AU653209B2 - Novel cimetidine polymorph and process for preparing same - Google Patents

Description

OPI DATE 15/09/92 AOJP DATE 29/10/92 APPLN. ID 12646 92 PCT NUMBER PCT/Hiiq2/nnn07 TREATY (PCT)

INTERNA.

(51) International Patent Classification 5 International Publication Number: WO 92/14713 C07D 233/64, A61K 31/415 A l (4 3 International Publica ,on Date: 3 September 1992 (03.09.92) (21) International Application Number: PCT/HUn2/00007 (74) Agent: DANUBIA; Bajcsy Zsilinszky it 16, H-1368 Budapest (HU).

(22, International Filing Date: 14 February 1992 (14.02.92) (81) Designated States: AT (European patent), AU, BE (Euro- Priority data: pean patent), CA, CH (European patent), DE (Euro- 502/91 15 February 1991 (15.02.91) HU pean patent), DK (European patent), ES (European patent), FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, KR, LU (71) Applicant (for all designated States except US): RICHTER (European patent), MC (European patent), NL (Euro- GEDEON VEGYESZETI GYAR RT. [HU/HU]; Gy- pean patent), SE (European patent), US.

6mri it 19-21, H-1000 Budapest (HU).

(72) Inventors; and Published Inventors/Applicants (for US only) JESZENSZKY, Andor With international search report.

[HU/HU]; Nagybinyai u. 51, H-1025 Budapest (HU).

VEGH, Ferenc [HU/HU]; Ferenczi Beni u. 3, H-2500 Esztergom BENCSIK, Peter [HU/HU]; Vonfs u.

12, H-1192 Budapest NAGY, LAszl6 [HU/HU]; pasareti u. 16, H-1026 Budapest HEGEDUS, B1la [HU/HU]; Bart6k Bela u. 82, H-1113 Budapest (HU).

GOROG, SBndor [HU/HU]; Somfa u. 13, H-1107 Budapest PAPNE SZIKLAI, Zs6fia [HU/HU1; Gozmozdony u. 10, H-1108 Budapest HAHNOCZY, Mariann [HU/HU]; Somfa u. 13, H-1107 Budapest VERECKEI, LAszl6 [HU/HU]; Pusztaszeri u.

89/b, H-1025 Budapest KOZMA, G6zAn& [HU/ HU]; J6zsef nAdor t6r H-1051 Budapest KA- PAS, Margit [HU/HU]; Kinizsi u. 3, H-1181 Budapest TOROK, Eva [HU/HU]; Csomor u. 13, H-1104 Budapest (HU).

(54)Title: NOVEL CIMETIDINE POLYMORPH AND PROCESS FOR PREPARING SAME (57) Abstract The invention relates to the novel polymorph modification of N-cyano-N'-methyl-N"(2-[(5-methyl-imidazol-4-yl)-methylthio]-ethyll-guanidine (cimetidine characterized by infrared spectroscopical characteristics. According to the process of the invention cimetidine 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 of cimetidine shows better rheological and flowing properties in comparison to those of cimetidine and provides several advantages concerning pharmaceutical technology.

1 WO 92/14713 PCT/HU92/00007 NOVEL CIMETIDINE POLYMORPH AND PROCESS FOR PREPARING SAME The invention relates to a novel polymorph modification of imidazol]-4-yl)-methylthio]-ethyl}-guanidine. Furthermore, the invention relates to a process for the preparation of the novel polymorph modification.

It is known that, due to its H 2 receptor-blocking action, 4-yl)-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 has been the active ingredient in the pharmaceutical compositions. The modification 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. Hegedus and S.

Gbrbg [Pharm. and Bio. Analysis 3, 303 (1985)], who reported on four anhydrous and three hydrate water- -containing cimetidine modifications. In addition to the modification mentioned above, the modifications and (recently called were also identified among the anhydrous modifications. It is of course that the practical importance of the various modifications is not identical. Some polymorphs proved to be unstable or difficult to prepare.

WO92/14713 2 PC/HJ92/00007 Based on the physical and chemical characteristics defined in the pharmacopoeas, the polymorph modification 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 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 Snovel 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 by us.

WO 92/14713 3 PCT/HU92/00007 Thus, the present invention relates to a novel polymorph crystal modification of N-cyano-N'-methyl- -N"-{2-[(5-methylimidazol-4-yl)-methythio]-ethyl guanidine (hereinafter cimetidine), i. e. cimetidine According to an other aspect of the invention, there is provided a process for the preparation of the novel cimetidine polymorph modification, which comprises accomplishing an aqueous system, which is supersaturated for cimetidine at a temperature below 30 OC and contains a water-miscible organic solvent in an amount of at most 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 OC or removing the water content of the crystals with an organic solvent and subsequently drying them.

C

1 -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 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 modifications [see Pharm. and Bio. Anal. 3, 303 (1985)] on the basis of the IR spectrum shown in Figure 1 (Figure 2 is the enlarged right side and Figure 3 is the left side WO 92/14713 4 PCT/HU92/00007 of the complete characteristic shown in Figure 1).

In the range of N-H bonds, the modification is characterized by a band of half-value width at 3311 cm 1 In the above range modification shows a medium broad doublet band pair with maxima at 3226 and 3142 cm 1 modification has a band system characterized by a main maximum at 3237 cm-1 and a secondary maximum at 3165 cm 1 modification possesses a main maximum at 3276*cm-1 and a secondary maximum at 3162 cm-1, whereas modification 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 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 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 is observed at 1605 and 1575 cm-1, respectively. This band pair appears at 1623, 1588 cm 1 for modification at 1614, 1587 cm- 1 for modification at 1615, 1587 cm-1 for modification and at 1614, 1587 cm-1 for modification This part of the spectrum makes possible to identify WO 92/14713 PCr/HU92/0007 5 and separate the modification 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 this 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 m dification Other modification do not possess any absorption band below 418 cm 1 Several other characteristic bands of the modification are at 1429, 1368, 1078, 1065, 835, 718 and 621 cm 1 Hereinafter, the pharmaceutical-technological advantages of cimetidine polymorph will be illustrated.

According to our investigations cimetidine has more advantageous rheological, flowing properties in comparison to those of modification Thus, the outflow rate of cimetidine is 10 sec/50 g, its angle of repose (tg a) equals 0.5 to 0.6. These data cannot be measured for modification 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 and "E" modification, respectively by using 15 kN compression force in a Korsch EKO DMS type instrumented tabletting WO 92/14713 PCY/HU92/00007 6 machine.

The breaking strength values (ERWEKA TB 28 type) of the compressed product obtained were found to be by to 50 higher for modification in comparison to those of modification The wear loss of the tablets containing modification 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 showed a cap-like disintegration (breaking).

The cimetidine 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 P:aethesia. 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 WO 92/14713 PCr/HU92/00007 7 Table I Treatment n Dose HCL production Inhibition i.p. during 4 hours HC1 producmg/kg calculated for tion 100 g of bodyweight /umol Control 10 31;.0 Cimetidine 10 50 151.0 52 The in vivo absorption of cimetidine according to the invention was also studied. In these experiments 200 mg of cimetidine and (as reference drug) cimetidine 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 libitun.

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 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 WO 92/14713 PC/HU92/00007 8 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 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 (sign A) after 90 minutes although no significant difference can be observed.

Cimetidine 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 OC, then it is combined under stirring with 20 sodium hydroxide solution being equivalent to 1.1 mol of the hydrochloric acid used for the dissolution. The temperature of the solution is maintained between 10 9C and 15 oC by cooling when necessary and it is crystallized while stirring and when necessary inoculated with a crystal of cimetidine WO 92/14713 9 PCT/HU92/00007 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 Analytical characteristics: melting point 142 to 145 OC Active agent content 99.71 total contamination 0.37 (determined by TLC) heavy metal content 0 Infrared spectrum see Figures 1 to 3.

Example 2 After suspending 1000 g of cimetidine modification (see the Hungarian patent specification No.

185,187 and its Great Britain equivalent No. 2A108,117) 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 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 usad instead of methanol and the crystallization is carried out at a temperature of 5 to 10 In this way 187 g (93.5 of cimetidine 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 is used as starting substance and the suspending is carried out with distilled water, to obtain 186.9 g (93.45 of cimetidine the quality characteristics of which are in complete agreement with those described in Example 1.

Example WO 92/14713 10 PCIP/HU9/00007 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 OC. In this way 185 g (92.5 of cime-idine are obtained, the quality characteristics of whin- are in complete agreement with those described in Example 1.

Example 6 Pharmaceutical composition Components Mg Cimetidine 200 Starch 56 Microcrystalline cellulose Lactose 56 Polyvinylpyrrolidone 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 (4)

1. Polymorph modification 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 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 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 OC 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 OC 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 mp r i s e s using a C1- 3 alkanol or ketone as water-miscible organic solvent. 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 polymorph modification defined in WO 92/14713 12 PCr/H.U92/00007 claim I. with carriers and/or additives commonly used in the pharmacy and transforming them to a pharmaceutical composition.