CA2104027A1 - Cimetidine polymorph and process for preparing same - Google Patents
Cimetidine polymorph and process for preparing sameInfo
- Publication number
- CA2104027A1 CA2104027A1 CA002104027A CA2104027A CA2104027A1 CA 2104027 A1 CA2104027 A1 CA 2104027A1 CA 002104027 A CA002104027 A CA 002104027A CA 2104027 A CA2104027 A CA 2104027A CA 2104027 A1 CA2104027 A1 CA 2104027A1
- Authority
- CA
- Canada
- Prior art keywords
- cimetidine
- modification
- methyl
- methylthio
- guanidine
- 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.)
- Abandoned
Links
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
Landscapes
- 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
The invention relates to the novel polymorph modification "E" of N-cyano-N'-methyl-N'' 2-[(5-methyl-imidazol-4-yl)-methylthio]-ethyl -guanidine (cimetidine "E") characterized by infrared spectroscopical characteristics. According to the process of the invention cimetidine "E" is prepared by 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. The novel modification "E" of cimetidine shows better rheological and flowing properties in comparison to those of cimetidine "A" and provides several advantages concerning pharmaceutical technology.
Description
2 ~ 2 7 W' ~/14713 PCT/HU92/~7 NOVEL CIMETIDINE POLYMORPH AND PROCESS FOR
PREPARING SAME
The invention relates to a novel polymorph modification of N-cyano-N'-methyl-N"-{2-t(5-methyl-imidazol]-4-yl)-methylthio]-ethyl~-guanidine. Further-more, the invention relates to a process for the 10 preparation of the novel polymorph modification.
It is known that, due to its H2 receptor-block-ing action, N-cyano-Nl-methyl-N''-{2-[(5-methylimidazol 4-yl)-methylthio]-ethyl}-guanidine (generic name:
cimetidine), is the active agent of the most successful 15 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 20 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 25 modifications, which can precisely be identified by infrared spectroscopy, was presented by B. Heged~s and S.
Gorog [Pharm. and Bio. Analysis 3, 303 (1985)], who reported on four anhydrous and three hydrate water--containing cimetidine modifications. In addition to the 30 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 the practical importance of the various modifications is not t identical. Some polymorphs proved to be unstable or 35 difficult to prepare.
2~027 3 - 2 - PCT/HU92/~07 _ 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. W0 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 invèntion 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.
210~027 WO92/14713 _ 3 _ PCT/HU92/~X~7 Thus, the present invention relates to a novel polymorph crystal modification of N-cyano-N'-methyl--N"-{2-[(5-methylimidazol-4-yl~-methylthio]-ethyl3-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.
Cl_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 l.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 in 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. 3, 303 (1985)] on the basis of the IR spectrum shown in Figure l (Figure 2 is the enlarged right side and Figure 3 is the left side ~1 V,l ~ ~
WO92/14713 _ ~ _ PCT/HU92/~OZ~
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~l.
In the above range - modification "A" shows a medium broad doublet band pair with maxima at 3226 and 3142 cm~1, - modification "8" has a band system characterized by a main maximum at 3237 cm~l and a secondary maximum at 3165 cm~1, - modification "C" possesses a main maximum at 3276 cm~l and a secondary maximum at 3162 cm~1, whereas - modification "D" 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~l, 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~l, whereas the absorption band of the CN group of other modifications in alphabetic order is present at 2178, 2174, 2166 and 2155 cm~l, respectively.
The most intense bands of the spectra of all cimetidine modifications are found near to 1600 cm~l, 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~l 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 2~0~027 W~92J14713 _ 5 _ PCT/HU92/~07 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~l, 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 this site only singlet bands with a small distorted shoulder, which is very difficult to resolve.
The medium intense band appearing at 405 cm~l is similarly suitable to determine the modification "E".
Other modification do not possess any absorption band below 418 cm~l.
Several other characteristic bands of the 20 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 ~) 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 EXO DMS type instrumented tabletting 2~ 0~027 W092/14713 - 6 _ PCT/HU92/~7_ 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".
` 210~027 W~2/14713 _ 7 _ PCT/HU92/~W~7 Table I
Treatment n Dose HCL production Inhlbition i.p. during 4 hours HCl produc-mg/kg calculated for tion 100 g of body-weight /umol 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 administration 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 (1~83)~, which is useful also in human experiments.
The calculation of the cimetidine content of unknown plasma samples was performed on a Hewlet-Packard ~ ~()27 WO92/14713 - 8 _ PCT/HU92/~OZ_ lO9l M HPLC diode-series device. The area under cur~e 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/ml 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 there-in 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 l 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 lO C, then it is combined under stirring with 20 % sodium hydroxide solution being equi~alent to l.l mol of the hydrochloric acid used for the dissolution. The temperature of the solution is maintained between lO C and 15 C by cooling when necessary and it is crystallized while stirring and when necessary inoculated with a crystal of cimetidine "E".
