JP2018177769A - Novel crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-piperidin-1-yl)-xanthine and method of producing the same - Google Patents
Novel crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-piperidin-1-yl)-xanthine and method of producing the same Download PDFInfo
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- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title abstract description 9
- 229960002397 linagliptin Drugs 0.000 claims abstract description 68
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims 2
- 239000013078 crystal Substances 0.000 description 16
- -1 4-methyl-quinazolin-2-yl Chemical group 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229940075420 xanthine Drugs 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CNJLMVZFWLNOEP-UHFFFAOYSA-N 4,7,7-trimethylbicyclo[4.1.0]heptan-5-one Chemical compound O=C1C(C)CCC2C(C)(C)C12 CNJLMVZFWLNOEP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000005070 ripening Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Description
本発明は、下記の化学式１の１−［（４−メチル−キナゾリン−２−イル）メチル］−３−メチル−７−（２−ブチン−１−イル）−８−（３−（Ｒ）−アミノ−ピペリジン−１−イル）−キサンチン（リナグリプチン、Ｌｉｎａｇｌｉｐｔｉｎ）の新規結晶形及び商業的に大規模生産が可能な新規結晶形の製造方法に関する。 The present invention relates to 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) of the following chemical formula 1 The present invention relates to a novel crystalline form of -amino-piperidin-1-yl) -xanthine (linagliptin, Linagliptin) and to a process for the preparation of a novel crystalline form that can be commercially produced on a large scale.
前記化学式１の化合物は、韓国登録特許第０８８３２７７号公報、韓国登録特許第１１５０４４９号公報及び国際公開第２００２／０６８４２０号、国際公開第２００４／０１８４６７号に開示されたＤＰＰ−４抑制剤であって、第２型糖尿病疾患を治療するのに治療学的価値を有する。 The compound represented by Chemical Formula 1 is a DPP-4 inhibitor disclosed in Korean Patent No. 0883277, Korean Patent No. 1150449 and International Publication Nos. 2002/068420 and 2004/018467. , Have therapeutic value in treating type 2 diabetes disease.
一つ以上の結晶形態で存在する物質の能力を多形性（Ｐｏｌｙｍｏｒｐｈｉｓｍ）と定義し、これらの異なる結晶形態は多形体と呼ばれる。一般に、物質の多形体形態は、度々結晶の習性及び結晶性固体上の特性において異なっており、これによって、物質の安定性、純度、吸湿性、流動性、圧縮性、溶解度などの異なる物理的及び薬剤学的特性を有し得る。多形性は多くの有機化合物で発見され得る。 The ability of a substance to exist in one or more crystalline forms is defined as polymorphism, and these different crystalline forms are called polymorphs. In general, the polymorphic forms of substances often differ in their crystal habits and properties on crystalline solids, which leads to differences in physical properties such as substance stability, purity, hygroscopicity, flowability, compressibility, solubility, etc. And have pharmacological properties. Polymorphism can be found in many organic compounds.
前記化学式１の化合物の結晶形態として、国際公開第２００７／１２８７２１号に多形体Ａ〜Ｅが公知となっているが、そのうち、多形体Ａ及びＢが好ましい結晶であると記述されている。より詳細に説明すると、前記特許では、多形体ＡとＢが２つのエナンチオトロピック（ｅｎａｎｔｉｏｔｒｏｐｉｃ）多形体の混合物として存在し、多形体Ａ、Ｂの熱力学的安定性の交差点は２５±１５℃であって、前記交差点を超える温度では、Ａ型がＢ型に比べて熱力学的により安定しており、前記交差点より低い温度では、Ｂ型がＡ型に比べて熱力学的により安定していると記述されている。このように、多形体ＡとＢの熱力学的交差点は２５±１５℃であって、この交差点には常温の温度条件が含まれており、医薬品を加工する間、一つの結晶形態から他の結晶形態への転換可能性を排除することができない。そのため、多形体ＡとＢは、一定の品質を維持しなければならない医薬品の製造に使用するのに適していない多形体である。 As crystalline forms of the compound of the above-mentioned chemical formula 1, polymorphs A to E are known in WO 2007/128721, and among them, polymorphs A and B are described as preferable crystals. More specifically, in the patent, polymorphic forms A and B exist as a mixture of two enantiotropic polymorphic forms, and the crossover point of the thermodynamic stability of polymorphic forms A and B is 25 ± 15 ° C. At temperatures above the intersection, type A is more thermodynamically stable than type B, and at temperatures below the intersection, type B is thermodynamically more stable than type A. It is written that. Thus, the thermodynamic crossover point of polymorphic forms A and B is 25 ± 15 ° C., which includes the temperature conditions of normal temperature, and from one crystalline form to the other during processing of pharmaceutical products. The possibility of conversion to crystalline form can not be excluded. As such, polymorphs A and B are polymorphs that are not suitable for use in the manufacture of pharmaceuticals that must maintain a certain quality.
