WO2016206660A1 - Formes solides de canagliflozine amorphe - Google Patents

Formes solides de canagliflozine amorphe Download PDF

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Publication number
WO2016206660A1
WO2016206660A1 PCT/CZ2016/000070 CZ2016000070W WO2016206660A1 WO 2016206660 A1 WO2016206660 A1 WO 2016206660A1 CZ 2016000070 W CZ2016000070 W CZ 2016000070W WO 2016206660 A1 WO2016206660 A1 WO 2016206660A1
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WO
WIPO (PCT)
Prior art keywords
solid solution
solution according
canagliflozin
pharmaceutically acceptable
acceptable excipient
Prior art date
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PCT/CZ2016/000070
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English (en)
Inventor
Iva OBADALOVA
Hana TOZICKOVA
Ondrej Dammer
Lukas KREJCIK
Jakub Hert
Original Assignee
Zentiva K.S.
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Publication date
Application filed by Zentiva K.S. filed Critical Zentiva K.S.
Publication of WO2016206660A1 publication Critical patent/WO2016206660A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the invention relates to novel solid forms of amorphous canagliflozin of formula I, having the chemical name (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]-methyl]-4- methylphenyl]-D-glucitol, their preparation methods and use in a dosage form.
  • These solid forms of amorphous canagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous canagliflozin.
  • Canagliflozin is a highly selective inhibitor of the common transporter of sodium and glucose of type 2 (SGLT2), responsible for renal reabsorption of glucose. Inhibition of SGLT-2 with the use of canagliflozin increases excretion of glucose by the kidneys, which leads to a decrease of glycaemia and an improvement of diabetes compensation virtually without any increase of the risk of hypoglycaemia. This is a unique action mechanism that is completely independent of the action of insulin.
  • canagliflozin is approved in the U.S. and in Europe for treatment of type 2 diabetes mellitus in monotherapy (in case of intolerance to metformin), or in combination with other antidiabetic drugs, including insulin.
  • canagliflozin Besides compensation of diabetes, administration of canagliflozin moderately reduces weight and the blood pressure. Thanks to its different action mechanism compared to other orally administered antidiabetic drugs and insulin canagliflozin may be a convenient choice in a combination treatment of diabetes.
  • Canagliflozin and its preparation is described in the patent application WO05012326.
  • the process described in this application provides amorphous canagliflozin.
  • the amorphous form of canagliflozin is characterized by chemical and polymorphic instability.
  • two forms of canagliflozin hemihydrate are known, which are described in the patent applications WO2008069327 and WO2009035969.
  • Canagliflozin hemihydrate described in the application WO2009035969 corresponds to the form that is present in the drug form Invokana .
  • cocrystals of canagliflozin are known, in particular with D- and L-proline, phenylalanine and citric acid, which are described in the patent applications WO2012154812 and WO 2013064909.
  • the amorphous form of canagliflozin is easy to obtain with the use of various preparation methods. However, at elevated temperatures and higher relative humidity it recrystallizes to the crystalline hemihydrate form, described in the patent application WO2009035969.
  • solid compositions solid dispersions, amorphous solid dispersions or solid solutions
  • polymers copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea, preferably especially with polymers, can be used.
  • the invention provides solid forms of amorphous canagliflozin with at least one pharmaceutically acceptable excipient, which may be selected from the group of polymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea.
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • HPMC AS hypromellose acetate succinate
  • PVP polyvinyl pyrrolidone
  • Eudragit LI 00, Eudragit SI 00 the copolymer polyvinyl capro lactam - polyvinyl acetate - polyethylene glycol
  • PVAc-PVCap- PEG the copolymer polyvinyl capro lactam - polyvinyl acetate - polyethylene glycol
  • SoluplusTM copovidone, D-saccharose.
  • These pharmaceutically acceptable excipients form solid solutions with canagliflozin that have a higher glass transition temperature than amorphous canagliflozin itself, which considerably supports its stability.
  • the prepared solid solutions then exhibit higher polymorphic and chemical stability at elevated temperatures and increased relative humidity.
  • a crystalline solid is characterized by a regular long-distance structure arrangement. On the other hand, amorphous solids do not exhibit this arrangement.
