WO2006109318A1 - Nouvelle forme polymorphique de la 3-hydroxy-3-(3’-sulfamyl-4’-chlorophényl)phtalimidine - Google Patents

Nouvelle forme polymorphique de la 3-hydroxy-3-(3’-sulfamyl-4’-chlorophényl)phtalimidine Download PDF

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Publication number
WO2006109318A1
WO2006109318A1 PCT/IN2005/000109 IN2005000109W WO2006109318A1 WO 2006109318 A1 WO2006109318 A1 WO 2006109318A1 IN 2005000109 W IN2005000109 W IN 2005000109W WO 2006109318 A1 WO2006109318 A1 WO 2006109318A1
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chlorthalidone
crystalline form
acid
crystalline
alkali
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PCT/IN2005/000109
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English (en)
Inventor
Ashok Kumar
Ashvini Saxena
Dharmendra Singh
Vijay Dhurandhare
Darpan Navinchandra Pandya
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Ipca Laboratories Limited
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Priority to PCT/IN2005/000109 priority Critical patent/WO2006109318A1/fr
Publication of WO2006109318A1 publication Critical patent/WO2006109318A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • This invention relates to a novel crystalline form of 3-hydroxy-3-(3'-sulfamyl-4'- chlorophenyl) phthalimidine designated as Form II, its solvates thereof, and processes for their preparation. More particularly, the invention relates to the preparation of this polymorph called Form II and to the isolation of this compound in this novel crystalline form, as well as to pharmaceutical compositions containing the new polymorph and its use in medicine.
  • the present invention further relates to novel processes for preparing Form I of chlorthalidone and its characterization.
  • the present invention also relates to processes for obtaining Form I chlorthalidone from the new polymorph, Form II.
  • Chlorthalidone is a member of the class of agents termed Diuretics.
  • Diuretics are effective antihypertensive drugs and in long-term trials, diuretics have been shown to reduce the incidence of stroke, congestive heart failure, coronary artery disease and total mortality from cardiovascular disease. Because diuretics blunt the sodium- and water- retaining effects of many other anti-hypertensive drugs, they are the most commonly used medication in combination with antihypertensive agents. Diuretics are not chosen as the first drug, but they are usually indicated as a second-step agent because their addition will enhance the effects of other agents.
  • beta blockers blunt the increase in the plasma renin level that is induced by diuretics, and diuretics decrease the sodium and water retention that is caused by beta blockers.
  • the combination of a beta blocker and a diuretic produces additive effects compared with monotherapy using either agent alone. At the same time, it is recognized that monotherapy will not provide adequate blood pressure control in a large proportion of patients, and that many patients will experience unacceptable side effects with higher dosages of a single agent. Fixed-dose combination anti-hypertensive medications are a useful and appropriate treatment option in this large group of patients. Therefore, chlothalidone is mainly used in combination anti-hypertensive pharmaceutical compositions.
  • the present invention relates to the solid state physical properties of chlorthalidone. These properties can be influenced by controlling the conditions under which chlorthalidone is obtained in solid form.
  • Solid state physical properties include, for example, the flowability/fluidity of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product/composition. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
  • Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous/lipid fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state properties of a compound may also affect its behavior on compaction and its storage stability.
  • the physical characteristics of a compound are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to different thermal behavior from that of the amorphous material or another polymorphic form.
  • Thermal properties of a pharmaceutical compound is measured in the laboratory by using techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetric (DSC) and can be used as a basic tool to distinguish some polymorphic forms from others.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetric
  • a particular polymorphic form will give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13 C NMR spectroscopy and infrared spectrophotometry.
  • a crystalline form of a substance has well-defined crystal lattices and distinct spectral characteristics when subjected to X-Ray crystallography; however, an amorphous form will-exhibit a "smearing" of some of those properties due to the lack of a specific crystal order.
  • An amorphous substance will produce a near featureless Powder X-Ray Diffraction (PXRD) pattern although the diffraction pattern of a crystalline form of the same substance may have many well-resolved reflections.
