EP0571463A1 - Novel cimetidine polymorph and process for preparing same - Google Patents

Novel cimetidine polymorph and process for preparing same

Info

Publication number
EP0571463A1
EP0571463A1 EP92904688A EP92904688A EP0571463A1 EP 0571463 A1 EP0571463 A1 EP 0571463A1 EP 92904688 A EP92904688 A EP 92904688A EP 92904688 A EP92904688 A EP 92904688A EP 0571463 A1 EP0571463 A1 EP 0571463A1
Authority
EP
European Patent Office
Prior art keywords
cimetidine
modification
methylthio
guanidine
methyl
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.)
Withdrawn
Application number
EP92904688A
Other languages
German (de)
French (fr)
Inventor
Andor Jeszenszky
Ferenc V Gh
Péter BENCSIK
László NAGY
Béla HEGEDU "S
Sándor Görög
Zsófia PAPN SZIKLAI
Mariann Hahn Czy
László VERECKEI
Gézáné KOZMA
Margit Kap S
va TÖRÖK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Publication of EP0571463A1 publication Critical patent/EP0571463A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles

Definitions

  • the invention relates to a novel polymorph modification of N-cyano-N l -methyl-N"- ⁇ 2-[(5-methyl- imidazol]-4-yl)-methylthio]-ethyl ⁇ -guanidine. Further ⁇ more, the invention relates to a process for the preparation of the novel polymorph modification.
  • N-cyano-N'-methyl-N"- ⁇ 2-[ (5-methylimidazol- 4-y1)-methylthio]-ethyl ⁇ -guanidine (generic name: cimetidine)
  • cimetidine a peculiar morphological modification
  • the modification "A” can be prepared by crystallization from an non-aqueous organic solvent (see the British patent specification No. 1,543,138). In the 80's several novel morphological modifications were described by the investigators.
  • the aim of the present invention is to provide a novel cimetidine polymorph modification showing more preferable parameters of pharmaceutical technology in comparison to any of the modifications known up to the present.
  • the invention is based on the recognition that a novel polymorph possessing advantageous pharmaceutical- -technological properties can be prepared from a supersaturated solution containing cimetidine by a treatment characterized by specific, well-defined parameters.
  • This novel cimetidine polymorph has been called cimetidine "E” by us.
  • the present invention relates to a novel polymorph crystal modification of N-cyano-N'-methyl- -N- . - ⁇ 2-[ (5-methylimidazol-4-yl)-methylthio]-ethyl ⁇ - guanidine (hereinafter cimetidine) , i. e. cimetidine » E".
  • a process for the preparation of the novel cimetidine "E" polymorph modification which comprises accomplishing an aqueous system, which is supersaturated for cimetidine at a temperature below 30 °C and contains a water-miscible organic solvent in an amount of at most 40 % by volume of water, crystallizing the solution or emulsion optionally by using an inoculating crystal, separating the crystals precipitated, drying them at a temperature below 20 °C or removing the water content of the crystals with an organic solvent and subsequently drying them.
  • alkanes and ketones are useful water-miscible organic solvents in the process according to the invention.
  • Suitable alkanols are e.g. methanol, ethanol or isopropanol; acetone is a particularly suitable ketone solvent.
  • the spectroscopical investigation of the novel crystal modification according to the invention was carried out by homogenizing a sample of 1.5 mg with 300 mg of potassium bromide and preparing pellets, which were examined on a NICOLET 20 DXC FT-IR device.
  • the modification "E” is characterized by a band of half-value width at 3311 cm -1
  • the above range - modification "A” shows a medium broad doublet band pair with maxima at 3226 and 3142 cm -1 ,
  • - modification "B” has a band system characterized by a main maximum at 3237 cm”" 1 and a secondary maximum at 3165 cm” 1
  • - modification "C” possesses a main maximum at
  • n D has a band pair with a nearly identical intensity at 3295 and 3213 cm -1 .
  • an other extremely sharp absorption band at 3113 cm"" 1 which can be assigned to the skeletal proton of the imidazole ring, is specifically characteristic.
  • the absorption band of the CN group in the modification "E” appears at 2159 cm -1
  • the absorption band of the CN group of other modifications in alphabetic order is present at 2178, 2174, 2166 and 2155 cm" 1 , respectively.
  • tablets were prepared from powder mixtures containing cimetidine "A” and “E” modification, respectively by using 15 kN compression force in a Korsch EKO DMS type instrumented tabletting machine.
  • the breaking strength values (ERWEKA TB 28 type) of the compressed product obtained were found to be by 30 to 50 % higher for modification "E” in comparison to those of modification "A".
