`for a New Drug Candidate: Selection of the Final
`Form via Integrated Chemical and Pharmaceutical
`Process Evaluation
`Speakers
`Cindy Starbuck, Patricia Hurter, Robert Wenslow
`Co-authors
`Joseph Armstrong, Alex Chen, Stephen Cypes,
`Russell Ferlita, Karl Hansen, Mahmoud Kaba, Ivan Lee, Dina Zhang
`
`Contributors
`
`Danielle Euler, Tom Gandek, Jeff Givand, Brad Holstine, Feng Li, Yun Liu, Ernestina
`Luna, Kari Lynn, Robert Meyers, James Ney, Saurabh Palkar, Leigh Shultz, Iris Xie
`
`Merck Exhibit 2122, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Outline
`
`Salt Selection
`Desired particle properties for early formulation work
`Crystallization studies
`Polymorph characterization
`Development targets
`Emergence of a new crystal form during late stage development
`Chemical/Physical characterization
`Formulation characterization
`Biocomparability
`
`2
`
`Merck Exhibit 2122, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Early Salt Selection Activities
`
`For rapid entry into Phase I, wanted dry filled capsule
`Salt selection focused on morphology as well as stability (v. soluble drug,
`bioavailability good)
`Targeted DC process for market formulation
`
`Salt A
`
`Salt B
`
`Phosphate
`
`3
`
`SEMs from Dina Zhang
`
`Merck Exhibit 2122, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Early Salt Selection - Stability
`
`All salts stable in bulk at 80oC/amb and 40oC/75%RH
`Hydrolysis and deamination occur in solution
`
`Deamination
`Free Base
`Phosphate
`Salt B
`Salt A
`
`0
`
`1
`
`3
`2
`Weeks
`
`4
`
`5
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`% Deamination in Solution
`
`Hydrolysis
`
`Free Base
`Phosphate
`Salt B
`Salt A
`
`0
`
`1
`
`3
`2
`Weeks
`
`4
`
`5
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`% Hydrolysis in Solution
`
`Phosphate salt chosen for Phase I, on the basis of morphology and
`stability
`
`4
`
`Merck Exhibit 2122, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Market Formulation Development
`
`Initial studies
`Probe formulations for excipient compatibility
`Investigation of physical stability, with wet granulation and compression
`Compaction simulator studies
`Investigation of feasible drug loading range (1% to max.)
`Process selection
`Wet granulation, roller compaction, direct compression options
`DC most desirable if particle characteristics amenable
`If DC promising, two processes in parallel until delivery of API from pilot
`plant lot
`
`5
`
`Merck Exhibit 2122, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Excipient/Process Choices
`
`PVP
`
`HPC
`
`PVP
`
`Dry - Avicel
`Dry - Mannitol
`Wet - Avicel
`Wet - Mannitol
`
`Dry process more stable
`API properties (flow,
`compactibility, bulk density)
`suitable for DC processing
`Blend uniformity not an issue,
`drug loading ~ 25%
`
`HPC
`PVP
`
`HPC
`
`-1
`
`-0.5
`
`0
`Drug load
`
`0.5
`
`HPC
`
`PVP
`HPC
`HPC
`PVP
`1
`
`1.5
`
`PVP
`
`DC selected as the lead process and RC developed
`as a back-up
`
`6
`
`3.5
`
`3
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`% area deg after 4 wk 60C/amb
`
`0
`-1.5
`
`Merck Exhibit 2122, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Desired Particle Characteristics for Early Development
`
`Particle size distribution
`Mean of 20-200µ, unimodal distribution, low fines
`Particle shape
`Not needles (rods, plates, cubic, spherical)
`Stickiness
`Hard to quantify, affected by size and morphology, residual solvent (?),
`polymorph (?)
`Bulk density
`High enough for processing
`Flow
`Acceptable flow for processing
`Compactability and compressibility
`Forms integral compacts with acceptable hardness at required drug
`loading
`
`7
`
`Merck Exhibit 2122, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Small-Scale Evaluation of API Characteristics
`
`Prior to first pilot plant campaign, extensive evaluation of effect
`of crystallization conditions on API characteristics and
`pharmaceutical processability
`SEM examination (morphology, agglomeration)
`Particle size distribution (mean, fines, unimodal, width of distribution)
`Compaction simulator
`Neat drug vs formulated
`Measure tensile strength, ejection force (binding)
`Sticking evaluation on manual single tablet press
`Flow evaluation
`Bulk/tap density, calculate Carrs I ndex
`
`8
`
`Merck Exhibit 2122, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Compaction Simulator Results
`Tensile Strength of Compacts
`
`Varying crystallization conditions affected tensile strength of neat
`drug and formulated compacts
`Tensile Strength of Neat Drug
`
`3
`
`100
`200
`300
`400
`Compaction Pressure (MPa)
`
`500
`
`9
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`0
`
`0
`
`Tensile Strength (MPa)
`
`Merck Exhibit 2122, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Small-Scale Evaluation of Particles
`
`Density
`(g/cc)
`Agg
`Bulk Tap
`?
