`
`
`
`
`
`
`
`Hurter, Patricia N; Ernst, Sharon L.; Givand, Jeffrey C.; Kube, Kenneth P; Luna,
`Ernestina A.; Lynn, Kari J; Palkar, Saurabh Arvind; Shelukar, Suhas D.; Shultz, Leigh;
`Gandek, Thomas P.; Zega, James A.; Winters, Conrad
`Armstrong, Joe D and Starbuck, Cindy
`
`S. Cypes, R. Ferlita, R. Wenslow, L. Wang, R. Wall, L. Allain, and D. Zhang
`
`09 APR 2003
`
`Physical Characterization of L-225715-66839-113 (115) and -125 (from ISAA)
`
`
`
`
`TO:
`
`CC:
`
`FROM:
`
`
`DATE:
`
`SUBJECT:
`
`Summary
`
`
`L-224715-66839-113 (115) and –125 from ISAA have a rod-like morphology. Many crystals
`display laminated structures. The aspect ratio of the crystals is in the range of 3-10. The bulk material
`has relatively low bulk densities and poor flowability. The PSD of the material matches well with those
`of A-Tab and Avicel PH 102. Upon sonication, the rod-like crystals were broken in directions both
`parallel and perpendicular to the long axis of the crystals. A strong sonication effect was observed,
`indicating crystal breakage. The preliminary data showed that L-225715-66839-113 caused less sticking
`than lot 24, based on the test on the pure bulk drug. Unlike lot 24 (Form II), no obvious form change was
`observed for the compressed monohydrate and the decrease in crystallinity of NB# 66839-113 seemed
`also smaller than that of lot 24. The monohydrate form displayed a slower intrinsic dissolution rate than
`all the anhydrous forms, about 40% slower.
`
`
`
`
`Morphology/Shape
`
`Lot 006F024
`20/80=H2O/EtOH
`
`
`NB# 66839-113 (115)
`ISAA
`
`
`NB# 66839-125
`ISAA
`
`
`Particle Size Son
`
`
`0s
`30s
`Density [g/cm3]
`Loose
`Tapped
`Carr’s Index
`Hausner Ratio
`Flodex
`
`
`
`
`
`
`
`D95
`
`422
`329
`
`
`
`Mean
`
`198
`165
`
`
`Mean
`
`83
`77
`
`
`
`D10
`
`19
`18
`
`0.55
`0.81
`32%
`1.47
`19
`
`
`
`
`Mean
`
`198
`143
`
`
`
`
`
`D95
`
`224
`206
`
`D10
`
`77
`52
`
`0.28
`0.55
`49%
`1.96
`32
`
`
`
`
`
`D95
`
`444
`415
`
`D10
`
`70
`50
`
`0.30
`0.56
`46%
`1.87
`28
`
`
`
`
`
`Merck Exhibit 2120, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`Morphology
`L-224715-66839-113 (-115 is the same batch as –113 but is overdried) and –125 from ISAA have
`a rod-like morphology. Many crystals display laminated structures. The aspect ratio of the crystals is in
`the range of 3-10. It seemed there was a larger variation in particle size for NB#66839-125 than
`NB#66839-113.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Particle Size Distribution
`
`The particle size distribution of NB#66839-125 seemed to be slightly wider than that of NB#
`66839-113, which is consistent with the SEM observation. However, the PSDs of the new materials are
`all narrower than that of Lot 24.
`
`NB# 66839-113 (115), -125, compared to lot 24
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`L-224715
`Sonication = 30 s
` NB# 66839-113
` NB# 66839-125
` Lot 24
`
`10
`
`8 6 4 2 0
`
`% Frequency
`
`1
`
`10
`
`100
`Particle Size (µm)
`
`1000
`
`
`
`
`
`
`
`
`
`
`NB# 66839-113
`
`
`
`NB# 66839-125
`
`Merck Exhibit 2120, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`Merck Exhibit 2120, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`Matching with Excipients
`The PSD of the material matches well with those of Calcium Phosphate, Dibasic Anhydrous (A-
`Tab) and Cellulose Microcrystalline PH 101 (Avicel PH 102), which are potential candidates as fillers.