  • the wear loss of the tablets containing modification "E” was found to be 0.3 to 0.6 % (ERWEKA TA type) , whereas 50 to 60 % of the compression products prepared from the powder mixture containing modification "A” showed a cap-like disintegration (breaking) .
  • the cimetidine "E” modification of the invention was subjected to pharmacological investigation by using the most simple test method, i.e. the so-called Shay's ulcer [Gastroenterology 56, 5 (1945) .
  • female W-Wistar rats weighing 120 to 150 g each were starved for 24 hours, then the pylorus of the animals was ligated under a mild ether anaethesia.
  • the compound to be tested was administered during the surgical intervention.
  • the hydrochloric acid production of the stomach was determined by titration. The results obtained are summarized in Table I. It can be seen from the results that the hydrochloric acid production of the stomachk is significantly inhibited by cimetidine "E".
  • cimetidine "E” The in vivo absorption of cimetidine "E” according to the invention was also studied.
  • 200 mg of cimetidine "E” and (as reference drug) cimetidine "A” each were orally administered in cachets to 6 beagle dogs in a "crossover" arrangement.
  • An interval of 8 days was inserted between the administratio of the two substances.
  • Cimetidine was given on empty stomach to the dogs.
  • the animals received food only by 4 hours following the administration. Water was allowed ad libitum.
  • Cimetidine "E” according to the invention can be transformed to pharmaceutical compositions by using the conventional methods of pharmaceutical formulation, preferably tabletting or encapsulation.
  • Active agent content 99.71 % total contamination 0.37 %
  • Example 4 The process described in Example 1 is followed, except that acetone is used instead of methanol and the crystallization is carried out at a temperature of 5 to 10 °C. In this way 187 g (93.5 %) of cimetidine "E" are obtained, the quality characteristics of which are in complete agreement with those described in Example 1.
  • Example 4
  • Example 1 The process described in Example 1 is followed, except that cimetidine "D” ("Z") is used as starting substance and the suspending is carried out with distilled water, to obtain 186.9 g (93.45 %) of cimetidine “E", the quality characteristics of which are in complete agreement with those described in Example 1.
  • Example 5 The process described in Example 1 is followed, except that the crystals obtained are washed 3 times with 80 ml of isopropanol each and the product obtained is dried at 60 °C. In this way 185 g (92.5 %) of cimetidine "E” are obtained, the quality characteristics of which are in complete agreement with those described in Example 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention a trait à une modification polymorphe nouvelle "E" de N-cyano-N'-méthyl-N''{2-[(5-méthylimidazole-4-yl)-méthylthio]-éthyl}-guanidine (cimétidine "E") se distinguant par ses caractéristiques spectroscopiques infrarouges. Selon le procédé de l'invention, la cimétidine "E" est élaborée en réalisant un système aqueux, qui est sursaturé pour N-cyano-N'-méthyl-N''-{2-[(5-méthylimidazole-4-il)-méthylthio]-éthyl}-guanidine à une température inférieure à 30 °C et contient un solvant organique miscible dans l'eau dans une proportion d'au moins 40 % en volume, cristallisant la solution ou l'émulsion en ajoutant un cristal d'inoculation, en séparant les cristaux précipités, en les asséchant à une température inférieure à 20 °C ou en extrayant le contenu en eau des cristaux à l'aide d'un solvant organique puis en les asséchant. Cette nouvelle modification "E" de cimétidine présente des caractéristiques rhéologiques et d'écoulement supérieures par rapport à celles de la cimétidine "A" et offre plusieurs avantages aux techniques pharmaceutiques.Disclosed is a novel polymorphic modification "E" of N-cyano-N'-methyl-N '' {2 - [(5-methylimidazol-4-yl) -methylthio] -ethyl} -guanidine (cimetidine " E ") distinguished by its infrared spectroscopic characteristics. According to the process of the invention, cimetidine "E" is produced by providing an aqueous system, which is supersaturated for N-cyano-N'-methyl-N '' - {2 - [(5-methylimidazole-4-il ) -methylthio] -ethyl} -guanidine at a temperature below 30 ° C and contains an organic solvent miscible with water in an amount of at least 40% by volume, crystallizing the solution or emulsion by adding a crystal inoculation, by separating the precipitated crystals, by drying them at a temperature below 20 ° C or by extracting the water content of the crystals with an organic solvent and then drying them. This novel "E" modification of cimetidine exhibits superior rheological and flow characteristics over those of cimetidine "A" and offers several advantages to pharmaceutical techniques.

