`
`
`M E M O
`
`TO:Drazen Ostovic
`
`CC:Trish Hurter
`Ivan Santos
`
`FROM:
`Leigh Shultz
`
`CONTIBUTORS:Tom Gandek
`Chris Lindemann
`Kiki Luna
`Kari Lynn
`Dina Zhang
`
`SUBJECT:Pharmaceutical Evaluation of L-224715
`
`DATE:09 Apr 2002
`
`L-224715 is a DP-IV inhibitor for the treatment of type II Diabetes Mellitus. The phosphate salt form
`has been chosen for development. The following report, written for inclusion in the SARC Technical
`Review Package, describes the chemical and physical properties of L-224715 phosphate known to date.
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 1
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`IPR2020-00040
`
`

`

`
`Summary
`1.
`
`L-224715 is a DP-IV inhibitor for the treatment of Type II Diabetes Mellitus. It is being developed as
`the crystalline phosphate salt, which exists as a single anhydrous polymorph to date. The phosphate salt
`is chemically stable in the bulk for 4 weeks under all conditions studied and is most stable in solution
`between pH 2-4. It consists of flake-like particles, with the mean particle size of the A-sheet delivery lot
`around 100 m. The material is cohesive and has good overall flow properties.
`
`L-224715 was dosed to both rats and dogs in solution and exhibited linear pharmacokinetics with no
`adverse effects noted. The Phase I formulation will be neat drug dry-filled into HPMC capsules using
`the Xcelodose 600 , which was able to fill 0.1 mg (free base equivalents) of drug into a capsule in
`trials run by PR&D. HPMC capsules containing L-224715 phosphate show acceptable dissolution
`profiles both initially and after 4 weeks of storage at 40 °C/75% RH; 20-mg potency HPMC capsules
`dosed orally to dogs show similar exposures to the 2 mg/kg solution dose.
`
`2.
`
`Description
`
`L-224715 is a DP-IV inhibitor for the treatment of Type II Diabetes Mellitus. It has an improved in
`vitro profile over the Probiodrug compound P32/98 (L-000826), previously in development, and its
`backup, L-221869.
`
`L-224715 is a -amino acid derivative with a molecular weight of 407.321 g/mol and a molecular
`formula of C16H16F6N5O. It is being developed as the monobasic phosphate salt (L-224715-006F),
`molecular weight 505.317 g/mol (salt factor 0.806). The structure of the phosphate salt is shown in the
`figure below.
`
`OH
`
`PO
`
`O
`
`H
`
`N
`
`N
`
`N
`
`O
`
`N
`
`NH3
`
`O
`
`F
`
`F
`
`F
`
`CF3
`Figure 1. Structure of L-224715-006F (monobasic phosphate salt)
`
`The phosphate salt is a white crystalline powder consisting of flake-like particles; this morphology
`affords good flow properties.
`
`3.
`
`Test Substances
`
`Chemical stability data were obtained using lot 70316-25 (bulk, gelatin mixtures, HPMC mixtures).
`Physical characterization data is primarily from the A-sheet delivery lot L-224715-006F006 (72471-11).
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
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`

`
`Solubility data (exceptions noted in text) were generated with lot 70316-25. Physical stability data and
`Biopharmaceutical data were generated from lot 70316-35. Mechanical properties were determined
`using lot 70316-31.
`
`4.
`
`Physical Characterization
`
`Microscopy
`Samples of L-224715 phosphate salt were examined by optical microscopy and SEM and were found to
`consist of flake-like particles with some agglomeration. A representative SEM image
`(L-224715-006F006, A-sheet delivery lot) is shown in Figure 4.1 below.
`
`Figure 4.1. SEM image of L-224715-006F006 (210X magnification)
`
`Particle Size Distribution
`The PSD of several lots of L-224715 phosphate salt were determined in Physical Measurements on the
`Microtrac SRA150 (Table 4.1). Samples were sonicated for 30 seconds in Isopar G prior to
`measurement.
`
`Table 4.1. Particle size of L-224715-006F
`Lot
`Mean ( m)
`95%< ( m) %<5 m
`70316-077 (006F003)
`38.4
`90.0
`1.5
`70316-079 (006F004)
`35.1
`75.8
`0.1
`72471-011 (006F006)
`92.3
`212.4
`5.6
`
`The mean particle size of the flakes increased in the A-sheet delivery lot (006F006) with respect to
`earlier lots. The particle size distributions are illustrated graphically in Figure 4.2 below.
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
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`
`