2~0~a27 W~2/14713 _ 9 _ PCT/HU92/~X~7 After stirring for 1 to 2 hours the crystalline, sand-like 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 10 Infrared spectrum see Figures 1 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,~08,117) 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 Exampie 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 WO92/14713 ~ 1 0 ~ ~ J ~ PCT/HU92/00007_ The process described in Example l 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 l.
Example 6 Pharmaceutical composition Com~onents mq Cimetidine !'E" 200 Starch 56 Microcrystalline cellulose 60 Lactose 56 15 Polyvinylpyrrolidone 12 Talc 12 Magnesium stearate 4 After preparing a well-compressible base mixture with good rheological properties from lOOO-fold of the above amounts lO00 tablets are obtained by compression.
PREPARING SAME
The invention relates to a novel polymorph modification of N-cyano-N'-methyl-N"-{2-t(5-methyl-imidazol]-4-yl)-methylthio]-ethyl~-guanidine. Further-more, the invention relates to a process for the 10 preparation of the novel polymorph modification.
It is known that, due to its H2 receptor-block-ing action, N-cyano-Nl-methyl-N''-{2-[(5-methylimidazol 4-yl)-methylthio]-ethyl}-guanidine (generic name:
cimetidine), is the active agent of the most successful 15 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 20 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 25 modifications, which can precisely be identified by infrared spectroscopy, was presented by B. Heged~s and S.
Gorog [Pharm. and Bio. Analysis 3, 303 (1985)], who reported on four anhydrous and three hydrate water--containing cimetidine modifications. In addition to the 30 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 the practical importance of the various modifications is not t identical. Some polymorphs proved to be unstable or 35 difficult to prepare.
2~027 3 - 2 - PCT/HU92/~07 _ 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. W0 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 invèntion 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.
210~027 WO92/14713 _ 3 _ PCT/HU92/~X~7 Thus, the present invention relates to a novel polymorph crystal modification of N-cyano-N'-methyl--N"-{2-[(5-methylimidazol-4-yl~-methylthio]-ethyl3-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.
Cl_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 l.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 in 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. 3, 303 (1985)] on the basis of the IR spectrum shown in Figure l (Figure 2 is the enlarged right side and Figure 3 is the left side ~1 V,l ~ ~
WO92/14713 _ ~ _ PCT/HU92/~OZ~
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~l.
In the above range - modification "A" shows a medium broad doublet band pair with maxima at 3226 and 3142 cm~1, - modification "8" has a band system characterized by a main maximum at 3237 cm~l and a secondary maximum at 3165 cm~1, - modification "C" possesses a main maximum at 3276 cm~l and a secondary maximum at 3162 cm~1, whereas - modification "D" 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~l, 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~l, whereas the absorption band of the CN group of other modifications in alphabetic order is present at 2178, 2174, 2166 and 2155 cm~l, respectively.
The most intense bands of the spectra of all cimetidine modifications are found near to 1600 cm~l, 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~l 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 2~0~027 W~92J14713 _ 5 _ PCT/HU92/~07 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~l, 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 this site only singlet bands with a small distorted shoulder, which is very difficult to resolve.
The medium intense band appearing at 405 cm~l is similarly suitable to determine the modification "E".
Other modification do not possess any absorption band below 418 cm~l.
Several other characteristic bands of the 20 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 ~) 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 EXO DMS type instrumented tabletting 2~ 0~027 W092/14713 - 6 _ PCT/HU92/~7_ 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".
` 210~027 W~2/14713 _ 7 _ PCT/HU92/~W~7 Table I
Treatment n Dose HCL production Inhlbition i.p. during 4 hours HCl produc-mg/kg calculated for tion 100 g of body-weight /umol 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 administration 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 (1~83)~, which is useful also in human experiments.
The calculation of the cimetidine content of unknown plasma samples was performed on a Hewlet-Packard ~ ~()27 WO92/14713 - 8 _ PCT/HU92/~OZ_ lO9l M HPLC diode-series device. The area under cur~e 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/ml 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 there-in 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 l 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 lO C, then it is combined under stirring with 20 % sodium hydroxide solution being equi~alent to l.l mol of the hydrochloric acid used for the dissolution. The temperature of the solution is maintained between lO C and 15 C by cooling when necessary and it is crystallized while stirring and when necessary inoculated with a crystal of cimetidine "E".
2~0~a27 W~2/14713 _ 9 _ PCT/HU92/~X~7 After stirring for 1 to 2 hours the crystalline, sand-like 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 10 Infrared spectrum see Figures 1 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,~08,117) 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 Exampie 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 WO92/14713 ~ 1 0 ~ ~ J ~ PCT/HU92/00007_ The process described in Example l 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 l.