Description

NOVEL CIMETIDINE POLYMORPH AND PROCESS FOR PREPARING SAME
The invention relates to a novel polymorph modification of N-cyano-Nl-methyl-N"-{2-[(5-methyl- imidazol]-4-yl)-methylthio]-ethyl}-guanidine. Further¬ more, the invention relates to a process for the preparation of the novel polymorph modification.
It is known that, due to its H2 receptor-block¬ ing action, N-cyano-N'-methyl-N"-{2-[ (5-methylimidazol- 4-y1)-methylthio]-ethyl}-guanidine (generic name: cimetidine) , is the active agent of the most successful class of antiulcer compositions of the last decade. It is also known that, up to the last years, a peculiar morphological modification (the so-called polymorph modification "A") has been the active ingredient in the pharmaceutical compositions. The modification "A" can be prepared by crystallization from an non-aqueous organic solvent (see the British patent specification No. 1,543,138). In the 80's several novel morphological modifications were described by the investigators. A good review summarizing these modifications, which can precisely be identified by infrared spectroscopy, was presented by B. Hegedtϊs and S. Gδrδg [Pharm. and Bio. Analysis 2, 303 (1985)], who reported on four anhydrous and three hydrate water- -containing cimetidine modifications. In addition to the modification "A" mentioned above, the modifications- "B", "C" and "Z" (recently called "D") were also identified among the anhydrous modifications. It is of course that th practical importance of the various modifications is not identical. Some polymorphs proved to be unstable or difficult to prepare. Based on the physical and chemical characteristics defined in the pharmacopoeas, the polymorph modification "A" of cimetidine occurs therein up to the present. However, some drawbacks of this morphological modification have also been observed in the practical use; thus, in the published European patent application No. 0,255,376 and published PCT application No. WO 88/0825 the authors indicate the liquid-base pharmaceutical compositions could be more advantageous since cimetidine is absorbed from the small intestine.
However, the aqueous suspensions of the cimetidine "A" polymorph are thermodynamically unstable and several parameters (characteristics) , e.g. the viscosity of the compositions obtained are also disadvantageous. Based on the above facts, the authors of the publications suggested the use of cimetidine "B" modification, which had previously been described.
It has been observed also in our own experiments concerning pharmaceutical technology that several formulation difficulties, particularly in the tablet formulation occurred due to the rheological and flowing properties of modification "A".
Thus, the aim of the present invention is to provide a novel cimetidine polymorph modification showing more preferable parameters of pharmaceutical technology in comparison to any of the modifications known up to the present.
The invention is based on the recognition that a novel polymorph possessing advantageous pharmaceutical- -technological properties can be prepared from a supersaturated solution containing cimetidine by a treatment characterized by specific, well-defined parameters.
This novel cimetidine polymorph has been called cimetidine "E" by us. Thus, the present invention relates to a novel polymorph crystal modification of N-cyano-N'-methyl- -N-.-{2-[ (5-methylimidazol-4-yl)-methylthio]-ethyl}- guanidine (hereinafter cimetidine) , i. e. cimetidine »E".
According to an other aspect of the invention, there is provided a process for the preparation of the novel cimetidine "E" polymorph modification, which comprises accomplishing an aqueous system, which is supersaturated for cimetidine at a temperature below 30 °C and contains a water-miscible organic solvent in an amount of at most 40 % by volume of water, crystallizing the solution or emulsion optionally by using an inoculating crystal, separating the crystals precipitated, drying them at a temperature below 20 °C or removing the water content of the crystals with an organic solvent and subsequently drying them.
C1---.3 alkanes and ketones are useful water-miscible organic solvents in the process according to the invention. Suitable alkanols are e.g. methanol, ethanol or isopropanol; acetone is a particularly suitable ketone solvent.
The spectroscopical investigation of the novel crystal modification according to the invention was carried out by homogenizing a sample of 1.5 mg with 300 mg of potassium bromide and preparing pellets, which were examined on a NICOLET 20 DXC FT-IR device.
