MERCK RESEARCH LABORATORIES PROGRESS REPORT
`
`MARCH 2002
`
`
`
`
`
`
`Title: Dipeptidyl-peptidase IV
` Category: Endocrine/Metabolic
`Target Class: dipeptidyl-peptidase IV
`Compound #:
`Disease: noninsulin-dependent diabetes mellitus Dosage Form/Potency: To Be Determined
`
`Cross Project Function:
`Reporting Area: Pharmaceutical Research & Development
`
`Project Team:
`Sub-Group: Pharmaceutical Chemistry – Rahway
`Dept. : 854 – Pharmaceutical Research
`Author(s): Shultz, Leigh
`Department Head: Michael Kaufman
`Key Words: L-224715; phosphate salt; stoichiometry; equilibrium solubilities; Chemical stability (bulk and solution); Physical
`stability; gelatin; HPMC; mannitol; Safety Assessment formulation
`
`Summary
`The phosphate salt of L-224715 is a monobasic salt, and only one anhydrous polymorph has been observed to date.
`The salt is chemically stable in the bulk for 4 weeks and is most stable in solution between pH 2-4. No physical
`changes are observed over 20 days on stability. Stability in binary mixtures with gelatin, HPMC, and 2 grades of
`mannitol has been assessed to aid in the Phase I formuation. The recommended vehicle for Safety Assessment
`studies is 5 mM HCl, which improves stability over deionized water. All Safety Assessment dosing can be done in
`solution using this vehicle.
`
`
`
`1. Stoichiometry of L-224715 phosphate salt [NB: (60659:169, 178)]
`
`Two samples of L-224715 phosphate (70316-43) in water were analyzed by HPLC against standard solutions of L-224715 to
`determine the stoichiometry of this batch. The average salt factor calculated from the data was 0.804; the theoretical salt factor for a
`monobasic phosphate salt of L-224715 is 0.806. These values are in excellent agreement; this batch of phosphate is therefore a
`monobasic phosphate salt.
`
`2. Comparative solubilities of L-224715 phosphate salt batches in ethanol [NB: (60659:169, 178)]
`
`The equilibrium solubilities of 4 different batches of L-224715 phosphate salt in absolute ethanol were determined and are reported in
`the table below.
`
`
`Batch
`
`Solubility in EtOH
`(mg/mL L-224715)
`0.187
`0.187
`0.181
`0.196
`
`70316-25
`70316-31
`70316-35
`70316-43
`
`
`The solubilties of the 4 batches of phosphate salt are very close, indicating that they are the same polymorph.
`
`3. Chemical stability (bulk and solution) of L-224715 phosphate salt [NB: (60659:153, 162, 168, 175)]
`
`The bulk stability data for the phosphoric acid salt of L-224715 are shown in the table below. Data are reported in area % relative to
`samples stored at –20 °C.
`
`
`Bulk thermal stability of L-224715 phosphate salt
`Conditions
`Rel Area % L-224715
`1 wk 2 wk 4 wk
`102.2
`100.4
`98.9
`99.8
`99.6
`99.9
`
`40 °C/75% RH
`80 °C/amb RH
`
`
`Minimal loss of parent is observed after 4 weeks at 40 °C/75% RH; the loss is not statistically significant, and no degradates are
`observed by HPLC.
`
`Merck Exhibit 2153, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MERCK RESEARCH LABORATORIES PROGRESS REPORT
`
`MARCH 2002
`
`
`
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`
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`
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`The solution stability data for the phosphate salt of L-224715 are shown in the table below. Data are reported in area % relative to
`samples stored at –20 °C.
`
`
`
`
`Page 2 of 8
`
`Conditions
`
`water
`pH 2
`pH 4
`pH 6
`pH 8
`pH 10
`
`Solution thermal stability of L-224715 phosphate salt
`Rel Area % L-224715, 40 °C
`Rel Area % L-224715, 80 °C
`1 wk 2 wk 4 wk
`1 wk 2 wk 4 wk
`93.9
`89.8
`75.9
`0.0
`0.0
`0.0
`99.9
`98.1
`100.6
`99.0
`100.3
`95.4
`101.8
`93.2
`94.1
`100.9
`93.6
`90.9
`99.0
`101.6
`98.5
`24.9
`5.0
`0.4
`88.2
`81.6
`60.2
`0.0
`0.0
`0.0
`83.1
`62.9
`36.5
`0.0
`0.0
`0.0
`
`
`The phosphate salt is most stable between pH 2 and 4, similar to other salts of L-224715. Although the stability of the salt in water at
`80 °C is poor, the stability of the salt at 40 °C in water shows a marked improvement over the other salts of this compound. This is
`likely a pH effect, as the phosphate salt solutions have a lower pH after storage at 40 °C than do solutions of other salts of L-224715.