本発明の目的は、公知のリナグリプチン多形体Ａより温度、湿度及び光に安定している新規なリナグリプチン多形体を提供することにあり、また、新規なリナグリプチン多形体の商業的な大量生産が容易な製造方法を提供することにある。 An object of the present invention is to provide a novel linagliptin polymorph that is more stable to temperature, humidity and light than known linagliptin polymorph A, and also facilitates commercial mass production of the novel linagliptin polymorph Providing a new manufacturing method.
前記課題を解決するために、本発明者らは、多様な有機溶媒（エタノール、メタノール、イソプロピルアルコールなどのアルコール性溶媒、酢酸エチル、テトラヒドロフラン、１，４−ジオキサン、ジメチルスルホキシド、トルエンなど）及びこれらの多様な組み合わせでリナグリプチン多形体Ａより安定している新規な多形体を得るために研究を繰り返し進めてきたが、新規なリナグリプチン多形体を収得することができず、むしろ、ほとんどの場合にリナグリプチン多形体Ａが収得されることを確認した。 In order to solve the above-mentioned subject, the present inventors have various organic solvents (Alcohol solvents such as ethanol, methanol and isopropyl alcohol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, toluene and the like) and these Studies have been repeated to obtain novel polymorphs that are more stable than linagliptin polymorph A in various combinations of, but it is not possible to obtain novel linagliptin polymorphs, but rather in most cases linagliptin It was confirmed that polymorphic form A was obtained.
そこで、本発明者らは、追加の研究で適切な良溶媒（ｇｏｏｄ ｓｏｌｖｅｎｔ）及び貧溶媒（ａｎｔｉｓｏｌｖｅｎｔ）の選択、各溶媒の投入方法、段階別温度条件及び結晶熟成時間などの各条件を細密に調節し、新規多形体の形成が可能であるかどうかを綿密に研究した結果、新規多形体を収得することができた。 Therefore, the present inventors carefully selected each condition such as selection of appropriate good solvent and antisolvent, addition method of each solvent, stepwise temperature condition and crystal ripening time in additional research. As a result of carefully studying whether it is possible to form and to form a new polymorphic form, it is possible to obtain a novel polymorphic form.
本発明者らが研究した新規多形体の一般的な製造方法は、次の通りである。 The general process for the preparation of the new polymorphs we have studied is as follows.
リナグリプチンをアルコール性溶媒と常水との混合溶媒下で加温して溶解させた後、特定の温度で常水を追加して加温・撹拌する。その次に、これを常温に冷却し、生成された結晶を１２時間以上熟成して撹拌した後、ろ過することによって新規多形体Ｆを得ることができる。 After linagliptin is dissolved by heating in a mixed solvent of an alcoholic solvent and normal water, ordinary water is added at a specific temperature, and the mixture is heated and stirred. Next, this is cooled to normal temperature, and the formed crystals are aged for 12 hours or more, stirred, and then filtered to obtain novel polymorphic form F.