  • PXRD Powder X-Ray Diffraction
  • molecular interactions caused by tight crystal packing make a substance more thermally stable and less soluble than the substance in an amorphous state.
  • thermal stability is a desirable characteristic of a pharmaceutical compound, it is often the case that increased, rather than decreased, solubility is desired.
  • the rate of dissolution of an active ingredient in a patient's gastric fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.
  • Increased solubility of a pharmaceutical agent in aqueous fluids therefore, can increase bioavailability.
  • the effect that the solid-state has on bioavailability may be so significant that a crystalline form of a drug cannot be considered bioequivalent to the amorphous form.
  • the synthesis of chlorthalidone was reported in patent (US patent no.
  • Example 1 of '904 patent says chlorthalidone was obtained by crystallization from aqueous ethanol/ alcoholic solvents that has a melting point of 215 0 C with decomposition. An exact reproduction of the crystallization from ethanol/aqueous ethanol yielded a crystalline form as substantially shown in the PXRD pattern figure 2.
  • EP 51215, EP51217 relates to new process for preparation of chlorthalidone, in which chlorthalidone was obtained by:
  • chlorthalidone shows a melting range of 215 to 264 depending upon the process of preparation, however, the PXRD pattern appears to be the same.
  • chlorthalidone can exist in different polymorphic crystalline forms which differ from each other by their stability, their physical properties, their spectral characteristics and the process for their preparation. This becomes the subject of the present invention
  • chlorthalidone is precipitated from an aqueous system by an acid- base treatment, a new, very stable crystalline form having a well-defined crystal structure is obtained. More particularly, it has been found that the novel crystalline form of chlorthalidone Form II, is at least as stable as the Form I obtained from prior processes and that it does not convert spontaneously into the previously known Form I.
  • the present invention relates to a new crystalline form of chlorthalidone which is hereinafter designated as Form II and its solvates thereof. More particularly, the present invention relates to a novel crystalline form of chlorthaidone denoted as Form II as characterized by a powder X-ray diffraction pattern with peaks at about 7.33, 14.36, 14.73, 16.22, 16.66, 17.09, 19.27, 22.33, 24.80, 27.27 and 28.99 degrees 2 theta angles.
  • the 'Form IF is also characterized by a Differential Scanning Calorimeter (DSC) thermogram having a melting point at 218.to 219 0 C temperature.
  • DSC Differential Scanning Calorimeter
  • the chlorthalidone 'Form II' of the present invention has a crystal content of at least 20 %, preferably 40% and more preferably 50 % or more having characteristic peak at about 7.33, 14.36, 14.73, 16.22, 16.66, 17.09, 19.27, 22.33, 24.80, 27.27 and 28.99 degrees 2 theta angles in a PXRD diagram.
  • the new crystalline polymorph of Chlorthalidone Form II is further characterized by Fourrier Infra-Red Spectrophotometry which shows characteristic absorptions at 3410, 3323, 3243, 3108, 2670, 1824, 1703, 1683, 1314, 1161, and 1059 cm '1 which are absent from Form I.
  • the present invention relates to a process for preparing chlorthalidone in crystalline 'Form IF including the steps of treating chlorthalidone in water with an alkali, preferably alkali metal carbonates or hydroxides; providing a solution of the chlorthalidone in the aqueous alkali at a temperature of about 5 to 5O 0 C; optionally treating with an adsorbant and filtering to remove the adsorbant; adding an acid to the chlorthalidone alkali solution & adjusting the pH between 3.5 to 5.0 whereby a suspension is formed; and cooling the suspension/solution to isolate chlorthalidone 'Form IF by filtration.
  • an alkali preferably alkali metal carbonates or hydroxides
  • the present invention also relates to characterization of chlorthalidone obtained in prior processes by powder X-ray diffraction analysis and other means like FTIR & DSC.
  • the crystalline form obtained in prior processes is herein denoted as 'Form F.
  • the 'Form F polymorph of chlorthalidone is characterized by a powder X-ray diffraction pattern with peaks at about 6.24, 12.13, 13.23, 17.61, 21.72, 23.93, 26.67 and 30.68 degrees 2 theta values.
  • Another characterization of 'Form F is differential scanning calorimetric thermogram having an endotherm at about 221 to 227 0 C.
  • the standard crystalline polymorph of Chlorthalidone i.e., 'Form F is further characterized by Fourier Infra Red spectophotometry and the IR spectra shows characteristic absorptions at 3357, 3254, 3088, 2788, 1829, 1689, 1348, 1171, 1041 and 597 cm "1 which are absent in new crystalline Form II.
  • the present invention further relates to processes for converting chlorthalidone having at least one characteristic of 'Form IF into the standard 'Form F Furthermore, the present invention relates to 'Form F prepared starting from 'Form IF characterized at least one of the PXRD peaks of 'Form F or 'Form IF
  • the present invention relates to the use of chlorthalidone 'Form IF and its solvates thereof for producing an anti-hypertensive/cardiovascular or diuretic effect in mammals, including human patients for treating hypertension either alone or in combination with other active agents.
  • Chlorthalidone 'Form IF and their solvates thereof can be formulated into a variety of compositions either alone or in combination with other agents, for administration to humans and mammals.
  • Pharmaceutical compositions of the present invention contain chlorthalidone and their solvates thereof, optionally as mixtures with crystalline 'Form F and/or other active ingredients such as antihypertensives or colochine.
  • the pharmaceutical compositions of the present invention may contain one or more commonly used pharmaceutical excipients. Excipients are added to the composition for a variety of purposes.
  • Figure 1 represents Powder X-Ray diffraction pattern (PXRD) of 'Form IF of chlorthalidone.
  • Figure 2 represents Powder X-Ray diffraction pattern (PXRD) of 'Form F of
  • Figure 3 represents Fourier transform Infra-Red Spectrograph of 'Form IF of
  • Figure 4 represents Fourier transform Infra-Red Spectrograph of 'Form F of
  • Figure 5 represents Differential Scanning Calorimeter thermogram of 'Form IF of
  • Figure 6 represents Differential Scanning Calorimeter record of 'Form F of
  • chlorthalidone 'Form I or Form IF where 'F and 'IF are Roman numerals/letters refers to a crystalline forms of Chlorthalidone that one of skill in the art can identify as a distinct entity distinguishable from other crystalline forms of chlorthalidone based on the characterization provided herein.
  • the phrase having "at least one characteristic of Form V, or 'Form II” refers to a crystalline form of Chlorthalidone that possesses one of the PXRD peaks or endotherms of a DSC thermogram provided herein.
  • a single or a combination of PXRD peaks which is not found in another crystalline form of chlorthalidone is enough to show at least one of the characteristics of Form 'IF.
  • a single or a combination of endotherms of a DSC thermogram may also serve the same purpose.
  • this invention provides characterization of chlorthalidone produced by crystallizing from ethanol, as well as ethyl acetate/toluene as taught by the '904 patent and EP51215/17 patent.
  • the crystalline form obtained from these processes is denoted as Chlorthalidone 'Form F.
  • the character of this crystalline form is confirmed by powder X-Ray Diffraction (PXRD) patterns and Differential Scanning Calorimeter (also referred as DSC) obtained from a sample thereof which are provided as figs. 2 and 6 respectively.
  • the PXRD pattern shows characteristic peaks at 6.24, 12.13, 13.23, 17.61, 21.72, 23.93, 26.67 and 30.68 degrees 2 theta values.
  • DSC shows a characteristic endotherm at about 221 to 227 0 C for Form I.
  • the differential enthalpy analysis (DSC) of the Forms 1 was carried out using a TA QlOO instrument using a standard open pan, calibrated by reference to indium.
  • DSC differential enthalpy analysis
  • 2.4 mg of Form I was used, as obtained in EXAMPLE 2, in a crimped and pierced aluminium cup in a temperature range from 30 to 250degree C with a rate of heating of 5 deg. C./minute.
  • the 'Form F was also characterized by infrared spectroscopy.
