KR20180113822A - Novel polymorphous 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 process for the preparation thereof) - Google Patents

Novel polymorphous 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 process for the preparation thereof) Download PDF

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KR20180113822A
KR20180113822A KR1020170045436A KR20170045436A KR20180113822A KR 20180113822 A KR20180113822 A KR 20180113822A KR 1020170045436 A KR1020170045436 A KR 1020170045436A KR 20170045436 A KR20170045436 A KR 20170045436A KR 20180113822 A KR20180113822 A KR 20180113822A
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methyl
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linagliptin
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권지숙
윤진영
권재욱
서명원
강재훈
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일동제약(주)
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    • C—CHEMISTRY; METALLURGY
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Abstract

The present invention relates to a novel crystal form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (linagliptin), which is a DDP-4 inhibitor, and a method for manufacturing the same. The novel crystal form according to the present invention is very stable in long-term light-harsh conditions and excellent in stability of the crystal form, and is useful for long-term storage.

Description

1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴의 신규한 결정형 및 그의 제조방법{Novel polymorphous 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 process for the preparation thereof)}1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- -N-methyl-7- (2-butyn-1-yl) -naphthalen-1-yl] -quinoxaline and a process for producing ) -8- (3- (R) -amino-piperidin-1-yl) -xanthine and process for the preparation thereof)

본 발명은 하기 화학식1의 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(리나글립틴, Linagliptin)의 신규한 결정형 및 상업적으로 대규모 생산이 가능한 신규결정형 제조방법에 관한 것이다. The present invention relates to a process for the preparation of 1- (4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- Amino-piperidin-1-yl) -xanthin (Linagliptin), and to a novel crystalline preparation method capable of commercial large-scale production.

[화학식1][Chemical Formula 1]

Figure pat00001

Figure pat00001

상기 화학식1의 화합물은 대한민국 특허 등록 제0883277호, 제1150449호 및 국제 공개공보 WO 제2002/068420호, WO 제2004/018467호에 개시된 DPP-4 억제제로서 제2형 당뇨병 질환들을 치료하는데 치료학적 가치를 갖는다.
The compound of Formula 1 is a DPP-4 inhibitor disclosed in Korean Patent Nos. 0883277 and 1150449 and International Patent Publication Nos. 2002/068420 and WO 2004/018467 for the treatment of type 2 diabetes mellitus Value.

하나 이상의 결정형태로 존재하는 물질의 능력을 다형성(Polymorphism)으로 정의하고 이들의 상이한 결정 형태는 다형체로 불린다. 일반적으로 물질의 다형체 형태는 종종 결정의 습성 및 결정성 고체상 특성에 있어 상이하며, 이에 따라 물질의 안정성, 순도, 흡습성, 유동성, 압축성, 용해도 등과 같은 상이한 물리적 및 약제학적 특성을 가질 수 있다. 다형성은 여러 유기 화합물에서 발견될 수 있다.
The ability of a substance to exist in more than one crystal form is defined as polymorphism and the different crystal forms of these are called polymorphs. In general, the polymorph form of the material often differs in crystalline habit and crystalline solid phase properties, and thus may have different physical and pharmaceutical properties such as stability, purity, hygroscopicity, flowability, compressibility, solubility, etc. of the material. Polymorphism can be found in many organic compounds.

상기 화학식1의 화합물의 결정 형태는 국제 공개공보 WO 제2007/128721호에 다형체 A ~ E가 공지되어있으나, 그 중 다형체 A 및 B가 바람직한 결정이라고 기술되어 있다. 좀 더 자세히 살펴보면, 상기 특허에서는 다형체 A와 B가 2가지 에난티오트로픽(enantiotropic) 다형체의 혼합물로서 존재하며, 다형체 A, B의 열역학적 안정성의 교차는 25 ± 15℃로 상기 교차점을 초과하는 온도에서는 A형이 B형에 비해 열역학적으로 더 안정하고 상기 교차점보다 낮은 온도에서는 B형이 A형에 비해 열역학적으로 더 안정함을 나타낸다고 기술되어 있다. 이처럼 다형체 A와 B의 열역학적 교차는 25 ± 15℃로 이 교차점은 상온의 온도 조건이 포함되어 있어 의약품을 가공하는 동안 한 결정 형태에서 또 다른 결정형태로의 전환가능성을 배제할 수 없다. 그러므로 다형체 A와 B는 일정한 품질을 유지하여야 하는 의약품의 제조에 사용하기에는 적절치 않은 다형체들이다.
The crystal form of the compound of Formula 1 is disclosed in WO 2007/128721 of WO2007 / 088721, wherein polymorphs A and B are preferred crystals. More specifically, in the above patent, polymorphs A and B are present as a mixture of two enantiotropic polymorphs, and the intersection of the thermodynamic stability of polymorphs A and B is 25 ± 15 ° C., , The type A is more thermodynamically stable than the type B and the type B is more thermodynamically stable than the type A at a temperature lower than the point of intersection. Thus, the thermodynamic crossing of polymorphic A and B is 25 ± 15 ° C, and the crossing point includes the temperature condition at room temperature, so it is not possible to exclude the possibility of conversion from one crystal form to another crystal form during the processing of pharmaceutical products. Therefore, polymorphs A and B are polymorphs that are not appropriate for use in the manufacture of pharmaceuticals that must maintain consistent quality.