`Y 0.27 0.37
`Y 0.26 0.40
`Less 0.25 0.44
`Less 0.25 0.44
`Y 0.25 0.43
`Y 0.24 0.45
`N 0.23 0.42
`Y 0.31 0.46
`
`Median
`Size
`Lot#
`(µm)*
`99
`A
`65
`B
`20
`C
`39
`D
`50
`E
`64
`F
`50
`G
`62
`H
`*30s sonication
`Crystallization conditions that would generate material similar to
`Lot A were chosen for the first pilot plant batch
`
`Tensile
`Strength
`Neat Form.
`2.27 3.50
`1.76 3.50
`1.81 3.75
`2.00 3.64
`2.00 2.80
`1.78 2.94
`1.80 3.40
`1.50 3.06
`
`Carr's
`Index
`27
`35
`43
`43
`42
`46
`45
`33
`
`10
`
`Merck Exhibit 2122, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`First pilot plant batch - process flow diagram
`
`Seed load,
`point,
`PSD optimized
`
`Solvent endpoint
`optimized for yield
`
`1 wt% seed
`
`Ethanol, water
`
`Crystallizer
`
`Drying
`temp stressed
`
`Agitated Filter Dryer
`
`Filter, dry at 40 C
`
`discharge
`
`11
`
`Merck Exhibit 2122, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`First pilot plant batch - results
`
`Wetcake found to be friable during filtration/drying
`Agitated filter dryer implemented in pilot plant (scaleable)
`Particle size decrease from 43µm (slurry) to 34 µm (wetcake) to 14 µm
`(dry cake)
`
`PSD shift w/ processing
`
`Sonication = 30s
`Drycake
`Wetcake
`Crystallization Slurry
`
`1
`
`10
`
`Particle Size (um)
`
`100
`
`1000
`
`12
`
`15
`
`10
`
`5 0
`
`Merck Exhibit 2122, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Early deliveries vs First Pilot Plant Batch
`
`Prep Lab
`
`Prep Lab
`
`Pilot Plant Batch 1
`
`Pilot Plant
`
`
` L-224715
`Sonication =30 s
` Lot # 006F0016
`Lot # 006F0017
` PPB#1-2
`
`Prep Lab
`
`Measured size = agglomerate
`size
`
`Agglomerates (+ single
`crystals) found to be shear
`sensitive at large scale
`
`15
`
`10
`
`5
`
`0
`
`Frequency (%)
`
`Frequency %
`
`1
`
`100
`10
`Particle Size (µm)
`Particle Size (um)
`
`1000
`13
`
`Merck Exhibit 2122, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Second pilot plant batch - process flow diagram
`
`Increase seed
`load to increase
`growth rate
`
`1 wt% seed
`
`Ethanol, water
`
`Crystallizer
`
`Agitated Filter Dryer
`
`Used minimal
`agitation during
`filtration
`
`Filter, dry at 40 C
`
`De-coupled filtration
`from drying; use lower
`shear dryer
`
`14
`
`Conical dryer
`
`discharge
`
`Merck Exhibit 2122, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Second pilot plant batch - results
`Batch #1
`Batch #2
`
`Batch #3
`
`B#1
`B#2
`B#3
`
`1
`
`10
`
`Particle Size (um)
`
`100
`
`1000
`
`15
`
`10
`
`5
`
`0
`
`% Frequency
`
`15
`
`Lot
`
`Batch#1
`Batch#2
`Batch#3
`
`Bulk Density
`Loose Tapped
`0.30
`0.56
`0.53
`0.76
`0.55
`0.81
`
`Mean
`PSD
`14
`55
`70
`
`Flowdex
`(<25 good)
`34
`18
`16
`
`Merck Exhibit 2122, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Flowability
`
`Larger PSD API from subsequent pilot plant campaigns improved flow
`and pharmaceutical processability
`
`45
`
`Bad Flow
`
`Flodex (mm)
`
`Good Flow
`
`40
`
`35
`
`30
`
`25
`
`20
`
`15
`
`Prep Lab
`
`Pilot Plant
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Particle Size (um)
`
`1
`
`2
`
`4
`3
`GMP Lots
`
`5
`
`6
`
`16
`
`Merck Exhibit 2122, Page 16
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`A new problem emerges: multiple polymorphs!
`
`Batch#
`
`B#1
`B#2
`B#3
`
`+ EtOH
`
`- EtOH
`
`Crystal Form
`Packaged from
`Dryer
`I + III
`II
`II
`
`Crystal Form upon
`Storage
`I + III
`I + III
`I + III
`
`Form II
`
`Form I
`
`?
`
`Form III
`
`Dry in
`Filter in
`Agitated Conical
`Filter/dryer
`Dryer
`
`Package
`
`17
`
`EtOH
`solvate
`
`Slurry
`
`Merck Exhibit 2122, Page 17
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Anhydrous Phases
`?
`
`?
`
`?
`
`Channel
`Solvate
`Critical Issues
`
`Form II
`
`Form I
`
`Form III
`
`Which are the MOST relevant phases
`Thermodynamic Stability/Kinetics of Transformation
`Water Solubility (Biopharm Performance)
`Chemical/Physical Stability (API and Tablets)
`Conversion upon drying/grinding/compaction (Pharm Processing)
`CRYSTALLIZATION OF PURE PHASE
`
`18
`
`Merck Exhibit 2122, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Solvate/Form II
`
`Solvent
`
`Form II
`
`Channel
`Solvate
`Conversion Conditions
`Isomorphic non-stoichiometric channel solvates with many solvents
`Solvate Formation at all solvent/H2O ratios
`Form II is de-solvate
`Identical XRPD/Raman compared to solvate
`SSNMR only method for Form II identification
`Early crystallizations formed solvate then dried to anhydrous Form
`Form II converts to Form I (<10 min) in water slurry
`
`19
`
`Merck Exhibit 2122, Page 19
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Form I/Form III
`
`Form I
`
`shear
`
`Form III
`
`Conversion Conditions (From Experience)
`Form III formed during drying/grinding/compaction
`Mixtures of Form I/III in API and formulations
`
`CRYSTALLIZE PURE, STABLE POLYMORPH
`
`Critical Experiments
`Determine thermodynamically stable polymorph at RT
`Identify kinetics of solid-solid conversion as well as solvent mediated conversion
`
`20
`
`Merck Exhibit 2122, Page 20
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Thermodynamic Stability
`
`4.98
`
`4.96
`
`4.94
`
`4.92
`
`4.9
`
`4.88
`
`4.86
`
`4.84
`
`4.82
`
`4.8
`
`Ln(Solubility)
`
`ln(solubility)
`
`4.78
`0.00322
`
`0.00324
`
`0.00326
`
`0.00328
`
`0.0033
`
`34 °C
`Forms I and III are very close in energy (10-2 kcal/mol)
`Likely to get mixtures
`solid state turnover during drying - morphology set by Form II template
`solid state turnover during compaction
`
`Form I
`
`Form III
`
`Form I
`
`Form III
`
`0.00334
`
`0.00336
`
`0.00338
`
`0.0034
`
`0.00342
`
`0.00332
`1/T (K-1)
`
`1/T (K-1)
`
`21
`
`Merck Exhibit 2122, Page 21
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Anhydrous Phases - characterized
`
`Channel
`Solvate
`
`Solvent
`
`Form II
`
`RT
`
`Form I
`
`shear
`
`Form III
`
`Ttrans = 34 °C
`
`Water Solubility vs.
`Temperature of pure Forms
`
`Drying induces polymorph conversion
`Compaction induces polymorph conversion
`
`MIXTURES
`
`22
`
`Merck Exhibit 2122, Page 22
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Polymorphism - Anhydrous Polymorphs
`
`API process produced mixtures of Form I/III
`Experiments were conducted to determine effect of polymorph conversion
`on pharmaceutical processability
`Particle size/fines had a larger effect on processability than form
`
`Flow (shear cell)
`
`Intrinsic Dissolution
`
`Form I
`Form II
`Form III
`
`80x10-3
`
`60
`
`40
`
`20
`
`0
`
`Concentration (mg/ml)
`
`Concentration (mg/ml)
`
`Form III
`Form I (converted Form III)
`
`Form II
`Form I (converted Form II)
`
`50
`100
`150
`200
`Consolidation Stress (g/cm^2)
`Consolidation Stress (g/cm2)
`
`250
`
`0
`
`5
`
`10
`15
`20
`Time (minutes)
`Time (minute)
`
`25
`
`30
`
`23
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`Unconfined Yield Stress (g/cm2)
`
`Unconfined Yield Stress (g/cm^2)
`
`Merck Exhibit 2122, Page 23
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Pure Step Development Goals for Campaign II
`
`Reduce drying time cycle
`Projected factory time cycle for drying > 24 hours
`Understand filtration/drying-mediated attrition
`Minimize fines production (=> associated with sticking?)