  • the Fourier transform (FT) IR spectra were obtained with a Perkin Elmer Spectrum- 1 spectrometer with a resolution of 1 cm “1 from 4000 cm “1 to 400 cm “1 .
  • the samples of 'Form F were analyzed as neat as well as prepared in the form of 0.3% KBr disks .
  • the disks were subjected to a compression of 8 to 10 tons for 5 minutes. Each sample was examined after 20 accumulated scans.
  • the FTIR Spectra shows characteristic absorptions at 3357, 3254, 3088, 2788, 1829, 1689, 1348, 1171, 1041 and 597 cm "1 as shown in Figure 4.
  • PXRD pattern was measured on a SIEMAN D500 40KV/30mA powder X-Ray Diffractometer with a solid state detector. Copper radiation of 1.5406 A 0 wavelength was used.
  • the crystalline 'Form F of chlorthalidone has X-ray powder diffraction pattern as substantially as shown in the Figure 2 and the characteristic peaks with their 2 theta value and corresponding d spacing and relative intensity in percentage are listed in the table given below.
  • this invention provides a novel Chlorthalidone in a specific & distinguishable crystalline form that is denoted as 'chlorthalidone Form II".
  • the character of this new form is confirmed by PXRD patterns and DSC obtained from a sample thereof which are provided in figs. 1 and 5 respectively.
  • the PXRD pattern shows at least one characteristic peak at about 14.36, 16.24 and 16.66 degrees2 theta. More particularly the PXRD pattern has characteristic peaks at 7.33, 14.36, 14.73, 16.22, 16.66, 17.09, 19.27, 22.33, 24.80, 27.27 and 28.99 degrees 2 theta angles.
  • the DSC thermogram of 'Form IF shows a characteristic endothermic peak at about 218 - 219 0 C.
  • the comparative differential enthalpy analysis (DSC) of the Forms II with 'Form F was carried out using a TA QlOO instrument using a standard open pan, calibrated by reference to indium.
  • DSC differential enthalpy analysis
  • 2.8 mg of 'Form IF was used, as obtained in example 1, in a crimped and pierced aluminum cup in a temperature range from 30 to 250 degree C with a rate of heating of 5deg. C./minute.
  • the DSC thermogram of 'Form IF shows characteristic endotherm at 218 to 219 0 C ( Figure 5)
  • the 'Form F shows endotherm at about 223 to 224 0 C (figure 6).
  • the 'Form IF was also characterized by infrared spectroscopy.
  • the Fourier transform (FT) IR spectra were obtained with a Perkin Elmer Spectrum- 1 spectrometer with a resolution of 1 cm “1 from 4000 cm “1 to 400 cm “1 .
  • the samples of 'Form IF were analyzed as neat as well as prepared in the form of 0.3% KBr disks. The disks were subjected to a compression of 8 to 10 tons for 5 minutes. Each sample was examined after 20 accumulated scans.
  • the FTIR Spectra of the new 'Form IF shows characteristic absorptions at 3410, 3323, 3243, 3108, 2670, 1824, 1703, 1683, 1314, 1161, and 1059 cm "1 which are absent from Form I as shown in Figure 3.
  • the PXRD pattern of the new form of chlorthalidone i.e., 'Form IF was measured on a SIEMAN D500 40KV/30mA powder X-Ray Diffractometer with solid state detector. Copper radiation of 1.5406 A 0 wavelength was used.
  • the crystalline 'Form IF of chlorthalidone has X-ray powder diffraction pattern as substantially as shown in the Figure 1 and the characteristic peaks that are absent in 'Form F with their 2 theta value and corresponding d spacing with relative intensity in percentage are listed in the table given below. The allowed variation is + 0.2 theta angels.
  • the present invention provides a process for preparing chlorthalidone and its solvates in a crystalline form that denoted as 'Form IF having at least one characteristic PXRD peak listed in table 2.
  • the present process for preparing chlorthalidone in crystalline 'Form IF includes the steps of treating chlorthalidone in water medium with an alkali; effecting dissolution of the chlorthalidone in the aqueous alkali solution; adding an acid to the chlorthalidone alkali solution whereby a suspension is formed; and cooling the suspension/solution to precipitate chlorthalidone 'Form IP that can be separated from the mixture by conventional means such as filtration and can be optionally dried at ambient or elevated temperatures.
  • the process may optionally include an adsorbant treatment of aqueous alkali solution and filtering to remove the adsorbant.
  • the chlorthalidone starting material can be dissolved in the aqueous alkali wherein heat may be used to effect dissolution.
  • the starting material is dissolved at 5 0 C to reflux temperature of the solvent.
  • the dissolution of starting chlorthalidone in aqueous alkali solution is preferably carried out at a temperature of about 10 to 50 0 C, and more preferably at about 25 to 40 0 C till a clear solution is obtained.
  • the solution is further treated with an adsorbent charcoal and is filtered to remove any undissolved particles and adsorbant.
  • the alkali used for dissolving the chlorthalidone is selected from inorganic bases particularly alkali metal carbonates or hydroxides. Particularly useful alkali metal carbonates are sodium and potassium carbonates.
  • the clear filtrate is then treated with an acid wherein the temperature of addition may be maintained at about 10 to 40 0 C temperature.
  • the pH is adjusted with the acid to pH around 3.5 to 5.0 to effect precipitation of 'Form IF crystals.
  • the acid used for precipitation of chlothalidone 'Form IF is selected from organic and inorganic acids such as acetic acid, hydrochloric acid, sulphuric acid, perchloric acid or phosphoric acid or the like.
  • the crystals are separated from the solvent by conventional means such as filtration, decantation, centrifugation or the like. The crystals may be washed with an appropriate solvent and dried by conventional techniques.
  • any crystalline 'Form F of chlorthalidone alone or its mixture with 'Form IF can be converted to crystalline pure 'Form IF by way of the present process described herein before.
  • the present invention provides process for preparing 'Form F from new crystalline form.
  • the new 'Form IF chlorthalidone is heated in water at about 90 degrees to reflux temperature, preferably at reflux for a period of 1 to 5 hours.
  • the new form changes its solid state properties to yield 'Form F chlorthalidone.
  • the 'Form IF chlorthalidone is converted to 'Form F chlorthalidone wherein the process comprises heating the starting 'Form IF chlorthalidone in 40 to 60 % aqueous acetic acid at a first temperature of about 80 to 110 0 C and cooling the solution to a second temperature of about 0 to 50 0 C to obtain 'Form F chlorthalidone.
  • the present invention provides yet another process for converting chlorthalidone 'Form IF into 'Form F that includes the step of dissolving 'Form IF chlorthalidone in aqueous alcoholic medium with an alkali and precipitating 'Form F chlorthalidone by addition of an acid.
  • the 'Form IF chlorthalidone is dissolved in aqueous alkali solution at a temperature of about 5 to reflux temperature, treating said solution with an adsorbent like charcoal; filtering to remove the insolubles; mixing the filtrate with a water miscible organic solvent; and precipitating 'Form F chlorthalidone by addition of acids at a pH of about 4 to 5.
  • the alkali used for dissolution of chlorthalidone is selected from alklai metal hydroxides or carbonates.
  • the acids suitable for precipitation of chlorthalidone are acetic acid, hydrochloric acid, phosphoric acid and sulfuric acid or the like.
  • the organic solvents used in the process is selected from Cl to C6 alcohols, acetonitrile, Cl to C5 ketone, N,N-dimthetyl formamide and dimethylacetamide or the like.
  • chlorthalidone 'Form IF and its solvates thereof are useful for treating patients with hypertension and for producing an anti I hypertensive/cardiovascular or diuretic effect in mammals, including human patients.
  • Chlorthalidone 'Form IF and its solvates thereof of the present invention can be formulated into a variety of compositions for administration to humans and mammals.
  • compositions of the present invention contain Chlorthalidone 'Form IF 5 optionally as mixture with other crystalline forms and/or other active ingredients such as antihypertensive drugs.
  • the pharmaceutical compositions of the present invention can contain one or more commonly used pharmaceutical excipients. Excipients are added to the composition for a variety of purposes.