본 발명의 목적은 공지의 리나글립틴 다형체 A보다 온도, 습도 및 빛에 안정한 신규의 리나글립틴 다형체를 제공하는 것이며, 또한 신규의 리나글립틴 다형체의 상업적으로 대량생산이 용이한 제조방법을 제공하는 것이다.
It is an object of the present invention to provide novel linalglyptin polymorphs which are stable to temperature, humidity and light as compared with known linalglyptin polymorph A, and also to provide a method for producing commercially available linalogliptin polymorphs Method.

상기 과제를 해결하기 위하여 본 발명자들은 다양한 유기용매들(에탄올, 메탄올, 이소프로필알콜 등의 알코올성 용매, 아세트산에틸, 테트라하이드로퓨란, 1,4-다이옥산, 디메틸설폭사이드, 톨루엔 등)과 이들의 다양한 조합으로 리나글립틴 다형체 A보다 안정한 신규의 다형체를 얻기 위해 연구를 거듭 진행하였으나, 신규의 리나글립틴 다형체를 수득하지 못하였고, 오히려 대부분의 경우에 리나글립틴 다형체 A가 수득되는 것을 확인하였다.
DISCLOSURE OF THE INVENTION In order to solve the above problems, the inventors of the present invention have found that various organic solvents (alcoholic solvents such as ethanol, methanol and isopropyl alcohol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dimethylsulfoxide, Although studies have been repeated to obtain novel polymorphs that are more stable than linalgintin polymorph A in combination, no new linalogliptin polymorphs were obtained, but in most cases linalogliptin polymorph A was obtained Respectively.

이에 본 발명자들은 추가 연구에서 적절한 양용매(good solvent) 및 반용매(antisolvent)의 선택, 용매들의 투입방법, 단계별 온도조건 및 결정 숙성시간 등 각 조건들을 세밀하게 조절하여 신규 다형체의 형성이 가능한지를 면밀히 연구한 끝에 신규 다형체를 수득할 수 있었다.
Accordingly, the present inventors have found that, in a further study, it is possible to precisely control the conditions such as the selection of a suitable good solvent and antisolvent, a method of introducing solvents, a temperature condition at each step, and a crystal aging time to form a new polymorph , A new polymorph could be obtained.

본 발명자들이 연구한 신규 다형체의 일반적인 제조방법은 다음과 같다. The general process for the preparation of novel polymorphs studied by the present inventors is as follows.

리나글립틴을 알코올성 용매와 상수의 혼합용매 하에서 가온하여 용해시킨 후에 특정한 온도에서 상수를 추가하고 가온교반한다. 그 다음 상온으로 냉각하고, 생성된 결정을 12시간 이상 숙성하며 교반한 다음에 여과하여 신규 다형체 F를 얻을 수 있다.After dissolving linagliptin in a mixed solvent of an alcoholic solvent and a constant water, it is added at a specific temperature and stirred with heating. Then, the solution is cooled to room temperature, and the resulting crystals are aged for 12 hours or more, stirred, and then filtered to obtain a novel polymorph F.