`

`
`
`10
`
`L-224715 Phosphate Salt
`Particle Size Distribution
`
` 'A-sheet Delivery'
` '70316-079'
` '70316-077'
`
`8
`
`6
`
`4
`
`2
`
`0
`
`%Channel
`
`0.1
`
`1
`
`10
`Size (microns)
`Figure 4.2. Particle size distributions for lots of L-224715-006F
`
`100
`
`1000
`
`Thermal Properties
`Samples of L-224715-006F were analyzed by DSC and TGA to determine the melting point and
`residual solvent level of the salt. Representative DSC and TGA traces are shown below (Figure 4.3).
`
`Sample: L-224715 Phosphate Salt A-sheet
`Size: 3.4280 mg
`Method: 10CPMTO250C
`Comment: 10 cpm, open cup, nitrogen (DSC-1)
`0
`
`DSC
`
`File: H:...\L224715\72471-011.001
`Operator: cml
`Run Date: 26-Mar-02 08:41
`
`50
`
`150
`100
`Temperature (°C)
`
`200
`
`250
`Universal V2.6D TA Instruments
`
`218.61°C
`
`-2
`
`-4
`
`Heat Flow (W/g)
`
`-6
`
`0
`
`Exo Up
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
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`

`
`
`Figure 4.3. DSC (top) and TGA (bottom) traces for L-224715-006F006
`
`DSC data were collected in an open pan with heating at 10 °C/min under nitrogen. The melting point of
`the salt is 218.6 °C. The melt endotherm cannot be quantitated due to immediate decomposition of the
`solid upon melting. TG analysis shows 0.056% weight loss between 50 °C and the onset of melting,
`indicating little solvent remaining on the solid.
`
`X-ray Powder Diffraction
`XRPD analysis of the phosphate salt of L-224715 shows several strong reflections between 2-40 °2,
`indicating this high crystallinity of the salt. No amorphous halo has been noted in any sample to date.
`The XRPD pattern for the A-sheet delivery lot is shown in Figure 4.4 below and is representative of the
`data obtained from samples of L-224715 phosphate salt from Process Research.
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
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`
`

`

`
`L-224715 Phosphate Salt
`X-ray Powder Diffraction
`
` '72471-011'
`
`4000
`
`3000
`
`2000
`
`1000
`
`counts/sec.
`
`10
`
`20
`°2theta
`Figure 4.4. XRPD pattern for L-224715-006F006
`
`30
`
`40
`
`Hygroscopicity
`The hygroscopicity of L-224715-006F006 (delivery lot) was measured using the VTI dynamic vapor
`sorption balance at 25 °C. The material is non-hygroscopic, showing a weight increase of less than 0.5
`wt% between 5 and 95% RH. On the time scale of the vapor sorption experiment, no hydrates form, and
`the material has the same physical form by DSC and XRPD after the hygroscopicity determination.
`
`L-224715 H3PO4 Salt
`Adsorption/Desorption Isotherm
`
`Adsorption
`Desorption
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`%RH
`
`0.600
`
`0.500
`
`0.400
`
`0.300
`
`0.200
`
`0.100
`
`0.000
`
`-0.100
`
`-0.200
`
`Weight (% change)
`
`Figure 4.5. Adsorption/Desorption Isotherm for L-224715-006F006
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
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`