`Based on this data, the phosphoric acid salt has a distinct advantage over the benzenesulfonate salt for development. The table below
`compares the degradation (both hydrolysis and de-amination) of L-224715 in the benzenesulfonate, phosphate, and tartrate salt forms
`at 0.1 mg/mL salt in water at 40 °C.
`
`
`
`
`The data clearly indicate that the phosphate salt is much more stable in unbuffered water. This is an advantage for the phosphate salt
`should some of the salt dissolve in a formulation. Also, it should be noted that both of the major degradation processes are aided by
`increasing pH, so acidifying the formulation should increase the stability of the drug.
`
`4. Physical stability of L-224715 phophate salt [NB: (60659:160, 163-164, 166, 169-170, 172-174)]
`
`Samples of bulk phosphate salt of L-224715 (anhydrous, only known polymorph) were placed in the 25 °C/60% RH, 40 °C/amb RH,
`and 40 °C/75% RH ovens to determine the physical stability of the polymorph. Small samples were removed from the vials after 11
`and 20 days, and these samples were analyzed by DSC and TGA to determine their forms. The thermal data appear in the table below.
`
`
`Conditions
`
`unstressed
`25 °C/60% RH
`25 °C/60% RH
`40 °C/amb RH
`40 °C/amb RH
`40 °C/75% RH
`40 °C/75% RH
`
`Time
`(days)
`0
`11
`20
`11
`20
`11
`20
`
`mp onset
`(°C)
`207.51
`207.55
`207.97
`208.37
`208.54
`208.69
`207.66
`
`heat of melting
`(J/g)
`166.4
`175.7
`142.8
`151.6
`136.1
`205.5
`148.7
`
`% volatiles
`
`0.053
`0.092
`0.104
`0.092
`-0.064
`0.020
`0.092
`
`
`The phosphate salt decomposes immediately upon melting, so integration of the melt endotherm is unreliable, widely variable, and
`cannot be used to quantify crystallinity. However, overlaying the DSC and TGA data of the stressed samples with those of the
`
`
`Salt of L-224715
`
`
`
`
`
`Comparison of degradation in salts of L-224715
`Rel Area %
`Hydrolysis
`1wk 2wk 4wk
`8.9
`20.4
`47.7
`Free Base
`3.8
`7.8
`19.5
`Phosphate
`8.3
`18.2
`41.3
`Benzenesulfonate
`6.3
`13.7
`no data
`L-Tartrate Hemihydrate
`Conditions: 0.1 mg/mL salt, 40 °C, unbuffered water
`
`Rel Area %
`De-amination
`1wk 2wk 4wk
`3.8
`11.8
`28.8
`2.3
`5.1
`9.1
`3.6
`7.4
`25.3
`4.2
`6.1
`no data
`
`Merck Exhibit 2153, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

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`unstressed material shows no physical changes over 20 days under the conditions studied. The samples stored at high humidity gain a
`slight amount of water on storage, but chemical stability assays have shown no degradation under these conditions.
`
`MERCK RESEARCH LABORATORIES PROGRESS REPORT
`
`MARCH 2002
`
`
`
`Page 3 of 8
`
` A
`
` sample of L-224715 phosphate salt was lyophylized from concentrated aqueous solution in an attempt to produce amorphous
`material. XRPD of the resulting material showed only an amorphous halo. However, the material mostly recrystallized upon standing
`at ambient temperature for 16 hours. DSC of the recrystallized material shows some amorphous character, with a slight Tg at 38.4 °C.
`The melting point onset for the material was 203.54 °C (121.2 J/g), but the sample appears to be the same polymorph as the original
`crystalline material and decomposes upon melting.
`
`5. Chemical and physical stability of L-224715 phosphate salt in binary dry mixtures with gelatin powder (type B) [NB:
`(60659:160-161, 163, 166, 170-172, 180-181)]
`
`
`The chemical and physical stability of L-224715 phosphate salt (5% drug load) in binary mixtures with type B (base-cured) gelatin
`powder were monitored by HPLC and solid-state NMR, respectively. The chemical stability data are shown in the grid below.
