Salt Selection for L-224715 and L-221869
`
`Leigh Shultz
`Pharmaceutical Chemistry - Rahway
`Pharmaceutical R&D
`
`28 February 2002
`
`DP-IV EDT Meeting
`
`1
`
`Merck Exhibit 2156, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Leigh Shultz
`Pharmaceutical Chemistry - Rahway
`Pharmaceutical R&D
`
`28 February 2002
`
`DP-IV EDT Meeting
`
`1
`
`Merck Exhibit 2156, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Contributors
`
`Process Research
`L-221869: Michael Palucki, Jaemoon Lee
`L-224715: Karl Hansen
`Analytical Research
`L-221869: Yaling Wang, Jason Dorwart
`L-224715: Chris Lindemann, Jason Dorwart
`Pharmaceutical Chemistry
`L-221869: Jules Remenar, James Qin, Leigh Shultz
`L-224715: Leigh Shultz
`Pharmaceutical Physics
`L-221869, L-224715: Dina Zhang
`Formulation Design
`L-221869, L-224715: Yun Liu, Tom Gandek
`
`DP-IV EDT Meeting
`
`2
`
`Merck Exhibit 2156, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Pharmaceutically Acceptable Salts
`
`• Soluble in water, wettable by water or organics
`Improve or maintain bioavailability
`Enable use of wet granulation to improve processibility
`• Non-disproportionating in water (large pKa difference)
`Maintains chemical form in water
`• Low toxicity of counterion
`e.g. oxalate
`• Low/no pharmacological activity of counterion
`e.g. amino acids
`• Non-hygroscopic
`• Acceptable morphology, compactibility
`
`DP-IV EDT Meeting
`
`3
`
`Merck Exhibit 2156, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Evaluation of Free Bases
`
`X
`
`F
`
`F
`
`NH2
`
`O
`
`N
`
`X = F L-221869
`X = H L-224715
`
`N
`
`N
`
`N
`
`CF3
`
`Both compounds:
`• Bioavailability >50% in all species
`• Hydrolysis of amide, de-amination observed
`• Most stable in solution between pH 2-4
`
`L-221869 free base
`• crystalline
`• pKa = 8.0
`• solubility 2.2 mg/mL in water
`
`L-224715 free base
`• crystalline
`• pKa ca. 8
`• solubility 5.9 mg/mL in water
`
`DP-IV EDT Meeting
`
`4
`
`Merck Exhibit 2156, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Formulation Plan for Phase I
`Keep formulations as simple as possible while still maintaining stability:
`1. Dry-filled capsules
`Drug or salt filled directly into a capsule
`• Need good morphology/flow, density, stability with capsule
`• Evaluation at Quintiles (Mar 2002)
`2. Drug/excipient mixture
`Binary mixture of drug and a suitable excipient
`filled in a capsule
`with good flow properties
`• Need stability with capsule and excipient
`• Evaluation at Quintiles (Mar 2002) with mannitol
`3. Liquid-filled hard or
`Drug suspension or solution filled in a capsule
`soft capsule
`•Need solubility and stability in liquid vehicle; stability with capsules
`
`Test capsule formulations versus solution/suspension in dogs
`Parallel development of tablet formulation for Phase II
`
`DP-IV EDT Meeting
`
`5
`
`Merck Exhibit 2156, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Salt Selection Timeline
`
`L-224715 approved
`Salt selection begins
`
`L-224715 phosphate
`tentatively selected
`
`Apr
`
`Feb
`
`Dec
`
`Mar
`
`Jan
`
`L-221869 tartrate
`tentatively selected
`
`Bulk drug form
`selection target
`
`Nov
`
`L-221869 approved
`Salt selection begins
`
`DP-IV EDT Meeting
`
`6
`
`Merck Exhibit 2156, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Salt Formation and Purity
`
`L-221869:
`Toluenesulfonate - from acetonitrile, highly crystalline, single form
