WO2005084674A1 - Forme amorphe de desloratadine et son procede de preparation - Google Patents

Forme amorphe de desloratadine et son procede de preparation Download PDF

Info

Publication number
WO2005084674A1
WO2005084674A1 PCT/US2005/006839 US2005006839W WO2005084674A1 WO 2005084674 A1 WO2005084674 A1 WO 2005084674A1 US 2005006839 W US2005006839 W US 2005006839W WO 2005084674 A1 WO2005084674 A1 WO 2005084674A1
Authority
WO
WIPO (PCT)
Prior art keywords
desloratadine
solid
composition
amorphous
crystalline
Prior art date
Application number
PCT/US2005/006839
Other languages
English (en)
Inventor
Sundaram Venkatraman
Gudipati Srinivasulu
Mayur Devjibhai Khunt
Madduri Srinivasa Reddy
Himesh Rameshehandra Majadia
Surya Narayana Devarkonda
Original Assignee
Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories, Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Publication of WO2005084674A1 publication Critical patent/WO2005084674A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • Desloratadine is an active metabolite of loratadine, which is orally active, long- acting histamine Hi receptor antagonist. It belongs to a second generation of Hi histamine receptor antagonists that are thought to offer advantages over the first generation compounds. The advantages are believed to include less sedation, low anticholinergic activity, and longer acting duration with the resulting improved patient compliance.
  • desloratadine and related compounds, and their uses see, e.g., U.S. Patent Nos. 6,506,767 and 4,659,716.
  • the invention relates to an amorphous form of desloratadine.
  • the invention also relates to a composition that includes desloratadine in a solid form, wherein at least 80 % by weight of the solid desloratadine is an amorphous form of desloratadine.
  • the invention also relates to a process for preparation of amorphous form of desloratadme.
  • the invention also relates to a pharmaceutical composition that contains an amo ⁇ hous form of desloratadine and one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition is a solid dosage form for oral administration.
  • DESCRIPTION OF THE ACCOMPANYING DRAWINGS Figure 1 is an X-ray powder diffractogram of an amorphous form of desloratadine.
  • a “compound” is a chemical substance that includes molecules of the same chemical structure.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
  • composition includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof.
  • composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • a “composition” may contain a single compound or a mixture of compounds.
  • composition is intended to encompass a product comprising the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • excipient means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent, carrier, and so on.
  • excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable excipient as used in the specification and claims includes both one and more than one such excipient.
  • isolated is used to indicate separation of the compound being isolated regardless of the purity of the isolated compound from any unwanted substance which presents with the compound as a mixture. Thus, degree of the purity of the isolated or separated compound does not affect the status of "isolating”.
  • substantially free of in reference to a composition, as used herein, means that said substance cannot be detected in the composition by methods known to those skilled in the art at the time of the filing of this application.
  • Desloratadine (8-chloro-6, ll-dihydro-11-4 (4- piperidinylidene)-5H- benzo [5,6] cyclohepta [1,2-b] pyridine
  • Amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random. Amorphous solids do not give a definitive x-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide rapid bioavailability.
  • amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in solid dosage form manufacture process such as compressibility, economically or environmentally suitable solvents or process, or higher purity or yield of the desired product.
  • desloratadine in an amorphous form An XRD spectrum of a sample of desloratadine obtained by the inventors is shown in Fig. 1. As seen therefrom, the XRD pattern is highly characteristic of an amorphous solid. The X-ray diffractogram was measured on Bruker Axe, DS Advance Powder X-ray Diffractometer with Cu K alpha- 1 Radiation source.
  • a particular process for preparation of the amorphous form of desloratadme includes: a) providing a solution of desloratidine in an organic solvent; and b) removing the solvent by spray drying or agitated thin film drying to obtain a solid residue which is the amorphous form of desloratidine.
  • the step of providing a solution of desloratadine may include dissolving any form of desloratadine in a suitable organic solvent or obtaining an existing solution from a previous processing step.
  • the preferred solvents are methanol, toluene, and cyclohexane.
  • the dissolution temperature may range from about 10 to about 45 °C; the preferred temperature is from about 20 to about 40 °C.
  • the concentration of solution of desloratadine before solvent removal may range from about 1% to about 20% by w/v, preferably from about 5% to about 12%, more preferably, from about 8% to about 11% by w/v.
  • Removal of the solvent is accomplished by using spray drying or agitated thin film evaporation.
  • One of the preferred methodologies involves vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled condition.
  • vertical agitated thin-film drying (or evaporation) ATFD-V
  • the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket.
  • the rotor rotation agitates the downside- flowing solution while the heating jacket heats it.
