(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`18 November 2010 (18.11.2010)
`
`(51) International Patent Classification:
`A61P 3/10 (2006.01)
`C07D 487/04 (2006.01)
`A61K 31/4985 (2006.01)
`
`(21) International Application Number:
`PCT/GB20 10/050772
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`11 May 2010 ( 11.05.2010)
`
`English
`
`English
`
`(30) Priority Data:
`723/KOL/2009
`
`11 May 2009 ( 11.05.2009)
`
`IN
`
`(71) Applicants
`except US):
`States
`(for all designated
`GENERICS [UK] LIMITED [GB/GB]; Albany Gate,
`Darkes Lane, Potters Bar, Hertfordshire EN6 IAG (GB).
`GENERICS UK LIMITED [GB/GB]; Albany Gate,
`Darkes Lane, Potters Bar, Hertfordshire EN6 IAG (GB).
`MYLAN INDIA PRIVATE LIMITED [IN/IN]; Plot 1
`A/2, M.I.D.C. Industrial Estate, Taloja, Panvel, District
`Raigad, Maharashtra 410 208 (IN).
`
`(10) International Publication Number
`WO 2010/131035 Al
`
`Industrial Estate, Taloja, Panvel, District Raigad, Maha
`rashtra 410 208 (IN). YADAV, Prashant [IN/IN]; Mylan
`India Private Limited, Plot 1 A/2, M.I.D.C. Industrial E s
`tate, Taloja, Panvel, District Raigad, Maharashtra 410 208
`(IN).
`
`(74) Agents: ELEND, Almut et al; Venner Shipley LLP, By
`ron House, Cambridge Business Park, Cowley Road,
`Cambridge Cambridgeshire CB4 OWZ (GB).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`(72) Inventors; and
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`(75) Inventors/Applicants (for US only): GORE, Vinayak
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`Govind [IN/IN]; Mylan India Private Limited, Plot 1 A/2,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`M.I.D.C.
`Industrial Estate, Taloja, Panvel, District
`LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,
`Raigad, Maharashtra 410 208 (IN). GADAKAR, Ma-
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`heshkumar [IN/IN]; Mylan India Private Limited, Plot 1
`GW, ML, MR, NE, SN, TD, TG).
`A/2, M.I.D.C. Industrial Estate, Taloja, Panvel, District
`Raigad, Maharashtra 410 208 (IN). BHOSLE, Priyanka Published:
`[IN/IN]; Mylan India Private Limited, Plot 1 A/2,
`Industrial Estate, Taloja, Panvel, District — with international search report (Art. 21(3))
`M.I.D.C.
`Raigad, Maharashtra 410208 (IN). SHINDE, Suresh [IN/
`IN]; Mylan India Private Limited, Plot 1 A/2, M.I.D.C.
`
`(54) Title: NOVEL CRYSTALLINE POLYMORPH OF SITAGLIPTIN DIHYDROGEN PHOSPHATE
`
`(57) Abstract: The present invention relates to a novel anhydrous crystalline form of sitagliptin dihydrogenphosphate (I), to pro-
`cesses for its preparation and to its use in pharmaceutical compositions.
`
`Merck Exhibit 2186, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`NOVEL CRYSTALLINE POLYMORPH OF SITAGLIPTIN
`DIHYDROGEN PHOSPHATE
`
`Field of the invention
`
`The present
`
`invention relates to a novel anhydrous crystalline form of sitagliptin
`
`dihydrogenphosphate (I), to processes for its preparation and to its use in pharmaceutical
`
`compositions.
`
`Background
`
`of the invention
`
`The manufacturing process for many pharmaceuticals is hindered by the fact that
`
`the
`
`organic compound, which is the active pharmaceutical
`
`ingredient
`
`(API), has handling
`
`difficulties during the manufacturing process and may impart undesirable properties to the
`
`final drug or dosage form. In addition it can be difficult to control the polymorphic form
`
`of the API throughout the manufacturing process.
`
`For pharmaceuticals in which the API can exist in more than one polymorphic form, it is
`
`particularly important
`
`to ensure that
`
`the manufacturing process for the API affords a
`
`single, pure polymorph with a consistent level of polymorphic purity. If the manufacturing
`
`process leads to a polymorph with varying degrees of polymorphic purity and/ or where the
`
`process does not control polymorphic interconversion, serious problems in dissolution
`
`and/or bioavailability can result in the finished pharmaceutical composition comprising the
`
`API.
