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`17-Apr-03
`Hurter, P.; Gandek, T.; Palkar, S.
`Ney, J.
`Meyer, R.; Wang, L.
`L-000224715 Monohydrate Evaluation
`L-224715 Formulation Team
`
`
`
`DATE:
`
`TO:
`
`
`FROM:
`CONTRIBUTORS:
`RE:
`
`CC:
`
`Summary
`
`This memorandum describes the preliminary evaluation of L-224715 monohydrate. Details on
`formulation sticking tendency, tablet hardness, and content uniformity are included.
`
`The following conclusions were drawn from the formulation development :
` L-224715 monohydrate shows less sticking to the punch surface than the anhydrous drug.
` The monohydrate is less compactable than the anhydrous drug. This is reflected in lower tablet
`hardness.
` The content uniformity percent claim variation was impacted mostly by the tablet weight variation.
` The content uniformity normalized % RSD values for monohydrate formulations are acceptable.
`
`
`Monohydrate Formulation Development
`
`L-224715 monohydrate (25g NB66839-125) was obtained from CERD for formulation analysis and
`development. Four formulations were produced using this material to evaluate its performance and
`compare it to formulations previously produced using L-224715006F024. The first two DC blends were
`based on the Phase IIB clinical formulation. The grade of Avicel was changed from PH101 to Ph102. This
`change was made in order to facilitate satisfactory flow with the large rod-like crystals of the monohydrate.
`The compositions for formulations DL612 and DL613 are shown compared to the Phase IIB clinical
`formulation (0431FCT002C001) in Table 1.
`
`Table 1. Phase IIB Formulation Comparison
`0431FCT002C001
`
`DL612
`Percentage (%)
`31.00
`0.00
`0.00
`32.50
`32.50
`0.00
`2.00
`2.00
`0.00
`0.00
`
`31.00
`0.00
`32.50
`0.00
`32.50
`0.00
`2.00
`2.00
`0.00
`0.00
`
`Component
`L-224715006F024*
`L-224715 Monohydrate**
`Avicel PH 101
`Avicel PH 102
`Mannitol SD100
`Dical Phosphate
`Cros Carm Na
`Mg St.
`Talc
`Cab-O-Sil
`*25% x 1.24 (conversion factor) = 31%
`**25% x 1.284 (conversion factor) = 32.1%
`
`Blends (20g) were prepared in a turbula blender and 100mg images were compressed on the Korsh tablet
`press using 8/32” standard concave tools. The press was set-up with one embossed and one plain upper
`punch. Tablets were compressed at approximately 9kN. Pictures of the punch faces were taken before and
`after each run. Figures 1-4 show a punch face comparison of the Phase IIB formulation
`
`DL613
`
`0.00
`32.10
`0.00
`31.95
`31.95
`0.00
`2.00
`2.00
`0.00
`0.00
`
`
`
`Merck Exhibit 2121, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

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`(0431FCT002C001) and DL612 after the run. Figures 1 and 2 show a uniform haze over the tool surface.
`However, figures 3 and 4 show severe sticking in the embossing. The formulation containing Avicel
`PH102 (DL612) shows greater sticking than the clinical formulation (0431FCT002C001) containing Avicel
`PH101.
`
`
`
`
`
`
`Figure 1 and 2. Phase IIB Clinical Formulation Upper Punches– 0431FCT002C001
`
`
`
`
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`Figure 3 and 4. DL612 Upper Punches (Clinical Formulation with Avicel PH102)
`
`Replacing L-224715006F024 with monohydrate, as in DL613, shows a decrease in adherence to the punch
`face (Figure 5 and 6).
`
`
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`
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`Figures 5 and 6. DL613 Upper Punches
`
`
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`Monohydrate “Best Case” Comparison
`
`Two monohydrate formulations (DL614 and RC21) were prepared based on formulations that were seen to
`reduce sticking with L-224715006F024 (anhydrous). These blends included dicalcium phosphate in place
`of the mannitol. The formulation ratio of dicalcium phosphate to mannitol was 2.5:1. DL614 (20g) was a
`DC blend prepared in the turbula blender. RC21 (60g) was roller compacted on the Vector TF-mini roller
`compactor. The resulting ribbons were milled on the Alexanderwork roller compactor RFGs. The
`compositions are shown in Table 2.