その一方、比較実施例１、２のように、同一の量及び同一の種類の溶媒を使用した場合にも、溶媒投入方法が異なったり段階別温度条件が変わると、リナグリプチン新規多形体Ｆではなく、公知の多形体Ａが得られるという事実を確認した。これは、本発明が、通常の技術者が単純に結晶化実験を繰り返すことによって容易に発見できるものではなく、前記のように非常に特定の条件でのみリナグリプチン多形体Ｆが製造され得ることを意味する。 On the other hand, even when using the same amount and the same type of solvent as in Comparative Examples 1 and 2, when the solvent feeding method is different or the stepwise temperature conditions are changed, not Linagliptin Novel Polymorph F but The fact was confirmed that the known polymorphic Form A was obtained. This means that the present invention can not be easily found by ordinary technicians simply by repeating the crystallization experiment, and as described above, linagliptin polymorph F can be produced only under very specific conditions. means.
本発明は、下記の段階を含むリナグリプチン多形体Ｆの製造方法を提供する。 The present invention provides a method of producing linagliptin polymorph F comprising the following steps:
段階１）リナグリプチンをアルコール性溶媒と常水との混合溶媒で加温して溶解させる段階；
段階２）段階１で製造した溶液に特定の温度で常水を追加する段階；
段階３）段階２で製造した懸濁液を加温した後で撹拌する段階；
段階４）段階３で製造した懸濁液を常温に冷却した後、撹拌してろ過する段階；を含むリナグリプチン多形体Ｆの製造方法。
Step 1) dissolving linagliptin in a mixed solvent of alcoholic solvent and normal water and dissolving it;
Stage 2) adding ordinary water to the solution prepared in stage 1 at a specific temperature;
Step 3) heating and then stirring the suspension prepared in step 2;
Step 4) A method for producing linagliptin polymorph F, comprising cooling the suspension prepared in step 3 to room temperature, stirring and filtering.
一具現例において、段階１）で使用されるアルコール性溶媒は、メタノール、エタノール及びイソプロパノールであり、このうち、エタノールであることが好ましい。 In one embodiment, the alcoholic solvents used in step 1) are methanol, ethanol and isopropanol, of which ethanol is preferred.
一具現例において、段階２）は、４０℃〜６０℃（好ましくは４５℃〜５５℃）の特定の温度条件で行われる。 In one embodiment, step 2) is performed at a specific temperature condition of 40 ° C to 60 ° C (preferably 45 ° C to 55 ° C).
一具現例において、段階３）は、７０℃〜９０℃（好ましくは７０℃〜８０℃）の範囲の温度で１時間以内に行われる。 In one embodiment, step 3) is performed within one hour at a temperature ranging from 70 <0> C to 90 <0> C (preferably 70 <0> C to 80 <0> C).
一具現例において、段階４）において、懸濁液を１２時間以上熟成して撹拌した後でろ過する。 In one embodiment, in step 4), the suspension is aged for 12 hours or more and stirred and then filtered.
本発明に使用された１−［（４−メチル−キナゾリン−２−イル）メチル］−３−メチル−７−（２−ブチン−１−イル）−８−（３−（Ｒ）−アミノ−ピペリジン−１−イル）−キサンチン（リナグリプチン）は、韓国登録特許第０８８３２７７号公報、韓国登録特許第１１５０４４９号公報及び国際公開第２００２／０６８４２０号、国際公開第２００４／０１８４６７号に開示された方法によって製造して使用することができ、特にこれに制限されない。 1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino- used in the present invention Piperidin-1-yl) -xanthine (linagliptin) can be prepared by the method disclosed in Korean Patent No. 0883277, Korean Patent No. 1150449 and WO 2002/068420 and WO 2004/018467. It can be manufactured and used, and is not particularly limited thereto.
