CY1306A - Aminoalkyl furan derivative - Google Patents
Aminoalkyl furan derivative Download PDFInfo
- Publication number
- CY1306A CY1306A CY130681A CY130681A CY1306A CY 1306 A CY1306 A CY 1306A CY 130681 A CY130681 A CY 130681A CY 130681 A CY130681 A CY 130681A CY 1306 A CY1306 A CY 1306A
- Authority
- CY
- Cyprus
- Prior art keywords
- ranitidine hydrochloride
- ranitidine
- vwd
- hydrochloride
- solution
- Prior art date
Links
- -1 Aminoalkyl furan derivative Chemical class 0.000 title description 5
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 claims description 66
- 229960001520 ranitidine hydrochloride Drugs 0.000 claims description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- VMXUWOKSQNHOCA-UKTHLTGXSA-N ranitidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-UKTHLTGXSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 229960000620 ranitidine Drugs 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 8
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 238000002329 infrared spectrum Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000005855 radiation Effects 0.000 claims description 4
- 239000012296 anti-solvent Substances 0.000 claims description 3
- 239000002480 mineral oil Substances 0.000 claims description 3
- 235000010446 mineral oil Nutrition 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 229910016523 CuKa Inorganic materials 0.000 claims description 2
- 238000005169 Debye-Scherrer Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 239000000243 solution Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000002002 slurry Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- 239000011928 denatured alcohol Substances 0.000 description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000015096 spirit Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- ZPLCXHWYPWVJDL-UHFFFAOYSA-N 4-[(4-hydroxyphenyl)methyl]-1,3-oxazolidin-2-one Chemical compound C1=CC(O)=CC=C1CC1NC(=O)OC1 ZPLCXHWYPWVJDL-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1
GB 2 084 580 A 1
SPECIFICATION Aminoalkyl Furan Derivative
The present invention is concerned with the hydrochloride salt of the H2-antagonist N-[2-[[[5-(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl-N1-methyl-2-nitro-1,1 -ethenediamine, which has 5 the approved name 'ranitidine', and its production and isolation. ^ 5
Ranitidine, as described and claimed in British Patent Specification 1,565,966, shows potent histamine H2-blocking activity and may be used in the treatment of conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration, as a prophylactic measure in surgical procedures, and in the treatment of allergic and inflammatory conditions where 1 o histamine is a known mediator. 10
The hydrochloride salt of ranitidine (hereinafter referred to as ranitidine hydrochloride) is of particular importance since it enables ranitidine to be conveniently formulated in, for example, tablets for oral administration. There is thus the need to produce ranitidine hydrochloride in as pure and as highly crystalline a condition as possible in order to fulfil exacting pharmaceutical requirements and ■\5 specifications. 15
The process by which the ranitidine hydrochloride is produced also needs to be one which is convenient to operate on a plant scale. In particular it is desirable that the hydrochloride should be prepared with concentrated hydrochloric acid and that the solvent for crystallisation should be readily recoverable.
20 'n addition, the product should be in a form that is readily filtered off and easily dried. It is also 20
desirable that, if required, the product can be recrystailised from the same solvent system.
Ranitidine hydrochloride has been obtained in a crystalline form, designated Form 1, by dissolving ranitidine in industrial methylated spirit containing hydrogen chloride and adding ethyl acetate to the solution, as described in the above mentioned British Patent specification. This procedure, however, 25 does not have the desirable features of a manufacturing process described above and Form 1 of the 25 hydrochloride salt has unsuitable filtration and drying characteristics.
It has now been discovered that ranitidine hydrochloride can be prepared in a new crystalline form having more advantageous properties and the manufacturing process for the said new crystalline form fulfills the desirable features described above. The present invention thus provides ranitidine 30 hydrochloride in a new crystalline form designated Form 2. Form 2 has been found generally to have 30 larger crystals than the hitherto known Form 1 and exhibits more favourable filtration and drying characteristics. Furthermore, Form 2 is less hygroscopic than Form 1, which is an additional advantage in view of the sensitivity of ranitidine hydrochloride to moisture.