반면 비교 실시예 1, 2와 같이 동일한 양과 동일한 종류의 용매를 사용하더라도 용매 투입 방법이 다르거나, 단계별 온도조건이 달라지면 리나글립틴 신규 다형체 F가 아닌 공지의 다형체 A가 얻어진다는 사실을 확인하였다. 이는 본 발명이 통상의 기술자가 단순히 결정화 실험을 반복하여 용이하게 발견할 수 있는 것이 아니며, 상기와 같이 매우 특정한 조건에서만 리나글립틴 다형체 F가 제조될 수 있다는 것을 의미한다.
On the other hand, even when the same amount and the same kind of solvent as in Comparative Examples 1 and 2 were used, it was confirmed that when the solvent introduction method was changed or the temperature condition was changed at each step, a known polymorph A was obtained instead of the new polymorph F Respectively. This means that the present invention can not easily be found by repeating the crystallization experiment simply by a person skilled in the art, and the lynagliptin polymorph F can be produced only under very specific conditions as described above.

본 발명은 하기 단계를 포함하는 리나글립틴 다형체 F의 제조방법을 제공한다.The present invention provides a process for preparing linalooligatin polymorph F comprising the following steps.

단계1) 리나글립틴을 알코올성 용매와 상수의 혼합용매에서 가온하여 용해시키는 단계;Step 1) heating and dissolving linalogliptin in a mixed solvent of an alcoholic solvent and a constant water;

단계2) 단계1에서 제조한 용액에 특정한 온도에서 상수를 추가하는 단계; Step 2) adding a constant at a specific temperature to the solution prepared in step 1;

단계3) 단계2에서 제조한 현탁액을 가온한 후 교반하는 단계;Step 3) heating and stirring the suspension prepared in Step 2;

단계4) 단계3에서 제조한 현탁액을 상온으로 냉각한 후, 교반하고 여과하는 단계Step 4) After cooling the suspension prepared in Step 3 to room temperature, stirring and filtering

를 포함하는 리나글립틴 다형체 F의 제조방법
≪ RTI ID = 0.0 > of Lynagliptin < / RTI >

일구현예에서, 단계1)에서 사용되는 알코올성 용매는 메탄올, 에탄올 및 이소프로판올이며, 바람직하게는 에탄올이다.In one embodiment, the alcoholic solvents used in step 1) are methanol, ethanol and isopropanol, preferably ethanol.

일구현예에서, 단계2)는 40 ~ 60℃(바람직하게는 45 ~ 55℃)의 특정한 온도조건에서 수행된다.In one embodiment, step 2) is performed at a specific temperature condition of 40-60 캜 (preferably 45-55 캜).

일구현예에서, 단계3)은 70 ~ 90℃(바람직하게는 70 ~ 80℃) 범위의 온도에서 1시간 내로 수행된다.In one embodiment, step 3) is carried out at a temperature in the range of 70 to 90 캜 (preferably 70 to 80 캜) within one hour.

일구현예에서, 단계4)는 12시간 이상 숙성하며 교반한 후 여과한다.
In one embodiment, step 4) is aged for at least 12 hours, stirred and filtered.

본 발명에 사용된 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(리나글립틴)은 대한민국 특허 등록 제0883277호, 제1150449호 및 국제 공개공보 WO 제2002/068420호, WO 제2004/018467호에 개시된 방법에 따라 제조하여 사용할 수 있으며, 특별히 제한되지 않는다.
Methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino- Piperazine-1-yl) -xanthin (linagliptin) was prepared according to the method disclosed in Korean Patent Registration Nos. 0883277 and 1150449 and International Patent Publications WO 2002/068420 and WO 2004/018467 And is not particularly limited.

또한, 본 발명은 X-선 분말 회절(X-Ray powder diffraction) 패턴 4.7°, 6.3°, 8.6°, 9.5°, 10.9°, 12.5°, 14.6° 및 16.8° 2θ ± 0.2° 2θ에서 특징적인 피크를 갖는 화학식1로 표시되는 화합물의 다형체 F를 제공한다. 다형체 F는 추가적으로 4.1°, 7.0°, 15.7°, 22.3°, 23.0° 및 23.8° 2θ ± 0.2° 2θ에서 피크를 포함할 수 있다.
Further, the present invention is characterized in that X-ray powder diffraction patterns have characteristic peaks at 4.7 °, 6.3 °, 8.6 °, 9.5 °, 10.9 °, 12.5 °, 14.6 ° and 16.8 ° 2θ ± 0.2 ° 2θ Lt; RTI ID = 0.0 > F < / RTI > Polymorph F may additionally comprise peaks at 4.1, 7.0, 15.7, 22.3, 23.0 and 23.8 2 &thetas; +/- 0.2 DEG 2 theta.

