GB2084580A - Aminoalkyl Furan Derivative - Google Patents

Aminoalkyl Furan Derivative Download PDF

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Publication number
GB2084580A
GB2084580A GB8129731A GB8129731A GB2084580A GB 2084580 A GB2084580 A GB 2084580A GB 8129731 A GB8129731 A GB 8129731A GB 8129731 A GB8129731 A GB 8129731A GB 2084580 A GB2084580 A GB 2084580A
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ranitidine hydrochloride
ranitidine
3vwd
hydrochloride
solution
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GB8129731A
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GB2084580B (en
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Glaxo Group Ltd
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Glaxo Group Ltd
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Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to CY130681A priority Critical patent/CY1306A/en
Priority to GB8129731A priority patent/GB2084580B/en
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    • 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

Abstract

A novel crystal form of ranitidine (N-[2-[[[5-(dimethylamino)methyl]-2- furanyl]methyl]thio]ethyl-N'-methyl- 2-nitro-1,1-ethenediamine) hydrochloride, designated Form 2, and having favourable filtration and drying characteristics, is characterised by its infra-red spectrum and x-ray powder diffraction pattern.

Description

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 the approved name 'ranitidine', and its production and isolation.
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 histamine is a known mediator.
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 fuifil exacting pharmaceutical requirements and specifications.
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.
In addition, the product should be in a form that is readily filtered off and easily dried. It is also desirable that, if required, the product can be recrystallised from the same solvent system.
Ranitidine hydrochloride has been obtained in a crystalline form, designated Form 1, by dissolvinc 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, does not have the desirable features of a manufacturing process described above and Form 1 of the 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 hydrochloride in a new crystalline form designated Form 2. Form 2 has been found generally to have larger crystals than the hitherto known Form 1 and exhibits more favourable filtration and drying characteristics. Furthermore, Form 2 is iess 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 and/or by its X-ray powder diffraction pattern. These will now be discussed in more detail.
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 cm-' 1130 The infra-red spectrum of the product of Example 1 below obtained in this way is shown in the accompanying drawing in which the ordinate is the transmittance in % and the abscissa is the wavenumber in cm-t.
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 method in a 114.6mum diameter camera by exposure for 12 hours to COKa radiation and for 3 hours to CuKa radiation (for 'd' < aA). The weighted mean values of X-ray wavelengths used for the calculations vvereCuKa 1.54171AandCoKa 1.79024A.
The X-ray powder diffraction pattern of Form 2 ranitidine hydrochloride in terms of 'd' spacings and relative intensities (I) is as foilows (s=strong, m=medium, w=weak, v=very, d=diffuse): d(A) I dFA) I 10.73 m 3.40 2vw 6.50 3vwd 3.35 2vwd 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 2vwd 3.60 vwd 2.30 3vwd 3.46 m 2.21 2vwd 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 pharmaceutically acceptable carrier or excipient and may also contain if required other active ingredients, e.g. H1-antagonists. Thus the hydrochloride salt 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 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 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.
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 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.
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 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 at an elevated temperature at up to 700 C, e.g. 40 to 600 C, particularly 48-520C, by addition of further quantities of propan-2-ol.Alternatively a solution of ranitidine in 2-methylpropan-2-ol, butan-2ol or ethanol can be treated with hydrochloric acid and the desired Form 2 ranitidine hydrochloride crystallised at a temperature up to 700 C, for example from room temperature to 600 C. It is preferable 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 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.
