CA1096387A - Process for the production of polymorph of cimetidine - Google Patents
Process for the production of polymorph of cimetidineInfo
- Publication number
- CA1096387A CA1096387A CA287,087A CA287087A CA1096387A CA 1096387 A CA1096387 A CA 1096387A CA 287087 A CA287087 A CA 287087A CA 1096387 A CA1096387 A CA 1096387A
- Authority
- CA
- Canada
- Prior art keywords
- cimetidine
- suspension
- solvent
- strong
- peak
- 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
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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A process is provided for the production of a substantially crystallographically pure polymorphic form of cimetidine having the struc-tural formula
A process is provided for the production of a substantially crystallographically pure polymorphic form of cimetidine having the struc-tural formula
Description
1~9G3~'7 This invention relates to a process for the production of a polymorphic form of cimetidine which is substantially crystallographically pure.(hereinafter referred to as cimetidine A). Such a process for the production of cimetidine A is suitable for the commercial production thereof.
Cimetidine, the full chemical name of which is N-methyl-N -cyano-N -[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-guanidine, is a potent antagonist of histamine H2 receptors, a utility which is described in de-tail in, for example, J. Int. Med. Research 1975, 3, No. 2, 86-92, by Brimblecombe et al and in British Specifications No. 1338169 and 1397436.
It has been found that cimetidine can exist in a number of poly-morphic forms and, particularly as it is known from studies on other drugs, that polymorphism may influence bio-availability. It is consequently an ob~ect of one aspect of the present invention to characterized one of these forms and to provide a process for its production.
Accordingly by one broad aspect of this invention, a process is provided for the production of cimetidine A, a substantially crystallo-graphically pure polymorphic form of cimetidine which is characterized by an infra red spectrum (1% KBr disc) having very strong, broad peaks at 1400 and 1385 cm 1, a strong, sharp peak at 1205 cm 1 and a medium-sharp peak at 1155 cm 1 and having no peak at 1180 cm 1 which comprises: dissolv-ing cimetidine in a hot, non-aqueous solvent; cooling the resultant solu-tion with sufficient agitation to ensure efficient heat transfer to yield a suspension of cimetidine A in such solvent, the suspension having good handling properties; and separating off the cimetidine A.
By a variant thereof, the solvent is selected from the group con-sisting of acetonitrile, acetone, methylisobutylketone and toluene.
By another variant thereof, the solvent is a lower alkanol, e.g., ethanol, isopropanol or n-butanol, preferably, isopropanol.
By a variation thereof, the cooling rate used is 10C. to 60C.
i . ~
1~)963~'7 ~..
per hour.
By another variation, the cimetidine A is separated from the sus-; pension centrifugation.
By a further variant, the suspension of cimetidine A is such thatit acts as a Newtonian fluid in a continuous shear test, is not by reason of its fluidity quantifiable on a cone penetration test and possesses a dy-namic modulus as assessed on a rheogoniometer in the range of from 0.01 to 1.0 Hz of less than 0.001.
By "substantially crystallographically pure" we mean cimetidine A which contains no more than 5%, preferably no more than 3% of any other polymorphic form of cimetidine, and has the formula ~ CN
CH ~ CH2scH2cH2NHc \
~ _ _ N~
and is characterized by an infra red spectrum (1% KBr disc) having very strong, broad peaks at 1400 and 1385 cm 1, a strong, sharp peak at 1205 cm and a medium-sharp peak at 1155cm 1 and having no peak at 1180 cm 1.
In the accompanying drawings, Figure 1 is a typical infra red spectrum of cimetidine A; and Figure 2 is a portion of the infra red spectrum of cimetidine B.
The words "very strong" and "medium" used in relation to the peaks of the infra red spectrum refer to the relative heights of the peaks. These ; terms are well known and understood to those accustomed to the interpre-tation of such spectra.
As seen in Figure 1, which is the relevant portion of a typical . infra red spectrum of cimetidine A, the four characteristic peaks are marked.