Form 2 ranitidine hydrochloride may be characterised by its infra-red spectrum in mineral oil 35 and/or by its X-ray powder diffraction pattern. These will now be discussed in more detail. 35
40
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infra-red Spectrum
The infra-red spectrum of Form 2 ranitidine hydrochloride as a mull in mineral oil shows the following main peaks:
3260
1075
3190
1045
3100
1021
2560
1006
2510
991
2470
972
1620
958
1590
810
1570
800
1263
760
1230
700
1220
660
1195
640
1163
620
1130
40
45
50
The infra-red spectrum of the product of Example 1 below obtained in this way is shown in the 55 accompanying drawing in which the ordinate is the transmittance in % and the abscissa is the 55
wavenumber in cm-1.
X-ray Diffraction
The X-ray diffraction pattern of Form 2 ranitidine hydrochloride may be obtained by loading the material into a 0.3mm diameter glass capillary and photographing the pattern by the Debye Scherrer 60 method in a 114.6mm diameter camera by exposure for 12 hours to CoKa radiation and for 3 hours to 60 CuKa radiation (for 'd'<aA). The weighted mean values of X-ray wavelengths used for the calculations were CuK. 1.54171A and CoKa 1.79024A.
BNSDOC1D: <GB 2084580A_I_>
2
GB 2 084 580 A 2
The X-ray powder diffraction pattern of Form 2 ranitidine hydrochloride in terms of'd' spacings and relative intensities (I) is as follows (s=strong, m=medium, w=weak, v=very, d=diffuse):
d(A)
/
d(h)
I
10.73
m
3.40
2vw
6.50
3vwd
3.35
2 vwd
6.13
m
3.25
wd
5.83
s
3.12
2vw
5.63
3vwd
3.04
2vwd
5.42
s
2.97
3vwd
5.06
2vw
2.93
3vwd
4.92
w
2.88
3vwd
4.59
2vw
2.81
vwd
4.40
s
2.72
vwd
4.28
w
2.66
3vwd
3.91
wd
2.47
2vwd
3.79
s
2.44
vw
3.71
m
2.34
2 vwd
3.60
vwd
2.30
3 vwd
3.46
m
2.21
2vwd
20 Form 2 ranitidine hydrochloride may be formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions comprising Form 2 ranitidine hydrochloride adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of a pharmaceutical^ acceptable carrier or excipient and may also contain if required other active ingredients, e.g. H,-antagonists. Thus the hydrochloride salt 25 according to the invention may be formulated for oral, buccal, topical, parenteral, or rectal administration. Oral administration is preferred, particularly in the form of tablets and capsules.
For oral administration, the pharmaceutical composition may take the form of for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable exceipients. For buccal administration the compositions may take the form of tablets or 30 lozenges formulated in conventional manner.
Form 2 ranitidine hydrochloride may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form in ampoules,. or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents 35 such as suspending stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
Form 2 ranitidine hydrochloride may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
40 For topical application. Form 2 ranitidine hydrochloride may be formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner.
For internal administration a convenient daily dosage regime of Form 2 ranitidine hydrochloride is 1 to 4 doses to the total of some 40 mg to 1.2 g per day, dependent upon the condition of the patient.
The present invention also provides a process for the preparation of Form 2 ranitidine 45 hydrochloride which comprises crystallising ranitidine hydrochloride from a solution thereof in a solvent under conditions which yield Form 2 ranitidine hydrochloride.
The precise conditions under which Form 2 ranitidine hydrochloride is formed may be empirically determined and it is only possible to give a number of methods which have been found to be suitable in practice.
50 Thus, for example. Form 2 ranitidine hydrochloride may be prepared by crystallisation under controlled conditions. In particular, it can be prepared either from the corresponding free base by reaction with hydrochloric acid or by recrystallisation of previously isolated ranitidine hydrochloride, in general the use of a hydroxylic solvent, e.g. a lower alkanol, is preferred. In order to dissolve the starting material it may be helpful to warm and/or to include some water in the solvent system. In some cases it 55 is necessary to add further organic solvent or a specific anti-solvent such as acetone in order to bring the Form 2 crystals out of solution.
When the starting material for the preparation of the desired Form 2 ranitidine hydrochloride is the free base, one preferred preparation involves treating a solution of ranitidine in propan-2-ol with hydrochloric acid, followed by crystallisation of the required form of the hydrochloride salt, preferably 60 at an elevated temperature at up to 70°C, e.g. 40 to 60°C, particularly 48—52°C, by addition of further quantities of propan-2-ol. Alternatively a solution of ranitidine in 2-methylpropan-2-ol, butan-2-ol or ethanol can be treated with hydrochloric acid and the desired Form 2 ranitidine hydrochloride crystallised at a temperature up"to 70°C, for example from room temperature to 60°C. It is preferable
5
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30
35
40
45
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55
60
<GB 2084580A l_>
3
GB 2 084 580 A 3
to use concentrated hydrochloric acid (e.g. 35 to 38% w/w) and, in general, molar equivalent proportions of hydrochloric acid and ranitidine should be employed. Under these conditions, salt formation, as well as crystallisation, should preferably be carried out at an elevated temperature, for example within the above mentioned temperature ranges. It has been found that it may be 5 advantageous to include in the starting solution, a small amount to water, additional to that in the hydrochloric acid e.g. up to 7%, preferably about 3% v/v. For example where ethanol is the solvent, this can be used in the form of industrial methylated spirit which contains about 2% v/v water.
When the starting material is ranitidine hydrochloride e.g. Form 1 or Form 2, the desired Form 2 salt may be crystallised using similar conditions for crystallisation to those described above. 10 Alternatively, the salt may be dissolved, e.g. by warming, in an organic solvent such as methanol or ethanol followed by cooling of the resulting solution, e.g. to 10 to 40°C, and stirring until crystallisation of the required form is complete. In the case of some solvents, e.g. methanol, it may be advantageous to add a miscible anti-solvent such as acetone or ethyl acetate to the solution to complete crystallisation.
15 It has frequently been found desirable to add 'seeds' of Form 2 ranitidine hydrochloride to the crystallisation solution in order to induce crystallisation.
Form 2 ranitidine hydrochloride has proved to be readily isolable and can be filtered off from the crystallisation medium, if desired after cooling, and washed and dried.
If desired, the Form 2 ranitidine hydrochloride prepared as above may further be recrystallised 20 using similar conditions for crystallisation to those described above.
In order that the invention may be more fully understood the following Examples are given by way of illustration only. All temperatures are in °C.The concentrated hydrochloric acid is 35% w/w and the industrial methylated spirit is 74° o.p. and contains 2% v/v water.
Example 1
25 Preparation of Form 2 Ranitidine Hydrochloride
One equivalent (about 5.3ml] of concentrated hydrochloric acid was added to a solution of ranitidine (20g) in a mixture of propan-2-ol (130ml) and water (4ml) at 45°. The mixture was heated at 50° whilst a further quantity of propan-2-ol (68ml) was added and the resulting solution was then stirred at 50° to allow the product to crystallise. The slurry was cooled to 10 to 12° and the product 30 was filtered off, washed with propan-2-ol (2x27ml) and dried at 50° under reduced pressure to give Form 2 ranitidine hydrochloride (21g) m.p. 139—141 °.
Example 2
Recrystallisation of Ranitidine Hydrochloride
Form 2 ranitidine hydrochloride (25g) was warmed in a mixture of propan-2-ol (66ml) and water 35 (9ml) and the resulting solution was stirred at 50°. A further quantity of propan-2-ol (150ml) was added over a period of 5 to 10 minutes and the product was allowed to crystallise at 50°. The slurry was cooled to 10 to 12° and the product was filtered off, washed with propan-2-ol (2x30) and dried at 50° under reduced pressure to give Form 2 ranitidine hydrochloride (23.6g) m.p. 139—141 °.
Example 3
40 Recrystallisation of Ranitidine Hydrochloride
Form 2 ranitidine hydrochloride (50g) was warmed in a mixture of propan-2-ol (132ml) and-water (18ml) and the resulting solution stirred at 55°. A further quantity of propan-2-ol (300ml) was added over a period of 5 to 10 minutes and the product was allowed to crystallise at 55°. The slurry was cooled to 10 to 12° and the product was filtered off, washed with propan-2-ol (2x60ml) and 45 dried at 50° under reduced pressure to give Form 2 ranitidine hydrochloride (48g) m.p. 141—142°.