`Benzenesulfonate - from IPAc, single form
`L-tartrate - from EtOH
`99.5-99.9% purity (2-3 impurities over 0.05%)
`99.9% enantiomeric purity
`
`L-224715:
`Benzenesulfonate - crystallizes immediately from IPAc; anhydrate formed
`L-tartrate - different crystallization solvents produce different polymorphs
`Phosphate - crystallized from EtOH/water or IPAc
`99.1-99.7% purity (2-3 impurities over 0.05%)
`99.9% enantiomeric purity
`
`DP-IV EDT Meeting
`
`7
`
`Merck Exhibit 2156, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Salts of L-224715: Solution Stability
`
`Hydrolysis of L-224715
`(Relative Area %)
`
`De-amination of L-224715
`(Relative Area %)
`
`28.8
`
`25.3
`
`11.8
`
`7.4
`
`3.8
`
`3.6
`
`6.1
`4.2
`
`5.1
`2.3
`
`FB
`
`BSA
`
`Salt Form
`
`TA
`
`PA
`
`4 w ks
`
`1 w k
`
`30
`25
`20
`15
`10
`
`05
`
`50
`
`40
`30
`20
`10
`0
`
`47.7
`
`41.3
`
`20.4
`
`18.2
`
`8.9
`
`8.3
`
`13.7
`
`6.3
`
`7.8
`3.8
`
`FB
`
`BSA
`
`Salt Form
`
`TA
`
`PA
`
`4 w ks
`
`1 w k
`
`Conditions: unbuffered water, 40 oC, 0.1 mg/mL salt
`
`DP-IV EDT Meeting
`
`8
`
`Merck Exhibit 2156, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Solubility
`
`Salts of L-224715
`
`Salt
`
`Form
`
`Benzenesulfonate
`
`L-tartrate
`
`Phosphate
`
`Form A
`(anhydrate)
`Hemi-
`hydrate
`Form A
`
`Water
`(mg/mL)
`>38.4
`
`0.01N HCl
`(mg/mL)
`>6.3
`
`EtOH
`(mg/mL)
`>20.8
`
`2-PrOH
`(mg/mL)
`3.94
`
`>8.3
`
`>81
`
`>7.8
`
`>58
`
`0.82
`
`0.036
`
`0.067
`
`0.079
`
`Salts of L-221869
`
`Salt
`
`Benzenesulfonate
`
`L-tartrate
`
`Toluenesulfonate
`
`Form
`
`Form A
`
`Hemi-
`hydrate
`Form A
`
`Water
`(mg/mL)
`>14
`
`0.01N HCl
`(mg/mL)
`>7
`
`>16.5
`
`10.43
`
`>14.3
`
`>8.6
`
`EtOH
`(mg/mL)
`
`2-PrOH
`(mg/mL)
`
`0.59
`
`0.12
`
`DP-IV EDT Meeting
`
`9
`
`Merck Exhibit 2156, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Physical Data on Salts
`
`L-224715
`• L-tartrate (at least 5 forms)
`• highly crystalline; mp 210 oC; hygroscopic, forms hemi-hydrate
`• Benzenesulfonate (5 forms identified)
`• Form A: mp 176 oC; forms hemi-hydrate above 85% RH
`• Phosphate (2 forms)
`• Form A: mp 216 oC; non-hygroscopic; physically stable for 1 week
`
`L-221869
`• Benzenesulfonate (1 form)
`• mp 174 oC; non-hygroscopic
`• L-tartrate (2 forms)
`• mp 204 oC; hygroscopic: fast, reversible formation of hemi-hydrate
`
`DP-IV EDT Meeting
`
`10
`
`Merck Exhibit 2156, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Morphologies
`
`Benzenesulfonate
`
`Flakes, aggregated
`
`Rods
`
`L-221869
`
`L-224715
`
`L-tartrate:
`fine needles
`
`Phosphate:
`Flakes
`
`DP-IV EDT Meeting
`
`11
`
`Merck Exhibit 2156, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Current Status of Salt Selection
`L-224715
`• Phosphate tentatively selected as lead due to stability, morphology
`• Identification/relative stability of polymorphs and pseudomorphs
`• Evaluation of stability with capsules and excipients
`• Further evaluation of physical properties
`
`L-221869
`• L-tartrate tentatively selected as lead due to stability
`• Identification/relative stability of polymorphs and pseudomorphs
`• Evaluation of stability with capsules and excipients
`• Further evaluation of physical properties
`
`DP-IV EDT Meeting
`
`12
`
`Merck Exhibit 2156, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
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