`
`Merck Exhibit 2186, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Sitagliptin dihydrogenphosphate, represented by structural formula (I), is chemically named
`
`as
`
`(2R)-4-oxo-4-[3-(tofluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-
`
`(2,4,5-trifluorophenyl)butan-2-amine dihydrogenphosphate.
`
`Sitagliptin is an oral antiliyperglycemic of the dipeptidyl peptidase-IV (DPP-IV) inhibitor
`
`class. Inhibition of dipeptidyl peptidase-IV, an enzyme that
`
`inactivates both glucose-
`
`dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-I), represents a
`
`recent approach to the treatment and prevention of type-2 diabetes, also known as non-
`
`insulin dependent diabetes mellitus (NIDDM).
`
`Therefore the novel crystalline form of the present
`
`invention can be used for
`
`the
`
`preparation of pharmaceutical compositions for the treatment and prevention of diseases
`
`and conditions for which an inhibitor of dipeptidyl peptidase-IV is indicated, in particular
`
`type-2 diabetes, hyperglycemia, insulin resistance, obesity, and high blood pressure. The
`
`novel crystalline form of the present invention can be used in combination with one or
`
`more other active ingredients if necessary.
`
`Various structural analogues and salts of sitagliptin are disclosed in patent US 6,699,871,
`
`but no polymorphic data is given.
`
`Solvate forms and three anhydrate polymorphs of sitagliptin dihydrogenphosphate (forms
`
`I, II and III) are disclosed in patent application US 2006/0287528. However, desolvated
`
`form II converts spontaneously to form I or III or a mixture thereof.
`
`A process for the preparation of sitagliptin dihydrogenphosphate is disclosed in patent
`
`application US 2005/0032804 wherein the salt is prepared in isopropyl alcohol and water to
`
`afford sitagliptin dihydrogenphosphate monohydrate. However,
`
`this monohydrate form
`
`converts to an unstable dehydrated form at temperatures above 4 O0C.
`
`In addition,
`
`crystalline anhydrate
`
`form IV is disclosed in patent
`
`application US
`
`2007/0021430, which is prepared from the sitagliptin dihydrogenphosphate monohydrate
`
`by heating at 120°C for 2 hours. However, form IV is metastable and converts into the
`
`Merck Exhibit 2186, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`ciystalline monohydrate slowly undeϊ ambient conditions or rapidly under high relative
`humidity.
`
`An amorphous
`
`form of sitagliptin dihydrogenphosphate
`
`salt
`
`is disclosed in patent
`
`application US 2007/0281941. However amorphous
`
`forms are not
`
`ideally suited for
`
`commercial production and crystalline forms are generally preferred.
`
`As discussed above,
`
`the six polymorphic
`
`forms of sitagliptin dihydrogenphosphate
`
`disclosed in the prior art suffer from several disadvantages which do not make them ideal
`
`forms for pharmaceutical development. In particular, the disadvantages associated with the
`
`prior art forms can include discolouration, polymorphic impurities and instability. The
`
`processes to prepare the respective prior art polymorphs suffer from the disadvantages of
`
`being inconsistent and difficult to reproduce. Consequently, the prior art processes can
`
`often produce polymorphically impure products. In addition, the prior art processes are
`
`particularly inconvenient for large scale production.
`
`If crystalline and amorphous forms are made with polymorphic impurities,
`
`this causes
`
`instability and it can accelerate significant interconversion to another polymorphic form.
`
`Therefore, for commercial production, it is crucial to produce forms, particularly crystalline
`
`forms, with very high polymorphic purity to avoid or minimize this interconversion.
`
`In view of the importance acquired by sitagliptin for the treatment of diabetes, there is a
`
`great need for developing an alternative, relatively simple, economical and commercially
`
`feasible process
`
`for
`
`the synthesis of sitagliptin crystalline forms with commercially
`
`acceptable yield, high polymorphic purity and polymorphic stability.