Example 4
Recrystallisation of Ranitidine Hydrochloride
Form 2 ranitidine hydrochloride (50g) was dissolved in industrial methylated spirit (200ml) at 70°. The solution was allowed to cool and the product crystallised out at 40°. The resulting slurry was 50 cooled to 0° and the product was filtered off, washed with industrial methylated spirit (20ml) and dried at 50° under reduced pressure to give Form 2 ranitidine hydrochloride (47.7g) m.p. 140—142°.
Example 5
Preparation of Form 2 Ranitidine Hydrochloride
Concentrated hydrochloric acid (1.4ml) was added to a solution of ranitidine (6g) in 2-55 methylpropan-2-ol. The mixture was stirred at 40° to allow the product to crystallise and the resulting slurry was cooled to 20°. Further concentrated hydrochloric acid (about 0.2ml) was added to the mixture and, after stirring for 1 h at 20° the product was filtered off, washed with 2-methylpropan-2-ol, and dried at 50° under reduced pressure to give Form 2 ranitidine hydrochloride (5.96g) m.p. 141 — 142°.
BNSDOCID: <GB 2084580A_I_>
5
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55
4
GB 2 084 580 A 4
Example 6
Preparation of Form 2 Ranitidine Hydrochloride
The process of Example 5 was repeated, using butan-2-ol instead of 2-methylpropan-2-ol and stirring the mixture at 55°, to give Form 2 ranitidine hydrochloride (6.1 g) m.p. 140—141 °.
5 Example 7 5
Recrystallisation of Form 1 Ranitidine Hydrochloride to Give Form 2 Ranitidine Hydrochloride
Form 1 ranitidine hydrochloride (25g) was warmed in a mixture of propan-2-ol (66ml) and water (9ml) and the resulting solution was stirred at 50°. A further quantity of propan-2-ol (150 ml) was added over a period of 5 to 10 minutes and the product was allowed to crystallise at 50°. The slurry 10 was cooled to 10 to 12° and the product was filtered off, washed with propan-2-ol (2 x30ml) and 10
dried at 50° under reduced pressure to give Form 2 rantidine hydrochloride (22.7g) m.p. 139—140°.
Example 8
Recrystallisation of Form 1 Ranitidine Hydrochloride to Give Form 2 Ranitidine Hydrochloride
Form 1 ranitidine hydrochloride (10g) was warmed in a mixture of methanol (15 ml) and acetone -15 (15ml). The solution was stirred at 50° whilst a further quantity of acetone (45ml) was added and the 15 resulting solution was then stirred at 50° to allow the product to crystallise. The slurry was cooled to 20° and the product was filtered off, washed with acetone (2x10ml), and dried at 50° under reduced pressure to give Form 2 ranitidine hydrochloride (9.5g) m.p. 141—142°.
Example 9
20 Preparation of Form 2 Ranitidine Hydrochloride 20
Ranitidine (6g) was dissolved in industrial methylated spirits (42ml) at ambient temperature (about 20°). One equivalent (about 1.6ml) of concentrated hydrochloric acid was added to the solution. The temperature rose to about 27° and the solution was seeded at this temperature to induce crystallisation. The product crystallised to give a thick slurry at 25—27°. After 0.5h the slurry was 25 cooled to 10—12° for 0.5h. The product was then filtered off, washed with industrial methylated 25
spirits (5ml) and dried at 50° under reduced pressure to give Form 2 ranitidine hydrochloride (5.4g) m.p. 139—140°.
Example 10—12
Preparation of Form 2 Ranitidine Hydrochloride
30 Ranitidine (50g) was dissolved in propan-2-ol (225ml) at 45—55°. Celite (Registered Trade 30
Mark) (0.6g) was added and the reaction mixture filtered. Propan-2-ol (100ml) heated to 45—55° was used to wash the filter. Water (see following Table—omitted in Example 12) was added to the combined filtrate and the reaction solution adjusted to the crystallisation temperature (see table).