`
`
`
`
`
`Avicel PH 102
`
`A-Tab
`
`NB# 66839-113
`ISAA
`
`Morphology/Shape
`
`
`
`
`
`
`
`Particle Size Son
`
`
`0s
`30s
`Density [g/cm3]
`Loose
`Tapped
`Carr’s Index
`Hausner Ratio
`Flodex
`
`
`
`Mean
`
`142
`136
`
`
`D10
`
`46
`46
`
`0.33
`0.42
`21%
`1.27
`17
`
`
`
`
`Mean
`
`141
`135
`
`
`
`
`
`D95
`
`314
`295
`
`
`
`
`
`D95
`
`267
`258
`
`
`
`Mean
`
`198
`143
`
`
`
`
`
`D95
`
`422
`329
`
`D10
`
`77
`52
`
`0.28
`0.55
`49%
`1.96
`32
`
`D10
`
`61
`57
`
`0.73
`0.88
`17%
`1.21
`-
`
`
`
`NB# 66839-113 compared to Excipients
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`L-224715
` A-Tab
` Di-Tab
` NB# 66839-113
` Avicel PH101
` Avicel PH102
`
`10
`
`Particle Size (um)
`
`100
`
`1000
`
`
`
`
`
`
`
`1
`
`16
`14
`12
`10
`
`8 6 4 2 0
`
`% Frequency
`
`Merck Exhibit 2120, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`Crystal Strength via Sonication Effect
`A strong sonication effect was observed, indicating crystal breakage. The rod-like crystals were
`broken in directions both parallel and perpendicular to the long axis of the crystals. All the crystals were
`chipped off at all edges.
`
`PSD of NB# 66839-113 upon sonication
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Morphology of NB# 66839-113 before and after 90 seconds of sonication
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`L-224715-66839-113
`
`
` Sonication = 0 s
` Sonication = 30 s
` Sonication = 90 s
`
`12
`
`10
`
`8 6 4 2 0
`
`% Frequency
`
`1
`
`10
`
`Particle Size (µm)
`
`100
`
`1000
`
`
`
`Original
`
`Merck Exhibit 2120, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` L-224715-006F024
` Lot 24 Compressed at 200 Mpa
`
` NB# 66839_113
` NB# 66839_113 Compressed at 200 Mpa
`
`2000
`
`
`
`1500
`
`1000
`
`500
`
`Pressure Effect
`
`
`1500
`
`1000
`
`Intensity
`
`500
`
`Unlike lot 24, no obvious form change was observed for the compressed L-224715-66839-113.
`The decrease in crystallinity of NB# 66839-113 seemed also smaller than that of lot 24.
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`Sticking
`
`
`
`Sticking
`
`
`20
`Diffraction Angle
`
`30
`
`40
`
`
`
`10
`
`20
`
`30
`
`40
`
`
`
`In contrast to Lot 24 (a layer of bulk drug covered the punch surfaces after compression), no
`obvious sticking was observed upon compressing L-224715-66839-113 with flat-surface tools. The
`sticking test done on the pure bulk drug (Carver Press with the punch surface embossed with MSD) also
`indicates that L-224715-66839-113 produces less sticking than lot 24. This is probably due to the
`combination of the nature of the monohydrate and the particle characteristics of this lot.
`
`
`
`L-224715
`Left at the Punch Surface
`(µg)
`
`350
`300
`250
`200
`150
`100
`50
`0
`
`
`
`
`
`Lot 24
`
`NB# 66839-113
`
`Series1
`
`
`
`
`
`Merck Exhibit 2120, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`Intrinsic Dissolution
`
`Intrinsic dissolution measures the dissolution of a crystal under a constant surface area and is a
`thermodynamic property of the crystal. The experiment was performed by compressing 100 mg of bulk
`drug to a rotating disk at a pressure of 2 metric tons. The dissolution rate was measured in an USP II
`apparatus (900 ml of DI water and 50 rpm). The dissolution solution was sampled over a period of 30
`minutes. The samples were then analyzed by HPLC (by L. Allain and R. Wall). L-224715 monohydrate
`displayed a slower intrinsic dissolution rate than all the anhydrous forms, about 40% slower. Since the
`drug is so soluble and wettable, the decrease in intrinsic dissolution should not cause big problems for
`tablet dissolution in which the surface area was not limited.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Conclusions:
`
`
`
`L-224715 monohydrate has a rod-like morphology, many crystals display laminated structures
`and the crystal strength is weak. The bulk material has relatively low bulk densities and poor flowability.
`The PSD of the material matches well with those of A-Tab and Avicel PH 102. A strong sonication effect
`was observed, indicating crystal breakage. The preliminary data showed that L-225715-66839-113
`caused less sticking than lot 24, based on the test on the pure bulk drug. Unlike the anhydrous forms, no
`obvious form change was observed for monohydrate upon compression. The monohydrate form
`displayed a slower intrinsic dissolution rate than all the anhydrous forms, about 40% slower.
`
`
`
`
`80x10-3
`
`60
`
`40
`
`20
`
`0
`
`Concentration (mg/ml)
`
` Form I
` Form II
` Form III
` Monohydrate
`
`5
`
`10
`
`15
`20
`Time (minute)
`
`25
`
`30
`
`
`
`
`
`
`
`Merck Exhibit 2120, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`