Merck Exhibit 2159, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`Memo
`To:
`
`22-Feb-2002
`Liu, Yun; Shultz, Leigh; Gandek, Thomas P.; Kwei, Gloria Y.; Ostovic, Drazen;
`Remenar, Julius F.; Kaufman, Michael J.; Armstrong, Joe D; Hansen, Karl; Palucki,
`Michael
`From: D. Zhang
`Subject: Physical characterization of L-224715 phosphate salt
`
`Summary
`
`The preliminary physical characterization was performed on L-224715 phosphate salt
`(NB# 70316-031). Unlike the tartrate and besylate salts, the phosphate displayed plate-like
`structures as primary crystals, which were packed to form agglomerates. The particle size
`distribution exhibited a main peak at ~ 74 m and a shoulder at ~ 19 m, with a mean particle
`size of 55 m. The loose and tapped density densities were 0.27 g/cm3 and 0.39 g/cm3,
`respectively, yielding a Carr s index of 31% and HR of 1.44. The drug was wettable by IPA;
`however, some changes were observed in the IPA granulated sample by DSC. Similar to the
`other two salts (tartrate and besylate), the phosphate also displayed capping/sticking upon
`compression, and changes in the compressed sample were indicated by XRPD and DSC.
`
`The preliminary physical assessment on the L-224715 phosphate salt indicated that given
`the morphology of agglomeration of plate-like crystals, the flowability of the drug has a good
`potential to be further improved upon tightening up the PSD. Since granulation and compression
`might have an effect on the drug crystallinity, the chemical stability of the amorphous form and
`the physical stability of the drug during processing should be monitored.
`
`Morphology
`
`Unlike the L-224715 besylate (rod-like) or tartrate (needle-like) salts, the phosphate salt
`displayed thin-plate-like structures as primary crystals. Most of the primary crystals were packed
`to form agglomerates of various sizes.
`
`Side-view
`
`Figure 1. SEM micrographs of L-224715-70316-031.
`
`Merck Exhibit 2159, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`Particle Size Distribution
`
`The particle size distribution was characterized by Microtrac using Isopropanol as
`flowing medium. The PSD had a main peak at ~ 74 m and a shoulder at ~19 m. The main
`peak shifted to smaller particle sizes and the lower shoulder grew upon sonication, indicating the
`breaking up of the agglomerates.
`
`L-224715-70316-031
` Sonication = 0 s
` Sonication = 30 s
` Sonication = 90 s
`
`12
`
`10
`
`8 6 4 2 0
`
`1
`
`10
`
`100
`
`Figure 2. PSD of L-224715-70316-031.
`
`Solvent and Pressure Effect
`
`L-224715-70316-031 was wettable by IPA. The solvent effect on the physical stability of
`the drug was examined by granulating L-224715 with IPA at a 50% L/S level. A decrease of 1
`°C in the endotherm was observed for the granulated sample.
`
`As to the pressure effect, similar to the other salts (tartrate and besylate), the phosphate
`also displayed capping/sticking upon compression at 22,000 psi, and changes in the compressed
`sample were observed by XRPD and DSC. Given the fact that granulation and compression
`might decrease the crystallinity of the drug, the chemical stability of the amorphous form and the
`physical stability of drug during processing should be monitored.
`
`Merck Exhibit 2159, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
` L-224715 phosphate
` Granulated with IPA
` Compressed at 22,000 psi
`
`210.1 °C
`
`211.6 °C
`
`195
`
`200
`
`205
`210
`Temperature (C)
`
`215
`
`220
`
`01
`
`-1
`
`-2
`
`-3
`
`-4
`
`-5
`
` L-224715 phosphate
` Compressed at 22,000 psi
`
`500
`
`400
`
`300
`
`200
`
`100
`
`Heat Flow (J/g)
`
`Intensity
`
`10
`
`20
`Diffraction Angle
`
`30
`
`40
`
`Figure 2. DSC of an IPA-granulated sample, and XRPD and DSC of a compressed (22,000 psi)
`sample, compared to those of L-224715-70316-031.
`
`Table 1. Summary of the physical properties of L-224715.
`
`Morphology
`Particle Size Distribution
`Particle Size ( m)
`Son.
`0s
`30
`90s
`Surface Area [m2/g]
`Densities [g/cm3]
`
`17
`15
`14
`
`L-224715-70316-031
`plate-like primary crystals and agglomerates
`Narrow but with a lower shoulder
`Mean ( m)
`D10 ( m)
`Vol
`65
`56
`49
` 5.78 ± 0.31
`Loose = 0.27
`Tapped = 0.39
`Carr s Index = 31%
`Flowability
`HR = 1.44
`Cohesivity
`Wettability/Hydrophilicity Wettable by IPA
`
`D50 ( m)
`
`62
`53
`45
`
`D95 ( m)
`
`132
`117
`101
`
`Merck Exhibit 2159, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`Conclusions:
`
`The phosphate salt had a better morphology than the besylate and tartrate salts from the
`perspective of processing. The current lot had a marginal flow, but the flowability has a good
`potential to be improved upon tightening up the PSD. Since granulation and compression might
`have an effect on the drug crystallinity, the chemistry stability of the amorphous form and the
`physical stability of the drug during processing should be monitored.
`
`Merck Exhibit 2159, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`