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 400 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.
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 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 OC. The concentrated hydrochloric acid is 35% w/w and the industrial methylated spirit is 740 o.p. and contains 2% v/v water.
Example 1 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 450. The mixture was heated at 500 whilst a further quantity of propan-2-ol (68ml) was added and the resulting solution was then stirred at 500 to allow the product to crystallise. The slurry was cooled to 10 to 120 and the product was filtered off, washed with propan-2-ol (2x27ml) and dried at 500 under reduced pressure to give Form 2 ranitidine hydrochloride (21g) m.p. 1391410.
Example 2 Recrystallisation of Ranitidine Hydrochloride Form 2 ranitidine hydrochloride (25g) was warmed in a mixture of propan-2-ol (66ml) and water (9ml) and the resulting solution was stirred at 500. A further quantity of propan-2-ol (1 50ml) was added over a period of 5 to 10 minutes and the product was allowed to crystallise at 500. The slurry was cooled to 10 to 120 and the product was filtered off, washed with propan-2-ol (2x30) and dried at 500 under reduced pressure to give Form 2 ranitidine hydrochloride (23.69) m.p. 139--1410.
Example 3 Recrystallisation of Ranitidine Hydrochloride Form 2 ranitidine hydrochloride (50g) was warmed in a mixture of propan-2-ol (132mi) and water (1 8ml) 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 120 and the product was filtered off, washed with propan-2-ol (2x60ml) and dried at 500 under reduced pressure to give Form 2 ranitidine hydrochloride (48g) m.p. 141--1420.
Example 4 Recrystallisation of Ranitidine Hydrochloride Form 2 ranitidine hydrochloride (50g) was dissolved in industrial methylated spirit (200ml) at 700. The solution was allowed to cool and the product crystallised out at 400. The resulting slurry was cooled to 0 and the product was filtered off, washed with industrial methylated spirit (20ml) and dried at 500 under reduced pressure to give Form 2 ranitidine hydrochloride (47.7g) m.p. 140--1420.
Example 5 Preparation of Form 2 Ranitidine Hydrochloride Concentrated hydrochloric acid (1.4ml) was added to a solution of ranitidine (6g) in 2methylpropan-2-ol. The mixture was stirred at 400 to allow the product to crystallise and the resulting slurry was cooled to 200. Further concentrated hydrochloric acid (about 0.2ml) was added to the mixture and, after stirring for 1 h at 200 the product was filtered off, washed with 2-methylpropan-2-ol, and dried at 500 under reduced pressure to give Form 2 ranitidine hydrochloride 15.96g) m.p. 141- 1420.
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 550, to give Form 2 ranitidine hydrochloride (6.1 g) m.p. 1401410.
Example 7 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 500. 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 500. The slurry was cooled to 10 to 120 and the product was filtered off, washed with propan-2-ol (2x30ml) and dried at 500 under reduced pressure to give Form 2 rantidine hydrochloride (22.7g) m.p. 139--1400.
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 (1 5ml). The solution was stirred at 500 whilst a further quantity of acetone (45ml) was added and the resulting solution was then stirred at 500 to allow the product to crystallise. The slurry was cooled to 200 and the product was filtered off, washed with acetone (2 xl OmI), and dried at 500 under reduced pressure to give Form 2 ranitidine hydrochloride (9.5g) m.p. 141--1420.
Example 9 Preparation of Form 2 Ranitidine Hydrochloride 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 2527 . After 0.5h the slurry was cooled to 1012 for 0.5h. The product was then filtered off, washed with industrial methylated spirits (5ml) and.dried at 500 under reduced pressure to give Form 2 ranitidine hydrochloride (5.4g) m.p.139--1400.
Example 10-12 Preparation of Form 2 Ranitidine Hydrochloride Ranitidine (50g) was dissolved in propan-2-ol (225ml) at 4555 . Celite (Registered Trade Mark) (0.6g) was added and the reaction mixture filtered. Propan-2-ol (100ml) heated to 4555 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 i.e. an aliquot of the reaction mixture turned bromothymol blue from green to yellow. Propan-2-ol (168ml) warmed to 4555 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 filtration the mixture was cooled to 812 for 1 2 hours. The mixture was filtered and the product washed with cold (812 ) propan-2-ol (2x62ml.). The Form 2 ranitidine hydrochloride product was dried in a vacuum oven at 500.
Table Example Vol. of Crystallisation Yield No. Water added (mI) Temp. fOC) (g) 10 2.1 40 52.2 11 2.1 55 51.0 12 1 50 54.0

Claims (1)