  • Another preferred method is spray-drying, in which a solution of desloratadine is sprayed into the spray drier at the flow rate ranging from 10 to 300 ml/hr, preferably flow rate is 40 to 210 ml/hr.
  • the air inlet temperature to the spray drier used may range from 70 °C to 150 °C, preferably from 85 °C to 110 °C and the outlet air temperature used may range from 30 °C to 80 °C.
  • the solid residue obtained after the solvent removal is isolated and, if desired, may be dried further using conventional methods.
  • the advantages of the process include simplicity, eco-friendliness and suitability for commercial use.
  • the amorphous form of desloratadine shown in Fig. 1 is produced by the described process.
  • the invention also relates to a composition of solid desloratadine wherein at least 80% of the total weight of desloratadine is in the amorphous form.
  • the solid desloratadine is suitable for use as a bulk active ingredient in formulating pharmaceutical products.
  • the remainder of the solid desloratadine in the composition i.e., 20% or less of the total weight of desloratadine, may be other forms of desloratadine, e.g., crystalline forms.
  • the composition may include at least 95% of the amorphous form of desloratadine with respect to total weight of the solid desloratadine in the composition.
  • the composition may include at least 99% of the amorphous form of i desloratadine with respect to total weight of the solid desloratadine in the composition.
  • the composition is substantially free of any forms of desloratadine other than its amorphous form.
  • a crystalline form of desloratadine is disclosed in U.S. Patent No. 4,659,716, which is incorporated by reference above.
  • Amorphous desloratadine may be differentiated from other solid forms of desloratadine by using X-ray powder diffraction (XPD).
  • XPD X-ray powder diffraction
  • amorphous desloratadine according to the present invention is characterized in providing an X-ray powder diffraction pattern containing one or more broad diffuse halos having very low counts in contrast to the sharp diffraction peaks characteristic of crystalline materials.
  • a mixture of detectable amounts of crystalline and amorphous desloratadine will exhibit both the characteristic sharp peaks and the diffuse halo(s) on XPD. This will be evident by an increase in the baseline and also a reduction in crystalline peak intensities.
  • X-ray diffraction also provides a convenient and practical means for quantitative determination of the relative amounts of crystalline and/or amorphous forms in a solid mixture.
  • X-ray diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture.
  • the percent composition of amorphous or crystalline forms of desloratadine in an unknown composition can be determined.
  • the measurements are made on solid powder desloratadme.
  • the X-ray powder diffraction patterns of an unknown composition can be compared to known quantitative standards containing pure crystalline forms of desloratadine to identify the percent ratio of a particular crystalline form.
  • the calibration curve may be created in a manner known to those of skill in the art. For example, five or more artificial mixtures of crystalline forms of desloratadine, at different amounts, maybe prepared, hi a non-limiting example, such mixtures may contain, 2%, 5%, 7%, 8%, and 10%) of desloratadine for each crystalline form.
  • X-ray diffraction patterns are obtained for each artificial mixture using standard X-ray diffraction techniques. Slight variations in peak positions, if any, may be accounted for by adjusting the location of the peak to be measured.
  • the intensities of the selected characteristic peak(s) for each of the artificial mixtures are then plotted against the known weight percentages of the crystalline form. The resulting plot is a calibration curve that allows determination of the amount of the crystalline forms of desloratadine in an unknown sample.
  • amorphous desloratadine For the unknown mixture of crystalline and amorphous forms of desloratadine, the intensities of the selected characteristic peak(s) in the mixture, relative to an intensity of this peak in a calibration mixture, may be used to determine the percentage of the given crystalline form in the composition, with the remainder determined to be the amorphous material.
  • amorphous desloratadine, or the presence of some amorphous desloratadine can be distinguished from crystalline desloratadine, using Raman spectroscopy, solution calorimetry, differential scanning calorimetry, solid state nuclear magnetic resonance spectra (ssNMR) or infra-red spectroscopy. Each of these techniques is well established in the art.
  • Amorphous desloratadine can also be identified based on the morphology of the particles seen under an electron microscope. Furthermore, amorphous desloratadine is likely to be much more soluble than crystalline desloratadine because the former is lack of lattice energy, providing another means of discriminating between the crystalline and amorphous desloratadine forms, or detecting an amount of amorphous form within a desloratadine preparation. As noted above, numerous techniques can be employed to detect a particular form of a compound within a mixture. The limits of detection of a particular form in admixture with another form, i.e.
  • crystalline in amorphous or vice versa are as follows: by XPD it is reported to be approximately 5% according to Hancock and Zografi (J. Pharm. Sci., 86:1- 12, 1997) and approximately 2.0% according to Surana and Suryanarayanan (Powder Diffraction, 15:2-6, 2000). The limit of detection by solution calorimetry is reported to be approximately 1% according Hogan and Buckton (International Journal of Pharmaceutics, 207:57-64, 2000). The limit of detection by solid state NMR is reported to be approximately 5-10% according to Saindonet al., (Pharmaceutical Research, 10:197-203, 1993).