Example 6 Pharmaceutical composition Com~onents mq Cimetidine !'E" 200 Starch 56 Microcrystalline cellulose 60 Lactose 56 15 Polyvinylpyrrolidone 12 Talc 12 Magnesium stearate 4 After preparing a well-compressible base mixture with good rheological properties from lOOO-fold of the above amounts lO00 tablets are obtained by compression.
Claims (5)
1. Polymorph modification "E" of N-cyano-N'-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-N'-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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU502/91 | 1991-02-15 | ||
| HU91502A HU208675B (en) | 1991-02-15 | 1991-02-15 | Process for producing a new cimetidine polymorph and pharmaceutical preparations comprising this compound |
| PCT/HU1992/000007 WO1992014713A1 (en) | 1991-02-15 | 1992-02-14 | Novel cimetidine polymorph and process for preparing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2104027A1 true CA2104027A1 (en) | 1992-08-16 |
Family
ID=10949875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002104027A Abandoned CA2104027A1 (en) | 1991-02-15 | 1992-02-14 | Cimetidine polymorph and process for preparing same |
Country Status (7)
| Country | Link |
|---|---|
| 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)
| 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 |
-
1991
- 1991-02-15 HU HU91502A patent/HU208675B/en not_active IP Right Cessation
-
1992
- 1992-02-14 WO PCT/HU1992/000007 patent/WO1992014713A1/en not_active Application Discontinuation
- 1992-02-14 AU AU12646/92A patent/AU653209B2/en not_active Ceased
- 1992-02-14 KR KR1019930702424A patent/KR930703265A/en not_active Application Discontinuation
- 1992-02-14 JP JP4505070A patent/JPH06505247A/en active Pending
- 1992-02-14 CA CA002104027A patent/CA2104027A1/en not_active Abandoned
- 1992-02-14 EP EP92904688A patent/EP0571463A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| HUT60474A (en) | 1992-09-28 |
| KR930703265A (en) | 1993-11-29 |
| AU653209B2 (en) | 1994-09-22 |
| HU910502D0 (en) | 1991-09-30 |
| AU1264692A (en) | 1992-09-15 |
| WO1992014713A1 (en) | 1992-09-03 |
| EP0571463A1 (en) | 1993-12-01 |
| JPH06505247A (en) | 1994-06-16 |
| HU208675B (en) | 1993-12-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2002350869B2 (en) | Polymorphous form of rimonabant, preperation method and pharmaceutical compositions containing same | |
| CA1292000C (en) | Solid forms of 2-ethoxy-4-[n-(1-(2-piperidino- phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid | |
| EP0906301B1 (en) | Benzofuryl derivatives and their use | |
| US20020177703A1 (en) | Novel crystalline forms of an antiviral benzimidazole compound | |
| JPS625145B2 (en) | ||
| JPH09508913A (en) | Composition containing micronized nebivolol | |
| KR100437307B1 (en) | New crystal modification ⅲ of torasemide | |
| EP0161599A2 (en) | Benzazepine derivatives, medicines containing these compounds and process for their preparation | |
| WO2008008394A1 (en) | Tizanidine succinate salt forms and methods of making and using the same | |
| CA2321369C (en) | Dosing regimens for lasofoxifene | |
| IE43711B1 (en) | N-propargyl-2-phenylamino-2-imidazolines | |
| AU653209B2 (en) | Novel cimetidine polymorph and process for preparing same | |
| EP0317855A2 (en) | Pharmaceutical products | |
| FI82045C (en) | PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYZED POLYMORPH FORM OF MONOETHANOLAMINOSALTET N- (2-PYRIDYL) -2-METHYL-4-HYDROXY-2H-1,2-BENZOTIAZINE-3-CARBOXIDE-1,1 | |
| JP3333545B2 (en) | Pharmaceutical preparation containing dirithromycin | |
| CN100549005C (en) | The opticity dihydrogen pyridine derivative | |
| DE2803688A1 (en) | NEW BENZENE SULPHONAMIDE AND BENZENE CARBOXAMIDE DERIVATIVES | |
| JPH09124644A (en) | Terazosin crystalline polymorph and its pharmaceutical composition | |
| EP1362030B1 (en) | Novel benzoylguanidine salt | |
| KR880001865B1 (en) | Process for preparing 4-(1-imidazolyl methyl)cinnamic acid hydro-chloride hydrate | |
| US4539402A (en) | Quinazolinone derivatives | |
| HU225956B1 (en) | 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anti-convulsive effect and process for their production, their use and pharmaceuticals containing the same | |
| NO145656B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-PHENYLETANOLAMINE DERIVATIVES | |
| CN101665498A (en) | Organic compounds | |
| NO333977B1 (en) | Oromucosal preparation and method of preparation thereof. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |