`MEMO
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Joe Armstrong
`
`
` TO:
`Cindy Starbuck
`
`Ivan Santos
`
`Patricia Hurter
`
`Conrad Winters
`
`Robert Wenslow
`Dina Zhang
`
`
`Yun Liu, Rebecca Wall; Angela Spartalis,
`Leonardo Allain, Feng Li; Russell Ferlita; Narayan
`Variankaval; Alex M. Chen; Leigh Shultz
`
` FROM:
`
`
`CONTRIB
`UTORS:
`
`
`
`
`
`
`
`
`
`
`a
`
`
`
`
`
`
`
`
`
`
`
` LOC:
`
` LOC:
`
`
`
`
`
`
`
` DATE: 26 Feb 2003
`
`
`
`
`
`
`SUBJECT:
`
`
`Compilation of L-224715 Phosphate Salt
`Anhydrous Polymorph Data
`
`
`
`Summary
`
`There are three known anhydrous polymorphs in the L-224715 phosphate salt system (Form I,
`II, and III).
`
`Form II has only been witnessed from de-solvation of the ethanol solvate and is a metastable
`Form, which converts to predominately Form I with some Form III upon storage. Heating or
`exposure to water vapor accelerates the conversion.
`
`The anhydrous polymorphs Form I and Form III are enantiotropically related. The
`thermodynamic conversion temperature, as measured by solubility in water using the shake-
`flask method, was determined to be 34°C. Form III is the thermodynamically stable form
`below 34°C, and Form I is the thermodynamically stable form above 34°C:
`
`XRPD and SSNMR methods have recently been developed to perform Form quantitation of
`Forms I and III in bulk API. Both methods have ~10% limit of detection for either Form I or
`Form III. IR and Raman are also capable of distinguishing and possibly quantifying Form I
`and Form III in bulk API. SSNMR is currently the only method developed for Form
`quantitation in drug product samples.
`
`
`
`
`1
`
`Merck Exhibit 2119, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Delivered lots of API to date have either been mixtures of Form I/Form III or Form II. Lots
`that were Form II on delivery converted to Form I in all stations except refrigeration. Lots
`that were mixtures of Form I/Form III do not change their polymorph content on stability.
`
`Form I and II change to a mixture of Form I and III upon compression. Increasing
`compaction pressure increased Form III content, however, pure Form III has not been
`observed in any compact analyzed. Form III appears less affected by compression pressure
`with minimal Form content change upon compaction.
`
`The difference in the flowability, intrinsic dissolution and compactability of the three forms
`are small. Overall, the impact of the form is relatively small compared to the particle
`characteristics.
`
`All tablets end up with a mixture of Form I and III regardless of the starting point (Form I, II
`or III). In addition no apparent difference in the dissolution profiles of the tablets made by
`using three different forms was observed. The tablets were completely dissolved by 7 minutes,
`with full release by 10 minutes.
`
`
`
`2
`
`Merck Exhibit 2119, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`TABLE OF CONTENTS
`
`
`
`
`Contents
`Characterization of delivered lots and physical stability
`
`Forms in capsules/tablets for clinical supply
`
`Effect of compression pressure on Form conversion
`
`Intrinsic dissolution of Forms
`
`Van’t Hofft plot/water solubility of Forms
`
`Form turnover in solid slurry samples
`
`Effect of wet granulation
`
`Effect of Form on processability
`
`Summary of Action Items
`
`Page Numbers
`4-5
`
`6-7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13-14
`
`15
`
`Section
`I
`
`II
`
`III
`
`IV
`
`V
`
`VI
`
`VII
`
`VIII
`
`
`
`
`
`3
`
`Merck Exhibit 2119, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`I. Forms in all API lots and physical stability of lots
`
`Below is a table with Physical Characteristic data for all delivered lots:
`
`
`Lot
`
`F006
`
`F007
`
`F016
`
`F017
`
`F019
`
`F020
`
`F023
`
`F024
`
`Crystal Form
`
`I/III
`
`I/III
`
`I/III
`
`I/III
`
`Particle Size
`Average (µm) 92
`95% < (µm)
`212
`%< 25 µm
`13
`
`Surface Area (m2/g) NT
`
`63
`143
`17
`
`7.77
`
`48
`118
`28
`
`2.33
`
`62
`139
`20
`
`2.78
`
`II
`
`42
`83
`22
`
`3.10
`
`15.8
`
`I/III
`
`II
`
`15
`30
`87
`
`47
`104
`21
`
`2.38
`
`II
`
`65
`167
`19
`
`4.59
`
`Morphology
`
`Source
`Amount
`
`NT
`
`plates
`
`plates
`
`plates
`
`plates
`
`plates
`
`plates
`
`plates
`
`Lab
`450 g
`
`Lab
`590 g
`
`Lab
`5.1 kg
`
`Lab
`4.4 kg
`
`Lab
`2.5 kg
`
`PP
`42.8 kg
`
`PP
`19.2 kg
`
`PP
`34.8 kg
`
`Currently in our lab we have an XRPD and fluorine SSNMR method to quantitate polymorph
`Form I and Form III in bulk API. At actual time of delivery for all lots, neither of these
`methods was fully developed. Therefore, we do not have quantitative numbers for lots at
`actual time of delivery. However, Form content of various lots on chemical stability are
`displayed below:
`
`
`Stability
`Time = 0
`Apr-02
`
`Jun-02
`
`Oct-02
`
`Oct-02
`
`Dec-02
`
`
`
`Lot #
`006F007
`006F007
`006F007
`006F007
`
`006F016
`006F016
`006F016
`
`006F019
`006F019
`006F019
`
`006F020
`006F020
`006F020
`
`006F024
`006F024
`006F024
`
`Time
`Point
`9 month
`9 month
`9 month
`6 month
`
`7 month
`7 month
`7 month
`
`3 month
`3 month
`3 month
`
`3 month
`3 month
`3 month
`
`1 month
`1 month
`1 month
`
`Station
`Freezer
`Refrig.
`25/60
`40/75
`
`Freezer
`25/60
`40/75
`
`Freezer
`25/60
`40/75
`
`Freezer
`25/60
`40/75
`
`Freezer
`25/60
`40/75
`
`XRPD
`-
`-
`-
`-
`
`Form I (%)
`58.9
`63.6
`65.3
`62.5
`
`Form III (%)
`41.1
`36.4
`34.7
`37.5
`
`-
`-
`-
`
`-
`-
`-
`
`-
`-
`-
`
`-
`-
`-
`
`74.6
`75.5
`73.1
`
`91.3
`87.1
`90.4
`
`81.2
`85.3
`86.1
`
`Form II + Form I
`89.5
`89.1
`
`25.4
`24.5
`26.9
`
`8.7
`12.9
`9.6
`
`18.8
`14.7
`13.9
`
`-
`10.5
`10.9
`
`4
`
`Merck Exhibit 2119, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`
`
`It is clear that all lots have converted to mixtures of Form I and Form III at elevated
`temperature and humidity conditions. If we assume the freezer sample is similar to what the
`Form content was at time of delivery, no significant Form conversion is occurring on stability.
`The only exception is lot 24 which originally contained Form II, this lot converts to Form
`I/Form III mixtures at elevated temperature and/or humidity. This suggests that Form I/Form
`III mixtures retain their form content on stability.
`
`Action Items;
`
`1.
`
`
`Continue monitoring physical form of delivered lots (will be performed as delivered
`and as pulled from stability station)
`
`
`
`5
`
`Merck Exhibit 2119, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`II. Forms in all capsules/tablets for clinical supply
`
`Currently, the only method available to monitor Form content in drug product (DP) tablets is
`fluorine SSNMR. This analysis has been completed on DC tablets from Phase I multi-dose
`studies as well as Phase IIB studies:
`
`Formulation
`Capsule
`Tablet
`Tablet
`
`Clinical Trial
`Phase I SD
`Phase I MD
`Phase IIB
`
`Drug Load
`
`25%
`25%
`
`Form of API Lot in Freezer
`Form III
`Form I
`58.9
`41.1
` 33.0
`67.0
`Form II + Form I
`
`Form in Formulation
`% Form III
`% Form I
`NA
`NA
`44.6
`55.4
`53.6
`46.4
`
`Lot of API used
`006F007
`006F017
`006F024
`
`Additionally, samples of purest phase content Form I (converted from Form II, lot 24), Form
`II (lot 24), and Form III (NB# 70223-156-S6) were separately mixed with excipients in
`formulation composition similar phase IIB at 25% drug load. The form content of these
`samples were analyzed before and after compaction:
`Form in mix before compaction
`Form I
`Form III
`71.2
`28.8
`89.2
`10.8
`14.5
`85.5
`
`Form Used
`Form I
`Form II
`Form III
`
`Sample ID
`DL51
`DL52
`DL53
`
`The dissolution profile of these tablets is given below:
`
`
`Form after compaction
`% Form I
`% Form III
`34.4
`65.6
`44.0
`56.0
`29.7
`70.3
`
`Tablets of different Forms of L-000224715 - 50 mg potency
`0.01N HCl, 50 RPM, USPII, 37oC, n=3
`
`Form I
`Form III
`Form II
`
`120.0
`
`100.0
`
`80.0
`
`60.0
`
`40.0
`
`20.0
`
`% claim
`
`0.0
`
`0
`
`10
`
`20
`
`30
`
`40
`Time (min)
`
`50
`
`60
`
`70
`
`
`As shown from the figure above, there is no apparent difference in the dissolution profiles of
`the tablets made by using three different forms. The variability at the 5-minute time-point is
`
`
`
`
`
`6
`
`Merck Exhibit 2119, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`due to tablet break-up and not drug dissolution. The tablets were completely dissolved by 7
`minutes, with full release by 10 minutes.
`
`In summary, compaction clearly affects Form content in DC tablets regardless of what Form
`of API is used. All DC tablets analyzed to date have been mixtures of Form I and Form III.
`There is no apparent difference in dissolution profile in separate tablets made from Form I,
`Form II, and Form III API.
`
`Action Plan:
`
`1.
`2.
`3.
`4.
`
`
`Analyze capsules used in Phase I single dose studies (by 14 March 2003)
`Monitor Form content in stability DC tablets (as pulled)
`Obtain data on RC tablets (by 15 March 2003)
`Perform analysis of form content in vehicle used for safety assessment studies (14
`March 2003)
`
`
`
`7
`
`Merck Exhibit 2119, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`III. Effect of Compression pressure on Form conversion
`
`Samples of purest phase content Form I, Form II, and Form III were separately compacted at
`150 and 250Mpa. The form content before and after compaction is given below:
`
`
`Form Used
`Form I (Lot 20)
`Form II (Lot 24)
`Form III (Cogeim)
`
`
`Form of API before compaction
`Form III
`Form I
`81.2
`18.8
`Form II and Form I
`-
`14.7
`85.3
`
`Form after 150MPa Compaction
`% Form I % Form III
`52.3
`47.7
`48.1
`51.9
`21.3
`78.7
`
`Form after 250MPa Compaction
`% Form I % Form III
`NA
`NA
`29.7
`70.3
`23.0
`77.0
`
`
`Forms I and II change to a mixture of form I and III upon compression. It appears the higher
`the compaction pressure, the higher the amount of Form III that is formed. However, pure
`Form III is not produced under any compaction pressure attempted. Form III appears less
`affected by compression pressure with minimal Form content change upon compaction. This
`data is consistent with DC tablet data indicating that regardless of starting Form content, all
`DC tablet or pure API compacts are Form I/Form III mixtures of varying Form content.
`
`
`
`
`
`
`8
`
`Merck Exhibit 2119, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`IV. Intrinsic dissolution of different forms:
`
`The intrinsic dissolution of Form I, Form II, and Form III was investigated. The experiment
`was performed by compressing 100 mg of bulk API at 250 Mpa. The form content before and
`after compaction are given below:
`Form of API before compaction
`Form I
`Form III
`67.0
`33.0
`Form II and Form I
`-
`14.7
`85.3
`
`Form after Compaction (250MPa)
`% Form I
`% Form III
`25.8
`74.2
`29.7
`70.3
`23.0
`77.0
`
` Form I
` Form II
` Form III
`
`
`
`80x10-3
`
`60
`
`40
`
`20
`
`0
`
`Concentration (mg/ml)
`
`Form Used
`Form I (Lot 17)
`Form II (Lot 24)
`Form III (Cogeim)
`
`
`The dissolution rate was measured in an USP II apparatus (900 ml and 50 RSP). The
`dissolution solution was sampled over a period of 30 minutes. The samples were then
`analyzed by HPLC. The data showed that the intrinsic dissolution of Form III was slightly
`faster than form I and II.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`
`5
`
`10
`
`15
`Time (minute)
`
`20
`
`25
`
`30
`
`
`
`
`
`9
`
`Merck Exhibit 2119, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`V. Van’t Hofft Plot/Water solubility of Forms
`
`Form II is a metastable anhydrous Form that is a de-solvated EtOH solvate. Form II converts
`to primarily Form I when exposed to water vapor or elevated temperature. In water Form II
`converts to Form I in less than ten minutes, making an accurate determination of the Form II
`equilibrium solubility practically impossible. However, the solubility in water of Form II can
`be assumed to be as high as that of Form I .
`
`The solubility in water at 23.9oC for Form I and Form III are given below:
`
`
`Form Content Before Solubility
`Form I
`Form III
`95.6
`4.4
`16.6
`83.4
`
`Form Used
`Form I (73047-033)
`Form III (Cogeim)
`
`The anhydrous polymorphs Form I and Form III are enantiotropically related. The
`thermodynamic conversion temperature, as measured by solubility in water using the shake-
`flask method, was determined to be 34°C. Form III is the thermodynamically stable form
`below 34°C, and Form I is the thermodynamically stable form above 34°C:
`
`
`Solubility in Water at 23.9C
`129.6 mg/ml
`124.7 mg/ml
`
`Solubility vs Temperature in Water
`L-000224715 Phosphate Salt
`
`y = 1632279.0529x2 - 11589.2522x + 25.3817
`R2 = 0.9995
`
`y = 3473146.2910x2 - 24120.2795x + 46.6640
`R2 = 1.0000
`
`4.98
`
`4.96
`
`4.94
`
`4.92
`
`4.9
`
`4.88
`
`4.86
`
`4.84
`
`4.82
`
`4.8
`
`ln(solubility)
`
`4.78
`0.00322
`
`0.00324
`
`0.00326
`
`0.00328
`
`0.0033
`
`0.00332
`1/T (K-1)
`
`0.00334
`
`0.00336
`
`0.00338
`
`0.00342
`
`0.0034
`Form I
`Form III
`
`
`
`
`
`10
`
`Merck Exhibit 2119, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`VI. Form turnover in Solid slurry samples of Form I/Form III mixtures in water as a
`function of temperature
`
`Approximately 50/50 mixtures of Form I and Form III were slurred in water at 5, 25, and 45oC
`for 48 hours. Two trials were completed at each temperature. The solids remaining were air
`dried and analyzed for form content. The data is given below:
`
`Form before slurry
`% Form I
`%Form III
`56.4
`43.6
`56.4
`43.6
`
`
`56.4
`43.6
`56.4
`43.6
`
`Slurry Temp
`5
`5
`
`25
`25
`
`Form after water slurry for 48 hours
`% Form I
`% Form III
`52.6
`47.4
`46.4
`53.6
`
`
`52.6
`47.4
`NA
`NA
`
`56.4
`56.4
`
`43.6
`43.6
`
`45
`45
`
`73.6
`75.4
`
`26.8
`24.6
`
`
`At 5 and 25oC, a minimal conversion to Form III is observed. At 45oC, clear conversion to
`Form I is occurring. This data is consistent with the determined thermodynamic transition
`temperature of 34oC (see above). The kinetics of form conversion, however, appear to be quite
`slow, especially the Form I to Form III conversion.
`
`
`Action Plan
`
`1.
`
`
`
`2.
`
`
`
`
`
`Repeat slurry turnover experiments using an extended temperature range (completed
`by 31March 2003).
`
`Determination of Kinetics of Form I/III conversion and activation energies (Early
`April 2003).
`
`
`
`11
`
`Merck Exhibit 2119, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`VII. Forms after Wet Granulation in water/IPA, spray coating onto Avicel
`
`To understand the physical stability of L-224715 in wet processes, Form I, II and III were
`granulated with water at a 50% L/S level. No significant form changes were observed for
`Form I and III after the granulation. However, Form II was converted to mostly Form I, as
`indicated by XRPD. In addition, it was found that recrystallization of L-224715 from water
`yielded mostly Form I. The recrystallized material had broad diffraction peaks, suggesting a
`decrease in crystallinity, which was further confirmed by SSNMR.
`
`Morphological examination on the wet granulated and recrystallized samples revealed that
`little change occurred during wet granulation, however, the morphology of the recrystallized L-
`221715 was markedly different from that of the original sample.
`
`
`
`Initial
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recrystallized
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Wet Granulated
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Action Plan
`
`1.
`2.
`3.
`
`Assess amorphous content in wet granulated samples (14 March 2003)
`Analyze samples for quantitative polymorph content (14 March 2003)
`Analyze recrystallized sample for amorphous content (14 March 2003)
`
`
`
`12
`
`Merck Exhibit 2119, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`VIII. Effect of Form on processability, relative effect of PSD
`
`Material used in processability experiments:
`Form Content of Material
`Form I
`Form III
`100.0
`0.0
`Form II and Form I
`-
`14.7
`85.3
`
`Form Used
`Form I (Made from Lot 24)
`Form II (Lot 24)
`Form III (Cogeim)
`
` •
`
`10U
`
` Form II
` Form I (converted from form II)
`
`50
`
`200
`100
`150
`Consolidation Stress (g/cm^2)
`
`250
`
`
`
`
`
`13
`
`Flowability:
`
`To deconvolute effects of the form and particle size, the flowability of Form II and Form I
`converted from Form II was compared. Similar experiments were performed on Form III and
`Form I converted from Form III. The preliminary data showed that the flowability of Form I
`was slightly better than that of Form III with the same particle characteristics and the
`flowability of Form I and II was similar.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Form III
` Form I (converted from form III)
`
`35
`
`30
`
`25
`
`20
`
`15
`
`nconfined Yield Stress (g/cm^2)
`
`Merck Exhibit 2119, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

` •
`
`
`
`
`
`
`
`
`Compactability:
`
`The compactability of Form II and Form I converted from Form II was compared; and so was
`the compactability of Form III and Form I converted from Form III. The data showed that the
`impact of the form on the compactability is relatively small compared to the effect of particle
`characteristics.
`
`
`
`
`
`
`
`
`
`
`
`
`
`3
`
`2
`
`1
`
`0
`
`Lot 006F024
`Form III
`006F024 Form I from Form II
`006F024 Form I from Form III
`
`0
`
`
`
`100
`
`
`
`
`300
`200
`Compaction Pressure (MPa)
`
`400
`
`500
`
`
`
`
`
`
`Action Items
`
`1.
`
`
`Perform stickiness comparison (14 March 2003)
`
`
`
`14
`
`Merck Exhibit 2119, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`SUMMARY OF ACTION ITEMS
`
`
`Continue monitoring physical form of delivered lots (will be performed as delivered
`and as pulled from stability station).
`
`Analyze capsules used in Phase I single dose studies (14 March 2003)
`
`Monitor Form content in stability DP tablets (as pulled)
`
`Obtain data on RC tablets (by 15 March 2003)
`
`Perform analysis of form content in vehicle used for safety assessment studies (14
`March 2003)
`
`Repeat slurry turnover experiments using an extended temperature range (completed
`by 31March 2003).
`
`Determination of Kinetics of Form I/III conversion and activation energies (Early
`April 2003).
`
`Assess amorphous content in wet granulated samples (14 March 2003)
`
`Analyze samples for quantitative polymorph content (14 March 2003)
`
`Analyze recrystallized sample for amorphous content (14 March 2003)
`
`Perform stickiness comparison (14 March 2003)
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`1.
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`2.
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`5.
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`6.
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`7.
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`8.
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`10.
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`11.
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`15
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`Merck Exhibit 2119, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`