[화학식1][Chemical Formula 1]

Figure pat00002
Figure pat00002

본 발명에 의해 제공되는 리나글립틴 다형체 F는 Karl fischer 수분분석기를 사용하여 측정시 2.0 ~ 4.0%의 수분을 함유하며, 열중량분석(Thermal Gravimetric Analysis)시 도 4와 같이 특징적으로 100℃ 미만에서 탈수로 인한 2.0 ~ 3.0% 수준의 무게감소를 나타낸다.
The linagliptin polymorph F provided by the present invention contains 2.0 to 4.0% of water when measured using a Karl fischer moisture analyzer, and when analyzed by a thermal gravimetric analysis, Which is a weight reduction of 2.0 ~ 3.0% due to dehydration.

본 발명에 따른 화학식1 화합물인 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(리나글립틴)의 신규한 다형체 F는 다형체 A 및 수화물 형태의 다형체 C(국제 공개공보 WO 제2007/128721호 청구항 3에 기재된 물질)와 비교 했을 때에 광 가혹 조건에서 매우 안정하고, 온도 및 수분에 대한 안정성도 우수하여 약제학적 조성물의 유효성분으로 장기간 고품질을 유지할 수 있는 장점을 가진다.
1- (4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn- (Laminagliptin) is a polymorph A and a polymorph C in the form of a hydrate (as described in International Patent Publication WO 2007/128721, Claim 3 It has an advantage that it can maintain high quality for a long time as an active ingredient of a pharmaceutical composition because it is very stable under light harsh conditions and excellent in temperature and moisture stability.

또한, 본 발명의 리나글립틴 다형체 F는 소량의 에탄올과 상수를 이용하여 제조함으로써 에탄올과 3급-부틸메틸에테르 조합에서 수득되는 다형체 A의 제조방법(국제공보 WO 제2007/128721의 실시예 1)보다 훨씬 경제적이고 친환경적으로 제조할 수 있다는 장점을 가진다.In addition, the ligazliptin polymorph F of the present invention can be produced by using a small amount of ethanol and a constant to prepare a polymorph A obtained by the combination of ethanol and tert-butyl methyl ether (International Publication WO 2007/128721 It is advantageous in that it can be produced more economically and environmentally friendly than Example 1).

즉, 본 발명은 안정한 리나글립틴 신규 다형체 F 및 상업적으로 대량생산이 용이하고 경제적인 리나글립틴 신규 다형체 F의 제조방법을 제공한다.
That is, the present invention provides a stable polymorph F of linagliptin and a method of producing novel polymorph F of lignagliptin which is economical and easy to mass-produce commercially.

도 1은 본 발명에 따른 리나글립틴 신규 다형체 F의 분말 X-선 분말회절 분광도(Powder X-ray Diffraction pattern)를 나타낸 것이다.
도 2는 리나글립틴 다형체 A의 분말 X-선 분말회절 분광도(Powder X-ray Diffraction pattern)를 나타낸 것이다.
도 3은 리나글립틴 다형체 C의 분말 X-선 분말회절 분광도(Powder X-ray Diffraction pattern)를 나타낸 것이다.
도 4는 본 발명에 따른 리나글립틴 신규 다형체 F의 열중량분석(Thermo Gravimetric Analysis)을 나타낸 것이다.
도 5는 본 발명에 따른 리나글립틴 신규 다형체 F와 리나글립틴 다형체 A 및 C의 광 안정성을 확인하기 위해 광 조사 전, 후에 따른 함량(%) 변화 및 결정의 색상변화를 비교한 것이다.
도 6은 본 발명에 따른 리나글립틴 신규 다형체 F와 리나글립틴 다형체 A 및 C의 가속조건에서의 시간에 따른 함량(%) 변화를 비교한 것이다.
도 7은 본 발명에 따른 리나글립틴 신규 다형체 F와 리나글립틴 다형체 A 및 C의 열안정성을 확인하기 위해 가혹조건에서의 시간에 따른 함량(%) 변화를 비교한 것이다.
도 8은 본 발명에 따른 리나글립틴 신규 다형체 F의 가속조건에서의 결정 안정성을 나타낸 것이다.1 is a powder X-ray diffraction pattern of a novel polymorph F of linagliptin according to the present invention.
Figure 2 shows the powder X-ray diffraction pattern of the powder of linalgintin polymorph A.
FIG. 3 is a powder X-ray diffraction pattern of the powdered X-ray powder diffraction pattern of lignagliptin polymorph C. FIG.
Figure 4 shows thermogravimetric analysis of the novel polymorph F of linagliptin according to the present invention.
Figure 5 compares the change in the content (%) and the change in color of the crystals before and after light irradiation in order to confirm the light stability of the novel polymorph F and the ligazliptin polymorphs A and C according to the present invention .
Figure 6 compares the content (%) change of the novel polymorph F of linagliptin according to the present invention with the time course of the linagliptin polymorphs A and C under accelerated conditions.
Figure 7 compares the change in content (%) over time in harsh conditions to confirm the thermal stability of the novel polymorph F of linagliptin and polymorphs A and C of linagliptin according to the present invention.
Fig. 8 shows the crystal stability of the novel polymorph F of linagliptin according to the present invention under accelerated conditions.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예, 비교실시예 및 실험예를 제시한다. 그러나 하기의 실시예, 참고예, 비교실시예 및 실험예는 본 발명을 보다 쉽게 이해하기 위하여 제고하는 것 일뿐, 이들에 의해 본 발명의 내용이 한정되는 것은 아니다.
Hereinafter, preferred embodiments, comparative examples, and experimental examples are shown to facilitate understanding of the present invention. However, the following examples, reference examples, comparative examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

[[ 참고예Reference example 1]  One] 리나글립틴Linagliptin 다형체Polymorph A합성  A synthesis

국제공보 WO 제2007/128721의 실시예 1에 개시된 방법으로 리나글립틴 다형체 A를 제조하였다.
Linagliptin Polymorph A was prepared by the method described in Example 1 of International Publication WO 2007/128721.

[[ 참고예Reference example 2]  2] 리나글립틴Linagliptin 다형체Polymorph C형 합성  C-type synthesis

국제공보 WO 제2007/128721의 실시예 3에 개시된 방법으로 리나글립틴 다형체 C를 제조하였다.
Linagliptin Polymorph C was prepared by the method described in Example 3 of International Publication WO 2007/128721.

[[ 실시예Example 1]  One] 리나글립틴Linagliptin 다형체Polymorph F 합성-I F synthesis-I

1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(리나글립틴) 1 g을 95 % 에탄올 1 ㎖ 및 상수 1 ㎖의 혼합용매 하에서 가온하여 용해한 후, 반응액이 50℃에 도달했을 때에 상수 19 ㎖를 서서히 추가한다. 그 다음 강하게 교반하며 70℃까지 승온한 뒤, 이 온도에서 1시간 동안 추가 교반 후 상온으로 냉각한다. 석출된 결정을 하루 동안 교반하고 여과한 후, 진공 하에 상온에서 20시간 동안 건조하여 백색의 리나글립틴 다형체 F를 0.85 g 수득하였다.
1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- 1 g of xanthin (linagliptin) was dissolved by heating in a mixed solvent of 1 ml of 95% ethanol and 1 ml of a constant water, and the constant 19 ml was gradually added when the reaction solution reached 50 ° C. The mixture was then stirred vigorously and heated to 70 ° C and then further stirred at this temperature for 1 hour and then cooled to room temperature. The precipitated crystals were stirred for one day, filtered, and then dried under vacuum at room temperature for 20 hours to obtain 0.85 g of white linalgiptin polymorph F.

[[ 실시예Example 2]  2] 리나글립틴Linagliptin 다형체Polymorph F 합성- F synthetic- IIII

1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(리나글립틴) 100 g을 95 % 에탄올 200 ㎖ 및 상수 200 ㎖의 혼합용매 하에서 가온하여 용해한 후, 반응액이 50℃에 도달했을 때에 상수 1,800 ㎖를 서서히 추가한다. 그 다음 강하게 교반하며 70℃까지 승온한 뒤, 이 온도에서 1시간 동안 추가 교반 후 상온으로 냉각한다. 석출된 결정을 하루 동안 교반하고 여과한 후, 진공 하에 상온에서 20시간 동안 건조하여 백색의 리나글립틴 다형체 F를 87 g 수득하였다.
1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- -Yl) -xantin (linagliptin) (100 g) is dissolved in 200 ml of 95% ethanol in a mixed solvent of ethanol (200 ml) and water (200 ml). When the reaction solution reaches 50 캜, constant 1,800 ml is slowly added. The mixture was then stirred vigorously and heated to 70 ° C and then further stirred at this temperature for 1 hour and then cooled to room temperature. The precipitated crystals were stirred for one day, filtered, and dried under vacuum at room temperature for 20 hours to obtain 87 g of white linalgiptin polymorph F.

[비교 [compare 실시예Example 1]  One]

1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(리나글립틴) 1 g을 95 % 에탄올 2 ㎖ 및 상수 20 ㎖의 혼합용매 하에서 70℃에서 1시간 동안 가온 교반 후 상온으로 냉각한다. 결정을 하루 동안 교반하고 여과한 후, 진공 하에 상온에서 20시간 동안 건조한다. 수득한 결정을 XRD로 분석한 결과, 다형체 A로 확인되었다.
1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- -Yl) -xantin (linagliptin) is stirred in a mixed solvent of 95% ethanol (2 ml) and water (20 ml) at 70 ° C for 1 hour and then cooled to room temperature. The crystals are stirred for one day, filtered, and then dried under vacuum at room temperature for 20 hours. The crystals obtained were analyzed by XRD and found to be polymorph A.

[비교 [compare 실시예Example 2]  2]

1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(리나글립틴) 1 g을 95 % 에탄올 2 ㎖에 가온하여 용해한 후, 상수 20 ㎖를 서서히 추가한다. 그 다음 강하게 교반하며 70℃까지 승온한 뒤, 이 온도에서 1시간 동안 추가 교반 후 상온으로 냉각한다. 결정을 하루 동안 교반하고 여과한 후, 진공 하에 상온에서 20시간 동안 건조한다. 수득한 결정을 XRD로 분석한 결과, 다형체 A로 확인되었다.
1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- -Yl) -xanthine (linalogliptin) is dissolved in 2 ml of 95% ethanol to dissolve, and then the constant 20 ml is gradually added. The mixture was then stirred vigorously and heated to 70 ° C and then further stirred at this temperature for 1 hour and then cooled to room temperature. The crystals are stirred for one day, filtered, and then dried under vacuum at room temperature for 20 hours. The crystals obtained were analyzed by XRD and found to be polymorph A.

<< 실험예Experimental Example 1>  1> 광안정성Light stability 시험  exam

리나글립틴 다형체 F와 리나글립틴 다형체 A 및 C 100 ㎎씩을 각각 투명한 유리용기에 넣어 광안정성 챔버에서 광원에 노출시킨 채로 6일 동안 보관하였다. CARON Photostability Chamber Model 6545을 사용하였으며, 광노출양은 Overall illumination(전체조명)이 240만 lux-hr/m2, Near UV(근자외선)가 400 W·hr/m2이다. 참고로 ICH 가이드라인에서는 illumination(전체조명)이 120만 lux-hr/m2, Near UV(근자외선)가 200 W·hr/m2 이상을 충족해야 한다. 광원에 노출시킨 뒤 6일 후 시료를 5 ㎎씩 취하여 HPLC를 이용하여 분석하였다. 그 결과를 하기 표 1과 도 5에 나타내었다.
100 mg of linagliptin polymorph F and 100 mg of linagliptin polymorphs A and C were each stored in a transparent glass container for 6 days while exposed to a light source in a light stability chamber. CARON Photostability Chamber Model 6545 was used. Overall exposure (total illumination) was 2.4 million lux-hr / m 2 and Near UV (near-ultraviolet) was 400 W hr / m 2 . For reference, the ICH Guideline should meet illumination at 1.2 million lux-hr / m 2 and Near UV at 200 W hr / m 2 . Six days after exposure to light, 5 mg samples were taken and analyzed by HPLC. The results are shown in Table 1 and FIG.

Figure pat00003
Figure pat00003

상기 표 1의 결과로부터 리나글립틴 다형체 F는 빛에 노출되어도 다형체 A 및 C에 비하여 월등하게 높은 안정성을 나타냄을 확인할 수 있다.
From the results shown in Table 1, it can be confirmed that linalogliptin polymorph F exhibits significantly higher stability than polymorph A and C even when exposed to light.