`
`Solubility
`The phosphate salt of L-224715 is highly water soluble, and equilibrium solubilities have not been
`obtained to date due to the large material requirements for such a soluble compound. The available
`solubility data in both aqueous and organic systems is shown in Table 4.2 below.
`
`Solvent
`
`Table 4.2. Solubility of L-224715-006F
`L-224715-006F
`L-224715-000T
`pHinitial
`(mg/mL)
`(mg/mL)
`>100, <150
`>81, <121
`water
`>72
`>58
`saline
`>75
`>61
`0.01 N HCl
`0.41
`0.33
`methanol
`0.24
`0.19
`ethanol
`0.098
`0.079
`2-propanol
`>154
`>124
`DMSO**
`*volume of solution too low to measure pH
`**measured using lot 70316-35
`
`6.13
`5.57
`2.08
`n/a
`n/a
`n/a
`n/a
`
`pHfinal
`
`*
`*
`*
`n/a
`n/a
`n/a
`n/a
`
`Although the final volume of the aqueous solutions was too low to measure pH, solutions of increasing
`concentration were prepared by dissolving L-224715 (lot 70316-43) in deionized water, and the pH of
`these solutions was measured after 24 hours of equilibration. The pH data for these solutions appears in
`Table 4.3 below.
`
`Table 4.3. pH values for L-224715
`phosphate salt solutions
`L-224715-000T
`(mg/mL)
`0.40
`2.07
`4.03
`9.99
`12.27
`36.25
`
`pH
`6.02
`5.70
`5.67
`5.30
`5.13
`4.72
`
`The pHs of aqueous solutions of the phosphate salt of L-224715 decrease with increasing concentration,
`consistent with an acidic salt.
`
`Dissolution and Solution Properties
`L-224715-006F dissolves readily in water, acidic solution, and simulated gastric fluid. Dissolution rate
`should not limit the bioavailability of this compound, and 0.1N HCl can be used as a dissolution
`medium.
`
`5.
`Stability
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
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`

`
`
`Bulk Stability
`The bulk stability data for the phosphoric acid salt of L-224715 are shown in Table 5.1 below. Data are
`reported in area % relative to samples stored at 20 °C.
`
`Table 5.1. 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; no degradates are detected by
`HPLC.
`
`Solution Stability
`The solution stability data for the phosphate salt of L-224715 are shown in Table 5.2. Data are reported
`in area % relative to samples stored at 20 °C.
`
`Conditions
`
`water
`pH 2
`pH 4
`pH 6
`pH 8
`pH 10
`
`Table 5.2. 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 the free base 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 free base and other salts of this compound which were considered for
`development. 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. Salt selection was completed on 01 Mar 2002 based
`primarily on this stability data.
`
`Degradation Mechanism
`Degradation of L-224715 occurs via two major pathways: amide bond cleavage and elimination (de-
`amination). Table 5.3 shows the growth of both types of degradates in solution samples of
`L-224715-006F over time as a function of pH. Only one of the two amide bond cleavage products is
`shown in the table.
`
`Table 5.3. Degradation of L-224715-006F as a function of pH at 40 °C
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
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`

`2.0
`
`4.0
`
`6.0
`
`8.0
`
`
`pH Time (wks) Area % amide
`Area %
`bond cleavagea
`elimination
`ndb
`nd
`1
`nd
`nd
`2
`nd
`nd
`4
`nd
`nd
`1
`nd
`nd
`2
`nd
`nd
`4
`0.25
`nd
`1
`0.54
`nd
`2
`1.15
`0.45
`4
`6.13
`2.92
`1
`12.13
`4.10
`2
`22.43
`10.65
`4
`11.44
`3.45
`1
`22.10
`6.46
`2
`39.81
`9.64
`4
`acleavage product at RRT 0.91
`bnot detected
`
`10.0
`
`
`
`The proposed degradation products are shown in Figure 5.1.
`
`F
`
`F
`
`F
`
`F
`
`F
`
`F
`
`NH2
`
`O
`
`L-224715
`
`N
`
`N
`
`base
`or
`acid
`
`N
`
`N
`
`CF3
`
`O
`
`N
`
`N
`
`N
`
`N
`
`CF3
`
`F
`
`F
`
`F
`
`F
`
`F
`
`F
`
`F
`
`F
`
`F
`
`NH2
`
`O
`
`HN
`
`O
`
`N
`
`N
`
`N
`
`CF3
`
`OR
`
`HN
`
`O
`
`amide bond cleavage
`degradates
`
`O
`
`N
`
`N
`
`N
`
`N
`
`CF3
`
`elimination (de-amination) degradates
`
`Figure 5.1. Proposed degradation pathways for L-224715
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
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`

`
`Amide bond cleavage increases with increasing pH and was originally proposed to be due to base-
`catalyzed hydrolysis, producing the triazolopiperidine and the -amino acid. The presence of the
`triazolopiperidine in degraded samples has been confirmed by comparison to samples of the fragment
`provided by Process Research. However, the other amide bond cleavage degradate does not match the
`HPLC retention time of the -amino acid, and the UV spectrum of this degradate indicates that it has the
`same chromophore as the parent molecule. It is possible that amide bond cleavage occurs via attack of
`the primary amine on the amide carbonyl to form a -lactam, producing the triazolopiperidine as a side
`product. NMR studies to confirm this hypothesis are underway. De-amination is thermally induced and
`produces both unsaturated species shown in Figure 5.1. This elimination pathway was observed in the
`bulk free base on stability, but no elimination degradates were observed over 4 weeks in the phosphate
`salt. Both of these degradation pathways are best avoided by keeping the material protonated (in a low-
`pH environment) and crystalline.
`
`Physical Stability
`The phosphate salt of L-224715 is known to exist as a single crystalline polymorph, which is an
`anhydrate. The physical stability of L-224715-006F001 was monitored on storage at 25 °C/60% RH
`(open dish), 40 °C/amb RH (closed dish), and 40 °C/75% RH (open dish). No physical changes were
`observed in the salt by DSC or TGA over 3 weeks under these storage conditions.
`
`Excipient Compatibility
`In order to investigate the stability of L-224715-006F in the presence of capsule materials, dry blends of
`L-224715 phosphate salt were prepared with gelatin powder (base-cured) and HPMC powder at 5%
`loading. The stability data for these blends is presented in Tables 5.4 and 5.5.
`
`Table 5.4. Stability of L-224715-006F in dry blends with gelatin
`Conditions
`Time (wks) Rel Area % L-224715 Rel % Claim
`40 °C/amb RH
`1
`72.5
`73.4
`40 °C/amb RH
`2
`104.9
`117.7
`40 °C/amb RH
`4
`82.3
`87.8
`40 °C/75% RH
`1
`70.6
`72.3
`40 °C/75% RH
`2
`116.6
`125.3
`40 °C/75% RH
`4
`96.5
`100.0
`
`Table 5.5. Stability of L-224715-006F in dry blends with HPMC
`Conditions
`Time (wks) Rel Area % L-224715 Rel % Claim
`40 °C/amb RH
`1
`99.4
`100.0
`40 °C/amb RH
`2
`99.0
`97.9
`40 °C/amb RH
`4
`99.8
`96.8
`40 °C/75% RH
`1
`99.6
`94.6
`40 °C/75% RH
`2
`99.1
`98.9
`40 °C/75% RH
`4
`99.8
`83.9
`
`Gelatin presents analytical problems that skew the data for the gelatin blends and obscure any trend that
`might be observed in the data. Gelatin was intially predicted to present stability problems with
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 10
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`
`

`

`
`L-224715 due to its high levels of equilibrium moisture and residual hydroxide levels (caused by the
`curing process). HPMC does not present the same analytical problems, and the stability data for the
`HPMC blends indicates compatibility with L-224715-006F. Based on this data and the analytical
`problems with gelatin, HPMC capsules were chosen for the Phase I formulation. Some drop in % claim
`is noted after 4 weeks of storage at 40 °C/75% RH with HPMC, but this observation is not borne out by
`dissolution testing (see section 9).
`
`6.
`
`Analytical Methods
`
`High Performance Liquid Chromatography
`The HPLC method used to quantify degradation in the bulk and in solution is as follows:
`
`System:
`Column:
`Mobile phase:
`Flow:
`Detector:
`Temperature:
`Inj.vol:
`Diluent:
`Gradient:
`
`Perkin Elmer Series 200
`MetaSil AQ C18 3 m 100X4.6 mm
`A) 0.1% phosphoric acid B) acetonitrile
`1.0 mL/min
`210 nm
`ambient
`20 L
`0.1% phosphoric acid
`A
`B
`
`time
`0
`1.5
`2.5
`8
`10.5
`14
`
`98
`98
`95
`50
`10
`10
`
`2
`2
`5
`50
`90
`90
`
`L-224715 elutes at 9.3 minutes using this method.
`
`The method was modified by PAC and will be used for probe and ICH stability assays.
`
`System:
`Column:
`Mobile phase:
`Flow:
`Detector:
`Temperature:
`Inj.vol:
`Diluent:
`Sample conc.
`Gradient:
`
`HP 1100
`YMC-Pack ODS-AM 5 m 250X4.6mm
`A) 0.1% phosphoric acid B) acetonitrile
`1.0 mL/min
`210 nm
`40 °C
`20 L
`0.1% phosphoric acid
`0.1mg/mL of L224715/L221869
`A
`B
`
`time
`2
`98
`0
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
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`