  • the limit of detection by near infra red spectroscopy is reported to be approximately 2-5% according to Blanco and Villar (Analyst, 125:2311-2314, 2000).
  • the limit of detection by Modulated Differential Scanning Calorimetry (MDSC) is reported to be approximately 6% according to Saklatvala et al., (International Journal of Pharmaceutics, 192: 55-62, 1999).
  • the limit of detection by FTRaman spectroscopy is reported to be approximately 2% according to Taylor and Zografi (Pharm. Res. 15:755- 761, 1998). All of the above detection limits are general guidelines and apply to crystalline forms.
  • the amount of the amorphous form can be determined by determining the total amount of the sample and the percentage of the crystalline fraction.
  • the invention provides pharmaceutical compositions containing the amorphous form of desloratadine, which can be formulated with a one or more pharmaceutically acceptable carriers, also known as excipients, which ordinarily lack pharmaceutical activity, but have various useful properties which may, for example, enhance the stability, sterility, bioavailability, and ease of formulation of a pharmaceutical composition.
  • These carriers are pharmaceutically acceptable, meaning that they are not harmful to humans or animals when taken appropriately and are compatible with the other ingredients in a given formulation.
  • the carriers may be solid, semi-solid, or liquid, and may be formulated with the compound in bulk.
  • the resulting mixture may be manufactured in the form of a unit-dose formulation (i.e., a physically discrete unit containing a specific amount of active ingredient) such as a tablet or capsule.
  • a unit-dose formulation i.e., a physically discrete unit containing a specific amount of active ingredient
  • the pharmaceutical compositions of the invention may be prepared by uniformly admixing the active ingredient with liquid or solid carriers and then shaping the product into the desired form.
  • the pharmaceutical compositions may be in the form of suspensions, solutions, elixirs, aerosols, or solid dosage forms. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed.
  • a tablet may be prepared by direct compression, wet granulation, or molding, of the active ingredient(s) with a carrier and other excipients in a manner known to those skilled in the art.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets may be made on a suitable machine. A mixture of the powdered compound moistened with an inert liquid diluent is suitable in the case of oral solid dosage forms (e.g., powders, capsules, and tablets). If desired, tablets may be coated by standard techniques.
  • the compounds of this invention may be formulated into typical disintegrating tablets, or into controlled or extended release dosage forms. The amount of active ingredient included in a unit dosage form depends on the type of formulation that is formulated.
  • a pharmaceutical composition of the invention will generally include about 0.1 % by weight to about 99% by weight of active ingredient, preferably about 1% by weight to 50% by weight.
  • Suitable carriers include but are not limited to fillers, binders, lubricants, inert diluents, surface active/dispersing agents, flavorants, antioxidants, bulking and granulating agents, adsorbants, preservatives, emulsifiers, suspending and wetting agents, glidants, I disintegrants, buffers and pH-adjusting agents, and colorants.
  • carriers include celluloses, modified celluloses, cyclodextrins, starches, oils, polyols, sugar alcohols and sugars, and others.
  • Formulations for oral administration may optionally include enteric coatings known in the art to prevent degradation of the formulation in the stomach and provide release of the drug in the small intestine.
  • enteric coatings known in the art to prevent degradation of the formulation in the stomach and provide release of the drug in the small intestine.
  • pharmaceutical tablet of the amorphous desloratadine may include, as inactive ingredients, hypromellose 2910, i lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol
  • the filtered solution was spray-dried to remove the solvent under the following condition: flow rate 58-195 ml/hr, air inlet temperature between 90-100 °C and air outlet temperature between 40-46 °C, hot air flow rate 12.5-17.5 m 3 /hr and N 2 pressure for atomizer 1.8-2.0 kg/cm 2 to afford amorphous desloratadine.
  • EXAMPLE 2 15 grams of desloratadine were dissolved in 100 ml methanol under stirring at about 25-35 °C for 5-10 minutes. The resulting solution was filtered through hyflowbed. The filtered solution was spray-dried to remove the solvent under the following condition: flow rate 58-195 ml/hr, air inlet temperature about 105 °C and air outlet temperature about 70 °C, hot air flow rate 12.5-17.5 m /hr and N 2 pressure for atomizer 1.8-2.0 kg/cm to afford amorphous desloratadine.
  • Soluble granules containing an amorphous desloratadine may have the following content:
  • Dispersible tablet containing an amo ⁇ hous desloratadine may have the following content:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à une forme amorphe de desloratadine et des procédés de fabrication de forme amorphe ainsi qu'à des compositions, des compositions pharmaceutiques, et des procédés d'utilisation de forme cristallines.
PCT/US2005/006839 2004-03-03 2005-03-02 Forme amorphe de desloratadine et son procede de preparation WO2005084674A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN183CH2004 2004-03-03
IN183/CHE/2004 2004-03-03
US59180004P 2004-07-28 2004-07-28
US60/591,800 2004-07-28