' -~9638~7 We have discovered that cimetidine may crystal]ise in at ]eastthree different forms, one of which is cimetidine A. The other forms re-ferred to as cimetidine B and cimetidine C do not have an infra red spec-trum containing the abovementio1led four character;stic peaks of cimetidine but do have a very strong, sharp peak at 11~0 cm . Th;s can be seen from Figuré 2 whicll is the relevant portion of the iuf1-a rcd spectl-um of c;meti-dine B.
C;met;dine A ;s preferred to either of the other two {orms since it is more easily obtai1)able in a crystallographically pure state. It is also slightly more water so]uble than either of these forms preferably hav-ing a rate of dissolution at 25C from the flat surface of a standard com-pressed disc of at least 0.20 mg/1n;n/cm . A further advantage is that cimetidine A is rather more easy to handle, particularly in large scale operations such as centrifugation. The easier hand]ing of suspensions of cimetidine A as compared with other forms of cimetidine is demonstrated by the following comparative tests carried out on a 25% (w/v) suspension of cimetidine A in isopropanol and a 25% (w/v) suspension of a cimetidine B/
cimetidine C mixture in isopropanol/water (3.l).
(a) Co ti_u us shear A Rllec)1nat R~130 rheo1neter thennostatted at 25C was employed.
Cup and bob system A w.ls used for cimetidine A suspension to obtain rates of sl1ear from 0 to approximately 700 sec l.
~ 1~963~37 The following data was obtained for cimetidine A suspension:-Shear rate (sec ~ lean Shear stress (dyne cm 2) O O
17.5 1.19 32.4 2.38 59.9 3.21 111.0 5.59 205.0 10.12 378.0 18.45 514.0 22.59 698.0 34-7 These data show that the suspension behaved as a Newtonian Fluid with a viscosity of 0.0496 poise.
Because of the solid properties of cimetidine B/C suspension, it was not possible to obtain continuous shear data.
(b) Cone penetration To quantify the solid properties of cimetidine Form B/C
. suspension, a Seta Universal Penetrometer was employed fitted with a 1806 cone and 150 g. loading weight.
; 2~
.~lean depth of penetration of cone 5.5 mm at 20 C.
Because of the fluid properties of Cimetidine Form A, it ~- was not possible to obtain penetrometer results with this suspension.
(c) Oscillatory testing A modified R16 Weissenberg Rheogoniometer equipped with 3.75 cm radius parellel plates was used in the oscillatory 3~ mode at 25C. Using oscillation frequencies ranging from 0.01 to 1~.5 Hz, data were obtained for both cimetidine suspensions with the aid of a Solartron Transfer Function 1~963~37 L Analyser (J~11600/JX1606). Computer analysis of the data produced the following values for dynamic modulus:-Oscillation frequency (Hz) Dynamic modulus (G') Cimetidine Form A Cimetidine Form B/C
O . 01 0 . 0007 4 0.06646 0.1 0.00063 0.06402 0.5 0.00080 0.06206 1.0 0.00082 0.06574
Cimetidine, the full chemical name of which is N-methyl-N -cyano-N -[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-guanidine, is a potent antagonist of histamine H2 receptors, a utility which is described in de-tail in, for example, J. Int. Med. Research 1975, 3, No. 2, 86-92, by Brimblecombe et al and in British Specifications No. 1338169 and 1397436.
It has been found that cimetidine can exist in a number of poly-morphic forms and, particularly as it is known from studies on other drugs, that polymorphism may influence bio-availability. It is consequently an ob~ect of one aspect of the present invention to characterized one of these forms and to provide a process for its production.
Accordingly by one broad aspect of this invention, a process is provided for the production of cimetidine A, a substantially crystallo-graphically pure polymorphic form of cimetidine which is characterized by an infra red spectrum (1% KBr disc) having very strong, broad peaks at 1400 and 1385 cm 1, a strong, sharp peak at 1205 cm 1 and a medium-sharp peak at 1155 cm 1 and having no peak at 1180 cm 1 which comprises: dissolv-ing cimetidine in a hot, non-aqueous solvent; cooling the resultant solu-tion with sufficient agitation to ensure efficient heat transfer to yield a suspension of cimetidine A in such solvent, the suspension having good handling properties; and separating off the cimetidine A.