`
`Object of the invention
`
`Therefore an object of the invention is to provide a new polymorphic form of sitagliptin
`
`dihydrogenphosphate, which is convenient
`
`to manufacture and has improved properties
`
`suitable for a marketed pharmaceutical composition.
`
`Summary of the invention
`
`Merck Exhibit 2186, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`- A-
`
`The term "sitagliptin" as used herein throughout
`
`the description and claims means
`
`sitagliptin and/ or any salt, hydrate, solvate or tautomer thereof unless specified otherwise.
`
`A first aspect of the present invention provides sitagliptin dihydrogenphosphate form M,
`characterised by an XRPD spectrum comprising the following degrees 2q peaks: 5.0, 14.3,
`18.6, 24.0 ± 0.2 degrees 2q
`characterised by an XRPD spectrum comprising four or more (preferably five or more,
`
`. Preferably sitagliptin dihydrogenphosphate
`
`form M is
`
`preferably six or more, preferably seven or more, preferably eight or more, preferably nine
`
`or more, preferably ten or more, preferably eleven or more, preferably twelve or more,
`
`preferably thirteen or more, preferably fourteen or more, preferably fifteen) of the
`following degrees 2q peaks: 5.0, 9.7, 13.7, 14.3, 15.4, 18.6, 19.5, 19.7, 20.3, 22.4, 24.0, 24.5,
`25.7, 27.0, 27.3 ± 0.2 degrees 2q
`
`.
`
`Preferably,
`
`the
`
`first
`
`aspect
`
`of
`
`the
`
`present
`
`invention
`
`provides
`
`sitagliptin
`
`form M, characterised by an XRPD spectrum substantially
`dihydrogenphosphate
`comprising the following degrees 2q peaks (± 0.2 degrees 2q ) :
`
`Merck Exhibit 2186, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Preferably,
`
`the
`
`first
`
`aspect
`
`of
`
`the
`
`present
`
`invention
`
`provides
`
`sitagliptin
`
`dihydiOgenphosphate form M, characterised by an XRPD spectrum substantially as shown
`
`in Figure 1.
`
`Preferably,
`
`the
`
`first
`
`aspect
`
`of
`
`the
`
`present
`
`invention
`
`provides
`
`sitagliptin
`
`dihydrogenphosphate form M, characterised by a DSC thermogram with an endothermic
`
`peak at about 216.3 + 2.0 0C, preferably characterised by a DSC thermogram with an
`
`endothermic peak at about 216.3 ± 1.0 0C .
`
`Preferably,
`
`the
`
`first
`
`aspect
`
`of
`
`the
`
`present
`
`invention
`
`provides
`
`sitagliptin
`
`dihydrogenphosphate form M, characterised by a DSC thermogram substantially as shown
`
`in Figure 2.
`
`Preferably,
`
`the
`
`first
`
`aspect
`
`of
`
`the
`
`present
`
`invention
`
`provides
`
`sitagliptin
`
`dihydrogenphosphate form M, characterised by a TGA curve substantially as shown in
`
`Figure 3.
`
`A second aspect of the present
`
`invention provides a process for the preparation of
`
`sitagliptin dihydrogenphosphate
`
`form M, comprising contacting sitagliptin base with
`
`orthophosphoric
`
`acid at -10 to 100°C in an organic solvent and crystallisation of the
`
`resultant product.
`
`Preferably, the organic solvent is an alcohol, more preferably the alcohol is a C1 to C6
`alcohol which can be either straight chain, branched or cyclic. Preferably, the alcohol is
`
`selected from methanol,
`
`ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol,
`
`tert-
`
`butanol, 2-pentanol, 3-pentanol, 4-penten-2-ol, 1,6-hexanediol, 1-hexanol, 5-hexen-l-ol,
`
`glycerol, 1-heptanol, 2-heptanol, 1-octanol, 2-octanol, 3-octanol or mixtures thereof. Most
`
`preferably, the alcohol is 2-propanol.
`
`Preferably, in a process according to the second aspect of the invention, the organic solvent
`
`is mixed with water. Preferably, the amount of water is less than 30% v/v with respect to
`
`the organic solvent, more preferably less than 20% v/v with respect to the organic solvent,
`
`preferably less than 10% v/v with respect to the organic solvent, preferably less than 5%
`
`Merck Exhibit 2186, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`v/v with respect
`
`to the organic solvent. Most preferably,
`
`the amount of water is about 15-
`
`20% v/v with respect to the organic solvent.