`
`2
`98
`2
`13
`59
`41
`16
`59
`41
`25
`30
`70
`27
`30
`70
`28
`98
`2
`36
`98
`2
`
`7.
`
`Biopharmaceutical Properties
`
`Summary of Absorption Kinetics for L-224715 Phosphate Salt in Rats and Dogs
`Fasted, male Sprague-Dawley rats (Charles River) were used for the rat studies. Fasted male Beagle dogs
`(Marshall Farms) were used for the dog studies. All animals were fasted for 16 hours prior to dosing. In both rats
`and dogs, L-244715 displayed linear kinetics with both mean AUC and Cmax values increasing proportionally with
`dose (Tables 7.1 and 7.2). Absorption was rapid with Tmax occurring within 2 hours for all dose levels. Plasma
`clearance of the oral doses is constant, as reflected in the parallel elimination phases in figures 7.1 and 7.2. No
`adverse effects were noted in any of the animals.
`
`Table 7.1. Absorption Kinetics for L-224715 Phosphate Salt Orally Dosed at
`2, 10 and 50 mg/kg to Fasted Beagle Dogs
`(Mean ± Standard Deviation)
`
`Dose
`
`2 mg/kg
`10 mg/kg
`50 mg/kg
`
`AUC0-24hr
`( Mhr)
`9.59
` 1.46
`59.0
` 8.5
`399
` 50
`
`AUC0-
`( Mhr)
`9.76
` 1.49
`60.3
` 9.1
`414
` 52
`
`Cmax
`( M)
`1.69
` 0.44
`9.54
` 1.24
`52.3
` 16.0
`
`Tmax
`(hr)
`0.58
` 0.38
`0.42 ± 0.14
`1.33 ± 0.58
`
`Table 7.2. Absorption Kinetics for L-224715 Phosphate Salt Orally Dosed at
`20, 60 and 180 mg/kg to Fasted Rats
`(Mean ± Standard Deviation)
`
`Dose
`
`20 mg/kg
`60 mg/kg
`180 mg/kg
`
`AUC0-24hr
`( Mhr)
`15.7
` 2.3
`52.2
` 5.8
`208
` 28
`
`AUC0-
`( Mhr)
`15.8
` 2.2
`52.6
` 6.1
`209
` 28
`
`Cmax
`( M)
`4.55
` 0.57
`15.6
` 2.7
`32.3
` 10.5
`
`Tmax
`(hr)
`0.42
` 0.14
`0.42 ± 0.14
`1.67 ± 0.58
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
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`

`
`
`L-224715 Phosphoric Acid Salt Solutions Orally Dosed
`To Fasted Beagle Dogs at 2, 10 and 50 mg/kg
`(arithmetic mean ± SD)
`
`100
`
`10
`
`1
`
`0.1
`
`2 mpk
`L-224715 Plasma Concentration, µM
`50 mpk
`10 mpk
`
`0.01
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time, hours
`
`Figure 7.1. Mean plasma concentration time profiles for L-224715 Phosphate Salt in Beagle Dogs
`
`L-224715 Phosphate Salt Orally Dosed to
`Fasted Male Rats at 20, 60 and 180 mg/kg
`(arithmetic mean ±SD)
`
`20 mg/kg
`60 mg/kg
`180 mg/kg
`
`100
`
`10
`
`1
`
`0.1
`Plasma Concentration, µM
`
`0.01
`
`0
`
`4
`
`8
`
`12
`Time, hours
`Figure 7.2. Mean plasma concentration time profiles for L-224715 Phosphate Salt in Rats
`
`16
`
`20
`
`24
`
`8.
`Mechanical Properties
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
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`

`

`
`
`A preliminary physical characterization was performed on L-224715-006F. The phosphate salt 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. The phosphate also displayed capping/sticking upon compression, and changes in the compressed sample
`were indicated by XRPD and DSC.
`
`Morphology
`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 8.1. SEM micrographs of L-224715-70316-031.
`
`Particle Size Distribution
`The particle size distribution was characterized by Microtrac using Isopropanol as the 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.
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 14
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`
`

`

`
`
`L-224715-70316-031
` Sonication = 0 s
` Sonication = 30 s
` Sonication = 90 s
`
`12
`
`10
`
`8 6 4 2 0
`
`1
`
`10
`
`100
`
`Figure 8.2. PSD of L-224715-70316-031.
`
`Solvent and Pressure Effects
`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, the phosphate salt 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.
`
` 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
`
`Heat Flow (J/g)
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 15
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`IPR2020-00040
`
`

`

`
`
` L-224715 phosphate
` Compressed at 22,000 psi
`
`500
`
`400
`
`300
`
`200
`
`100
`
`Intensity
`
`10
`
`20
`Diffraction Angle
`
`30
`
`40
`
`Figure 8.3. 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 8.1. 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
`
`9.
`
`Phase I Formulation
`
`The Phase I formulation for L-224715 is dry-filled capsules (DFC) containing neat drug. The capsules
`will be filled using Meridicas Xcelodose
` 600 dry powder dispensing/capsule filling equipment. The
`equipment uses a novel tapping method to dispense a discrete amount of powder for each tap, which
`depends on powder properties as well as the size and number of holes in the selected dispense screen.
`Capsules are separated, filled, recapped, and sorted into accepts and rejects based on specified limits
`(Figure 9.1). During powder filling, individual capsules are set on a six-place balance, tared, and
`weighed. Individual fill weights are recorded, and capsules outside specified limits are rejected.
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 16
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`
`

`

`
`
`capsule
`separation
`(capsule feeder
`not shown)
`
`re-capping
`and
`discharge
`station
`
`rejects
`
`accepts
`
`hopper
`
`capsule holder
`
`balance
`
`Figure 9.1. Xcelodose 600
`
`Feasibility trials were completed in March using this technology with three laboratory batches of
`L-224715. The three batches had different morphologies and flow properties, but all three could be
`accurately dispensed by selecting appropriate dispense screens. Trial results are summarized in Table
`9.1.
`
`Table 9.1. Xcelodose Capsule Filling Results with L-224715-phosphate salt
`
`Capsule
`
`Potency Fill weight
`L-224715-006F001
`0.8 mg
`1.0 mg
`0.8 mg
`1.0 mg
`0.8 mg
`1.0 mg
`8 mg
`10 mg
`L-224715-006F004
`75 mg
`93 mg
`L-224715-006F003
`Shionogi HPMC #0
`75 mg
`93 mg
`Shionogi HPMC #2
`0.5 mg
`0.62 mg
`0.1 mg
`0.124 mg Shionogi HPMC #2
`
`Capsugel gelatin #2
`Capsugel HPMC #2
`Shionogi HPMC #2
`Shionogi HPMC #2
`
`Shionogi HPMC #0
`
`# capsules
`filled
`
`RSD
`
`35
`117
`131
`12
`
`80
`
`23
`107
`68
`
`2.2%
`1.8%
`2.0%
`1.8%
`
`2.0%
`
`1.1%
`2.0%
`2.2%
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 17
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`IPR2020-00040
`
`