`
`
`L-224715 Phosphate salt
`Chemical stability with gelatin
`
`Excipient used: Fisher lab grade, type B
`Lot No: 987519
`Drug lot used: 70316-25
`Drug loading: 5.2%
`NB Reference: 60659-155
`
`calibration not reliable due to overlap of gelatin and 715 at 210 nm
`
`Sample Temp (C) %RH Time (wk) Sam wt (mg) Drug wt (mg) Calc conc Calc area
`A1 gel
`5
`amb
`1
`20.32
`1.06
`0.117
`5048391
`C1 gel
`40
`amb
`1
`19.76
`1.03
`0.114
`4909262
`D1 gel
`40
`75
`1
`19.48
`1.01
`0.113
`4839698
`A2 gel
`5
`amb
`2
`20.72
`1.08
`0.120
`5147769
`C2 gel
`40
`amb
`2
`19.56
`1.02
`0.113
`4859573
`D2 gel
`40
`75
`2
`20.25
`1.05
`0.117
`5031000
`A4 gel
`5
`amb
`4
`20.24
`1.05
`0.117
`5028516
`C4 gel
`40
`amb
`4
`19.68
`1.02
`0.114
`4889387
`D4 gel
`40
`75
`4
`20.00
`1.04
`0.116
`4968889
`
`Area
`Area %
`8.41 4725583.82
`6.10 3398101.55
`5.94 3272985.83
`7.60 4060611.26
`7.97 4538837.07
`8.86 5000447.81
`8.91 4147063.76
`7.34 3526076.05
`8.60 4085671.00
`
`% Claim
`0.94
`0.69
`0.68
`0.79
`0.93
`0.99
`0.82
`0.72
`0.82
`
`detection at 210 nm, checked by detection at 260/270 nm
`
`A1 gel 260
`C1 gel 260
`D1 gel 260
`A2 gel 270
`C2 gel 270
`D2 gel 270
`A4 gel 270
`C4 gel 270
`D4 gel 270
`
`5
`40
`40
`5
`40
`40
`5
`40
`40
`
`amb
`amb
`75
`amb
`amb
`75
`amb
`amb
`75
`
`1
`1
`1
`2
`2
`2
`4
`4
`4
`
`average
`SD
`
`0.82
`0.11
`
`76.09
`68.35
`67.16
`75.49
`77.11
`80.50
`79.08
`73.44
`77.48
`
`601376.95
`411921.53
`396596.97
`529436.75
`591815.26
`661214.67
`533550.09
`441646.37
`527253.85
`
`
`
`
`The data indicate no trend for degradation of the drug in the presence of gelatin. However, the presence of gelatin in the sample
`prevents detection of the main hydrolysis degradate both at 210 and 260/270 nm. The calibration and % claim data are also unreliable
`here due to the presence of the gelatin. Therefore, no conclusions can be drawn from this data at this time.
`
`The gelatin mixture was evaluated by SSNMR (19F) before and after storage at 40 °C/amb RH and 40 °C/75% RH. The overlaid –CF3
`region of the spectra is shown in the graph below.
`
`
`Merck Exhibit 2153, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MERCK RESEARCH LABORATORIES PROGRESS REPORT
`
`MARCH 2002
`
`
`
`Page 4 of 8
`
` Gel RT
` Gel 40C/amb RH
` Gel 40C/75 RH
`
`-66
`
`-68
`
`-70
`
`-72
`
`
`
`-58
`
`-60
`
`-62
`
`-64
`
`δ (ppm)
`
`
`
`
`
`
`
`
`x106
`
`8
`
`6
`
`4
`
`2
`
`0
`
`
`The sample does not appear to change upon storage at 40 °C/75% RH. However, significant differences are observed in the sample
`stressed at 40 °C/amb RH. It is unclear at this time what causes these changes. The major cause for concern in this data is the fact
`that the spectrum of the unstressed material is significantly different from that of the unstressed HPMC mixture (see below), even
`though they were made from the same batch of bulk phosphate salt. This indicates that whatever physical changes occur with gelatin
`take place immediately at room temperature. Experiments to determine the nature of these changes are ongoing.
`
`6. Chemical and physical stability of L-224715 phosphate salt in binary dry mixtures with HPMC powder [NB: (60659:160-161,
`164, 170-172, 179)]
`
`
`The chemical and physical stability of L-224715 phosphate salt (5% drug load) in binary mixtures with HPMC powder were
`monitored by HPLC and solid-state NMR, respectively. The chemical stability data are shown in the grid below.