`
`Most preferably,
`
`the solvent is a mixture of 2-propanol and water.
`
`Preferably,
`
`in a process according to the second aspect of the invention, 1 to 10 molar
`
`equivalents of orthophosphoric
`
`acid is used. More preferably, 1.5 to 3.0 molar equivalents
`
`of orthophosphoric
`
`acid is used.
`
`A third aspect of the present
`
`invention provides sitagliptin dihydrogenphosphate
`
`form M
`
`as prepared by a process according to the second aspect of the present
`
`invention.
`
`Preferably,
`
`the sitagliptin dihydrogenphosphate
`
`form M of the first or third aspect of the
`
`present
`
`invention comprises less than:
`
`(i)
`
`(ii)
`
`(iii)
`
`(iv)
`
`(v)
`
`(vi)
`
`10% of sitagliptin dihydrogenphosphate
`
`in other polymorphic forms; and/or
`
`5% of sitagliptin dihydrogenphosphate
`
`in other polymorphic forms; and/ or
`
`1% of sitagliptin dihydrogenphosphate
`
`in other polymorphic forms; and/or
`
`0.5% of sitagliptin dihydrogenphosphate
`
`in other polymorphic forms; and/ or
`
`0.2% of sitagliptin dihydrogenphosphate
`
`in other polymorphic forms; and/or
`
`0.1% of sitagliptin dihydrogenphosphate
`
`in other polymorphic forms;
`
`as measured by XRPD.
`
`A fourth aspect of the present
`
`invention provides sitagliptin dihydrogenphosphate
`
`form M
`
`comprising less than 10% of sitagliptin dihydrogenphosphate
`
`in other polymorphic forms
`
`(as measured
`
`by XRPD). Preferably,
`
`the
`
`sitagliptin dihydrogenphosphate
`
`form M
`
`comprises less than 5% of sitagliptin dihydrogenphosphate
`
`in other polymorphic
`
`forms,
`
`more preferably less than 1% of sitagliptin dihydrogenphosphate
`
`in other polymorphic
`
`forms, more preferably less than 0.5% of sitagliptin dihydrogenphosphate
`
`in other
`
`polymorphic forms, more preferably less than 0.2% of sitagliptin dihydrogenphosphate
`
`in
`
`other
`
`polymorphic
`
`forms,
`
`and most
`
`preferably
`
`less
`
`than
`
`0.1% of
`
`sitagliptin
`
`dihydrogenphosphate
`
`in other polymorphic forms (as measured by XRPD).
`
`Merck Exhibit 2186, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Preferably, the sitagliptin dihydrogenphosphate form M of the first, third or fourth aspect
`
`of the present invention has a chemical purity of 99% or more, 99.5% or more, or 99.85%
`
`or more (as measured by HPLC).
`
`Preferably, the sitagliptin dihydrogenphosphate form M of the first, third or fourth aspect
`
`of the present invention is suitable for use in medicine, preferably for treating or preventing
`
`a disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective,
`
`preferably for treating or preventing diabetes, hyperglycemia, insulin resistance, obesity, or
`
`high blood pressure, preferably for treating or preventing diabetes type-2.
`
`A fifth aspect of the present invention provides a pharmaceutical composition, comprising
`
`the sitagliptin dihydrogenphosphate form M according to the first, third or fourth aspect of
`
`the present invention or as prepared by a process according to the second aspect of the
`
`present invention.
`
`A sixth
`
`aspect of
`
`the present
`
`invention
`
`provides
`
`a use
`
`of
`
`the
`
`sitagliptin
`
`dihydrogenphosphate form M according to the first, third or fourth aspect of the present
`
`invention or as prepared by a process according to the second aspect of the present
`
`invention or a use of the pharmaceutical composition according to the fifth aspect of the
`
`present invention, in the manufacture of a medicament for the treatment or prevention of a
`
`disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective.
`
`Preferably, the medicament is for the treatment or prevention of diabetes, hyperglycemia,
`
`insulin resistance, obesity, or high blood pressure. More preferably, the medicament is for
`
`the treatment or prevention of diabetes type-2.
`
`A seventh aspect of the present invention provides a method of treating or preventing a
`
`disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective, the
`
`method comprising administering to a patient
`
`in need thereof a therapeutically or
`
`prophylactically effective amount of the sitagliptin dihydrogenphosphate form M according
`
`to the first, third or fourth aspect of the present invention or as prepared by a process
`
`according to the second aspect of
`
`the present
`
`invention or a therapeutically or
`
`prophylactically effective amount of the pharmaceutical composition according to the fifth
`
`aspect of the present invention. Preferably, the method is for the treatment or prevention
`
`Merck Exhibit 2186, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`of diabetes, hyperglycemia,
`
`insulin resistance, obesity, or high blood pressure. More
`
`preferably, the method is for the treatment or prevention of diabetes type-2. Preferably the
`
`patient is a mammal, preferably a human.
`
`In the use according to the sixth aspect of the present
`
`invention or in the method
`
`according to the seventh aspect of the present
`
`invention, optionally the sitagliptin
`
`dihydrogenphosphate form M is used in combination with one or more other active
`
`pharmaceutical
`
`ingredients, wherein the other
`
`active ingredient(s), which may be
`
`administered separately or in the same pharmaceutical composition, may be selected from
`
`insulin sensitizers such as glitazones (such as troglitazone, pioglitazone, englitazone and
`
`rosiglitazone); fenofibric acid derivatives (such as gemfibrozil, clofibrate, fenofibrate and
`
`bezafibrate); biguanides (such as metformin and phenformin);
`
`sulfonylureas (such as
`
`glipizide); or mixtures thereof.
`
`Brief description of the accompanying
`
`figures
`
`Figure 1 shows
`
`an X-ray powder
`
`diffraction
`
`(XRPD)
`
`spectrum of
`
`sitagliptin
`
`dihydrogenphosphate form M .
`
`Figure 2 shows a differential scanning calorimetry (DSC)
`
`thermogram of sitagliptin
`
`dihydrogenphosphate form M .
`
`Figure
`
`3
`
`shows
`
`a
`
`thermo-gravimetric
`
`analysis
`
`(TGA)
`
`curve
`
`of
`
`sitagliptin
`
`dihydrogenphosphate form M .
`
`Detailed description
`
`of the invention
`
`As outlined above, the present
`
`invention provides a new crystalline form of sitagliptin
`
`dihydrogenphosphate, form M, which is non-hygroscopic, polymorphically pure and stable,
`
`and has beneficial properties which avoid the problems associated with prior art forms.
`
`A major advantage of this invention is the reproducible conditions of the process to obtain
`
`the novel polymorph and the polymorphic purity and stability of the form M . The
`
`Merck Exhibit 2186, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`polymorphic form of the present invention also allows sitagliptin dihydrogenphosphate to
`
`be easily purified and obtained in very high chemical purity.
`
`The present
`
`inventors have surprisingly found that,
`
`if required, crystalline sitagliptin
`
`dihydrogenphosphate form M can be conveniently used to prepare other known crystalline
`
`forms of sitagliptin or salts of sitagliptin, such as sitagliptin dihydrogenphosphate, with very
`
`high chemical and/ or polymorphic purity.
`
`Sitagliptin dihydrogenphosphate form M can be prepared by reacting sitagliptin free base
`
`and orthophosphoric acid in an organic solvent optionally in the presence of water. The
`
`orthophosphoric acid is used preferably at 1.0 to 3.0 molar equivalents and more preferably
`
`at about 1.5 molar equivalents. The orthophosphoric acid can be used in solid form or as a
`
`solution, such as an aqueous solution or a solution in an alcohol such as 2-propanol.
`
`The organic solvent may be a protic or aprotic solvent. Preferably the organic solvent is an
`
`alcohol, a ketone, an ether, an alkane, a cycloalkane, a formamide, an acetate, a halogenated
`
`solvent, or a mixture thereof, optionally in the presence of water.
