade powder, Oleotec Ltd.

Compaction
The tablets were compressed using a 10 station instrumented Piccola (Riva) rotary tablet press using size B, 5/16" flat-faced beveled edge tooling. Compaction and ejection force data were acquired using Director software (SMI Inc.). The target tablet weight was 200mg (50mg hydrochlorothiazide).

Tablet Hardness Testing

Tablet breaking force was determined using a Multicheck (Erweka Instrument Inc.) tablet tester.

Powder Flowability
Each of the powder blends was tested using an Erweka GDT funnel type flow testing apparatus. A constant amplitude vibratory device was employed for all tests.

Dissolution Methodology
USP method 219.990. Apparatus I (baskets) Media: 0.1N HCL Q (pass) = N.L.T. 60% dissolved in 60 minutes

Film Adhesion
Tablets from four of the batches were coated to a 3.0% weight gain with Opadry YS-1-10547A.
Tablet breaking force (k

Effect of Magnesium Stearate on Tablet Hardness

10.0

8.5

0.25% Mg. Stearate

Film adhesion measurements were conducted using a Lloyds materials tester EZ L1000R (Lloyds Instruments Ltd.).

7.0
0.50% Mg. Stearate

5.5
0.75% Mg. Stearate 1.0% Mg. Stearate

4.0

RESULTS Starch 1500/Magnesium Stearate

Effect of Magnesium Stearate on Powder Flowability
6.0 5.8 Powder Flow (g/sec) 5.5 5.3 5.0 4.8

2.5

1.0 5 10 15 20 25 30 Compaction Force (KN)

The effect of increasing magnesium stearate levels had a profound effect on tablet hardness. At levels over 0.25%, significant tablet softening occurred.
Effect of Magnesium Stearate on Dissolution
100 90 80
0.25% Mg. Stearate 1.0% Mg. Stearate

4.5 0.25
% Released

70

0.50

0.75

1.00

60 50 40 30 20 10 0 0 10 20 30 40 Time (minutes) 50 60 70 80

Magnesium Stearate Level (%)

Contrary to the expectation that increasing lubricant levels would improve flowability, the opposite was observed. Under vibratory conditions, the increased lubricant level may have been responsible for a reduction in interparticulate friction. This resulted in closer particle packing and densification, thus impeding the flow of powder through the funnel orifice.
Effect of Magnesium Stearate on Ejection Forces
0.45
0.25% Mg. Stearate

Note: Tablets of comparable hardness (5.5 - 6kp) were used for dissolution testing

Comparison of the dissolution profiles shows a slight slowing of dissolution at the higher magnesium stearate level.

Starch 1500/Stearic Acid

As an alternative to magnesium stearate, stearic acid was evaluated as a lubricant at a 1.0% usage level.
Effect of Stearic Acid on Powder Flowability
0.50% Mg. Stearate 0.75% Mg. Stearate 1.0% Mg. Stearate

0.40 Tablet ejection force (kN

0.35

0.30

6. 5 6.3 6. 0 Powder Flow (g/sec) 5.8 5.5 5. 3 5.0 4.8 4.5

1.0% Stearic acid

0.25

0.20

0.15 5 10 15 20 25 30 Compaction Force (KN)

The primary function of a lubricant is to ensure that tablets will eject cleanly, with minimal stress, from the die at high speeds. The data show that in this formulation, increasing the magnesium stearate level past 0.5% had very little incremental effect in further reducing ejection forces. 2

0.25

0.50

0.75

1.00

Magnesium Stearate Level (%)

The flowability of the powder blend was improved compared to the previous batches containing magnesium stearate.

Effect of Stearic Acid on Tablet Ejection Forces

0.45
0.25% Mg. Stear ate

Effect of Magnesium Stearate or Stearic Acid

0.40 Tablet ejection force (kN

1.10

0.35

1.03 Work to break (Nmm

0.30

0.50% Mg. Stear ate 0.75% Mg. Stear ate 1.0% Mg. Stearate

0.95

1.0 % Stearic acid

0.88

0.25

0.80

0.20

0.73
0.15 5 10 15 20 25 30

0.65
0.25% Magnesium stearate 0.50% Magnesium stearate 0.75% Magnesium stearate 1.0% St earic acid

Compaction Force (KN)

Overall, ejection force values were actually lower when 1.0% magnesium stearate was replaced with 1.0% stearic acid.
Effect of Stearic Acid on Tablet Hardness
10.0
1.0 % Stearic acid

Film adhesion to the tablet surface was reduced at magnesium stearate levels greater than 0.25%. 1.0% Stearic acid in the formulation resulted in the highest measured adhesion values.

MCC / Magnesium Stearate

Microcrystalline cellulose was substituted for Starch 1500 in two of the formulations as an example of another type of plastically deforming excipient that may be adversely impacted by magnesium stearate.

8.5 Tablet breaking force (k

0.25% Mg. Stearate

7.0
0.50% Mg. Stearate

5.5
0.75% Mg. Stearate 1.0% Mg. Stear ate

4.0

2.5

1.0 5 10 15 20 25 30 Compaction Force (KN)

A significant improvement in tablet hardness was seen compared to any of the formulations containing magnesium stearate.
Effect of Stearic Acid on Dissolution
100 90 80 70 % Released 60 50 40 30 20 10 0 0 10 20 30 40 Time (minutes) 50 60 70 80
0.25% Mg. Stearate

1.0 % Stearic acid

1.0% Mg. Stearate

As with Starch 1500, the flow was decreased with an increasing magnesium stearate. The overall flowability was lower with MCC in the formulation.

Note: Tablets of comparable hardness (5.5 - 6kp) were used for dissolution testing

Dissolution was unaffected by the addition of stearic acid to the formulation.

Effect of Magnesium Stearate on Tablet Hardness

0
0.25% Mg. Stearate

CONCLUSIONS
The multiple advantages of Starch 1500 as a flow aid, disintegrant, and dissolution aid may not be fully realized if proper lubricant types and levels are not identified.

1.0% Mg. Stearate

Because of the tendency of magnesium stearate to coat the individual particles, detrimental effects of magnesium stearate can be exacerbated when using plastically deforming excipients.
Stearic acid has good lubricant properties and remains a discreet particle within the mixture without forming a waxy or hydrophobic coating on powder surfaces. Stearic acid can be used to reduce or eliminate magnesium stearate levels in formulations which exhibit lubricant sensitivity.
Reprint of poster presented at AAPS, Indianapolis Nov. 2000.

0 5 10 15 20 25 30
Compaction Forc e (KN)

Tablet hardness was also severely impacted at the 1.0% magnesium stearate usage level.
Effect of Magnesium Stearate on Dissolution
100 90 80 70 % Released 60 50 40 30 20 10 0 0 10 20
1.0% Mg. Stearate 0.25% Mg. Stearate

Note: Tablets of comparable hardness (5.5 - 6kp) were used for dissolution testing
30 40 Time (minutes) 50 60 70 80

Magnesium stearate in combination with MCC had a much greater impact on dissolution than in the formulations containing Starch 1500. The time to 60% released was reduced by 40 minutes at the 1.0% magnesium stearate usage level.

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The information contained herein, to the best of our knowledge is true and accurate. Any recommendations or suggestions are made without warranty or guarantee, since the conditions of use are beyond our control. Any information contained herein is intended as a recommendation for use of our products so as not to infringe on any patent. Colorcon, 2005. The information contained in this document is proprietary to Colorcon and may not be used or disseminated inappropriately. tds_opt_lub_use2sbu.doc