`
`
`Merck Exhibit 2121, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
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`Table 2. “Best Case” Monohydrate Formulations
`RC21
`DL614
`Component
`Percentage (%)
`0.000
`L-224715006F024
`21.404
`L-224715 Monohydrate**
`0.000
`Avicel PH 101
`20.884
`Avicel PH 102
`0.000
`Mannitol SD100
`52.211
`Dical Phosphate
`2.000
`Cros Carm Na
`3.000
`Mg St.
`0.000
`Talc
`0.500
`Cab-O-Sil
`**16.67% x 1.284 (conversion factor) = 21.404%
`
`Tablets (100mg) were compressed on the Korsh press using one embossed and one plain 8/32” standard
`concave tool. Compacts were compressed at approximately 9kN. Figures 7-10 show the upper punches
`after compression. Both DL614 and RC21 show almost no sticking.
`
`
`0.000
`21.404
`0.000
`20.884
`0.000
`52.211
`2.000
`3.000
`0.000
`0.500
`
`
`
`
`Figures 7 and 8. DL614 – DC “Best Case” with Monohydrate Upper Punches
`
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`Figures 9 and 10. RC21 – Roller Compacted “Best Case” with Monohydrate Upper Punches
`
`
`Monohydrate Tablet Hardness
`
` A
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` reduction in tablet hardness was observed for the monohydrate formulations as compared to the
`anhydrous drug formulations (DL612 and DL613). This reduction is greater for the DC formulations.
`Table 3 shows the average tablet hardness achieved for each formulation.
`
`Merck Exhibit 2121, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`
`
`
`Table 3. Average Tablet Hardness
`Formulation
`Description
`0431FCT002C001 Phase IIB Clinical
`DL612
`Phase IIB Clinical with Avicel 102
`DL613
`DL612 with monohydrate drug
`
`
`
`Tablet Hardness
`6.80
`7.74
`5.40
`
`DC "Best Case"
`RC "Best Case"
`DC "Best Case" with monohydrate and Avicel 102
`RC "Best Case" with monohydrate and Avicel 102
`
`5.97
`4.2
`4.75
`4.13
`
`DL505
`RC20
`DL614
`RC21
`
`Monohydrate Content Uniformity
`
`Table 4 shows content uniformity for 10 random tablets from formulation DL613. The RSD is higher than
`was typically seen for formulations containing the anhydrous drug. Given that the monohydrate prefers to
`stay agglomerated, it may be difficult to blend at small scale. It is unsure if increasing the batch size will
`improve this problem. The added shear in larger batches may be helpful in breaking agglomerates. High
`shear blending could also be used.
`
`Table 4. Content Uniformity- DL613
`Samples Weight (mg) %Claim % Normalized Claim
`1
`99.23
`102.0
`102.8
`2
`107.47
`105.5
`98.2
`105.98
`107.9
`101.8
`3
`4
`107.27
`103.3
`96.3
`5
`108.78
`107.6
`98.9
`6
`104.07
`99.2
`95.3
`7
`99.08
`97.6
`98.5
`8
`108.61
`107.9
`99.3
`9
`103.33
`101.0
`97.7
`10
`107.55
`109.2
`101.5
`105.1
`104.1
`99.0
`Ave.
`3.4
`3.9
`2.4
`%RSD
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`Merck Exhibit 2121, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`Table 5 shows content uniformity results for RC21. Despite the lower drug loading as compared to DL613
`(16.67% vs. 25%), the roller compaction process yields better uniformity.
`
`Table 5 Content Uniformity – RC21
`Samples Weight (mg) %Claim % Normalized Claim
`1
`104.69
`103.1
`98.5
`2
`101.03
`98.4
`97.4
`3
`102.39
`100.7
`98.3
`4
`99.44
`97.6
`98.1
`5
`101.04
`100.2
`99.2
`6
`99.49
`97.2
`97.7
`7
`100.34
`98.4
`98.1
`8
`101.06
`98.4
`97.4
`9
`106.83
`103.3
`96.7
`10
`101.32
`99.0
`97.7
`101.8
`99.6
`97.9
`Ave.
`2.3
`2.2
`0.7
`%RSD
`
`
`
`Merck Exhibit 2121, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`