Publications (1)

Publication Number Publication Date
WO2005084674A1 true WO2005084674A1 (fr) 2005-09-15

Family

ID=34921520

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/006839 WO2005084674A1 (fr) 2004-03-03 2005-03-02 Forme amorphe de desloratadine et son procede de preparation

Country Status (1)

Country Link
WO (1) WO2005084674A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1860105A1 (fr) * 2006-05-24 2007-11-28 Ranbaxy Laboratories Limited Procédé de préparation de desloratadine
WO2008138563A1 (fr) * 2007-05-11 2008-11-20 Ratiopharm Gmbh Composition pharmaceutique comprenant de la desloratadine
EP2727592A1 (fr) 2012-11-05 2014-05-07 Kücükgüzel, Sükriye Güniz Combinaison de desloratadine et de paracétamol

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6054463A (en) * 1997-02-11 2000-04-25 Sepracor Inc. Methods for treating dermatitis using descarboethoxyloratadine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6054463A (en) * 1997-02-11 2000-04-25 Sepracor Inc. Methods for treating dermatitis using descarboethoxyloratadine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GIORDANO F.: "Polymorphism in Pharmaceutical Solids.", 1999, MARCEL DEKKER INC., XP004234538 *
LIEBERMAN H.: "Pharmaceutical Dosage Forms.", 1990, MARCEL DEKKER INC. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1860105A1 (fr) * 2006-05-24 2007-11-28 Ranbaxy Laboratories Limited Procédé de préparation de desloratadine
WO2008138563A1 (fr) * 2007-05-11 2008-11-20 Ratiopharm Gmbh Composition pharmaceutique comprenant de la desloratadine
EP2727592A1 (fr) 2012-11-05 2014-05-07 Kücükgüzel, Sükriye Güniz Combinaison de desloratadine et de paracétamol

Similar Documents

Publication Publication Date Title
JP7174006B2 (ja) 抗癌性組成物
US20210308060A1 (en) Anticancer Compositions
KR102348325B1 (ko) 항암 조성물
EP2409975B1 (fr) Dispersion solide comprenant un corps amorphe composé d'un composé hétérocyclique anti-tumoral
US20080014280A1 (en) Amorphous pregabalin and process for the preparation thereof
JP2017505796A (ja) Ｎ−｛４−［（６，７−ジメトキシキノリン−４−イル）オキシ］フェニル｝−ｎ’−（４−フルオロフェニル）シクロプロパン−１，１−ジカルボキサミドの結晶性固体形態、製造プロセス、及び使用方法
JP6018041B2 (ja) Ｓｔ−２４６の多形型および調製方法
WO2009084023A2 (fr) Rameltéon amorphe et son procédé de préparation
KR102572035B1 (ko) 무정형 형태의 빌란테롤 트리페나테이트 및 이의 제조방법
US20060111417A1 (en) Amorphous telmisartan
WO2005084674A1 (fr) Forme amorphe de desloratadine et son procede de preparation
KR101962189B1 (ko) 아리피프라졸의 공결정 및 그의 제조방법
CA3099196A1 (fr) Sel d'addition de l'agoniste du recepteur s1p1, forme cristalline de celui-ci, et composition pharmaceutique
CN110003193B (zh) 一种制备易于粉碎的利伐沙班及其制备方法
CN114644642B (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
CN101601673B (zh) 用于固体制剂的索非那新或其盐的组合物
US20080014263A1 (en) Amorphous eprosartan mesylate and process for the preparation thereof
CN109963565A (zh) 一种药物组合物及其制备方法
US20040242658A1 (en) Amorphous form of rosiglitazone maleate and process for preparation thereof
US20040266787A1 (en) Novel amorphous form of [2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]ethoxy]acetic acid and process for the preparation thereof
WO2004062667A1 (fr) Forme amorphe du maleate de rosiglitazone et procede de preparation
CN106660965A (zh) 乐伐替尼的对甲苯磺酸盐、其结晶形式及制备方法
WO2014193866A1 (fr) Forme cristalline du n,n-dicyclopropyl-4-(1,5-diméthyl-1h-pyrazol-3-ylamino)-6-éthyl-1-méthyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide pour traiter les maladies myéloprolifératives
TW200902023A (en) Methods of separation and detection of bazedoxifene acetate in pharmaceutical compositions
Harish Formulation and evaluation of bosentan solid dispersion

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase