JPS6234759B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel polymorph of a heterocyclic compound, and more particularly to a novel crystallographically substantially pure polymorph of cimetidine (hereinafter referred to as cimetidine A) and a method for producing the same. In particular, the present invention relates to a process for the preparation of Cymetidine A suitable for commercial production. Cymetidine has the chemical name N-methyl-N'-
It is a compound of cyano-N''-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, which has histamine H ₂ -receptor antagonistic activity, and its usefulness has been described, for example, by Brimbrecombe et al. (Brimblecombe et al., Journal of Medical Research)
al.J.Med.Research), 1975, 3, No. 2, 86-92)
and our British Patent Specifications No. 1338169 and No. 1397436. It has previously been found that cymetidine can exist in many polymorphic forms, and studies with other drugs have shown that polymorphism affects bioavailability. One object of the present invention is to provide a polymorphic form of cymetidine, and another object is to provide a process for its preparation. Therefore, the present invention provides 1400 and 1385 cm ^-1
Characterized by an infrared spectrum (1% KBr disc) with a very strong, broad peak, a strong, sharp peak at 1205 cm ^-1 and a moderately sharp peak at 1155 cm ^-1 and no peak at 1180 cm ^-1 The present invention provides a crystallographically substantially pure polymorphic form of cymetidine (cymetidine A), which is characterized by the following properties: As used herein, the term "substantially crystallographically pure" refers to Cymetidine A containing no more than 5%, preferably no more than 3%, of any other polymorphic form of Cymetidine. When referring to peaks in an infrared spectrum, the terms "very strong,""strong," and "moderate" refer to the relative height of the peak, and the terms "broad" and "sharp" refer to the relative height of the peak. It means the width. These terms are well known as expressions of the infrared spectrum. The relevant part of a typical infrared spectrum of Cymetidine A is shown in the accompanying Figure 1. Figure 1 shows 4
The two distinctive peaks are marked. The inventors have discovered that cymetidine crystallizes in at least three different forms. One is Cymetidine A. The other forms are called Cymetidine B and Cymetidine C, which do not have the four characteristic peaks mentioned above in their infrared spectra, but have a very strong, sharp peak at 1180 cm ^-1 . Cymetidine B is shown in the attached Figure 2.
The relevant part of the infrared spectrum of is shown. Cymetidine A is preferred over the other two forms because it is more easily obtained and in crystallographically pure form. Cymetidine A is also slightly more soluble in water than the other two forms, with a dissolution rate of at least 0.2 mg/min/cm ² at 25° C. from the smooth surface of a typical tablet. Further advantageously, Cymetidine A can be easily handled, especially in large-scale operations such as centrifugation. The easier handling of the suspension of Cymetidine A compared to the other two forms of Cymetidine is due to the fact that a 25% (w/v) suspension of Cymetidine A in isopropanol and a mixture of Cymetidine B and C in isopropanol. −
This is illustrated by the following comparative experiment performed on a 25% (W/V) suspension in water (3:1). Comparative experiment (a) Continuous shear Rheomat temperature controlled at 25℃
An RM30 rheometer was used. For suspensions of Cymetidine A, shear rates from 0 to about 700 sec ^-1 were obtained using the cup and rotor of System A.
Table 1 below shows the results for Cymetidine A suspension.

TABLE This data shows that the suspension behaved as a Newtonian fluid with a viscosity of 0.0496 poise. Due to the solid nature of the Cymetidine B and C suspensions, it was not possible to obtain continuous shear data. (b) Cone penetration In order to quantify the solid properties of cymetidine B and C suspensions, an 1806 cone was equipped and a 150
Seta universal (Seta
Universal) penetrometer was used. The average penetration depth of the cone at 20°C was 5.5 mm. Due to its liquid properties, it was impossible to measure the penetration level of Cymetidine A suspension. (c) Vibration test Modified with parallel plates of radius 3.75 cm
An R16 Weissenberg rheogoniometer was used for vibration testing at 25°C. The vibration frequency ranged from 0.01 to 12.5Hz. The data was collected using the Solartron Transfer Function Analyzer.
Function Analyser (JM1600/JX1606)] from both cymetidine suspensions. Computer analysis of the data yielded the dynamic modulus shown in Table 2 below.