`
`
`L-224715 phosphate salt
`Chemical stability with HPMC
`
`Excipient used: USP, 6 cps
`Lot No: 23537
`Drug lot used: 70316-25
`Drug loading: 5.3%
`NB Reference: 60659-155
`
`sample prep: extracted with 0.1% H3PO4 (3x3.0 mL), syringe-filtered
`
`Sample Temp (C) %RH Time (wk) Sam wt (mg) Drug wt (mg)
`A1 HPMC
`5
`amb
`1
`20.14
`1.07
`C1 HPMC
`40
`amb
`1
`20.52
`1.09
`D1 HPMC
`40
`75
`1
`20.47
`1.08
`A2 HPMC
`5
`amb
`2
`19.95
`1.06
`C2 HPMC
`40
`amb
`2
`21.79
`1.15
`D2 HPMC
`40
`75
`2
`20.84
`1.10
`A4 HPMC
`5
`amb
`4
`20.56
`1.09
`C4 HPMC
`40
`amb
`4
`21.34
`1.13
`D4 HPMC
`40
`75
`4
`20.23
`1.07
`
`Calc conc
`0.119
`0.121
`0.121
`0.117
`0.128
`0.123
`0.121
`0.126
`0.119
`
`Area
`Calc area Area %
`5099896
`97.62 4706732.25
`5196120
`97.03 4762186.93
`5183459
`97.27 4499538.14
`5051783
`98.64 4762116.84
`5517712
`97.66 5051196.58
`5277151
`97.80 4881854.89
`5206249
`98.41 4863821.52
`5403762
`98.17 4866112.71
`5122686
`98.12 3970451.80
`
`% Claim
`0.92
`0.92
`0.87
`0.94
`0.92
`0.93
`0.93
`0.90
`0.78
`
`
`The data indicate no trend for degradation of the drug in the presence of HPMC. Only the data point at 40 °C/75% RH, 4 weeks
`shows a statistically significant deviation from the average % claim. Special attention will thus be paid to probe stability samples in
`HPMC capsules under these conditions.
`
`The HPMC mixture was evaluated by SSNMR (19F) before and after storage at 40 °C/amb RH and 40 °C/75% RH. The overlaid
`–CF3 region of the spectra is shown in the graph below.
`
`
`average
`SD
`
`0.90
`0.05
`
`Merck Exhibit 2153, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MERCK RESEARCH LABORATORIES PROGRESS REPORT
`
`MARCH 2002
`
`
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`Page 5 of 8
`
` HPMC RT
` HPMC 40C/amb RH
` HPMC 40C/75 RH
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`
`
`
`
`
`
`
`x106
`
`-58
`
`-60
`
`-62
`
`-64
`
`-66
`
`-68
`
`-70
`
`-72
`
`
`
`
`The sample appears to have changed little upon storage under either condition, though the shoulder at –63 ppm does seem to grow in
`intensity after storage at 40 °C/amb RH. Experiments are ongoing to identify the cause of the shoulder in the spectra.
`
`7. Chemical and physical stability of L-224715 phosphate salt in binary dry mixtures with mannitols [NB: (60659:164, 167, 168,
`170, 172, 182-183)]
`
`
`The chemical stability of L-224715 phosphate (10% drug load) in dry binary mixtures with mannitols was evaluated after 2 weeks by
`HPLC. The data for Pearlitol and SPI mannitol, respectively, are shown in the grids below.