また、本発明は、Ｘ−線粉末回折（Ｘ−Ｒａｙ ｐｏｗｄｅｒ ｄｉｆｆｒａｃｔｉｏｎ）パターン４．７゜、６．３゜、８．６゜、９．５゜、１０．９゜、１２．５゜、１４．６゜及び１６．８゜ ２θ±０．２゜ ２θで特徴的なピークを有する化学式１で表示される化合物の多形体Ｆを提供する。さらに、多形体Ｆは、４．１゜、７．０゜、１５．７゜、２２．３゜、２３．０゜及び２３．８゜ ２θ±０．２゜ ２θでピークを含んでもよい。 Also, the present invention provides X-Ray powder diffraction patterns 4.7 °, 6.3 °, 8.6 °, 9.5 °, 10.9 °, 12.5 °, 14 Provided is a polymorphic form F of the compound represented by the formula 1 having characteristic peaks at 6 ° and 16.8 ° 2θ ± 0.2 ° 2θ. Additionally, polymorph F may contain peaks at 4.1 °, 7.0 °, 15.7 °, 22.3 °, 23.0 ° and 23.8 ° 2θ ± 0.2 ° 2θ.
本発明によって提供されるリナグリプチン多形体Ｆは、カールフィッシャー（Ｋａｒｌ
ｆｉｓｃｈｅｒ）水分計を使用して測定したとき、２．０％〜４．０％の水分を含有し、熱重量分析（Ｔｈｅｒｍａｌ Ｇｒａｖｉｍｅｔｒｉｃ Ａｎａｌｙｓｉｓ）時、図４のように、特徴的に１００℃未満で脱水による２．０％〜３．０％水準の重さの減少を示す。
Linagliptin polymorph F provided by the present invention is
containing 2.0% to 4.0% moisture as measured using a fischer) moisture meter and characteristically less than 100 ° C. as shown in FIG. 4 when thermal gravimetric analysis (Thermal Gravimetric Analysis) It shows a decrease in weight of 2.0% to 3.0% level due to dehydration.
本発明に係る化学式１の化合物である１−［（４−メチル−キナゾリン−２−イル）メチル］−３−メチル−７−（２−ブチン−１−イル）−８−（３−（Ｒ）−アミノ−ピペリジン−１−イル）−キサンチン（リナグリプチン）の新規多形体Ｆは、多形体Ａ及び水和物形態の多形体Ｃ（国際公開第２００７／１２８７２１号の請求項３に記載の物質）と比較したとき、光苛酷条件で非常に安定しており、温度及び水分に対する安定性にも優れるので、薬剤学的組成物の有効成分として高品質を長期間維持できるという長所を有する。 1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R), which is a compound of the chemical formula 1 according to the present invention The novel polymorph F of -amino-piperidin-1-yl) -xanthine (linagliptin) is a polymorph A and the polymorph C of the hydrate form (substance according to claim 3 of WO 2007/128721) Since it is very stable under light severe conditions and excellent in stability to temperature and moisture as compared with the above, it has an advantage of maintaining high quality as an active ingredient of a pharmaceutical composition for a long time.
また、本発明のリナグリプチン多形体Ｆは、少量のエタノール及び常水を用いて製造することによって、エタノールと３級−ブチルメチルエーテルとの組み合わせで収得される多形体Ａの製造方法（国際公報第２００７／１２８７２１号の実施例１）より遥かに経済的で、且つ環境にやさしく製造できるという長所を有する。 In addition, the linagliptin polymorph F of the present invention is produced by using a small amount of ethanol and ordinary water to obtain a polymorph A obtained by combining ethanol with tertiary-butyl methyl ether (International Publication No. It has the advantage of being much more economical than Example 1) of 2007/128721 and environmentally friendly.
すなわち、本発明は、安定したリナグリプチン新規多形体Ｆ、及び商業的な大量生産が容易で、且つ経済的なリナグリプチン新規多形体Ｆの製造方法を提供する。 That is, the present invention provides a stable linagliptin novel polymorphic form F, and a method for producing linagliptin novel polymorphic form F which is easy for mass production and economical.
以下、本発明の理解を促進させるために、好ましい実施例、比較実施例及び実験例を提示する。しかし、下記の実施例、参考例、比較実施例及び実験例は本発明をより理解しやすくさせるために提供するものに過ぎなく、これらによって本発明の内容が限定されることはない。 Hereinafter, preferred examples, comparative examples and experimental examples are presented to facilitate understanding of the present invention. However, the following examples, reference examples, comparative examples and experimental examples are merely provided to make the present invention easier to understand, and the present invention is not limited thereto.