Since four cimetidine base modifications are known addition to the three water-containing hydrate forms and several salt forms, it is not sufficient to define the characteristic, assignable absorption bands but it is also necessary to relate them to the other four modifica¬ tions [see Pharm. and Bio. Anal. 2, 303 (1985)] on the basis of the IR spectrum shown in Figure l (Figure 2 is th enlarged right side and Figure 3 is the left side of the complete characteristic shown in Figure 1) .
In the range of N-H bonds, the modification "E" is characterized by a band of half-value width at 3311 cm-1 In the above range - modification "A" shows a medium broad doublet band pair with maxima at 3226 and 3142 cm-1,
- modification "B" has a band system characterized by a main maximum at 3237 cm""1 and a secondary maximum at 3165 cm"1, - modification "C" possesses a main maximum at
3276 cm-1 and a secondary maximum at 3162 cm-1, whereas
- modification nD" has a band pair with a nearly identical intensity at 3295 and 3213 cm-1.
Thus, the above absorption at 3311 cm"1 is specifically chracteristic of the modification "E".
Similarly, an other extremely sharp absorption band at 3113 cm""1, which can be assigned to the skeletal proton of the imidazole ring, is specifically characteristic. The absorption band of the CN group in the modification "E" appears at 2159 cm-1, whereas the absorption band of the CN group of other modifications in alphabetic order is present at 2178, 2174, 2166 and 2155 cm"1, respectively.
The most intense bands of the spectra of all cimetidine modifications are found near to 1600 cm-1, which can be interpreted as the absorption of C=N double bonds or the conjugated system, respectively. In this range (region) the band pair of modification "E" is observed at 1605 and 1575 cm-1, respectively. This band pair appears
- at 1623, 1588 cm"1 for modification "A",
- at 1614, 1587 cm"1 for modification "B",
- at 1615, 1587 cm"1 for modification "C", and
- at 1614, 1587 cm"1 for modification "D". This part of the spectrum makes possible to identify and separate the modification "E" from the known modifications.
Since the morphological purity of individual samples cannot usually be judged only on the basis of assignatable bands, it is believed that some highly characteristic bands of the fingerprint range should also be mentioned in the spectroscopic characterization.
The most obvious characteristic feature seems to be the band with a high intensity at 1185 cm"1, aside with a well-resolved secondary band with half intensity at 1170 cm"1 but sufficiently sharp outlines. This is very characteristic since other modifications show in thi site only singlet bands with a small distorted shoulder, which is very difficult to resolve. The medium intense band appearing at 405 cm"1 is similarly suitable to determine the modification "E". Other modification do not possess any absorption band below 418 cm"1.
Several other characteristic bands of the modification "E" are at 1429, 1368, 1078, 1065, 835, 718 and 621 cm"1.
Hereinafter, the pharmaceutical-technological advantages of cimetidine "E" polymorph will be illustrated. According to our investigations cimetidine "E" has more advantageous rheological, flowing properties in comparison to those of modification "A". Thus, the outflow rate of cimetidine "E" is 10 sec/50 g, its angle of repose (tg α) equals 0.5 to 0.6. These data cannot be measured for modification "A": it has no free flow.
These advantages appear in the compression of the powder mixture, too. Thus, tablets were prepared from powder mixtures containing cimetidine "A" and "E" modification, respectively by using 15 kN compression force in a Korsch EKO DMS type instrumented tabletting machine.
The breaking strength values (ERWEKA TB 28 type) of the compressed product obtained were found to be by 30 to 50 % higher for modification "E" in comparison to those of modification "A".
The wear loss of the tablets containing modification "E" was found to be 0.3 to 0.6 % (ERWEKA TA type) , whereas 50 to 60 % of the compression products prepared from the powder mixture containing modification "A" showed a cap-like disintegration (breaking) .
The cimetidine "E" modification of the invention was subjected to pharmacological investigation by using the most simple test method, i.e. the so-called Shay's ulcer [Gastroenterology 56, 5 (1945) . According to this method female W-Wistar rats weighing 120 to 150 g each were starved for 24 hours, then the pylorus of the animals was ligated under a mild ether anaethesia. The compound to be tested was administered during the surgical intervention. The hydrochloric acid production of the stomach was determined by titration. The results obtained are summarized in Table I. It can be seen from the results that the hydrochloric acid production of the stomack is significantly inhibited by cimetidine "E".
Treatment n
Control 10 312.0
Cimetidine
"E" 10 50 151.0 52
The in vivo absorption of cimetidine "E" according to the invention was also studied. In these experiments 200 mg of cimetidine "E" and (as reference drug) cimetidine "A" each were orally administered in cachets to 6 beagle dogs in a "crossover" arrangement. An interval of 8 days was inserted between the administratio of the two substances. Cimetidine was given on empty stomach to the dogs. The animals received food only by 4 hours following the administration. Water was allowed ad libitum.
In predetermined intervals blood samples of 5 g each were taken from the animals. The coagulation of blood was prevented by using 3.8 % sodium citrate solution.
The extraction and determination were carried out by using a method described by us in an earlier publication [J. of Chromatography 273, 223 (1983)], which is useful also in human experiments.
The calculation of the cimetidine content of unknown plasma samples was performed on a Hewlet-Packard 1091 M HPLC diode-series device. The area under curve was calculated by using a two-compartment model. The deviation (± SC) and significance were calculated by using Student's "t" trial. The results are shown in Figure 4. The plasma level of cimetidine (X axis,s ng/ l values) was plotted against the time (Y axis) . It can be seen that the concentration in the blood of the cimetidine "E" modification (sign E) is more advantageous than that of cimetidine "A" (sign A) after 90 minutes although no significant difference can be observed.
Cimetidine "E" according to the invention can be transformed to pharmaceutical compositions by using the conventional methods of pharmaceutical formulation, preferably tabletting or encapsulation.
Thus, the most important advantage of the invention consists therein that, by using a simple, well-reproducible technology, a novel, effective cimetidine polymorph can be provided which shows highly favourable advantages concerning pharmaceutical technology The invention is illustrated in detail by the aid of the following non-limiting Examples. Example 1
After suspending 200 g of cimetidine (with a total contamination content of 0.4 %) in a mixture of 900 ml water with 200 ml of methanol, concentrated hydrochlorid acid solution is added to the suspension while stirring until the complete dissolution of the crystals. The temperature of the solution is adjusted to 10 °C, then it is combined under stirring with 20 % sodium hydroxide solution being equivalent to 1.1 ol of the hydrochloric acid used for the dissolution. The temperature of the solution is maintained between 10 °C and 15 °C by cooling when necessary and it is crystallized while stirring and when necessary inoculated with a crystal of cimetidine "E". After stirring for 1 to 2 hours the crystalline, sand-lik precipitate is filtered, washed with distilled water and dried to yield 186.5 g (93.2 %) of cimetidine "E". Analytical characteristics: melting point 142 to 145 °C
Active agent content 99.71 % total contamination 0.37 %
(determined by TLC) heavy metal content O Infrared spectrum see Figures l to 3.
Example 2
After suspending 1000 g of cimetidine "D" ("Z") modification (see the Hungarian patent specification No. 185,187 and its Great Britain equivalent No. 2,408,117) in a mixture containing 4500 ml of water and 1100 ml of ethanol the process described in Example 1 is followed to give 935 g (93.5 %) of cimetidine "E".
The quality characteristics of the product obtained are in complete agreement with those described in Example 1.
Example 3
The process described in Example 1 is followed, except that acetone is used instead of methanol and the crystallization is carried out at a temperature of 5 to 10 °C. In this way 187 g (93.5 %) of cimetidine "E" are obtained, the quality characteristics of which are in complete agreement with those described in Example 1. Example 4
The process described in Example 1 is followed, except that cimetidine "D" ("Z") is used as starting substance and the suspending is carried out with distilled water, to obtain 186.9 g (93.45 %) of cimetidine "E", the quality characteristics of which are in complete agreement with those described in Example 1. Example 5 The process described in Example 1 is followed, except that the crystals obtained are washed 3 times with 80 ml of isopropanol each and the product obtained is dried at 60 °C. In this way 185 g (92.5 %) of cimetidine "E" are obtained, the quality characteristics of which are in complete agreement with those described in Example 1.
Example 6
Pharmaceutical composition Components mg
Cimetidine "E" 200
Starch 56
Microcrystalline cellulose 60
Lactose 56 Polyvinylp rrolidone 12
Talc 12
Magnesium stearate 4
400 After preparing a well-compressible base mixture with good rheological properties from 1000-fold of the above amounts 1000 tablets are obtained by compression.