`
`
`L-224715 phosphate salt
`Chemical stability with Pearlitol 200SD
`
`Excipient used: Pearlitol 200 SD
`Lot No: 5053
`Drug lot used: 70316-35
`Drug loading: 10.2%
`NB Reference: 60659-164
`
`sample prep: diluted to 20.0 mL with 0.1% H3PO4
`
`Sample Temp (C) %RH Time (wk) Sam wt (mg) Drug wt (mg) Calc conc Calc area
`A1 Pearl
`5
`amb
`1
`22.22
`2.27
`0.113
`4872846
`C1 Pearl
`40
`amb
`1
`20.08
`2.05
`0.102
`4403544
`D1 Pearl
`40
`75
`1
`20.41
`2.08
`0.104
`4475913
`A2 Pearl
`5
`amb
`2
`20.36
`2.08
`0.104
`4464948
`C2 Pearl
`40
`amb
`2
`21.23
`2.17
`0.108
`4655739
`D2 Pearl
`40
`75
`2
`22.68
`2.31
`0.116
`4973724
`A4 Pearl
`5
`amb
`4
`20.43
`2.08
`0.104
`4480299
`C4 Pearl
`40
`amb
`4
`21.09
`2.15
`0.108
`4625037
`D4 Pearl
`40
`75
`4
`21.05
`2.15
`0.107
`4616265
`
`Area
`Area %
`97.89 4008565.60
`98.41 3706919.81
`96.76 3894088.06
`96.85 3790639.36
`96.84 3922894.07
`98.38 4193858.00
`
`% Claim
`0.82
`0.84
`0.87
`0.85
`0.84
`0.84
`0.00
`0.00
`0.00
`
`
`
`average
`SD
`
`0.84
`0.02
`
`Merck Exhibit 2153, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

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`MERCK RESEARCH LABORATORIES PROGRESS REPORT
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`MARCH 2002
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`
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`Page 6 of 8
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`L-224715 phophate salt
`Chemical stability with SPI mannitol
`
`Excipient used: SPI mannitol
`Lot No: 24340
`Drug lot used: 70316-35
`Drug loading: 10.3%
`NB Reference: 60659-164
`
`sample prep: diluted to 20.0 mL with 0.1% H3PO4
`
`Area
`Sample Temp (C) %RH Time (wk) Sam wt (mg) Drug wt (mg) Calc conc Calc area Area %
`A1 SPI
`5
`amb
`1
`22.56
`2.32368
`0.116184
`4995912
`98.47 4574692.10
`C1 SPI
`40
`amb
`1
`21.65
`2.22995
`0.1114975
`4794393
`95.69 4148614.43
`D1 SPI
`40
`75
`1
`20.17
`2.07751
`0.1038755
`4466647
`96.86 3886933.31
`A2 SPI
`5
`amb
`2
`21.43
`2.20729
`0.1103645
`4745674
`97.61 4244451.11
`C2 SPI
`40
`amb
`2
`24.5
`2.5235
`0.126175
`5425525
`97.77 4526441.87
`D2 SPI
`40
`75
`2
`20.89
`2.15167
`0.1075835
`4626091
`97.32 3879434.74
`A4 SPI
`5
`amb
`4
`21.48
`2.21244
`0.110622
`4756746
`C4 SPI
`40
`amb
`4
`20.67
`2.12901
`0.1064505
`4577372
`D4 SPI
`40
`75
`4
`23.13
`2.38239
`0.1191195
`5122139
`
`% Claim
`0.92
`0.87
`0.87
`0.89
`0.83
`0.84
`0.00
`0.00
`0.00
`
`
`No degradates are observed in any of the mannitol blends after two weeks on stability. In addition, no significant drop in % claim is
`observed with Pearlitol after two weeks, but the fact that the % claim for the 5 °C reference samples is 82-84% is troubling; it is
`possible that a drop in % claim occurs immediately rather than on stability. With SPI mannitol, the initial % claim is higher (92-89%),
`but a trend in loss of drug does seem to exist at 1 and 2 weeks. The 4-week data will be needed to confirm this trend.
`
`The 2 mannitol blends were evaluated by 19F solid state NMR before they were put on stability. The overlaid –CF3 region of the
`spectra is shown in the graph below along with the spectrum of the same batch of bulk drug for comparison.
`
`
`average
`SD
`
`0.87
`0.03
`
` lot 35 bulk drug
` 10% in Pearlitol 200SD RT
` 10% in SPI mannitol RT
`
`-66
`
`-68
`
`-70
`
`-72
`
`
`
`
`The intial spectrum of the blend with SPI mannitol can be overlaid with the spectrum of the bulk drug. However, the spectrum of the
`Pearlitol blend indicates that significant changes have occurred in the material upon mixing. The nature of these changes will have to
`be investigated further, and the blends will be assessed again by NMR after storage at 40 °C/amb RH and 40 °C/75% RH.
`
`8. Safety Assessment formulation for L-224715 [NB: (60659:173), (26180:1-3)]
`
`
`δ (ppm)
`
`-58
`
`-60
`
`-62
`
`-64
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`x106
`
`Merck Exhibit 2153, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MERCK RESEARCH LABORATORIES PROGRESS REPORT
`
`MARCH 2002
`
`
`
`Page 7 of 8
`
`
`
`
`
`
`
`Solutions of L-224715 phosphate salt were made in two different dosing vehicles (deionized water and 5 mM HCl) to measure their
`pHs and monitor pH stability over 24 hours at ambient temperature. The concentrations of the solutions were based on the
`concentrations needed for dosing in Safety Assessment. The individual solutions are listed in the table below with their intial and final
`pH values.
`
`
`
`No unusual changes in the pH of the solutions were observed over 24 hours at ambient temperature. The pH of the 5 mM HCl
`solutions is in the most stable region for L-224715; quantitative chemical stability measurements (to be done in PAC) should show
`that 5 mM HCl is a superior dosing vehicle (in terms of stability) for L-224715. Note that even the high dose can be dosed as a
`solution in either vehicle.
`
`
`
`Vehicle
`
`deionized water
`deionized water
`deionized water
`deionized water
`deionized water
`deionized water
`5 mM hydrochloric acid
`5 mM hydrochloric acid
`5 mM hydrochloric acid
`5 mM hydrochloric acid
`5 mM hydrochloric acid
`5 mM hydrochloric acid
`
`Conc L-224715
`(mg/mL)
`0.40
`2.07
`4.03
`9.99
`12.27
`36.25
`0.42
`2.02
`4.03
`10.00
`12.00
`36.05
`
`pHinitial
`
`pHfinal
`
`5.59
`5.48
`5.47
`5.14
`5.01
`4.63
`2.56
`2.67
`2.82
`3.03
`3.07
`3.44
`
`6.02
`5.70
`5.67
`5.30
`5.13
`4.72
`2.65
`2.72
`2.85
`3.06
`3.10
`3.49
`
`Title: L-221869 (dipeptidyl-peptidase IV)
` Category: Endocrine/Metabolic
`Target Class: dipeptidyl-peptidase IV
`Compound #: 0726
`Disease: noninsulin-dependent diabetes mellitus Dosage Form/Potency: To Be Determined
`
`Cross Project Function:
`
`Project Team:
`Dept. : 854 – Pharmaceutical Research
`Department Head: Michael Kaufman
`Key Words: Safety Assessment formulation; solubility; water; DMSO
`Summary
`Solutions of L-221869 tartrate were prepared in water to determine if Safety Assessment dosing could be done in
`solution with deionized water as the vehicle. Solutions are attainable at concentrations above the high dose, and
`these solutions are in the stable pH range for L-221869. The solubility of L-221869 tartrate in DMSO is greater
`than 42 mg/mL L-221869.
`
`
`Reporting Area: Pharmaceutical Research & Development
`Sub-Group: Pharmaceutical Chemistry – Rahway
`Author(s): Shultz, Leigh
`
`
`1. Safety Assessment formulation for L-221869 tartrate salt [NB: (60659:167-168, 172), (26180:4)]
`
`In order to determine if solubility of L-221869 tartrate hemi-hydrate in water would allow all SA studies to be done in solution (di
`water only), a sample of L-221869 tartrate salt (005B002, 51.85 mg) was weighed into a centrifuge tube, and 1.50 mL of di water
`were added in 0.50-mL increments. The salt did not dissolve intially, so the sample was placed on the rotator. It was removed after
`10 days, and all of the solid had dissolved. HPLC analysis of the solution indicated that no degradation had occurred over this time.
`This indicates that the solubility of L-221869-005B in water is at least 34.6 mg/mL salt (24.5 mg/mL free base equivalents).
`
`In support of Biopharmaceutical studies for L-221869, a sample was prepared in water to determine if solution was attainable. A
`sample of L-221869-005B002 (60.24 mg) was placed in a vial, and 1.00 mL of deionized water was added. The resulting suspension
`
`Merck Exhibit 2153, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`MERCK RESEARCH LABORATORIES PROGRESS REPORT
`
`MARCH 2002
`
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`was sonicated for 25 minutes (monitored visually every 5 minutes for dissolution), resulting in complete dissolution of the solid. The
`pH of this 60.2-mg/mL solution (42.7 mg/mL free base equivalents) was 3.44, in the stable range for the drug. This concentration is
`above the high dose needed for Biopharmaceutical and Safety Assessment studies (36 mg/mL free base). Thus, all animal studies for
`L-221869 can be done in solution using deionized water as the vehicle, and no added acid will be needed to stabilize the formulation.
`
`The solubility of L-221869 tartrate hemi-hydrate in DMSO was also measured to support Safety Assessment. A sample of L-221869-
`005B002 (20.5 mg) was placed in a centrifuge tube with 0.200 mL DMSO. The sample was equilibrated overnight, after which time
`the drug had completely dissolved. The solubility in DMSO is therefore greater than 72.8 mg/mL L-221869 (102.5 mg/mL tartrate
`salt).
`
`
`
`Page 8 of 8
`
`Merck Exhibit 2153, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`