Table: Plotting the logarithm of the dynamic modulus against the logarithm of the vibration frequency reveals that for both suspensions, the dynamic modulus does not correlate with frequency in the range 0.01-0.1 Hz. Cymetidine B and C
The solidity of cymetidine A is such that its dynamic modulus is greater than 0.06 in this frequency range, whereas cymetidine A
This is clear from the dynamic elastic modulus of less than 0.001. The sample of Cymetidine A obtained is also characterized by its density being less than or equal to 1.30 g/cc. The inventors have demonstrated that Cymetidine A can be obtained by properly selecting the solvent for crystallization, carefully controlling the cooling rate of the solvent just before and during crystallization, and
It has also been found that by carefully controlling the agitation of the solvent immediately before and during crystallization, formation can be achieved with good reproducibility. Suitable solvents for crystallization include acetonitrile,
Acetone, methyl isobutyl ketone, toluene and lower alkanols (e.g. ethanol,
Non-aqueous solvents such as isopropanol and n-butanol are included. Isopropanol is particularly suitable for practical use because it is relatively cheap, readily available, and has no problems with effluent disposal. Stirring during cooling should be sufficient to maintain efficient heat transfer throughout the liquid phase. On a commercial scale, efficient heat transfer through the cooling surfaces of the vessels used is also desirable. Cooling rate is 10-60
°C/hour was found to be effective. The following example illustrates a commercial scale production of Cymetidine A. Example 245 kg of Cymetidine was mixed with hot isopropanol (80 kg
850 °C) and the resulting solution is clarified by filtration. liquid on a heat transfer surface of 4.8m ² and 200Kcal/
Place in a 300 gallon glass-lined container equipped with a standard stirring impeller, having a U-value of m2 ^· h·°C. The solution is cooled from 80° C. to 15° C. over 2 hours while rotating the stirring blade at 90 rpm. The resulting precipitate has a well-grown prismatic shape, which is easily separated by centrifugation and dried in a fluidized bed dryer. The obtained product is 1600 ~
It has an infrared spectrum between 200 cm ^-1 and a density of
1.28g/cc, dissolution rate in water at 25°C (from the smooth surface of a 9.6mm diameter tablet) is 0.21mg/min/
^cm2 . Cymethylene A can be combined with a solid pharmaceutical carrier to form a pharmaceutical composition, and administration thereof results in blockade of histamine _H2 -receptors. Examples of solid carriers include lactose, microcrystalline cellulose, china clay, sucrose, talc, starch, gelatin, agar, pectin, polyvinylpyrrolidone, axia, magnesium stearate, stearic acid, and the like. A variety of dosage forms can be employed and administered in any desired manner. That is, it can be in the form of tablets, hard gelatin-containing powders, or granules. In this case, the amount of solid support can vary widely, but approximately 25
A range of mg to about 1 g is preferred. Injectable solutions or topical creams or ointments can also be used. The pharmaceutical composition is manufactured by conventional methods including mixing, granulating, and tabletting. Initial milling methods are preferred. It has been found that this method improves the uniformity of the product without sacrificing its outstanding ease of handling. Therefore, finely divided Cymetidine A, preferably passed through a 60 mesh sieve at the mill outlet (eg, a Pittsburgh Hammer Mill), is also within the scope of this invention. Kocova and Pilpel, Powder Technology [Kocova and
Pilpel, Powder Technology 5, 329 (1971/
In an agglomeration test conducted using a shear cell apparatus described in [72], this finely ground cymetidine A was found to have a
It has an internal friction angle of ~38°. Cymetidine A is present in the composition in an amount effective to block histamine H-receptors. Preferably, each dosage unit contains about 50 doses of the active ingredient.
~750 mg, preferably 200-600 mg. The active ingredient is preferably administered from 1 to 6 times per day. A daily dose of about 500 to about 1500 mg is preferred. Combination compositions of Cymetidine A and other active ingredients can also be used. Examples of such active ingredients include histamine _H1 such as mepyramine.
- Receptor antagonists and anti-inflammatory compounds such as aspirin, naproxen, ibuprofen or ketoprofen.

[Brief explanation of the drawing]

Figures 1 and 2 respectively show cymetidine A
and an infrared spectrum of Cymetidine B.

Claims (1)

[Claims] 1. Very strong, broad peaks at 1400 and 1385 cm ^-1 , strong, sharp peaks at 1205 cm ^-1 and 1155 cm
^-1 with a medium sharp peak and 1180cm ^-1
Crystallographically, substantially pure N-methyl-N'-cyano-N''-[2-
((5-methyl-4-imidazolyl)methylthio)
A new polymorph of ethyl]guanidine (cymetidine) (cymetidine A). 2 Cymetidine according to item 1 above, wherein the content of other polymorphic forms of Cymetidine is 3% or less. 3 The dissolution rate in water at 25°C from the smooth surface of a standard tablet is at least 0.20 mg/min/cm ²
The cymetidine of item 1 or item 2 above. 4 Continuous shear data of a 25% (W/V) suspension in isopropanol at a shear rate of 0 to 700 sec ^-1 indicates that it is a Newtonian fluid, and dynamic elasticity in a vibration test with a vibration frequency of 0.01 to 1.0 Hz. Cymetidine according to any one of the above items 1 to 3, which has a ratio of 0.001 or more. 5 Cymetidine according to any one of Items 1 to 4 above, which has a density of 1.30 g/cc or less. 6 Cymetidine is dissolved in a non-aqueous thermal solvent, the resulting solution is cooled with sufficient stirring to maintain efficient heat transfer, and the polymorphic form of Cymetidine (Cymetidine A) is dissolved in the solvent with good handling properties. A commercial process for the production of Cymetidine A, characterized in that a suspension is obtained and Cymetidine A is separated. 7. The method of item 6 above, wherein the solvent is acetonitrile, acetone, methyl isobutyl ketone, toluene or lower alkanol. 8. The method of item 7 above, wherein the solvent is a lower alkanol. 9. The method of item 8 above, wherein the solvent is isopropanol. 10. The method according to any one of items 6 to 9 above, wherein the cooling rate is 10 to 60°C/hour. 11. The production method according to any one of Items 6 to 10 above, wherein Cymetidine A is separated from the suspension by a centrifugation method.