Claims

Claims
1. Polymorph modification "E" of N-cyano-N1- methyl-N"-{2-[ (5-methylimidazol-4-il)-methylthio]- ethyl}-guanidine (cimetidine) characterized by the infrared spectrospocipal characteristics shown in Figure 1.
2. A pharmaceutical composition, which c o m p r i s e s as active ingredient the novel polymorph modification "E" of N-cyano-N'- methyl-N"-{2-[ (5-methylimidazol-4-il)-methylthio]- ethyl}-guanidine defined in claim 1 in admixture with carriers and/or additives commonly used in the pharmacy.
3. A process for the preparation of the novel polymorph modification "E" of N-cyano-N1- methyl-N"-{2-[ (5-methylimidazol-4-il)-methylthio]- ethyl}-guanidine, which c o m p r i s e s accomplishing an aqueous system, which is supersaturated for N-cyano-N'-methyl-N"-{2-[ (5-methylimidazol-4-il)- methylthio]-ethyl}-guanidine at a temperature below 30 °C and contains a water-miscible organic solvent in an amount of at most 40 % by volume, crystallizing the solution or emulsion optionally by adding an inoculating crystal, separating the crystals precipitated, drying them at a temperature below 20 °C or removing the water content of the crystals with an organic solvent and subsequently drying them.
4. A process as claimed in claim 3, which c o m p r i s e s using a C1-3 alkanol or ketone as water-miscible organic solvent.
5. A process for the preparation of a pharmaceutical composition, which c o m p r i s e s mixing as active ingredient the novel N-cyano-N' methyl-N"-{2-[ (5-methylimidazol-4-il)-methylthio]- ethyl}-guanidine "E" polymorph modification defined in claim 1 with carriers and/or additives commonly used in the pharmacy and transforming them to a pharmaceutical composition.
EP92904688A 1991-02-15 1992-02-14 Novel cimetidine polymorph and process for preparing same Withdrawn EP0571463A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU91502A HU208675B (en) 1991-02-15 1991-02-15 Process for producing a new cimetidine polymorph and pharmaceutical preparations comprising this compound
HU50291 1991-02-15

Publications (1)

Publication Number Publication Date
EP0571463A1 true EP0571463A1 (en) 1993-12-01

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EP (1) EP0571463A1 (en)
JP (1) JPH06505247A (en)
KR (1) KR930703265A (en)
AU (1) AU653209B2 (en)
CA (1) CA2104027A1 (en)
HU (1) HU208675B (en)
WO (1) WO1992014713A1 (en)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9214713A1 *

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HUT60474A (en) 1992-09-28
KR930703265A (en) 1993-11-29
AU653209B2 (en) 1994-09-22
CA2104027A1 (en) 1992-08-16
HU910502D0 (en) 1991-09-30
AU1264692A (en) 1992-09-15
WO1992014713A1 (en) 1992-09-03
JPH06505247A (en) 1994-06-16
HU208675B (en) 1993-12-28

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