［参考例１］リナグリプチン多形体Ａの合成 [Reference Example 1] Synthesis of linagliptin polymorphic form A
国際公開第２００７／１２８７２１号の実施例１に開示された方法でリナグリプチン多形体Ａを製造した。 Linagliptin polymorph A was prepared by the method disclosed in Example 1 of WO 2007/128721.
［参考例２］リナグリプチン多形体Ｃの合成 [Reference Example 2] Synthesis of linagliptin polymorph C
国際公開第２００７／１２８７２１号の実施例３に開示された方法でリナグリプチン多形体Ｃを製造した。 Linagliptin polymorph C was prepared by the method disclosed in Example 3 of WO 2007/128721.
［実施例１］リナグリプチン多形体Ｆの合成−Ｉ Example 1 Synthesis of Linagliptin Polymorph F-I
１−［（４−メチル−キナゾリン−２−イル）メチル］−３−メチル−７−（２−ブチン−１−イル）−８−（３−（Ｒ）−アミノ−ピペリジン−１−イル）−キサンチン（リナグリプチン）１ｇを９５％のエタノール１ｍｌ及び常水１ｍｌの混合溶媒下で加温して
溶解した後、反応液が５０℃に到逹したとき、常水１９ｍｌを徐々に追加する。その次に、これを強く撹拌して７０℃まで昇温させた後、この温度で１時間にわたって追加的に撹拌した後で常温に冷却する。析出された結晶を一日撹拌してろ過した後、真空下で常温で２０時間にわたって乾燥させることによって白色のリナグリプチン多形体Ｆを０．８５ｇ収得した。
1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -After 1 g of xanthine (linagliptin) is dissolved by heating in a mixed solvent of 1 ml of 95% ethanol and 1 ml of normal water, when the reaction solution reaches 50 ° C., 19 ml of normal water is gradually added. Then it is vigorously stirred and warmed to 70 ° C., then additionally stirred at this temperature for 1 hour and then cooled to ambient temperature. The precipitated crystals were stirred for 1 day, filtered, and dried at room temperature under vacuum for 20 hours to obtain 0.85 g of white linagliptin polymorph F.
［実施例２］リナグリプチン多形体Ｆの合成−II [Example 2] Synthesis of linagliptin polymorph F-II
１−［（４−メチル−キナゾリン−２−イル）メチル］−３−メチル−７−（２−ブチン−１−イル）−８−（３−（Ｒ）−アミノ−ピペリジン−１−イル）−キサンチン（リナグリプチン）１００ｇを９５％のエタノール２００ｍｌ及び常水２００ｍｌの混合溶媒下で加温して溶解した後、反応液が５０℃に到逹したとき、常水１，８００ｍｌを徐々に追加する。その次に、これを強く撹拌して７０℃まで昇温させた後、この温度で１時間にわたって追加的に撹拌した後で常温に冷却する。析出された結晶を一日撹拌してろ過した後、真空下で常温で２０時間にわたって乾燥させることによって白色のリナグリプチン多形体Ｆを８７ｇ収得した。 1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -After dissolving 100 g of xanthine (linagliptin) in a mixed solvent of 200 ml of 95% ethanol and 200 ml of ordinary water and dissolving it, when the reaction liquid reaches 50 ° C., gradually add 1,800 ml of ordinary water . Then it is vigorously stirred and warmed to 70 ° C., then additionally stirred at this temperature for 1 hour and then cooled to ambient temperature. The precipitated crystals were stirred for 1 day, filtered, and dried at room temperature under vacuum for 20 hours to obtain 87 g of white linagliptin polymorph F.