`Understand/eliminate drying-mediated polymorph turnover
`Search for alternate (non-solvating) solvent?
`Deliver samples to Pharm R&D for comparative testing
`
`24
`
`Merck Exhibit 2122, Page 24
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Solvent screening performed to find non-solvating solvent
`
`Solvent
`
`Water*
`Methanol
`Ethanol
`1-Propanol
`2-Propanol
`t-Butanol
`Cyclohexanol
`Ethyl Acetate
`Acetone
`MIBK
`Butyl Ether
`THF
`n-Hexane
`Cyclohexane
`n-Heptane
`Toluene
`Acetonitrile
`DMF
`DMAC
`DMSO
`MTBE
`Methylene Chloride
`Diethoxymethane
`Methyl Benzoate
`Isoamyl Alcohol
`
`Form a
`Solvate?
`N
`Y
`Y
`Y
`Y
`N
`N
`Y
`Y
`N
`Y
`Y
`N
`N
`N
`N
`Y
`Y
`Y
`Y
`N
`Y
`Y
`N
`N
`
`Becomes
`Amorphous?
`N
`N
`N
`N
`N
`Y
`Y
`N
`N
`N
`N
`N
`N
`N
`N
`Y
`N
`N
`N
`N
`N
`N
`N
`
`N
`
`* = As of Feb 2003
`
`Free Base
`Soluble?
`N
`Y
`Y
`
`Y
`
`Y
`
`Y
`N
`N
`N
`Y
`
`Y
`Y
`Y
`
`Y
`
`25
`
`Phosphate
`Salt Soluble?
`Y
`
`Degrades
`Product?
`N
`
`Miscible with
`Phosphoric
`Acid?
`Y
`
`N
`
`N
`
`N
`N
`N
`N
`Gels
`
`Y
`N
`N
`
`Sparingly
`N
`
`N
`
`Y
`
`N
`
`N
`
`Y
`
`Y
`
`Y
`
`Y
`N
`N
`
`Y
`
`Merck Exhibit 2122, Page 25
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Lab work with non-solvating solvent: enter the
`Monohydrate!
`
`Successfully generated Form I directly
`from isoamyl alcohol needle morphology
`
`Incorporated 5% water to improve particle
`size and morphology
`new crystal form emerged !!
`(Monohydrate!)
`
`An aside. . .van t Hoff plot for Forms I/III: solubilities
`measured in water!
`
`26
`
`Merck Exhibit 2122, Page 26
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Properties of monohydrate
`
`Water Solubility (free base eq) = 68 mg/ml (Anhydrous = 108 mg/ml)
`Morphology is rod-like
`Non-hygroscopic, picks up <1% at 75%RH (4.5% at 95%RH)
`All anhydrous forms, when put in water, now turn over to monohydrate
`(previously, Form I)
`
`300 µm
`
`100 µm
`
`50 µm
`
`27
`
`Merck Exhibit 2122, Page 27
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`New Physical Property Action Plan
`
`Water solubility/tablet dissolution
`Dehydration potential
`Higher hydrates?
`Chemical/Physical API stability
`Physical stability during Milling/Compaction
`
`28
`
`Merck Exhibit 2122, Page 28
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Kinetics of Water Loss for Monohydrate
`Isothermal TG N2 Flow
`
`Time (min)
`
`29
`
`Weight %
`
`Merck Exhibit 2122, Page 29
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Form Conversion Starting with Monohydrate
`?
`?
`?