Concentrated hydrochloric acid (approximately 14ml) was added until the end-point was reached 35 i.e. an aliquot of the reaction mixture turned bromothymol blue from green to yellow. Propan-2-ol 35
(168ml) warmed to 45—55° was added and the temperature of the solution adjusted to the crystallisation temperature chosen. The solution was seeded with Form 2 ranitidine hydrochloride, if necessary, and left to stir for 3 hours.
The reaction mixture was then cooled to room temperature and stirred overnight. Prior to 40 filtration the mixture was cooled to 8—12° for 1 £ hours. The mixture was filtered and the product 40 washed with cold (8—12°) propan-2-ol (2x62ml.). The Form 2 ranitidine hydrochloride product was dried in a vacuum oven at 50°.
Table
Example Vol. of Crystallisation Yield
45 No. Water added (m!) Temp.(°C) (g) 45-
10 2.1 40 52.2
11 2.1 55 51.0
12 — 50 54.0 *
Claims (1)
- Claims50 1 • Form 2 ranitidine hydrochloride characterised by an infra-red spectrum as a mull in mineral oil 50showing the following main peaks:55 2560 1006 55326010753190104531001021256010062510991247097216209581590810: <GB 2084580A l_5GB 2 084 580 A 5157080012637601230700122066011956401163620 cm11302. Form 2 ranitidine hydrochloride characterised by the following x-ray powder diffraction pattern expressed in terms of "d" spacings and relative intensities (1) (s=strong, m=medium, w=weak, v=very, 10 d=diffuse) and obtained by the Debye Scherrer method in a 114.6 mm diameter camera by exposure 1 o for 12 hours to CoKa radiation and for 3 hours to CuKa radiation:d(k)/10.73m6.503vwd6.13m5.83s5.633vwd5.42s5.062vw4.92w4.592vw4.40s4.28w3.91wd3.79s3.71m3.60vwd3.46m d(N/3.402w3.352vwd3.25wd3.122vw3.042vwd2.973 vwd2.933vwd2.883 vwd2.81vwd2.72vwd2.663vwd2.472vwd2.44vw2.342 vwd2.303vwd2.212 vwd3. A process for the preparation of Form 2 ranitidine hydrochloride as defined in Claim 1 or Claim30 2 which comprises crystallising ranitidine hydrochloride from a solution thereof in a solvent under 30 conditions which yield Form 2 ranitidine hydrochloride.4. A process as claimed in Claim 3, wherein the Form 2 ranitidine hydrochloride is prepared from ranitidine free base by reaction with hydrochloric acid.5. A process as claimed in Claim 4 carried out in a hydroxylic solvent.35 6. A process as claimed in Claim 5 which comprises treating a solution of ranitidine in propan-2- 35ol with hydrochloric acid at a temperature of up to 70°C, followed by crystallisation of Form 2 ranitidine hydrochloride by addition of further propan-2-ol.7. A process as claimed in Claim 5 which comprises treating a solution of ranitidine in 2-methylpropan-2-ol, butan-2-ol or ethanol with hydrochloric acid at a temperature of up to 70°C,40 followed by crystallisation of Form 2 ranitidine hydrochloride. 408. A process as claimed in Claim 6 or 7, wherein the starting solution contains up to 7% v/v water.9. A process as claimed in Claim 3, wherein Form 2 ranitidine hydrochloride is prepared by recrystallisation of ranitidine hydrochloride.45 10. A process as claimed in Claim 9, wherein recrystallisation takes place from a hydroxylic 45solvent.11. A process as claimed in Claim 9, wherein the solvent is propan-2-ol, methanol or ethanol.12. A process as claimed in Claim 10 or 11, wherein a miscible anti-solvent is added to the solution to complete crystallisation.50 13. A pharmaceutical composition comprising Form 2 ranitidine hydrochloride as defined in 50 Claim 1 or Claim 2 together with at least one inert pharmaceutical^ acceptable carrier or diluent.14. A pharmaceutical composition comprising Form 2 ranitidine hydrochloride when prepared by a process as claimed in any of Claims 3 to 12 together with at least one inert pharmaceuticaily acceptable carrier or diluent.55 15. A pharmaceutical composition as claimed in Claim 13 or 14 in a form adapted for oral 55administration.Printed for Her MajestY's Stationery Office by the Courier Press, Leamington Spa, 1982. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1 AY. from which copies may be obtained.BNSDOCID: <GB 2084580A l_>