［比較実施例１］ Comparative Example 1
１−［（４−メチル−キナゾリン−２−イル）メチル］−３−メチル−７−（２−ブチン−１−イル）−８−（３−（Ｒ）−アミノ−ピペリジン−１−イル）−キサンチン（リナグリプチン）１ｇを９５％のエタノール２ｍｌ及び常水２０ｍｌの混合溶媒下で７０℃で１時間にわたって加温・撹拌した後で常温に冷却する。結晶を一日撹拌してろ過した後、真空下で常温で２０時間にわたって乾燥させる。収得した結晶をＸＲＤで分析した結果、多形体Ａであることが確認された。 1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -1 g of xanthine (linagliptin) is warmed and stirred for 1 hour at 70 ° C in a mixed solvent of 2 ml of 95% ethanol and 20 ml of ordinary water, and then cooled to room temperature. The crystals are stirred for one day and filtered and then dried under vacuum at ambient temperature for 20 hours. As a result of analyzing the obtained crystals by XRD, it was confirmed to be polymorph A.
［比較実施例２］
１−［（４−メチル−キナゾリン−２−イル）メチル］−３−メチル−７−（２−ブチン−１−イル）−８−（３−（Ｒ）−アミノ−ピペリジン−１−イル）−キサンチン（リナグリプチン）１ｇを９５％のエタノール２ｍｌに加温して溶解した後、常水２０ｍｌを徐々に追加する。その次に、これを強く撹拌して７０℃まで昇温させた後、この温度で１時間にわたって追加的に撹拌した後で常温に冷却する。結晶を一日撹拌してろ過した後、真空下で常温で２０時間にわたって乾燥させる。収得した結晶をＸＲＤで分析した結果、多形体Ａであることが確認された。
Comparative Example 2
1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -After 1 g of xanthine (linagliptin) is dissolved by heating in 2 ml of 95% ethanol, 20 ml of ordinary water is gradually added. Then it is vigorously stirred and warmed to 70 ° C., then additionally stirred at this temperature for 1 hour and then cooled to ambient temperature. The crystals are stirred for one day and filtered and then dried under vacuum at ambient temperature for 20 hours. As a result of analyzing the obtained crystals by XRD, it was confirmed to be polymorph A.
＜実験例１＞光安定性試験 <Experimental Example 1> Photostability Test
リナグリプチン多形体Ｆ、リナグリプチン多形体Ａ及びＣを１００ｍｇずつそれぞれ透明なガラス容器に入れ、光安定性チャンバーで光源に露出させた状態で６日間保管した。ＣＡＲＯＮ光度安定度テストチャンバーモデル（Ｐｈｏｔｏｓｔａｂｉｌｉｔｙ Ｃｈａｍｂｅｒ Ｍｏｄｅｌ）６５４５を使用し、光露出量は、全体照明が２４０万ｌｕｘ−ｈｒ／ｍ２で、近紫外線が４００Ｗ・ｈｒ／ｍ２である。参考までに、ＩＣＨガイドラインでは、全体照明が１２０万ｌｕｘ−ｈｒ／ｍ２、近紫外線が２００Ｗ・ｈｒ／ｍ２以上を充足しなければならない。光源に露出させてから６日後、試料を５ｍｇずつ採集してＨＰＬＣを用いて分析した。その結果を下記の表１及び図５に示した。 100 mg each of linagliptin polymorph F and linagliptin polymorphs A and C were each placed in a transparent glass container, and stored in a light stability chamber for 6 days while exposed to a light source. Using a CARON photometric stability test chamber model (Photostability Chamber Model) 6545, the amount of light exposure is 2.4 million lux-hr / m 2 for the overall illumination, and 400 W · hr / m 2 for near-ultraviolet light. For reference, according to the ICH guidelines, the total illumination must satisfy 1.2 million lux-hr / m 2 and the near-ultraviolet rays must meet 200 W · hr / m 2 or more. Six days after exposure to the light source, 5 mg samples were collected and analyzed using HPLC. The results are shown in Table 1 below and FIG.
前記表１の結果から、リナグリプチン多形体Ｆは、光に露出した場合にも多形体Ａ及びＣに比べて遥かに高い安定性を示すことを確認することができる。 From the results in Table 1 above, it can be confirmed that linagliptin polymorph F exhibits much higher stability compared to polymorphs A and C even when exposed to light.
＜実験例２＞熱及び水分に対する安定性比較実験（加速試験、４０±２℃、７５±５％ＲＨ） <Experimental Example 2> Stability comparison experiment against heat and moisture (acceleration test, 40 ± 2 ° C., 75 ± 5% RH)
リナグリプチン多形体Ｆ、リナグリプチン多形体Ａ及びＣをそれぞれ５０ｍｇずつガラス容器に入れ、４０±２℃、７５±５％ＲＨで保管した。１週、２週、４週及び８週後に試料を５ｍｇずつ採集してＨＰＬＣを用いて分析した。その結果を下記の表２及び図６に示した。 Linagliptin Polymorph F and Linagliptin Polymorphs A and C were each placed in a glass container by 50 mg, and stored at 40 ± 2 ° C., 75 ± 5% RH. After 1 week, 2 weeks, 4 weeks and 8 weeks, 5 mg samples were collected and analyzed using HPLC. The results are shown in Table 2 below and FIG.
前記表２の結果から分かるように、リナグリプチン多形体Ｆは、多形体Ａ及びＣに比べて、加速試験で８週間の間に柔軟物質がほとんど生成されない非常に安定した物質であることを確認することができる。 As can be seen from the results shown in Table 2 above, linagliptin polymorph F is confirmed to be a very stable substance that hardly generates a soft substance in 8 weeks in the accelerated test as compared with polymorphs A and C. be able to.
＜実験例３＞固体状態の苛酷安定性比較実験（温度苛酷試験、６０℃） <Experimental Example 3> Severe stability comparison experiment in solid state (temperature severe test, 60 ° C.)
リナグリプチン多形体Ｆ、リナグリプチン多形体Ａ及びＣをそれぞれ５０ｍｇずつガラス容器に入れて６０℃で保管した。３日、１週、２週、４週及び８週後に試料を５ｍｇずつ採集してＨＰＬＣを用いて分析した。その結果を下記の表３及び図７に示した。 Linagliptin polymorph F and linagliptin polymorphs A and C were each stored in a glass container at 50 ° C. and stored at 60 ° C. After 3 days, 1 week, 2 weeks, 4 weeks and 8 weeks, 5 mg samples were collected and analyzed using HPLC. The results are shown in Table 3 below and FIG.
前記表３の結果から分かるように、リナグリプチン多形体Ｆは、６０℃で多形体Ａ及びＣより優れた熱安定性を示すことを確認することができる。これは、リナグリプチン多形体Ｆにおいて、他の多形体に比べて物理化学的安定性が大きく改善されたことを示す。 As can be seen from the results in Table 3 above, it can be confirmed that linagliptin polymorph F exhibits better thermal stability at 60 ° C. than polymorphs A and C. This indicates that linagliptin polymorph F has greatly improved physicochemical stability as compared to other polymorphs.
＜実験例４＞多形体Ｆの結晶安定性試験 <Experimental Example 4> Crystal Stability Test of Polymorph F
結晶形自体の安定性を確認するために、結晶安定性試験を加速条件（４０℃／７５％Ｒ
Ｈ）で８週間行い、その結果をＸＲＤで分析して下記の図８に示した。
In order to confirm the stability of the crystal form itself, the crystal stability test was accelerated under the conditions (40 ° C./75% R
H) for 8 weeks and the results are analyzed by XRD and shown in FIG. 8 below.
図８の結果から分かるように、リナグリプチン多形体Ｆは、加速条件で８週間保管した後でも結晶安定性を示すことを確認することができる。 As can be seen from the results in FIG. 8, it can be confirmed that linagliptin polymorph F exhibits crystal stability even after storage for 8 weeks under accelerated conditions.