`
`Preferably, the organic solvent is an alcohol, preferably a straight chain, branched or cyclic
`C1 to C6 alcohol. More preferably, the alcohol is selected from one or more of methanol,
`ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 2-pentanol, 3-pentanol,
`
`4-penten-2-ol, 1,6-hexanediol, 1-hexanol, 5-hexen-l-ol, glycerol, 1-heptanol, 2-heptanol, 1-
`
`octanol, 2-octanol, or 3-octanol, preferably in presence of water. The most preferred
`
`solvent is 2-propanol in the presence of water.
`
`Preferred embodiments of
`
`the process according to the present
`
`invention involve
`
`dissolution of sitagliptin free base in about 5 to 50 volumes of 2-propanol and about 2 to
`
`10 volumes of water to obtain a clear solution. Preferably, about 8 to 12 or about 8 to 10
`
`volumes of 2-propanol and about 2 to 4 volumes of water are used to obtain a clear
`
`solution. To the clear solution, orthophosphoric acid is preferably added at about -10 to
`
`85°C, preferably at about 15-30°C. The suspension or clear solution is preferably stirred at
`
`about 70-75°C for up to 10 hours until completion of the reaction. The precipitated
`
`product
`
`is preferably further stirred for 15 minutes to 12 hours at about 25-30°C until
`
`Merck Exhibit 2186, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`complete precipitation. The precipitated product
`
`is preferably maintained at 0-5°C for 1
`
`hour and then preferably filtered at 0-5 0C. The isolated product
`
`is preferably dried under
`
`reduced pressure at 45-500C for 1-10 hours, more preferably for 1-3 hours. The product
`
`can be recrystallised if necessary.
`
`Preferably, the mixture is heated to dissolve the sitagliptin. Preferably, the mixture is heated
`
`between 40-1000C, more preferably at about 70-75 0C.
`
`Preferably, the mixture is cooled before isolation of the sitagliptin dihydrogenphosphate
`
`form M . Preferably, the mixture is cooled to between -5 to 3 O0C, more preferably to about
`
`0-50C.
`
`The crystalline sitagliptin dihydrogenphosphate form M preferably comprises less than
`
`0.2% of sitagliptin dihydrogenphosphate in other polymorphic forms.
`
`The crystalline sitagliptin dihydrogenphosphate form M obtained is preferably dried under
`
`vacuum until a constant weight is obtained. Preferably, the crystalline form M obtained is
`
`dried until the moisture content falls below 1%, preferably to below about 0.5%.
`
`As discussed above, sitagliptin dihydrogenphosphate monohydrate is disclosed in patent
`
`application US 2005/0032804. However, this monohydrate form converts to an unstable
`
`dehydrated form at temperatures above 4 O0C. The present
`
`inventors have surprisingly
`
`found that by reducing the amount of water used in the organic solvent medium, a novel,
`
`stable, anhydrous, solvent-free, crystalline form M can be reproducibly prepared. A solvent
`
`mixture comprising a ratio of 10:2 v/v 2-propanol:water (about 16% water v/v), afforded
`
`exclusively novel anhydrous form M . Even the wet cake obtained by following the process
`
`of the present invention exhibited an XRPD pattern identical to that of form M .
`
`The XRPD d-values of the sitagliptin dihydrogenphosphate form M thus obtained are
`
`different from those of the reported forms I to IV and the reported monohydrate form and
`
`this XRPD data is summarised in Table 2.
`
`Merck Exhibit 2186, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Table 2: XRPD d-values of prior art forms and form M
`
`Merck Exhibit 2186, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Typical XRPD 2q values and intensity of form M are illustrated in Table 3 .
`
`Table 3 : XRPD 2q values and intensity of form M
`
`Merck Exhibit 2186, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`The pharmaceutical composition according to the fifth aspect of the present invention can
`
`be a solution or a suspension, but is preferably a solid oral dosage form. Preferred oral
`
`dosage forms in accordance with the invention include tablets, capsules and the like which,
`
`optionally, may be coated if desired. Tablets can be prepared by conventional
`
`techniques,
`
`including direct compression, wet granulation and dry granulation. Capsules are generally
`
`formed from a gelatine material and can include a conventionally prepared granulate of
`
`excipients in accordance with the invention.