By a variant thereof, the solvent is selected from the group con-sisting of acetonitrile, acetone, methylisobutylketone and toluene.
By another variant thereof, the solvent is a lower alkanol, e.g., ethanol, isopropanol or n-butanol, preferably, isopropanol.
By a variation thereof, the cooling rate used is 10C. to 60C.
i . ~
1~)963~'7 ~..
per hour.
By another variation, the cimetidine A is separated from the sus-; pension centrifugation.
By a further variant, the suspension of cimetidine A is such thatit acts as a Newtonian fluid in a continuous shear test, is not by reason of its fluidity quantifiable on a cone penetration test and possesses a dy-namic modulus as assessed on a rheogoniometer in the range of from 0.01 to 1.0 Hz of less than 0.001.
By "substantially crystallographically pure" we mean cimetidine A which contains no more than 5%, preferably no more than 3% of any other polymorphic form of cimetidine, and has the formula ~ CN
CH ~ CH2scH2cH2NHc \
~ _ _ N~
and is characterized by an infra red spectrum (1% KBr disc) having very strong, broad peaks at 1400 and 1385 cm 1, a strong, sharp peak at 1205 cm and a medium-sharp peak at 1155cm 1 and having no peak at 1180 cm 1.
In the accompanying drawings, Figure 1 is a typical infra red spectrum of cimetidine A; and Figure 2 is a portion of the infra red spectrum of cimetidine B.
The words "very strong" and "medium" used in relation to the peaks of the infra red spectrum refer to the relative heights of the peaks. These ; terms are well known and understood to those accustomed to the interpre-tation of such spectra.
As seen in Figure 1, which is the relevant portion of a typical . infra red spectrum of cimetidine A, the four characteristic peaks are marked.
' -~9638~7 We have discovered that cimetidine may crystal]ise in at ]eastthree different forms, one of which is cimetidine A. The other forms re-ferred to as cimetidine B and cimetidine C do not have an infra red spec-trum containing the abovementio1led four character;stic peaks of cimetidine but do have a very strong, sharp peak at 11~0 cm . Th;s can be seen from Figuré 2 whicll is the relevant portion of the iuf1-a rcd spectl-um of c;meti-dine B.
C;met;dine A ;s preferred to either of the other two {orms since it is more easily obtai1)able in a crystallographically pure state. It is also slightly more water so]uble than either of these forms preferably hav-ing a rate of dissolution at 25C from the flat surface of a standard com-pressed disc of at least 0.20 mg/1n;n/cm . A further advantage is that cimetidine A is rather more easy to handle, particularly in large scale operations such as centrifugation. The easier hand]ing of suspensions of cimetidine A as compared with other forms of cimetidine is demonstrated by the following comparative tests carried out on a 25% (w/v) suspension of cimetidine A in isopropanol and a 25% (w/v) suspension of a cimetidine B/
cimetidine C mixture in isopropanol/water (3.l).
(a) Co ti_u us shear A Rllec)1nat R~130 rheo1neter thennostatted at 25C was employed.
Cup and bob system A w.ls used for cimetidine A suspension to obtain rates of sl1ear from 0 to approximately 700 sec l.
~ 1~963~37 The following data was obtained for cimetidine A suspension:-Shear rate (sec ~ lean Shear stress (dyne cm 2) O O
17.5 1.19 32.4 2.38 59.9 3.21 111.0 5.59 205.0 10.12 378.0 18.45 514.0 22.59 698.0 34-7 These data show that the suspension behaved as a Newtonian Fluid with a viscosity of 0.0496 poise.
Because of the solid properties of cimetidine B/C suspension, it was not possible to obtain continuous shear data.
(b) Cone penetration To quantify the solid properties of cimetidine Form B/C
. suspension, a Seta Universal Penetrometer was employed fitted with a 1806 cone and 150 g. loading weight.
; 2~
.~lean depth of penetration of cone 5.5 mm at 20 C.
Because of the fluid properties of Cimetidine Form A, it ~- was not possible to obtain penetrometer results with this suspension.
(c) Oscillatory testing A modified R16 Weissenberg Rheogoniometer equipped with 3.75 cm radius parellel plates was used in the oscillatory 3~ mode at 25C. Using oscillation frequencies ranging from 0.01 to 1~.5 Hz, data were obtained for both cimetidine suspensions with the aid of a Solartron Transfer Function 1~963~37 L Analyser (J~11600/JX1606). Computer analysis of the data produced the following values for dynamic modulus:-Oscillation frequency (Hz) Dynamic modulus (G') Cimetidine Form A Cimetidine Form B/C
O . 01 0 . 0007 4 0.06646 0.1 0.00063 0.06402 0.5 0.00080 0.06206 1.0 0.00082 0.06574
2 . 5 0 . 0007 9 0 . 05977 5 . O O . 0007 4 0.0~400 10.0 0.00039 0.02463 12.6 O. 00007 ~ O . 00462 From a plot of log dynamic modulus vs log oscillation it is evident that for both suspensions the dynamic modulus is independent of frequency within the range of 0.01 to 1.0 Hz.
~he solid nature of cimetidine B/C suspension is evident from the fact that its dynamic modulus in this frequency range is greater than 0.06 whereas that of cimetidine A is less than 0 .001 .
Samples of cimetidine A which we have obtained are also characterised by a density of less than 1.30 g/cc. We have found that cimetidine A may be reproduceably formed by selecting the correct solvent for crystallisation, by carefully controlling the rate of cooling of the solvent just prior to and during crystallisation and by also carefully controlling the agitation of the solvent just prior . to and during crystallisation.
Suitable solvents for crystallisation include non-aqueous solvents, e.~., acetonitrile, acetone, methylisobutylketone,
~he solid nature of cimetidine B/C suspension is evident from the fact that its dynamic modulus in this frequency range is greater than 0.06 whereas that of cimetidine A is less than 0 .001 .
Samples of cimetidine A which we have obtained are also characterised by a density of less than 1.30 g/cc. We have found that cimetidine A may be reproduceably formed by selecting the correct solvent for crystallisation, by carefully controlling the rate of cooling of the solvent just prior to and during crystallisation and by also carefully controlling the agitation of the solvent just prior . to and during crystallisation.
Suitable solvents for crystallisation include non-aqueous solvents, e.~., acetonitrile, acetone, methylisobutylketone,
3~ toluene and lower alkanols e.g., ethanol, isopropanol and n-butanol. Isopropanol is particularly suitable in ~9638'~
L practice because of its rela~ive cheapness, ready availability and lack of effluent disposal problems.
Agitation during cooling should be sufficient to ensure efficient heat transfer throughout the liquid phase. On a commercial scale, efficient heat transfer through the cooling surfaces of the vessel used is also desirable.
A cooling rate of from 10C to 60C per hour has been found to be effective. A commercial scale process for the production of cimetidine A is illustrated by the following example: .
Cimetidine (245 Kg) was dissolved in hot (80 C) isopropanol (850 l) and the resultant solution clarified by filtration.
The filtrate was placed in a 300 gallon glass-lined vessel la having a heat transfer surface of 4.8M2 and a U-value of - 200 Kcal/M .h.C. and fitted with a standard impellor/
agitator. With the agitator rotating at 90 r.p.m. the solution was cooled from 80C to 15C over a period of 2 hours.
The precipitated produced was in the form of well developed prisms which were readily separated by-centrifugation, and then dried on a fluid bed drier.
The product obtained had an infra red spectrum between 1600 and 200 cm l as shown in Figure l, a density of 1.28 g/cc and a rate of dissolution in water at 25C (from the flat surface of a 9.6 mm diameter compressed disc) of 0.21 mg/min/cm2.
Pharmaceutical compositions comprising cimetidine A and a solid pharmaceutical carrier also provided herein. Exemplary of solid carriers are lactose! microcrystalline cellulose, terra alba, sucrose, talc, starch, gelatin, agar pectin, polyvinylpyrrolidone, 3~ acacia, magnesium stearate, stearic acid and the like.
1~963~37 A wide variety of pharmhceutical forms can be employed, and these will normally be ~appropriate to the desired mDde of administration. Thus the preparation can be tableted or placed in a hard gelatin capsule in p~w-der or pellet form. In these cases the amount of solid carrier will vary widely but preferably will be from 25 mg to 1 g. Alternatively an injecta-ble solution or a cream or ointment for topical administration may be used.
me pharmaceutical ocmpositions are prepared by conventional tech-niques involving procedures e.g. mixing, granulating and compressing. An initial milling process is preferably carried out. It is found that this improves the uniformity of the product without affecting its excellent handling characteristics. Milled cimetidine A preferably that which has been passed through a 60 mesh screen on the mill outlet ~e.g., a Fitz-patrick hammer mill) is also therefore a subject of the present invention.
Cohesion tests carried out using a sh OE cell apparatus as described by Kocova and Pilpel, Powder Technology 5 329 ~197V72) showed that samples ; of this milled cimetidine A had an angle of internal friction of from 34 to 38.
Cimetidine A will be present in the ccmpositions in an effective amount to block histamine H2-receptors.
Preferably, each dosage unit will contain the active ingredient in an amount of from 50 mg to 750 mg, preferably 200 mg to 600 mg.
me active ingredient will preferably be administered one to six times per day. mis daily dosage regimen will preferably be from 500 mg to 1500 mg.
Combination preparations ccmprising cimetidine A and another ac-tive ingredient may also be used. Examples of such active ingredients in-clude histamine Hl-receptor antagonists e.g. meypramine or anti-inflammatory compounds e.g. acetylsalicyclic acid, naproxen, ibuprofen or ketoprofen.
L practice because of its rela~ive cheapness, ready availability and lack of effluent disposal problems.
Agitation during cooling should be sufficient to ensure efficient heat transfer throughout the liquid phase. On a commercial scale, efficient heat transfer through the cooling surfaces of the vessel used is also desirable.
A cooling rate of from 10C to 60C per hour has been found to be effective. A commercial scale process for the production of cimetidine A is illustrated by the following example: .
Cimetidine (245 Kg) was dissolved in hot (80 C) isopropanol (850 l) and the resultant solution clarified by filtration.
The filtrate was placed in a 300 gallon glass-lined vessel la having a heat transfer surface of 4.8M2 and a U-value of - 200 Kcal/M .h.C. and fitted with a standard impellor/
agitator. With the agitator rotating at 90 r.p.m. the solution was cooled from 80C to 15C over a period of 2 hours.
The precipitated produced was in the form of well developed prisms which were readily separated by-centrifugation, and then dried on a fluid bed drier.
The product obtained had an infra red spectrum between 1600 and 200 cm l as shown in Figure l, a density of 1.28 g/cc and a rate of dissolution in water at 25C (from the flat surface of a 9.6 mm diameter compressed disc) of 0.21 mg/min/cm2.
Pharmaceutical compositions comprising cimetidine A and a solid pharmaceutical carrier also provided herein. Exemplary of solid carriers are lactose! microcrystalline cellulose, terra alba, sucrose, talc, starch, gelatin, agar pectin, polyvinylpyrrolidone, 3~ acacia, magnesium stearate, stearic acid and the like.
1~963~37 A wide variety of pharmhceutical forms can be employed, and these will normally be ~appropriate to the desired mDde of administration. Thus the preparation can be tableted or placed in a hard gelatin capsule in p~w-der or pellet form. In these cases the amount of solid carrier will vary widely but preferably will be from 25 mg to 1 g. Alternatively an injecta-ble solution or a cream or ointment for topical administration may be used.
me pharmaceutical ocmpositions are prepared by conventional tech-niques involving procedures e.g. mixing, granulating and compressing. An initial milling process is preferably carried out. It is found that this improves the uniformity of the product without affecting its excellent handling characteristics. Milled cimetidine A preferably that which has been passed through a 60 mesh screen on the mill outlet ~e.g., a Fitz-patrick hammer mill) is also therefore a subject of the present invention.
Cohesion tests carried out using a sh OE cell apparatus as described by Kocova and Pilpel, Powder Technology 5 329 ~197V72) showed that samples ; of this milled cimetidine A had an angle of internal friction of from 34 to 38.
Cimetidine A will be present in the ccmpositions in an effective amount to block histamine H2-receptors.
Preferably, each dosage unit will contain the active ingredient in an amount of from 50 mg to 750 mg, preferably 200 mg to 600 mg.
me active ingredient will preferably be administered one to six times per day. mis daily dosage regimen will preferably be from 500 mg to 1500 mg.
Combination preparations ccmprising cimetidine A and another ac-tive ingredient may also be used. Examples of such active ingredients in-clude histamine Hl-receptor antagonists e.g. meypramine or anti-inflammatory compounds e.g. acetylsalicyclic acid, naproxen, ibuprofen or ketoprofen.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of cimetidine A, a substantially crystallographically pure polymorphic form of cimetidine which is charac-terized by an infra red spectrum (1% KBr disc) having very strong, broad peaks at 1400 and 1385 cm-1, a strong, sharp peak at 1205 cm-1 and a medium-sharp peak at 1155 cm-1 and having no peak at 1180 cm-1 which comprises:
dissolving cimetidine in a hot, non-aqueous solvent; cooling the resultant solution with sufficient agitation to ensure efficient heat transfer to yield a suspension of cimetidine A in said solvent, said suspension having good handling properties; and separating off said cimetidine A.
dissolving cimetidine in a hot, non-aqueous solvent; cooling the resultant solution with sufficient agitation to ensure efficient heat transfer to yield a suspension of cimetidine A in said solvent, said suspension having good handling properties; and separating off said cimetidine A.
2. The process of claim 1 wherein said solvent is selected from the group consisting of acetonitrile, acetone, methylisobutylketone and toluene.
3. The process of claim 1 wherein said solvent is a lower alkanol.
4. The process of claim 3 wherein said lower alkanol is selected from the group consisting of ethanol, isopropanol and n-butanol.
5. The process of claim 3 wherein said lower alkanol is isopro-panol.
6. The process of claims 1, 2 or 3 wherein a cooling rate of from 10°C. to 60°C. per hour is employed.
7. The process of claims 1, 2 or 3 wherein said cimetidine A is separated from said suspension by centrifugation.
8. The process of claim 1 wherein said suspension of cimetidine A is such that it acts as a Newtonian fluid in a continuous shear test, is not by reason of its fluidity quantifiable on a cone penetration test, and possesses a dynamic modulus as assessed on rheogoniometer in the range of from 0.01 to 1.0 Hz of less than 0.001.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3906576A GB1543238A (en) | 1976-09-21 | 1976-09-21 | Polymorph of cimetidine |
| GB39065/76 | 1976-09-21 | ||
| GB2716/77 | 1977-01-24 | ||
| GB271677 | 1977-01-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1096387A true CA1096387A (en) | 1981-02-24 |
Family
ID=26237687
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA287,087A Expired CA1096387A (en) | 1976-09-21 | 1977-09-20 | Process for the production of polymorph of cimetidine |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5340771A (en) |
| AU (1) | AU510629B2 (en) |
| BE (1) | BE858432A (en) |
| CA (1) | CA1096387A (en) |
| DE (1) | DE2742531A1 (en) |
| FR (1) | FR2364906A1 (en) |
| IE (1) | IE45873B1 (en) |
| IL (1) | IL52784A (en) |
| LU (1) | LU78142A1 (en) |
| NZ (1) | NZ184893A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4579954A (en) * | 1981-06-26 | 1986-04-01 | Richter Gedeon Vegyeszeti Gyar Rt. | Cimetidine monohydrate |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56104868A (en) * | 1980-01-24 | 1981-08-20 | Fujimoto Seiyaku Kk | Conversion between polymorphous crystals of cimetidine |
| JPS56164122A (en) * | 1980-05-21 | 1981-12-17 | Fujimoto Seiyaku Kk | Drug composition comprising cimetidine as main agent |
| HU185457B (en) * | 1981-09-25 | 1985-02-28 | Richter Gedeon Vegyeszet | Process for preparating cimetidine-z |
| JPS5888366A (en) * | 1981-11-19 | 1983-05-26 | Fujimoto Seiyaku Kk | Preparation of guanidine derivative |
| JPS59128375A (en) * | 1983-01-10 | 1984-07-24 | Tokawa Tetsuo | Preparation of imidazole compound |
| JPS59130274A (en) * | 1983-01-14 | 1984-07-26 | Tokawa Tetsuo | Preparation of imidazole compound |
| JPS59130273A (en) * | 1983-01-14 | 1984-07-26 | Tokawa Tetsuo | Preparation of imidazole compound |
| HU196184B (en) * | 1986-09-11 | 1988-10-28 | Richter Gedeon Vegyeszet | Process for producing cimetidine-a modification |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1397436A (en) * | 1972-09-05 | 1975-06-11 | Smith Kline French Lab | Heterocyclic n-cyanoguinidines |
| GB1533380A (en) * | 1974-09-02 | 1978-11-22 | Smith Kline French Lab | Process for the preparation of heterocyclic substituted thioureas and h-cyanoguanidines |
| GB1531231A (en) * | 1974-09-02 | 1978-11-08 | Smith Kline French Lab | Process for the production of cyanoguanidine derivatives |
| CA1064940A (en) * | 1975-08-20 | 1979-10-23 | Wilford L. Mendelson | Reduction process for the preparation of 4-(hydroxymethyl) imidazole compounds |
-
1977
- 1977-08-10 NZ NZ184893A patent/NZ184893A/en unknown
- 1977-08-22 IL IL52784A patent/IL52784A/en unknown
- 1977-09-06 BE BE180694A patent/BE858432A/en not_active IP Right Cessation
- 1977-09-14 AU AU28792/77A patent/AU510629B2/en not_active Expired
- 1977-09-15 FR FR7727887A patent/FR2364906A1/en not_active Withdrawn
- 1977-09-16 JP JP11209377A patent/JPS5340771A/en active Granted
- 1977-09-19 LU LU78142A patent/LU78142A1/xx unknown
- 1977-09-20 CA CA287,087A patent/CA1096387A/en not_active Expired
- 1977-09-21 DE DE19772742531 patent/DE2742531A1/en not_active Withdrawn
- 1977-09-21 IE IE1932/77A patent/IE45873B1/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4579954A (en) * | 1981-06-26 | 1986-04-01 | Richter Gedeon Vegyeszeti Gyar Rt. | Cimetidine monohydrate |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ184893A (en) | 1980-11-28 |
| BE858432A (en) | 1978-03-06 |
| DE2742531A1 (en) | 1978-03-23 |
| JPS5340771A (en) | 1978-04-13 |
| IL52784A (en) | 1980-09-16 |
| IE45873B1 (en) | 1982-12-15 |
| FR2364906A1 (en) | 1978-04-14 |
| IE45873L (en) | 1978-07-24 |
| IL52784A0 (en) | 1977-10-31 |
| LU78142A1 (en) | 1978-01-17 |
| JPS6222967B2 (en) | 1987-05-20 |
| AU510629B2 (en) | 1980-07-03 |
| AU2879277A (en) | 1979-03-22 |
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