`

`
`Size #00 capsules will be required to contain the highest requested Phase I potency (100 mg). Parts were
`not available at the time of the feasibility work but will be available in time for Phase I manufacture.
`
`Formulations to be manufactured for Phase I are:
`
`
`Potency
`0.5 mg
`2.5 mg
`25 mg
`100 mg
`
`Capsule
`Fill weight
`Opaque Shionogi HPMC #2
`0.62 mg
`Opaque Shionogi HPMC #2
`3.1 mg
`Opaque Shionogi HPMC #2
`31 mg
`124 mg Opaque Shionogi HPMC #00
`
`Capsule Dissolution Studies
`L-224715-006F was hand-filled into both HPMC and gelatin capsules (10-mg potency). Dissolution
`testing was performed in Simulated Gastric Fluid. Samples were tested initially and after 4 weeks of
`storage at 40 °C/75% RH (open dish). Dissolution conditions are listed below.
`
`Dissolution Parameters (n=3)
`Apparatus: USP II (paddles)
`Agitation: 50 RPM
`Medium:
`Simulated Gastric Fluid (without enzymes)
`Volume:
`900mL, 10-mg potency
`Temperature: 37
` 0.5 °C
`Sample Times: 4 mL at 0, 5, 10, 15, 30, 60, 75 min (at 75 min was set at 150RPM)
`Sinkers:
`Helical
`
`Results are summarized in Figures 9.1 and 9.2 below. Results indicated fast dissolution and more
`consistent profiles for HPMC capsules compared to gelatin capsules. Results for gelatin capsules
`showed more variability, and based on visual observations the variability is related to clumping of the
`gelatin during initial dissolution of the capsules. Stressing the capsules for 4 weeks made negligible
`changes in their dissolution profiles.
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 18
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`IPR2020-00040
`
`

`

`
`L-715 HPMC capsules
`Initial and after 4 weeks storage at 40C/75RH (open dish)
`SGF, 37C, USP II, N=3
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`HPMC Initial
`
`L-715 HPMC in SGF after 4 wk.
`
`0
`
`10
`
`20
`
`30
`Time (Min.)
`Figure 9.1. Average dissolution profiles for L-224715-006F in HPMC capsules
`
`40
`
`50
`
`60
`
`L-715 Gelatin Capsules
`Initial and after 4 weeks storage at 40C/75%RH (open dish)
`SGF, 37C, 50 rpm, USP II (n=3)
`
`4 weeks
`
`Initial
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`10
`
`20
`
`Figure 9.2. Average dissolution profiles for L-224715-006F in gelatin capsules
`
`30
`Time (Min.)
`
`40
`
`50
`
`60
`
`Absorption Kinetics for L-224715 Phosphate Salt Capsules in Dogs
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 19
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`Hand-filled HPMC capsules containing 20 mg of L-224715 (free base equivalents) were dosed orally to fasted
`male beagle dogs to determine the exposure relative to a 2 mg/kg oral solution dose.
`
`L-224715 was well absorbed from the capsule formulation (Figure 9.3). The mean AUC and Cmax values after
`capsule or solution formulation are not statistically different (Table 9.2). The mean Tmax value from the capsule
`formulation was delayed relative to the solution formulation, possibly due to the time lag required for dissolution
`of the capsule and compound.
`
`Table 9.2. Absorption Kinetics for L-224715 Phosphate Salt Orally
`Dosed to Fasted Beagle Dogs
`(Mean ± Standard Deviation)
`
`Dose
`
`AUC0-24hr
`( Mhr)
`2 mg/kg Solution*
`9.59
` 1.46
`20 mg Capsule
`8.53
` 1.32
`* Solution data from Table 7.1 above
`
`AUC0-
`( Mhr)
`9.76
` 1.49
`8.76
` 1.40
`
`Cmax
`( M)
`1.69
` 0.44
`1.26
` 0.17
`
`Tmax
`(hr)
`0.58
` 0.38
`2.33 ± 1.53
`
`L-224715 Phosphate Orally Dosed to Beagle Dogs
`(arithmetic mean ± SD, n=3)
`
`1
`
`0.1
`
`Plasma Concentration, µM
`
`2 mg/kg Solution
`20 mg Capsule
`
`0.01
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time, hours
`Figure 9.3. Mean Plasma Concentration Time Profiles for
`L-224715 Phosphate Salt in Beagle Dogs
`
`U:\L224715\Pharm Eval SARC Tech Rev L-224715.doc
`
`Merck Exhibit 2147, Page 20
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`