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8031634 | 1980-10-01 | ||
| GB8129731A GB2084580B (en) | 1980-10-01 | 1981-10-01 | Aminoalkyl furan derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CY1306A true CY1306A (en) | 1985-12-06 |
Family
ID=26277058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CY130681A CY1306A (en) | 1980-10-01 | 1981-10-01 | Aminoalkyl furan derivative |
Country Status (2)
| Country | Link |
|---|---|
| CY (1) | CY1306A (en) |
| GB (1) | GB2084580B (en) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL90245A (en) * | 1988-05-11 | 1994-04-12 | Glaxo Group Ltd | Resin adsorption containing ranitidine together with synthetic resin replaces cations, its preparation and pharmaceutical preparations containing it |
| GB8904182D0 (en) * | 1989-02-23 | 1989-04-05 | Glaxo Canada | Pharmaceutical compositions |
| US5338871A (en) * | 1991-12-20 | 1994-08-16 | Torcan Chemical Ltd. | Preparation of form 1 ranitidine hydrochloride |
| CA2120874E (en) * | 1994-04-08 | 2002-01-08 | Keshava Murthy | Form of form 1 ranitidine |
| GB9713730D0 (en) | 1997-06-30 | 1997-09-03 | Ciba Geigy Ag | Organic compounds |
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
| US7508500B2 (en) | 2004-10-27 | 2009-03-24 | Eastman Kodak Company | Characterizing organic materials in a thin film |
| DE102004054054A1 (en) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines |
| DE102005035891A1 (en) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals |
| CN109503584A (en) | 2006-05-04 | 2019-03-22 | 勃林格殷格翰国际有限公司 | Polymorphic |
| PE20080251A1 (en) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | USES OF DPP IV INHIBITORS |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| PE20091730A1 (en) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | FORMULATIONS INVOLVING A DPP4 INHIBITOR |
| BRPI0916997A2 (en) | 2008-08-06 | 2020-12-15 | Boehringer Ingelheim International Gmbh | DPP-4 INHIBITOR AND ITS USE |
| UY32030A (en) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN" |
| AU2009290911A1 (en) | 2008-09-10 | 2010-03-18 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| US8865729B2 (en) | 2008-12-23 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Salt forms of a xanthine compound |
| AR074990A1 (en) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY |
| KR20240090632A (en) | 2009-11-27 | 2024-06-21 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
| CA3070513C (en) | 2010-05-05 | 2023-01-03 | Boehringer Ingelheim International Gmbh | A dpp-4 inhibitor for use in treatment of skin-alterations or necrosis |
| ES2953123T3 (en) | 2010-06-24 | 2023-11-08 | Boehringer Ingelheim Int | Diabetes therapy |
| AR083878A1 (en) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | VASOPROTECTORA AND CARDIOPROTECTORA ANTIDIABETIC THERAPY, LINAGLIPTINA, TREATMENT METHOD |
| CN103781788B (en) | 2011-07-15 | 2016-08-17 | 勃林格殷格翰国际有限公司 | Quinazoline, its preparation and the purposes in pharmaceutical composition thereof being substituted |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| EP2849755A1 (en) | 2012-05-14 | 2015-03-25 | Boehringer Ingelheim International GmbH | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| ES2950384T3 (en) | 2014-02-28 | 2023-10-09 | Boehringer Ingelheim Int | Medical use of a DPP-4 inhibitor |
| JP2019517542A (en) | 2016-06-10 | 2019-06-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Combination of linagliptin and metformin |
| WO2021079183A1 (en) * | 2019-10-21 | 2021-04-29 | Sms Pharmaceuticals Limited | Isopropyl alcohol solvent free crystalline ranitidine hydrochloride form-2 which is free of nitrosamine (ndma) impurity |
-
1981
- 1981-10-01 CY CY130681A patent/CY1306A/en unknown
- 1981-10-01 GB GB8129731A patent/GB2084580B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2084580B (en) | 1984-07-04 |
| GB2084580A (en) | 1982-04-15 |
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