`
`Monohydrate
`
`Dehydrated
`monohydrate
`
`Form IV
`
`Form I
`
`Hot stage XRPD
`RT (monohydrate)
`90oC 4 hours (dehydrated monohydrate)
`110oC new spectrum (Form IV confirmed by SSNMR)
`130oC (Form I)
`Back to Ambient (Form I)
`
`INTERCONVERSION
`
`30
`
`Merck Exhibit 2122, Page 30
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Hygroscopicity vs. Temperature
`
`Pure Monohydrate
`No Dryer Step, Long Equilibration Time, Lowest RH = 0.8%
`25°C
`40°C
`
`Monohydrate NEVER loses water at 25°C and 40°C >0.8%RH
`Material remains Monohydrate
`
`31
`
`Merck Exhibit 2122, Page 31
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Extended Temperature Hygroscopicity Data
`
`Pure Monohydrate
`
`60°C
`
`80°C
`
`0.080
`0.060
`0.040
`0.020
`0.000
`0.00
`
`Weight%
`
`0.250
`0.200
`0.150
`0.100
`0.050
`0.000
`0.00
`
`Adsorption
`Starting Weight
`
`10.00
`
`15.00
`
`20.00
`
`5.00
`
`4.00
`RH%
`60°C Returns to original water content at ~6% RH
`80°C Returns to original water content at ~10% RH
`Material remains Monohydrate
`
`Weight%
`
`Adsorption
`Starting weight
`
`2.00
`
`6.00
`
`8.00
`
`32
`
`Merck Exhibit 2122, Page 32
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Solid Phases in Monohydrate System
`
`ambient
`
`DEAD END
`
`Monohydrate
`
`40°C 130°C
`N2 flow
`
`Dehydrated
`monohydrate
`
`60°C 130°C
`
`Form IV
`(anhydrous)
`
`130 ~ 180 C
`
`Form I
`
`RH=98%, RT
`
`Water slurry with
`or without
`monohydrate seed
`
`33
`
`Merck Exhibit 2122, Page 33
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`API perspective - the case for monohydrate
`
`Monohydrate
`
`Anhydrous (I/III)
`
`Crystallization IPA/Water or IAA/Water
`IPA/Water or EtOH/Water
`Thermo stab regions mapped vs. H2O content Thermo stab regions mapped vs. water content
`Monohydrate crystallized directly
`
`Agglomerated morphology; Form II template
`
`Drying
`
`No potential for dehydration if dried
`without sweep
`
`Polymorph conversion Form II to I/III mixtures
`
`Bulk Chem Stab 4 wk no degradation
`-20C, 40C, 40C/75RH, 80C
`
`Physical Stab No Physical change on stability
`Bulk and Tablets
`
`Regulatory
`
`Single crystal form
`
`12 month no degradation
`-20C, 40C, 40C/75RH, 60C
`
`Mixtures going into stab
`No change in mixture content on stab
`(bulk and tablets)
`Mixtures; must be controlled
`
`34
`
`Merck Exhibit 2122, Page 34
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Pharm processing: evaluation of monohydrate
`
` Anhydrous
`
`Monohydrate
`
`Morphology/Shape
`
`Density [g/cm3]
`Loose
`Tapped
`
`Flodex
`
`Sticking (mg/ml)
`
`Mean Particle Size
`(µm)
`
`0.55
`0.81
`
`19
`
`0.124
`
`77
`
`35
`
`0.28
`0.55
`
`32
`
`0.0043
`
`143
`
`Merck Exhibit 2122, Page 35
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
` Monohydrate
` Compressed at 200 Mpa
`
`Effect of Compaction on Form Conversion
`
`Monohydrate
`No form conversion
`
`2000
`
`1500
`
`1000
`
`500
`
`Intensity
`
`Anhydrous:
`Compaction:
`Form II Form I/III
`Form I Form I/III
`Form III Form I/III
`Compaction always results in
`Form I/III mixture
`
` Form II
` Form III
` Compressed Form II
`
`10
`
`20
`Diffraction Angle
`
`30
`
`40
`
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`0
`
`Intensity
`
`10
`
`20
`Diffraction Angle
`
`30
`
`40
`
`36
`
`Merck Exhibit 2122, Page 36
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Drug Product Processing Effect
`
`Anhydrous
`After Shearing
`All forms (I, II, III)
`Particle breakage
`
`Monohydrate
`No form conversion
`No particle breakage
`
`I/III mix
`
`Monohydrate
`Sheared at 300 rpm
`Sheared at 600 rpm
`
`3
`
`4 5 6 7 8
`
`10
`
`3
`
`2
`
`4 5 6 7 8
`100
`Particle Size (µm)
`
`2
`
`3
`
`4 5 6 7
`
`12
`
`10
`
`8 6 4 2 0
`
`% Frequency
`
`37
`
` Form III
` Shearing
` Tubula Blending
` V-Shell Blending
` FormII
`
`5
`
`10
`
`15
`20
`Diffraction Angle
`
`25
`
`30
`
`35
`
`7000
`
`6000
`