<< 실험예Experimental Example 2> 열과 수분에 대한 안정성 비교 실험(가속시험, 40 ± 2℃, 75 ± 5 %  2> Comparison of stability against heat and moisture (accelerated test, 40 ± 2 ℃, 75 ± 5% RHRH ))

리나글립틴 다형체 F와 리나글립틴 다형체 A 및 C를 각각 50 ㎎씩 유리 용기에 넣고 40 ± 2℃, 75 ± 5% RH에서 보관하였다. 1주, 2주, 4주 및 8주 후에 시료를 5㎎씩 취하여 HPLC를 이용하여 분석하였다. 그 결과를 하기 표 2와 도 6에 나타내었다.
Linalogliptin polymorph F and linalogliptin polymorphs A and C were stored in a glass container at 40 ± 2 ° C and 75 ± 5% RH, respectively. After 1 week, 2 weeks, 4 weeks and 8 weeks, 5 mg samples were taken and analyzed by HPLC. The results are shown in Table 2 and FIG.

Figure pat00004
Figure pat00004

상기 표 2의 결과로부터 알 수 있듯이 리나글립틴 다형체 F는 다형체 A 및 C에 비해 가속시험에서 8주 동안 유연물질이 거의 생성되지 않는 매우 안정한 물질임을 확인할 수 있다.
As can be seen from the results in Table 2, linalogliptin polymorph F can be confirmed to be a very stable substance in which almost no flexible substance is generated for 8 weeks in the accelerated test as compared with polymorph Form A and C.

<< 실험예Experimental Example 3> 고체상태의 가혹 안정성 비교 실험(온도 가혹시험, 60℃) 3> Comparative test of severe stability of solid state (temperature harsh test, 60 ℃)

리나글립틴 다형체 F와 리나글립틴 다형체 A 및 C를 각각 50 ㎎씩 유리 용기에 넣고 60℃에서 보관하였다. 3일, 1주, 2주, 4주 및 8주 후에 시료를 5 ㎎씩 취하여 HPLC를 이용하여 분석하였다. 그 결과를 하기 표 3과 도 7에 나타내었다.
Linalogliptin polymorph F and linalogliptin polymorphs A and C were each stored in glass containers at 60 50. After 3 days, 1 week, 2 weeks, 4 weeks and 8 weeks, 5 ㎎ samples were taken and analyzed by HPLC. The results are shown in Table 3 and FIG.

Figure pat00005
Figure pat00005

상기 표 3의 결과에서 보듯이 리나글립틴 다형체 F는 60℃에서 다형체 A 및 C보다 우월한 열 안정성을 나타냄을 확인할 수 있다. 이는 리나글립틴 다형체 F가 다른 다형체들에 비하여 물리화학적 안정성이 크게 개선되었음을 나타낸다.
As can be seen from the results of Table 3 above, it can be seen that linalooligatin polymorph F exhibits superior thermal stability to polymorphic A and C at 60 ° C. This indicates that the lysine Glyptin polymorph F has significantly improved physico-chemical stability compared to other polymorphs.

<< 실험예Experimental Example 4>  4> 다형체Polymorph F의 결정 안정성 시험 F crystal stability test

결정형 자체의 안정성을 확인하기 위하여 결정 안정성 시험을 가속조건(40℃ /75 % RH)에서 8주간 수행하고, 그 결과를 XRD 분석하여 하기 도 8에 나타내었다. In order to confirm the stability of the crystal form itself, the crystal stability test was carried out under accelerated conditions (40 DEG C / 75% RH) for 8 weeks, and the results were analyzed by XRD analysis and shown in FIG.

도 8 결과에서 보듯이 리나글립틴 다형체 F는 가속조건 8주간 보관에도 결정 안정성을 나타냄을 확인할 수 있다.
As can be seen from FIG. 8, it can be seen that the crystalline L-glutinate polymorph F exhibits crystal stability even after storage for 8 weeks under accelerated conditions.

<< 실험예Experimental Example 5> X-선 분말  5> X-ray powder 회절diffraction 측정  Measure

리나글립틴 다형체 F를 X-선 분말 회절기 BRUKER D8 ADVANCE Xray Diffractometer(XRD)를 이용하여 측정하였다. 방사선은 CuK α(40kv, 40mA)를 사용하였고, 상온(25℃)에서 2θ가 4 ~ 40도이며, 단계 크기는 0.0200도, 단계별 계수 시간은 0.1000초인 조건에서 데이터를 수집하였다. 그 결과는 도 1에 나타내었다.
Rinagliptin polymorph F was measured using an X-ray powder diffractometer BRUKER D8 ADVANCE Xray Diffractometer (XRD). The data were collected under the conditions of CuK α (40 kv, 40 mA) at room temperature (25 ℃), 2θ of 4 ~ 40 degrees, step size of 0.0200 degree, and step counting time of 0.1000 second. The results are shown in Fig.