  1. Claims
    1. Form 2 ranitidine hydrochloride characterised by an infra-red spectrum as a mull in mineral oil showing 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 11 63 620cm-1 1130 2.Form 2 ranitidine hydrochloride characterised by the following x-ray powder diffraction pattern expressed in terms of "d" spacings and relative intensities (I) (s=strong, m=medium, w=weak, v=very, d=diffuse) and obtained by the Debye Scherrer method in a 114.6 mm diameter camera by exposure for 12 hours to COKa radiation and for 3 hours to CuKa radiation: d(A) I d(A) I
    10.73 m 3.40 2w
    6.50 3vwd 3.35 2vwd
    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 2vwd
    3.60 vwd 2.30 3vwd
    3.46 m 2.21 2vwd 3.A process for the preparation of Form 2 ranitidine hydrochloride as defined in Claim 1 or Claim 2 which comprises crystallising ranitidine hydrochloride from a solution thereof in a solvent under 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.
    6. A process as claimed in Claim 5 which comprises treating a solution of ranitidine in propan-2ol with hydrochloric acid at a temperature of up to 700C, 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 2methylpropan-2-ol, butan-2-ol or ethanol with hydrochloric acid at a temperature of up to 700 C, followed by crystallisation of Form 2 ranitidine hydrochloride.
    8. 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.
    1 0. A process as claimed in Claim 9, wherein recrystallisation takes place from a hydroxylic solvent.
    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.
    13. A pharmaceutical composition comprising Form 2 ranitidine hydrochloride as defined in Claim 1 or Claim 2 together with at least one inert pharmaceutically 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 pharmaceutically acceptable carrier or diluent.
    1 5. A pharmaceutical composition as claimed in Claim 13 or 14 in a form adapted for oral administration.
GB8129731A 1980-10-01 1981-10-01 Aminoalkyl furan derivative Expired GB2084580B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CY130681A CY1306A (en) 1980-10-01 1981-10-01 Aminoalkyl furan derivative
GB8129731A GB2084580B (en) 1980-10-01 1981-10-01 Aminoalkyl furan derivative

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Application Number Priority Date Filing Date Title
GB8031634 1980-10-01
GB8129731A GB2084580B (en) 1980-10-01 1981-10-01 Aminoalkyl furan derivative

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GB2084580B GB2084580B (en) 1984-07-04

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Cited By (31)

* Cited by examiner, † Cited by third party
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DE3915347A1 (en) * 1988-05-11 1989-11-16 Glaxo Group Ltd HARZADSORBATE AND PROCESS FOR ITS MANUFACTURE
GB2229094B (en) * 1989-02-23 1993-01-06 Glaxo Canada Pharmaceutical capsules containing ranitidine
EP0626381A1 (en) * 1993-04-01 1994-11-30 TORCAN CHEMICAL Ltd Preparation of form 1 ranitidine hydrochloride
WO1995027709A1 (en) * 1994-04-08 1995-10-19 Acic (Canada) Inc. Form 1 ranitidine hydrochloride with increased density
US6423722B1 (en) 1997-06-30 2002-07-23 Novartis Ag Crystalline macrolides and process for their preparation
US7508500B2 (en) 2004-10-27 2009-03-24 Eastman Kodak Company Characterizing organic materials in a thin film
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US8541450B2 (en) 2004-11-05 2013-09-24 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines
US8637530B2 (en) 2005-07-30 2014-01-28 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8664232B2 (en) 2002-08-21 2014-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8673927B2 (en) 2006-05-04 2014-03-18 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US9149478B2 (en) 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
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
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3915347C2 (en) * 1988-05-11 1994-11-03 Glaxo Group Ltd Harzadsorbate, process for their preparation and pharmaceutical preparations containing them
DE3915347A1 (en) * 1988-05-11 1989-11-16 Glaxo Group Ltd HARZADSORBATE AND PROCESS FOR ITS MANUFACTURE
AT401727B (en) * 1989-02-23 1996-11-25 Glaxo Canada GELATINE CAPSULES CONTAINING RANITIDINE (SALT)
GB2229094B (en) * 1989-02-23 1993-01-06 Glaxo Canada Pharmaceutical capsules containing ranitidine
EP0626381A1 (en) * 1993-04-01 1994-11-30 TORCAN CHEMICAL Ltd Preparation of form 1 ranitidine hydrochloride
WO1995027709A1 (en) * 1994-04-08 1995-10-19 Acic (Canada) Inc. Form 1 ranitidine hydrochloride with increased density
US6423722B1 (en) 1997-06-30 2002-07-23 Novartis Ag Crystalline macrolides and process for their preparation
US9321791B2 (en) 2002-08-21 2016-04-26 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9556175B2 (en) 2002-08-21 2017-01-31 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions
US10202383B2 (en) 2002-08-21 2019-02-12 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10023574B2 (en) 2002-08-21 2018-07-17 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8664232B2 (en) 2002-08-21 2014-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
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