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`0
`
`Intensity
`
`Merck Exhibit 2122, Page 37
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Tablet Sticking reduced with Monohydrate
`
`5 minute compression run on Korsch press (9kN force)
`Comparable formulations with monohydrate exhibited less punch
`sticking than those with anhydrous polymorph
`
`Anhydrous API Formulation
`
`Monohydrate API Formulation
`
`38
`
`Merck Exhibit 2122, Page 38
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Color formation in formulations
`
`Stressed formulations discolor, linked to low levels of impurities in
`excipients
`Monohydrate API less susceptible to discoloration
`Drug substance stressed with impurities at
`various RH, 50oC
`
`Anhydrous
`
`Monohydrate
`
`0.03
`
`0.02
`
`0.01
`
`0.00
`
`Absorbance at
`
`350nm
`
`20
`
`40
`60
`Relative Humidity (%)
`
`80
`
`39
`
`Merck Exhibit 2122, Page 39
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Chemical Stability of Monohydrate vs Anhydrous
`
`Chemical stability of monohydrate formulations superior to anhydrous
`
`Open Dish Stability of Comparable Formulations (40oC/75%RH)
`1
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0
`
`Anhydrous I/III
`
`Monohydrate
`
`Total Degradates (% claim)
`
`0
`
`2
`
`4
`
`6
`
`8
`10
`12
`Time (weeks)
`
`40
`
`14
`
`16
`
`18
`
`20
`
`Merck Exhibit 2122, Page 40
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Compactability of Monohydrate vs Anhydrous
`
`Initially, monohydrate formulations appeared to have lower tensile
`strength than anhydrous formulations
`
`Tablet Hardness
`
`Anhydrous
`Monohydrate
`
`25% Drug Load
`Formulation A
`
`33% Drug Load
`Formulation B
`
`41
`
`012345678
`
`Tablet Hardness (kPa)
`
`Merck Exhibit 2122, Page 41
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Effect of Crystallization Solvent on Monohydrate Properties
`
`Comparing monohydrate from IPA/water vs ISAA/water
`Higher tensile strength
`Stronger crystal strength
`More difficult to lose crystalline water
`
`ISAA/Water
`
`IPA/Water
`
`IPA/Water
`
`ISAA/Water
`
`L-224715-010X011
`66839-113 (unmilled monohydrate)
`L-224715-70223-211
`
`200
`300
`100
`Compaction Pressure (MPa)
`Compaction Pressure (MPa)
`
`400
`
`42
`
`3
`
`2
`
`1
`
`0
`
`0
`
`Tensile Strength (MPa)
`
`Tensile Strength (MPa)
`
`Merck Exhibit 2122, Page 42
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Crystal Structure by Atomic Force Microscopy
`IPA/Water
`ISAA/Water
`
`1 µ m
`
`100 nm
`
`2 µ m
`
`Layered
`Structure with a
`thickness of 3.5-
`4.2 nm
`
`1 µ m
`
`43
`
`Merck Exhibit 2122, Page 43
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Biopharmaceutical Comparison
`
`High solubility API (68 mg/ml), no effect on absorption expected
`Dog study disaster check confirms no effect on dog PK
`
`Anhydrous and Monohydrate Forms in an HPMC
`Capsule Dosed Orally to Beagle Dogs (n=4)
`
`Anhydrous
`Monohydrate
`
`Plasma Concentration, µM
`
`Time, hours
`
`44
`
`Merck Exhibit 2122, Page 44
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`Decision to Switch to Monohydrate Form
`
`Physical stability
`Monohydrate showed improved physical stability over anhydrous forms
`Anhydrous Forms undergo form conversion; loss of crystallinity during drying
`and compaction
`Chemical Stability
`Less color development with monohydrate-based tablets
`Lower levels of degradation with monohydrate vs anhydrous
`Dessicant not required for monohydrate packaging
`Biopharmaceutical equivalence
`Animal studies (mice, rats, dogs) showed exposure levels (PK) equivalent
`Chem Processability
`Reduced concern over Form change and particle breakage during drying.
`Improved yield; streamlined process.
`Pharm Processability
`Reduced sticking on tablet punch.
`
`45
`
`Merck Exhibit 2122, Page 45
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`