  • the molecular arrangement of an amorphous solid may be represented by "frozen liquid" with rheological properties of a solid.
  • amorphous solids have a different internal structure and a larger surface area, and therefore they exhibit a higher solubility.
  • solubility and bioavailability of pharmaceutically active substances needs to be increased, they should be preferably prepared in an amorphous form.
  • the glass transition temperature is advantageous for the glass transition temperature to be at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions.
  • a low glass transition temperature of an amorphous form there is a higher risk of transition to another form (e.g. crystalline), or increase of the contents of impurities, degradants.
  • the glass transition temperature of an amorphous form can be increased by formation of a solid composition with another, more stable substance. Then, the prepared composition generally exhibits higher polymorphic and chemical stability.
  • a solid composition consisting at least of two components, the active pharmaceutical ingredient (API) and another at least one chemical compound (matrix), can have several forms.
  • the matrix for API stabilization is considered to consist of one component only. In fact, this matrix may consist of one, two, or more components (chemical compounds).
  • pharmaceutically acceptable excipients i.e. for example compounds of the type of polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea, can be preferably used.
  • solid dispersion represents a solid composition of an active pharmaceutical ingredient (API) that is dispersed in a matrix, while this matrix manifests a crystalline character.
  • API active pharmaceutical ingredient
  • the matrix e.g. polymer
  • a solid dispersion is characterized by the glass transition temperature of the amorphous API and the melting point of the crystalline matrix.
  • a typical "amorphous solid dispersion” then represents a solid composition where the active pharmaceutical ingredient (API) and the matrix show an amorphous character, measured by XRPD. Measured by differential scanning calorimetry, this "amorphous solid dispersion” exhibits at least two glass transitions (Tg), one for the dispersed component (active pharmaceutical ingredient) and the other one for the matrix, the number of glass transitions of the matrix depending on the number of the components of the matrix.
  • Tg glass transitions
  • the solid solution form is more advantageous for stabilization and it is preferred to a dispersion.
  • the amorphous solid only exhibits one glass transition temperature (Tg) in the record, while in the case of an amorphous solid dispersion the DSC record exhibits two glass transitions, separately for the API and the excipient.
  • the glass transition temperature is at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions.
  • the glass transition temperature of amorphous canaglifiozin is 41°C and in its non-stabilized condition it is subject to crystallization during storage.
  • the amorphous form of canaglifiozin should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent said crystallization.
  • Tg glass transition temperature
  • the prepared solid composition of canaglifiozin is then more stable at elevated temperatures and at an increased relative humidity.
  • a possibility of stabilizing amorphous canaglifiozin consists in creating solid compositions with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea, preferably especially with polymers.
  • These polymers may come from the group of polymers that are soluble or insoluble in water.
  • Typical water-soluble polymers for stabilization of canaglifiozin include polyvinyl pyrrolidone (PVK 30 povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, the copolymer polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (PVAc-PVCap-PEG; SoluplusTM), and the like.
  • Typical water-insoluble polymers for stabilization of canagliflozin include methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethylcellulose etc.
  • HPMC AS hypromellose acetate succinate
  • cellulose acetate phthalate carboxymethylcellulose etc.
  • One of the preparation methods of stabilized amorphous forms of canagliflozin consists in the dissolution process.
  • the solvent may be water or any organic solvent.
  • suitable organic solvents methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, dichloromethane, tetrahydrofuran etc. may be mentioned.
  • a substance stabilizing the active pharmaceutical ingredient is added to this solution or suspension.
  • the solvent is quickly removed and amorphous solid matter is produced.
  • the solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrospinning, solvent freeze-drying, etc.
  • amorphous substances include solvent-free processes.
  • the active pharmaceutical ingredient canagliflozin
  • a stabilizing substance e.g. a polymer
  • This mixture is heated up and melted, producing a melt.
  • Common temperatures for the formation of a melt vary in the range of 20°C to 40°C above the Tg temperature, where the mixture is melted and has a suitable viscosity for its processing.
  • the melt is subsequently cooled down, which produces an amorphous solid.
