JPH0413343B2 - - Google Patents
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- Publication number
- JPH0413343B2 JPH0413343B2 JP57035345A JP3534582A JPH0413343B2 JP H0413343 B2 JPH0413343 B2 JP H0413343B2 JP 57035345 A JP57035345 A JP 57035345A JP 3534582 A JP3534582 A JP 3534582A JP H0413343 B2 JPH0413343 B2 JP H0413343B2
- Authority
- JP
- Japan
- Prior art keywords
- cimetidine
- monohydrochloride
- infrared absorption
- absorption spectrum
- cim
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明はシメチジン１塩酸塩多形体およびその
製造方法に関する。
下記の式で示されるＮ−メチル−N′−シアノ
−N″−〔２−｛（５−メチル−４−イミダゾリル）
メチルチオ｝エチル〕グアニジン塩酸塩（シメチ
ジン１塩酸塩）は、ヒスタミンH2−受容体拮抗
作用を有し、抗潰瘍剤として有用な化合物であ
る。
シメチジンは、ヒスタミンH2−受容体拮抗作
用を有する化合物であり、これには多数の多形体
結晶の存在が知られている。シメチジンは水に比
較的難溶性（1.14％、37℃）で、溶解性が低いた
め、製剤への応用には問題が多いが、これを塩酸
塩に変換することにより、溶解性が高められ、多
種類の製剤への応用が可能となる。
本発明者等は、シメチジン塩酸塩に関する研究
過程で、偶然にも、シメチジンをその１塩酸塩に
変換する際に結晶形の異なるものを得た。シメチ
ジン１塩酸塩について、これまで多形体の存否は
全く知られていない。更に研究を進めた結果、そ
の変換反応に使用される反応溶媒の含水量によつ
て異なる結晶形を有するものが得られることを見
出した。
本発明者等が分離に成功したシメチジン１塩酸
塩の多形体結晶は２種あり、本明細書では、その
一方を結晶形Ａ体（このものは3/4水和物であ
る）、他方を結晶形Ｂ体と称する。
本発明に係るシメチジン１塩酸塩多形体は結晶
形Ｂ体であり、このものは、融点175〜179℃で、
赤外吸収スペクトルの波数 3430，2750，2650，
2160，1610，1590，1375，1240，1220，1085およ
び910（cm-1）の吸収を特徴としている。第２図に
その赤外吸収スペクトルのパターンを示す。
もう一方の１塩酸塩多形体結晶Ａ体は融点169
〜174℃で、赤外吸収スペクトルの波数 3470，
2800，2760，2200，1620，1575，1410，1385，
1355，1270，1205，930，910および720（cm-1）の
吸収を有している。第１図はその赤外吸収スペク
トルのパターンである。
上記２種の多形体結晶の赤外吸収スペクトルの
パターンは、シアノグアニジンによる特性吸収に
著しい差異があり、シアノグアニジン部分が結晶
形に大きく寄与していることを示している。
上記結晶形Ａ体および結晶形Ｂ体のいずれも、
後記実施例の欄に示したように、シメチジンより
著しく高い溶解性を有し、殊に本発明に係る結晶
形Ｂ体は、従来の製造法でシメチジン１塩酸塩と
して得られている結晶との比較においても、これ
に勝る良好な溶解性を有している。
本発明に係るシメチジン１塩酸塩多形体の結晶
形Ｂ体は、シメチジンを、塩酸含有非水溶媒によ
り、例えば、ピリジン塩酸塩などのようにイミダ
ゾールよりも解離定数の小さい有機アミン化合物
を含む低級アルコール、クロロホルムまたはジク
ロルメタン等の含ハロゲン化物、あるいはベンゼ
ン、トルエン等の非極性溶媒中で処理することに
より得られる。
他方の結晶形Ａ体は、シメチジンを塩酸水溶液
中で処理することにより得られ、このものはエタ
ノール等の非水溶媒中で処理することにより結晶
形Ｂ体に変換することができる。なお結晶形Ａ体
とＢ体とは相互に変換可能で、結晶形Ｂ体は、例
えば水を溶媒として処理することにより結晶形Ａ
体に変換される。
次に、本発明の実施例について説明する。以下
の説明中、CIMはシメチジン、CIM・HCl−Ａお
よびCIM・HCl−Ｂはそれぞれシメチジン１塩酸
塩多形体の結晶形Ａ体および同Ｂ体である。
実施例 １
CIM→CIM・HCl−Ｂ
シメチジン原末25.2ｇ（0.1モル）をエタノー
ル500mlに溶解し、これにピリジン塩酸塩11.5ｇ
（0.1モル）を加え、１時間撹拌したのち、溶媒を
留去する。結晶をアセトンで洗浄後、減圧乾燥す
ることにより、CIM・HCl−Ｂ 26ｇを得る。
融点：175〜179℃
C10H16N6S・HCl
実測値 Ｃ 41.69，Ｈ 6.06，Ｎ 29.15（％）
理論値 Ｃ 41.59，Ｈ 5.93，Ｎ 29.10（％）
赤外吸収スペクトル（第２図）
3430，3280，3140，2780，2750，2650，2160，
1610，1590，1410，1375，1345，1250，1240，
1220，1160，1085，910，820，（cm-1）．
上記結晶形Ｂ体について、Ｘ線回折（対陰極：
Cu，走査速度：1deg／min）を第４図に、示差
熱分析のTG−DTA曲線（パン：Al、昇温速
度：５℃／min）を第６図にそれぞれ示す。
実施例 ２
(1) CIM→CIM・HCl−Ａ
シメチジン原末25.2ｇ（0.1モル）を氷冷した
1N塩酸100mlに溶解し、凍結乾燥する。残つた結
晶をアセトンで洗浄後、減圧乾燥することによ
り、CIM・HCl−Ａ 25ｇを得る。
融点：169〜174℃
C10H16N6S・HCl・３／4H2O
実測値 Ｃ 39.80，Ｈ 6.27，Ｎ 27.81（％）
理論値 Ｃ 39.73，Ｈ 6.17，Ｎ 27.80（％）
赤外吸収スペクトル（第１図）
3470，3430，3280，3150，2800，2760，2650，
2200，1620，1575，1410，1385，1355，1325，
1270，1250，1230，1205，1170，1020，960，
930，910，835，720 （cm-1）．
上記結晶形Ａ体について、Ｘ線回折（対陰極：
Cu，走査速度：1deg／min）を第３図に、示差
熱分析のTG−DTA曲線（パン：Al、昇温速
度：５℃／min）を第５図にそれぞれ示す。
(2) CIM・HCl−Ａ→CIM・HCl−Ｂ
CIM・HCl−Ａ 21ｇをエタノール120mlに加
熱溶解し、冷却すると、CIM・HCl−Ｂが析出す
る。収量19ｇ。
第１表は、上記実施例で得られたシメチジン１
塩酸塩多形体の結晶形Ａ体および結晶形Ｂ体につ
いて、水、および日本薬局方、一般試験法による
崩壊試験・第１液に対する溶解性を、従来のシメ
チジン１塩酸塩として得られた結晶（結晶晶出の
溶媒としてアセトニトリルを使用）、およびシメ
チジンのそれと比較して示している。
The present invention relates to cimetidine monohydrochloride polymorphs and methods for their production. N-methyl-N′-cyano-N″-[2-{(5-methyl-4-imidazolyl) represented by the following formula
Methylthio}ethyl]guanidine hydrochloride (cimetidine monohydrochloride) has a histamine H 2 -receptor antagonistic effect and is a compound useful as an antiulcer agent. Cimetidine is a compound that has histamine H 2 -receptor antagonistic activity, and is known to exist in many polymorphic crystal forms. Cimetidine is relatively sparingly soluble in water (1.14%, 37°C), and its low solubility causes many problems in its application to pharmaceutical preparations; however, by converting it to hydrochloride, its solubility can be increased. Application to many types of preparations becomes possible. In the course of research on cimetidine hydrochloride, the present inventors happened to obtain a different crystal form when converting cimetidine to its monohydrochloride. Regarding cimetidine monohydrochloride, the existence or non-existence of polymorphisms has not been known at all so far. As a result of further research, it was discovered that products with different crystal forms can be obtained depending on the water content of the reaction solvent used in the conversion reaction. There are two types of polymorphic crystals of cimetidine monohydrochloride that the present inventors have successfully isolated. It is called crystal form B. The cimetidine monohydrochloride polymorph according to the present invention is crystalline form B, which has a melting point of 175-179°C,
Wave number of infrared absorption spectrum 3430, 2750, 2650,
It is characterized by absorption at 2160, 1610, 1590, 1375, 1240, 1220, 1085 and 910 (cm -1 ). Figure 2 shows the pattern of its infrared absorption spectrum. The other monohydrochloride polymorphic crystal form A has a melting point of 169
~174℃, wave number of infrared absorption spectrum 3470,
2800, 2760, 2200, 1620, 1575, 1410, 1385,
It has absorptions of 1355, 1270, 1205, 930, 910 and 720 (cm -1 ). FIG. 1 shows the pattern of its infrared absorption spectrum. The infrared absorption spectrum patterns of the above two types of polymorphic crystals show that there is a significant difference in the characteristic absorption due to cyanoguanidine, indicating that the cyanoguanidine moiety greatly contributes to the crystal shape. Both of the above crystalline form A and crystalline form B,
As shown in the Examples section below, crystal form B, which has significantly higher solubility than cimetidine, and in particular according to the present invention, is different from the crystals obtained as cimetidine monohydrochloride by the conventional production method. Even in comparison, it has superior solubility. Crystal form B of the cimetidine monohydrochloride polymorph according to the present invention is obtained by preparing cimetidine with a lower alcohol containing an organic amine compound having a dissociation constant smaller than that of imidazole, such as pyridine hydrochloride, in a nonaqueous solvent containing hydrochloric acid. , a halide such as chloroform or dichloromethane, or a nonpolar solvent such as benzene or toluene. The other crystalline form A is obtained by treating cimetidine in an aqueous hydrochloric acid solution, and this can be converted to crystalline form B by treating it in a non-aqueous solvent such as ethanol. Crystal forms A and B are mutually convertible, and crystal form B can be converted into crystal form A by treating water as a solvent, for example.
transformed into a body. Next, examples of the present invention will be described. In the following description, CIM is cimetidine, CIM.HCl-A and CIM.HCl-B are crystal form A and form B of cimetidine monohydrochloride polymorph, respectively. Example 1 CIM→CIM・HCl-B 25.2 g (0.1 mol) of cimetidine bulk powder was dissolved in 500 ml of ethanol, and 11.5 g of pyridine hydrochloride was dissolved in this.
(0.1 mol) was added, and after stirring for 1 hour, the solvent was distilled off. After washing the crystals with acetone, they are dried under reduced pressure to obtain 26 g of CIM.HCl-B. Melting point: 175-179℃ C 10 H 16 N 6 S・HCl Actual value C 41.69, H 6.06, N 29.15 (%) Theoretical value C 41.59, H 5.93, N 29.10 (%) Infrared absorption spectrum (Figure 2) 3430, 3280, 3140, 2780, 2750, 2650, 2160,
1610, 1590, 1410, 1375, 1345, 1250, 1240,
1220, 1160, 1085, 910, 820, (cm -1 ). Regarding the above crystal form B, X-ray diffraction (anticathode:
Fig. 4 shows the TG-DTA curve of differential thermal analysis (pan: Al, heating rate: 5°C/min). Example 2 (1) CIM→CIM・HCl-A 25.2 g (0.1 mol) of cimetidine bulk powder was ice-cooled.
Dissolve in 100 ml of 1N hydrochloric acid and lyophilize. The remaining crystals are washed with acetone and dried under reduced pressure to obtain 25 g of CIM.HCl-A. Melting point: 169-174℃ C 10 H 16 N 6 S・HCl・3/4H 2 O Measured value C 39.80, H 6.27, N 27.81 (%) Theoretical value C 39.73, H 6.17, N 27.80 (%) Infrared absorption Spectrum (Figure 1) 3470, 3430, 3280, 3150, 2800, 2760, 2650,
2200, 1620, 1575, 1410, 1385, 1355, 1325,
1270, 1250, 1230, 1205, 1170, 1020, 960,
930, 910, 835, 720 (cm -1 ). X-ray diffraction (anticathode:
Fig. 3 shows the TG-DTA curve of differential thermal analysis (pan: Al, heating rate: 5°C/min). (2) CIM・HCl-A → CIM・HCl-B When heating and dissolving 21 g of CIM・HCl-A in 120 ml of ethanol and cooling, CIM・HCl-B is precipitated. Yield: 19g. Table 1 shows cimetidine 1 obtained in the above example.
Regarding crystalline form A and crystalline form B of the hydrochloride polymorph, the solubility in water and the disintegration test/first liquid according to the Japanese Pharmacopoeia, General Test Methods was determined using the crystals obtained as conventional cimetidine monohydrochloride ( (using acetonitrile as the solvent for crystallization) and compared with that of cimetidine.
【表】
前記実施例で得られたシメチジン１塩酸塩の結
晶形Ａ体を使用し、一般的な注射剤の製造方法に
従い、下記参考処方１によるシメチジン注射剤
（浸透圧比：1.9〜2.1、0.9％生理食塩水に対する
比）を製した。
参考処方１ １アンプル（２ml）中
シメチジン１塩酸塩結晶形Ａ体 …239.6mg
（シメチジンとして200mg）
日局 注射用蒸留水 …適量
日局 PH調整剤（PH 4.6〜6.0） …適量
また、実施例で得られたシメチジン１塩酸塩の
結晶形Ｂ体を使用し、一般的な坐剤の製造方法に
従い、下記参考処方によるシメチジン坐剤製剤を
製した。
参考処方２ １個（2.4ｇ）中
シメチジン１塩酸塩結晶形Ｂ体 …343.35mg
（シメチジンとして300mg）
日局 ポリソルベート80（安定剤） …240.0mg
局外規 ハードフアツト（基剤） …適量
上記参考処方１（結晶Ａ体使用）の注射剤各１
アンプルを10名に静脈投与した場合、および参考
処方２（結晶形Ｂ体使用）の坐剤各１個を７名に
直腸投与した場合のそれぞれについてシメチジン
の血中濃度を測定した。
その血中濃度測定において得られたシメチジン
の平均血中濃度の経時変化を第７図（：参考処
方１、：参考処方２）に、また平均血中濃度−
時間曲線下面積（AUC）および平均血中濃度半
減期（ｔ 1/2）の生物学的利用率を第２表に示
す。[Table] Using the crystal form A of cimetidine monohydrochloride obtained in the above example, cimetidine injection according to the following reference formulation 1 (osmolality ratio: 1.9-2.1, 0.9) was prepared according to the general method for manufacturing injections. % saline) was prepared. Reference prescription 1 1 ampoule (2 ml) of cimetidine monohydrochloride crystal form A...239.6 mg (200 mg as cimetidine) JP Distilled water for injection...appropriate amount JP PH regulator (PH 4.6-6.0)...appropriate amount Also, examples Using the crystal form B of cimetidine monohydrochloride obtained in , a cimetidine suppository formulation was prepared according to the following reference formulation according to a general suppository manufacturing method. Reference prescription 2 1 piece (2.4g) cimetidine monohydrochloride crystal form B...343.35mg (300mg as cimetidine) JP Polysorbate 80 (stabilizer)...240.0mg External regulations Hard fat (base)...appropriate amount Above reference prescription 1 (using crystal A form) injection each
The blood concentration of cimetidine was measured when an ampoule was administered intravenously to 10 people and when one suppository of Reference Formulation 2 (using crystalline form B) was administered rectally to 7 people. Figure 7 (Reference Prescription 1, Reference Prescription 2) shows the changes over time in the average blood concentration of cimetidine obtained in the blood concentration measurement.
The bioavailability of the area under the time curve (AUC) and mean blood concentration half-life (t 1/2) is shown in Table 2.
第１図および第２図は赤外吸収スペクトル、第
３図および第４図はＸ線回折（対陰極：Cu、走
査速度：1deg／min）、第５図および第６図は示
差熱分析のTG−DTA曲線（パン：Al、昇温速
度：５℃／min）をそれぞれ示すグラフ（第１
図、第３図、第５図：シメチジン１塩酸塩結晶形
Ａ体、第２図、第４図、第６図：同結晶形Ｂ体）、
第７図はシメチジンの血中濃度の経時変化を示す
グラフである。
Figures 1 and 2 are infrared absorption spectra, Figures 3 and 4 are X-ray diffraction (anticathode: Cu, scanning speed: 1deg/min), Figures 5 and 6 are differential thermal analysis. Graphs showing the TG-DTA curves (pan: Al, heating rate: 5°C/min) (first
Figures, Figures 3 and 5: cimetidine monohydrochloride crystalline form A, Figures 2, 4 and 6: crystalline form B),
FIG. 7 is a graph showing the change in blood concentration of cimetidine over time.
Claims (1)
3430，2750，2650，2160，1610，1590，1375，
1240，1220，1085および910（cm-1）の吸収を有す
ることを特徴とするシメチジン１塩酸塩多形体。 ２ シメチジンを塩酸含有非水溶媒中で処理する
ことを特徴とする、融点175〜179℃、赤外吸収ス
ペクトルの波数 3430，2750，2650，2160，
1610，1590，1375，1240，1220，1085および910
（cm-1）の吸収を有するシメチジン１塩酸塩多形
体の製造方法。 ３ シメチジンを塩酸水溶液中で処理することに
より、融点169〜174℃、赤外吸収スペクトルの波
数 3470，2800，2760，2200，1620，1575，
1410，1385，1355，1270，1205，930，910および
720（cm-1）の吸収を有するシメチジン１塩酸塩多
形体を得、ついでこれを非水溶媒中で処理するこ
とを特徴とする、融点175〜179℃、赤外吸収スペ
クトルの波数 3430，2750，2650，2160，1610，
1590，1375，1240，1220，1085および910（cm-1）
の吸収を有するシメチジン１塩酸塩多形体の製造
方法。[Claims] 1. Melting point 175-179°C, wave number of infrared absorption spectrum
3430, 2750, 2650, 2160, 1610, 1590, 1375,
Cimetidine monohydrochloride polymorph, characterized in that it has absorptions of 1240, 1220, 1085 and 910 (cm -1 ). 2 Cimetidine is treated in a non-aqueous solvent containing hydrochloric acid, melting point 175-179°C, infrared absorption spectrum wave number 3430, 2750, 2650, 2160,
1610, 1590, 1375, 1240, 1220, 1085 and 910
A method for producing cimetidine monohydrochloride polymorph having an absorption of (cm -1 ). 3 By treating cimetidine in an aqueous hydrochloric acid solution, it has a melting point of 169-174℃ and an infrared absorption spectrum wave number of 3470, 2800, 2760, 2200, 1620, 1575,
1410, 1385, 1355, 1270, 1205, 930, 910 and
A cimetidine monohydrochloride polymorph having an absorption of 720 (cm -1 ) is obtained, which is then treated in a non-aqueous solvent, with a melting point of 175-179°C and a wave number of infrared absorption spectrum of 3430, 2750. ,2650,2160,1610,
1590, 1375, 1240, 1220, 1085 and 910 (cm -1 )
A method for producing a cimetidine monohydrochloride polymorph having an absorption of .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57035345A JPS58152868A (en) | 1982-03-05 | 1982-03-05 | Polymorphic crystal of cimetidine hydrochloride and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57035345A JPS58152868A (en) | 1982-03-05 | 1982-03-05 | Polymorphic crystal of cimetidine hydrochloride and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58152868A JPS58152868A (en) | 1983-09-10 |
| JPH0413343B2 true JPH0413343B2 (en) | 1992-03-09 |
Family
ID=12439267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57035345A Granted JPS58152868A (en) | 1982-03-05 | 1982-03-05 | Polymorphic crystal of cimetidine hydrochloride and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58152868A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8618846D0 (en) * | 1986-08-01 | 1986-09-10 | Smithkline Beckman Corp | Chemical process |
| JPH064601B2 (en) * | 1987-11-04 | 1994-01-19 | 三井石油化学工業株式会社 | Method for purifying N-cyano-N'-methyl-N "-[2-{(5-methyl-1H-imidazol-4-yl) methylthio} ethylguanidine |
-
1982
- 1982-03-05 JP JP57035345A patent/JPS58152868A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58152868A (en) | 1983-09-10 |
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