<< 실험예Experimental Example 6>  6> 열중량분석Thermogravimetry

리나글립틴 다형체 F를 열중량분석기(Thermo Gravimetric Analyzer) TA사의 TGA Q50을 사용하여 10℃/분의 속도로 상온에서 400℃까지 가열하는 조건에서 분석하였다. 그 결과, 100℃ 미만에서 2.0 ~ 3.0%의 무게감소가 나타나며, 200℃ 이후에 물질이 분해되는 것을 확인할 수 있었다. 그 결과는 도 4에 나타내었다.
Linaloglyptin polymorph F was analyzed using a thermogravimetric analyzer (Thermo Gravimetric Analyzer) TA TGA Q50 under the condition of heating from room temperature to 400 DEG C at a rate of 10 DEG C / min. As a result, a weight loss of 2.0 to 3.0% was observed at less than 100 ° C, and it was confirmed that the material was decomposed after 200 ° C. The results are shown in Fig.

Claims (7)

X선 분말 회절(X-ray powder diffraction) 분광도에서 2θ값이 4.7°, 6.3°, 8.6°, 9.5°, 10.9°, 12.5°, 14.6° 및 16.8°(2θ ± 0.2°)인 피크를 포함하는 리나글립틴 다형체 F
X-ray powder diffraction Spectroscopy includes peaks at 2θ values of 4.7 °, 6.3 °, 8.6 °, 9.5 °, 10.9 °, 12.5 °, 14.6 ° and 16.8 ° (2θ ± 0.2 °) &Lt; RTI ID = 0.0 &gt; F
제1항에 있어서, X선 분말 회절 분광도에서 2θ값이 4.1°, 7.0°, 15.7°, 22.3°, 23.0° 및 23.8° (2θ ± 0.2°)인 피크를 추가로 포함하는 리나글립틴 다형체 F
2. The method of claim 1, wherein the X-ray powder diffraction spectroscopy further comprises a peak at 2? Values of 4.1, 7.0, 15.7, 22.3, 23.0 and 23.8 (2? Shape F
제1항 또는 2항에 있어서, 수분 2.0 ~ 4.0%를 함유하는 리나글립틴 다형체 F
3. The composition according to claim 1 or 2, characterized in that the linalooligatin polymorph F
단계1) 리나글립틴을 알코올성 용매와 상수의 혼합용매에서 가온하여 용해시키는 단계;
단계2) 단계1에서 제조한 용액에 40 ~ 60℃온도에서 상수를 추가하는 단계;
단계3) 단계2에서 제조한 현탁액을 가온한 후 교반하는 단계;
단계4) 단계3에서 제조한 현탁액을 상온으로 냉각한 후, 교반하고 여과하는 단계를 포함하는 리나글립틴 다형체 F의 제조방법
Step 1) heating and dissolving linalogliptin in a mixed solvent of an alcoholic solvent and a constant water;
Step 2) adding a constant at a temperature of 40 to 60 占 폚 to the solution prepared in Step 1;
Step 3) heating and stirring the suspension prepared in Step 2;
Step 4) Production of linalooligatin polymorph F comprising cooling the suspension prepared in step 3 to room temperature, followed by stirring and filtration
제4항에 있어서, 단계1에서 알코올성 용매는 메탄올, 이소프로판올 및 에탄올인 리나글립틴 다형체 F의 제조방법
5. The method according to claim 4, wherein in step 1, the alcoholic solvent is methanol, isopropanol, ethanol, a method of producing lignagliptin polymorph F
제4항에 있어서, 단계3에서 70 ~ 90℃에서 1시간 이내로 교반하는 방법
5. The method according to claim 4, wherein in step 3, stirring is carried out at 70 to 90 DEG C within 1 hour
제4항에 있어서, 단계4에서 12시간 이상 숙성하며 교반한 후 여과하는 방법

The method according to claim 4, which comprises aging for more than 12 hours in step 4,

KR1020170045436A 2017-04-07 2017-04-07 Novel polymorphous 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 process for the preparation thereof) KR20180113822A (en)

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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

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