  • hot melt extrusion, hot melt granulation, high shear mixer, solvent-free fluid bed granulation, etc. may be mentioned.
  • This invention is directed to the preparation of a pharmaceutical composition containing amorphous canagliflozin with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea, preferably especially with polymers.
  • the following polymers can be advantageously used for the preparation of polymer-stabilized amorphous solid forms of canagliflozin: polyvinyl pyrrolidone (PVP), copovidone (Kollidon VA64), hydroxypropyl celluloses ( lucel), hydroxypropyl methylcelluloses (Methocel), derivatized hydroxypropyl methylcelluloses (e.g.
  • HPMC AS HPMC AS
  • derivatives of polymethacrylate Eudragit LI 00, Eudragit SI 00
  • copolymer polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol PVAc-PVCap- PEG; SoluplusTM
  • polymers in this invention are polyvinyl pyrrolidone (PVP K30) with the molecular weight of approximately 50,000 Da (g mol), Methocel E5 (HPMC) with the molecular weight of approximately 22,000 Da (g/mol), Eudragit SI 00 with the molecular weight of approximately 125,000 Da (g/mol), copovidone (KoUidon VA64), hydroxypropyl cellulose (HPC, Klucel), SoluplusTM and hypromellose acetate succinate (HPMC AS-LF).
  • PVP K30 polyvinyl pyrrolidone
  • HPMC Methocel E5
  • Eudragit SI 00 with the molecular weight of approximately 125,000 Da (g/mol)
  • copovidone KoUidon VA64
  • HPC Klucel
  • SoluplusTM and hypromellose acetate succinate HPMC AS-LF.
  • glucose, saccharose, galactose or urea can be advantageously used.
  • canagliflozin For the preparation of the amorphous solid forms of canagliflozin (API), the method of removing the solvent by means of a rotary vacuum evaporator or lyophilization (freeze-drying of solvents) was used. With regard to relatively high dosage of canagliflozin, the weight ratio of canagliflozin to the excipient of 1 : 1 was preferentially selected.
  • Table 1 The products prepared this way are summarized in Table 1 together with the results of the DSC and X-ray powder analyses.
  • Amorphous canagliflozin stabilized in the form of a solid solution by Copovidone VA64 exhibits polymorphic stability under nearly all loading conditions. Only when loaded by 100% humidity for 10 days, its form changes from amorphous to crystalline. Samples that preserved their amorphous character were also checked for chemical purity and the results, which are summarized in Table 3, indicate a significant influence of humidity.
  • the solid solution of canagliflozin - Copovidone VA64 exhibits chemical stability under anhydrous conditions. Table 3:
  • Amorphous canagliflozin stabilized in the form of a solid solution by Povidone PVP K30 is the most stable one of all the tested samples from the chemical and polymorphic point of view. Partial crystallization of the amorphous API only occurs when loaded by 100% humidity for 10 days.
  • the solid solution of canaglifozin - Povidone PVP K30 is chemically stable under most conditions. All the samples that preserved their amorphous character were checked for chemical purity and a more significant increase of the content of impurities only occurred under extreme loading by the temperature of 80% and 75% relative humidity (see Table 4).
  • Amorphous canagliflozin can also be advantageously stabilized by means of saccharides, oligosaccharides, polysaccharides, fats, waxes or urea.
  • D-glucose, D-saccharose or urea were tested.
  • D-glucose and urea generally occur in their crystalline form; therefore, in combination with canagliflozin D-glucose and urea do not form typical solid solutions, but solid dispersions where the amorphous API (canagliflozin) is dispersed in a crystalline matrix (D-glucose or urea).
  • these solid dispersions exhibit the glass transition of the amorphous API (canagliflozin) and the melting point of D-glucose or urea.
  • a typical solid solution is formed showing one glass transition temperature in the DSC analysis record.
  • the DSC and X-ray powder analyses of the mixtures of canagliflozin with the saccharides and urea are summarized in Table 5.