`
`The pharmaceutical composition according to the present
`
`invention typically comprises
`
`one or more conventional pharmaceutically acceptable excipient(s) selected from the group
`
`comprising a filler, a binder, a disintegrant, a lubricant, and optionally further comprises at
`
`least one excipient selected from colouring agents, adsorbents, surfactants, film-formers
`
`and plasticizers.
`
`If the solid pharmaceutical formulation is in the form of coated tablets, the coating may be
`
`prepared from at
`
`least one
`
`film-former
`
`such as hydroxypropyl methyl
`
`cellulose,
`
`hydroxypropyl cellulose or methacrylate polymers which optionally may contain at least
`
`one plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other
`
`pharmaceutical auxiliary substances conventional for film coatings, such as pigments and
`
`fillers.
`
`Preferably the pharmaceutical compositions according to the present invention are in unit
`
`dosage form comprising sitagliptin in an amount of from 1 mg to 500 mg, such that the
`
`amount of sitagliptin administered is from 0.1 mg to 100 mg per kg per day.
`
`Preferably, the pharmaceutical compositions according to the fifth aspect of the present
`
`invention are for use in the treatment and prevention of diseases and conditions for which
`
`an inhibitor of dipeptidyl peptidase-IV is effective. Preferably, the use is in the treatment of
`
`diabetes, hyperglycemia,
`
`insulin resistance, obesity, or high blood pressure. More
`
`preferably, the use is in the treatment of diabetes type-2.
`
`Merck Exhibit 2186, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`The novel crystalline form of the present invention can be used in combination with other
`
`active ingredients. Examples of other active ingredients
`
`that may be administered in
`
`combination with the crystalline form of the present
`
`invention and either administered
`
`separately or in the same pharmaceutical composition,
`
`include but are not limited to other
`
`dipeptidyl peptidase IV (DP-IV) inhibitors;
`
`insulin sensitizers such as glitazones (such as
`
`troglitazone, pioglitazone, englitazone and rosiglitazone); fenofibric acid derivatives (such
`
`as gemfibrozil, clofibrate, fenofibrate and bezafibrate); biguanides (such as metformin and
`
`phenformin); sulfonylureas (such as glipizide); or mixtures thereof.
`
`The details of the invention, its objects and advantages are illustrated below in greater detail
`
`by a non-limiting example.
`
`Example
`
`Sitagliptin Dihydrogenphosphate Form M
`
`Sitagliptin free base (10.0 gm, 24.5 mmol) was charged in 2-propanol
`
`(80.0 ml, 8.0 vol) and
`
`water
`
`(20.0 ml, 2.0 vol) at 25-3O0C. The clear solution was stirred for 10 minutes.
`
`Meanwhile, a clear solution of orthophosphoric
`
`acid (85%) was prepared at 25-30°C [2.40
`
`gm (1.0 eq, 24.5 mmol) in 20.0 ml (2.0 vol) of 2-propanol]. Slow addition of the solution of
`
`orthophosphoric
`
`acid to the solution of sitagliptin free base was carried out at 25-3O0C .
`
`The addition was completed within 15-20 minutes. The thick solution was further diluted
`
`with 2-propanol
`
`(20.0 ml, 2.0 vol) and the white suspension was further heated at 70-75 0C
`
`and maintained for 1 hour before the reaction mixture was allowed to cool gradually at 25-
`
`300C within 1.5 hour. The white suspension was stirred at 25-300C for 1 hour until a white
`
`thick solution was obtained. After 1 hour of stirring at 25-30 0C, the mixture was cooled to
`
`0-50C and maintained at 0-50C for 1 hour. The product was filtered at 0-50C and washed
`
`with 2-propanol
`
`(50.0 ml, 5.0 vol). The product was suction filter dried for 30 minutes and
`
`then dried at 40-45 0C at reduced pressure for 1-2 hours
`
`to obtain crude sitagliptin
`
`dihydrogenphosphate. XRPD, DSC and TGA analysis data confirmed that
`
`the crude
`
`sitagliptin dihydrogenphosphate obtained is form M.