  • Chlorthalidone 'Form IF can be administered for treatment of hypertension or diuretic effect by any means that delivers the active pharmaceutical ingredient (s) to the site of the body wherein the chlorthalidone or its combination with antihypertensive agents exerts a therapeutic effect on the patient.
  • administration can be oral, buccal, parenteral (including subcutaneous, intramuscular, and intravenous) rectal, inhalant and ophthalmic.
  • the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • Chlorthalidone 'Form IF can be conveniently administered to a patient in oral unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs.
  • the active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
  • Chlorthalidone 'Form IF can be milled into a powder and be used in a pharmaceutical product/composition or physically modified such as by granulation to produce larger granules.
  • Chlorthalidone 'Form IF can also be used to prepare a liquid pharmaceutical composition by dissolving or dispersing or suspending/emulsifying it in a pharmaceutically acceptable liquid medium such as water, glycerin, vegetable oil and the like as discussed in greater detail below.
  • compositions When a dosage form such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure from a punch and dye.
  • Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • Chlorthalidone 'Form IF and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • Example 3 Chlorthalidone 'Form F from Chlorthalidone 'Form IF
  • 100 gm chlorthalidone 'Form IF prepared as per method given Example 1 was suspended in 400 ml water at 25 to 30 0 C. The mixture was heated to reflux under stirring and maintained for 1 to 5 hours. The mixture was cooled to temperature of 15 to 20 0 C and filtered on a crucible and dried at 80 to 85 0 C for 10 hours. The solid obtained which weighs 97 gm (yield 97%) shows a PXRD pattern of 'Form F as in Fig. 2 and a DSC thermogram of Fig. 6. The HPLC purity of chlorthalidone was 99.9%

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention décrit une nouvelle forme cristalline de la Chlorthalidone appelée Forme II, ses solvates ; leurs procédés de synthèse ; l'isolement de cette nouvelle forme ; et son emploi dans des préparations pharmaceutiques. La présente invention décrit en outre les nouveaux procédés de synthèse de la Forme I ainsi que sa caractérisation.
PCT/IN2005/000109 2005-04-11 2005-04-11 Nouvelle forme polymorphique de la 3-hydroxy-3-(3’-sulfamyl-4’-chlorophényl)phtalimidine WO2006109318A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS236209B1 (cs) * 1983-07-01 1985-05-15 Jaroslav Koerner Způsob čištění 2-chlor-5-(l-hydroxy-3-oxo-l-isoindolinyl) benzensulfonamidu
CS268944B1 (cs) * 1987-05-05 1990-04-11 Vera Ing Bartlova Způsob izolace chlortalidonu a metipranololu vedle sebe z pevného odpadu

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS236209B1 (cs) * 1983-07-01 1985-05-15 Jaroslav Koerner Způsob čištění 2-chlor-5-(l-hydroxy-3-oxo-l-isoindolinyl) benzensulfonamidu
CS268944B1 (cs) * 1987-05-05 1990-04-11 Vera Ing Bartlova Způsob izolace chlortalidonu a metipranololu vedle sebe z pevného odpadu

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE CAS ONLINE ON STN [online] 11 April 1990 (1990-04-11), BARTLOVA ET AL.: "Method of chlorthalidone and metipranolol recovery from soid manufacturing waste", Database accession no. (1991:254007) *
DATABASE CAS ONLINE ON STN [online] 15 May 1985 (1985-05-15), KOERNER ET AL.: "Purification of 2-chloro-5-(1-hydroxy-3-axo-1-isoindolinyl) benzenesulfonamide pharmaceutical", Database accession no. (1989:497075) *
DATABASE CAS ONLINE ON STN [online] 1985, MACGREGOR ET AL.: "Chlorthalidone pharmacodynamics in beagle dogs", Database accession no. (1985;528945) *
JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 74, no. 8, pages 851 - 856 *
KOUNTOURELLIS ET AL.: "X-ray Characterization of 12 Diuretics", J. CHEM. ENG.DATA, vol. 37, 1992, pages 187 - 191 *

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