  • Tg 53.0°C
  • T reC rys 100.2°C
  • Tg 30.3°C
  • Tm melting point of urea
  • the solid solution of canagliflozin - D-saccharose was also monitored by load tests. Partial conversion of the amorphous form of canagliflozin to a crystalline form was observed under the load of increased humidity. In case of anhydrous conditions (e.g. use of a desiccant or packing under nitrogen) this prepared solid solution of canagliflozin - D-saccharose is polymorphically stable even at elevated temperatures. Only the samples that preserved their amorphous character were tested for chemical purity; chemical purity only got worse in the case of the sample loaded by 80°C. The results of the tests are summarized in Table 6.
  • compositions from the group of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (HPMC AS), polyvinyl pyrrolidone (PVP), derivatives of polymethacrylate (Eudragit LI 00, Eudragit SI 00), the copolymer polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (PVAc-PVCap- PEG; SoluplusTM), copovidone, D-saccharose, with which a solid solution where the ingredients are mixed on the molecular level was successfully prepared, thus ensuring the best stabilization of the amorphous API, have proved to be especially suitable.
  • the solid solutions according to the invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets.
  • Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
  • These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
  • Fig. 1 DSC record of the solid solution of canagliflozin - HPC
  • Fig. 2 DSC record of the solid solution of canagliflozin - HPMC
  • Fig. 3 DSC record of the solid solution of canagliflozin - HPMC AS
  • Fig. 4 DSC record of the solid solution of canagliflozin - PVP K30
  • Fig. 5 DSC record of the solid solution of canagliflozin - Eudragit SI 00
  • Fig. 6 DSC record of the solid solution of canagliflozin - SoluplusTM
  • Fig. 7 DSC record of the solid dispersion of canagliflozin - PEG6000
  • Fig. 8 DSC record of the solid solution of canagliflozin - Copovidone VA64
  • Fig. 9 DSC record of the solid dispersion of canagliflozin - D-glucose
  • Fig. 10 DSC record of the solid solution of canagliflozin - D-saccharose
  • Fig. 11 DSC record of the solid dispersion of canagliflozin - urea
  • Fig. 12 XRPD pattern of the solid solution of canagliflozin - HPC
  • Fig. 13 XRPD pattern of the solid solution of canagliflozin - HPMC
  • Fig. 14 XRPD pattern of the solid solution of canagliflozin - HPMC AC
  • Fig. 15 XRPD pattern of the solid solution of canagliflozin - PVP K30
  • Fig. 16 XRPD pattern of the solid solution of canagliflozin - Eudragit SI 00
  • Fig. 17 XRPD pattern of the solid solution of canagliflozin - SoluplusTM
  • Fig. 18 XRPD pattern of the solid dispersion of canagliflozin - PEG6000
  • Fig. 19 XRPD pattern of the solid solution of canagliflozin - Copovidone VA64
  • Fig. 20 XRPD pattern of the solid solution of canagliflozin - D-glucose
  • Fig. 21 XRPD pattern of the solid solution of canagliflozin - D-saccharose
  • Fig. 22 XRPD pattern of the solid dispersion of canagliflozin - urea
  • Fig. 23 XRPD pattern of the solid dispersion of canagliflozin - D-glucose
  • Crystalline canagliflozin was prepared according to the procedure published in the patent application WO05012326. The chemical purity of canagliflozin prepared this way was 99.9% (HPLC).
  • the following ingredients were charged into a homogenizer: solid solution of canagliflozin - povidone PVP K30, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium crosscarmellose and water. The mixture was homogenized at 20 rpm for 15 min. Finally, magnesium stearate and Si0 2 was added and the mixture was homogenized at 20 rpm for another 3 min.
  • the tabletting matter produced in the above mentioned way was compressed in a rotary tabletting machine and used for the production of cores with the approximate weight of 255 mg.
  • the obtained cores may possibly be coated (a mixture of hypromellose, titanium oxide, iron oxide).
  • the measurement was carried out on a flat powder sample that was applied on a Si plate.
  • 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.

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Abstract

L'invention concerne de nouvelles formes solides de canagliflozine amorphe, ayant le nom chimique (1S)-1,5-anhydro-1-[3- [[5- (4-fluorophényl)-2-thiényl]-méthyl]-4-méthylphényl]-D-glucitol, leurs procédés de préparation et leur utilisation dans une forme posologique. Ces formes solides de canagliflozine amorphe peuvent être utilisées avantageusement pour augmenter la stabilité chimique et polymorphe de la canagliflozine amorphe.
PCT/CZ2016/000070 2015-06-25 2016-06-24 Formes solides de canagliflozine amorphe WO2016206660A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-435A CZ2015435A3 (cs) 2015-06-25 2015-06-25 Pevné formy amorfního canagliflozinu
CZPV2015-435 2015-06-25

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WO2016206660A1 true WO2016206660A1 (fr) 2016-12-29

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012326A1 (fr) 2003-08-01 2005-02-10 Tanabe Seiyaku Co., Ltd. Nouveaux composes possedant une activite inhibitrice dirigee contre le transporteur dependant du sodium
WO2008069327A1 (fr) 2006-12-04 2008-06-12 Mitsubishi Tanabe Pharma Corporation FORME CRISTALLINE DE 1- (β-D-GLUCOPYRANOSYL) -4 -MÉTHYLE- 3- [5- (4 -FLUOROPHÉNYL) -2-THIÉNYLMÉTHYLE] BENZÈNE HÉMIHYDRATE
WO2009035969A1 (fr) 2007-09-10 2009-03-19 Janssen Pharmaceutica N.V. Procédé pour la préparation de composés utiles en tant qu'inhibiteurs de sglt
WO2012154812A1 (fr) 2011-05-09 2012-11-15 Janssen Pharmaceutica Nv Co-cristaux de (2s,3r,4r,5s,6r)-2-(3-((5-(4-fluorophényl)thiophén-2-yl)méthyl)-4-méthylphényl)-6-(hydroxyméthyl)tétrahydro-2h-pyrane-3,4,5-triol avec de la l-proline et de l'acide citrique
WO2013064909A2 (fr) 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2
WO2014170026A1 (fr) * 2013-04-18 2014-10-23 Zentiva, K.S. Ticagrelor amorphe stabilisé
WO2014195966A2 (fr) * 2013-05-30 2014-12-11 Cadila Healthcare Limited Forme amorphe de canagliflozine et son procédé de préparation
WO2015011113A1 (fr) * 2013-07-22 2015-01-29 Sandoz Ag Formulations contenant de la dapagliflozine amorphe

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012326A1 (fr) 2003-08-01 2005-02-10 Tanabe Seiyaku Co., Ltd. Nouveaux composes possedant une activite inhibitrice dirigee contre le transporteur dependant du sodium
WO2008069327A1 (fr) 2006-12-04 2008-06-12 Mitsubishi Tanabe Pharma Corporation FORME CRISTALLINE DE 1- (β-D-GLUCOPYRANOSYL) -4 -MÉTHYLE- 3- [5- (4 -FLUOROPHÉNYL) -2-THIÉNYLMÉTHYLE] BENZÈNE HÉMIHYDRATE
WO2009035969A1 (fr) 2007-09-10 2009-03-19 Janssen Pharmaceutica N.V. Procédé pour la préparation de composés utiles en tant qu'inhibiteurs de sglt
WO2012154812A1 (fr) 2011-05-09 2012-11-15 Janssen Pharmaceutica Nv Co-cristaux de (2s,3r,4r,5s,6r)-2-(3-((5-(4-fluorophényl)thiophén-2-yl)méthyl)-4-méthylphényl)-6-(hydroxyméthyl)tétrahydro-2h-pyrane-3,4,5-triol avec de la l-proline et de l'acide citrique
WO2013064909A2 (fr) 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2
WO2014170026A1 (fr) * 2013-04-18 2014-10-23 Zentiva, K.S. Ticagrelor amorphe stabilisé
WO2014195966A2 (fr) * 2013-05-30 2014-12-11 Cadila Healthcare Limited Forme amorphe de canagliflozine et son procédé de préparation
WO2015011113A1 (fr) * 2013-07-22 2015-01-29 Sandoz Ag Formulations contenant de la dapagliflozine amorphe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REMINGTON: "The Science and Practice of Pharmacy", PHARMACEUTICAL PRESS

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