`
`Molar yield: 81% (10.0 gm)
`
`Chemical purity: >99.50% (measured by HPLC)
`
`Polymorphic purity: no levels of other polymorphic forms detected (measured by XRPD)
`
`Merck Exhibit 2186, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`The crude sitagliptin dihydiOgenphosphate (10.0 gm) was further crystallised from a
`
`mixture of 2-propanol (100.0 ml, 10.0 vol) and water (20.0 ml, 2.0 vol) to obtain very pure
`
`sitagliptin dihydrogenphosphate. XRPD, DSC and TGA analysis data confirmed that the
`
`pure sitagliptin dihydrogenphosphate obtained is form M .
`
`Molar yield: 85% (8.5 gm)
`
`Chemical purity: >99.85% (measured by HPLC)
`
`Polymorphic purity: no levels of other polymorphic forms detected (measured by XRPD)
`
`XRPD and DSC analysis data for the crude and pure products obtained from the example
`
`(see Figures 1 and 2) confirmed that the products obtained were a novel polymorph of
`
`sitagliptin dihydrogenphosphate. The novel polymorph obtained, crystalline form M, was
`
`substantially pure polymorphically with no levels of other forms detected.
`
`TGA analysis data (see Figure 3) showed that
`
`the novel crystalline anhydrous form of
`
`sitagliptin dihydrogenphosphate form M displays no weight loss in the temperature range
`
`of 5 O0C to 225 0C.
`
`The XRPD was recorded on a Bruker D 8 Advance Instrument, using copper radiation as
`the X-ray source and LynxEye as the detector, with a 2q
`size of 0.05° and a time/step of 1 sec.
`
`range of from 3° to 50°, a step-
`
`The DSC was recorded on a Perkin Elmer Pyris 6, with a temperature range of from 25°C
`
`to 2500C and a rate of heating of 10°C/min.
`
`The TGA was recorded on a Perkin Elmer Pyris 1, with a temperature range of from 250C
`
`to 25O0C and a rate of heating of 10°C/min.
`
`The crude and pure products were also subjected to two months accelerated stability
`
`studies, monitoring chemical and polymorphic purities, and it was found that the sitagliptin
`
`dihydrogenphosphate form M is stable. The accelerated stability studies were performed as
`
`follows. Sitagliptin dihydrogenphosphate form M was kept in a single polyethylene bag in a
`
`triple laminated aluminium pouch. This pouch was kept
`
`in a HDPE container. This
`
`Merck Exhibit 2186, Page 16
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`container was kept in a stability chamber at a temperature of 40°C ± 2°C and a relative
`
`humidity of 75% ± 5% for two months. The sitagliptin dihydrogenphosphate form M was
`
`found to be very stable chemically and very stable polymorphically with no conversion over
`
`time to other polymorphs.
`
`It will be understood that the present
`
`invention has been described above by way of
`
`example only. The example is not intended to limit the scope of the invention. Various
`
`modifications and embodiments can be made without departing from the scope and spirit
`
`of the invention, which is defined by the following claims only.
`
`Merck Exhibit 2186, Page 17
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Claims
`
`form M, characterised by an XRPD spectrum
`Sitagliptin dihydtogenphosphate
`1.
`comprising the following degrees 2q peaks: 5.0, 14.3, 18.6, 24.0 ± 0.2 degrees 2q
`
`.
`
`Sitagliptin dihydrogenphosphate form M according to claim 1, characterised by an
`2.
`XRPD spectrum substantially comprising the following degrees 2q peaks (+ 0.2 degrees
`2q ) :
`
`3.
`
`Sitagliptin dihydrogenphosphate form M according to claim 1 or 2, characterised by
`
`an XRPD spectrum substantially as shown in Figure 1.
`
`4.
`
`Sitagliptin dihydrogenphosphate
`
`form M according to any preceding claim,
`
`characterised by a DSC thermogram with an endothermic peak at about 216.3 + 2.0 °C.
`
`5 .
`
`Sitagliptin dihydrogenphosphate
`
`form M according to any preceding claim,
`
`characterised by a DSC thermogram substantially as shown in Figure 2.
`
`Merck Exhibit 2186, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`6.
`
`Sitagliptin dihydrogenphosphate
`
`form M according
`
`to any preceding
`
`claim,
`
`characterised by a TGA curve substantially as shown in Figure 3.
`
`7.
`
`A process for the preparation of sitagliptin dihydrogenphosphate
`
`form M according
`
`to any preceding claim, comprising contacting sitagliptin base