＜実験例５＞Ｘ−線粉末回折測定 <Experimental Example 5> X-ray powder diffraction measurement
リナグリプチン多形体ＦをＸ−線粉末回折装置（ＢＲＵＫＥＲ Ｄ８ ＡＤＶＡＮＣＥ
Ｘｒａｙ Ｄｉｆｆｒａｃｔｏｍｅｔｅｒ（ＸＲＤ））を用いて測定した。放射線としてはＣｕＫ α（４０ｋｖ、４０ｍＡ）を使用し、常温（２５℃）で２θが４度〜４０度で、段階の大きさは０．０２００度、段階別係数時間は０．１０００秒であるという条件でデータを収集した。その結果は図１に示した。
Linagliptin Polymorph F as an X-ray powder diffractometer (BRUKER D8 ADVANCE
It measured using Xray Diffractometer (XRD). CuK α (40 kv, 40 mA) is used as radiation, 2θ is 4 ° to 40 ° at ordinary temperature (25 ° C.), the size of the step is 0.0200 °, and the coefficient time by step is 0.1000 seconds Data was collected under the condition of The results are shown in FIG.
＜実験例６＞熱重量分析 Experimental Example 6 Thermogravimetric Analysis
リナグリプチン多形体Ｆを、熱重量分析機（Ｔｈｅｒｍｏ Ｇｒａｖｉｍｅｔｒｉｃ Ａｎａｌｙｚｅｒ）であるＴＡ ＩＮＳＴＲＵＭＥＮＴＳ社のＴＧＡ Ｑ５０を使用して１０℃／分の速度で常温から４００℃まで加熱する条件で分析した。その結果、１００℃未満で２．０％〜３．０％の重さ減少が示され、２００℃以降に物質が分解されることを確認することができた。その結果は図４に示した。
Linagliptin Polymorph F was analyzed using a thermogravimetric analyzer (Thermo Gravimetric Analyzer) TGA Q50 manufactured by TA INSTRUMENTS under conditions of heating from ambient temperature to 400 ° C. at a rate of 10 ° C./min. As a result, weight reduction of 2.0% to 3.0% was shown below 100 ° C., and it was possible to confirm that the substance was decomposed after 200 ° C. The results are shown in FIG.
Claims (7)
段階２）段階１で製造した溶液に４０℃〜６０℃の温度で常水を追加する段階；
段階３）段階２で製造した懸濁液を加温した後で撹拌する段階；
段階４）段階３で製造した懸濁液を常温に冷却した後、撹拌してろ過する段階；を含むリナグリプチン多形体Ｆの製造方法。 Step 1) dissolving linagliptin in a mixed solvent of alcoholic solvent and normal water and dissolving it;
Step 2) adding ordinary water to the solution prepared in step 1 at a temperature of 40 ° C to 60 ° C;
Step 3) heating and then stirring the suspension prepared in step 2;
Step 4) A method for producing linagliptin polymorph F, comprising cooling the suspension prepared in step 3 to room temperature, stirring and filtering.
The method for producing linagliptin polymorph F according to claim 4, wherein in step 4, the suspension is aged for 12 hours or more, stirred and then filtered.
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| WO2020042939A1 (en) * | 2018-08-28 | 2020-03-05 | 上海迪赛诺药业股份有限公司 | New crystal form of dpp-iv inhibitor hypoglycemic drug and preparation method thereof |
| JP2021535218A (en) * | 2018-08-28 | 2021-12-16 | シャンハイ ディサノ ファーマシューティカルズ インベストメント カンパニー リミテッドShanghai Desano Pharmaceuticals Investment Co., Ltd. | New crystalline form of DPP-IV inhibitor hypoglycemic agent and its preparation method |
| CN110305131A (en) * | 2019-07-03 | 2019-10-08 | 山东百诺医药股份有限公司 | Li Gelieting novel crystal forms and preparation method thereof |
| CN110305131B (en) * | 2019-07-03 | 2021-12-31 | 山东百诺医药股份有限公司 | Novel crystal form of linagliptin and preparation method thereof |
| WO2021250995A1 (en) * | 2020-06-10 | 2021-12-16 | 有機合成薬品工業株式会社 | Crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-peperidine-1-yl)-xanthine |
| WO2021251467A1 (en) * | 2020-06-10 | 2021-12-16 | 有機合成薬品工業株式会社 | Crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-peperidine-1-yl)-xanthine |
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