WO2019053491A1 - Formes solides cristallines de benidipine hcl et leurs procédés de préparation - Google Patents

Formes solides cristallines de benidipine hcl et leurs procédés de préparation Download PDF

Info

Publication number
WO2019053491A1
WO2019053491A1 PCT/IB2017/055586 IB2017055586W WO2019053491A1 WO 2019053491 A1 WO2019053491 A1 WO 2019053491A1 IB 2017055586 W IB2017055586 W IB 2017055586W WO 2019053491 A1 WO2019053491 A1 WO 2019053491A1
Authority
WO
WIPO (PCT)
Prior art keywords
benidipine hydrochloride
crystalline
benidipine
depicted
water
Prior art date
Application number
PCT/IB2017/055586
Other languages
English (en)
Inventor
Esen Bellur Atici
Bekir Karliga
Original Assignee
Deva Holding Anonim Sirketi
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 Deva Holding Anonim Sirketi filed Critical Deva Holding Anonim Sirketi
Priority to PCT/IB2017/055586 priority Critical patent/WO2019053491A1/fr
Publication of WO2019053491A1 publication Critical patent/WO2019053491A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to novel, stable, crystalline monohydrate solid forms C, D, E, F, G, H and I of benidipine hydrochloride,
  • Benidipine is a racemic mixture of two isomers [(S)-(S)(+)] and [(R)-(R)-(-)].
  • Hydrochloride salt of benidipine exists as four enantiomers and two couples of
  • a-Benidipine HCI (RR, SS) and ⁇ -Benidipine HCI (RS, SR).
  • Benidipine hydrochloride is an odourless yellow crystalline powder. It is very soluble in formic acid, soluble in methanol, sparingly soluble in ethanol, and almost insoluble in water.
  • Benidipine hydrochloride is used as an antihypertensive drug similar to the structurally related compounds, nifedipine and nicardipine.
  • Benidipine hydrochloride is a dihydropyridine calcium channel blocker and inhibits L-, N- and T-type Ca +2 channels. It is the only calcium antagonist that can inhibit all the three Ca +2 channels mentioned above.
  • Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases.
  • benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina.
  • benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate
  • benidipine is a useful calcium channel blocker in combination therapy for hypertension.
  • Benidipine is marketed under the tradename of Coniel by Kyowa Hakko Kogyo as a hydrochloride salt of benidipine.
  • Coniel is licensed for use in Japan and selected Southeast Asian countries, where it is sold in tablet form with strengths of 2 mg, 4 mg and 8 mg, and generally prescribed in regimes of once or twice daily.
  • EP 63365 B (KYOWA HAKKO KOGYO KK) 15.06.1994 discloses firstly 1 , 4-dihydropyridine derivatives and pharmaceutical compositions containing the same.
  • EP 106275 B (KYOWA HAKKO KOGYO KK) 13.03.1991 describes the diasteomers of benidipine hydrochloride.
  • benidipine hydrochloride of which has melting points of 196 °C to 202 °C is referred as ( ⁇ )-a-form
  • benidipine hydrochloride of which has melting points of 236 °C to 242 °C is referred as ( ⁇ )-p-form.
  • Polymorphism is defined as the ability of a substance to exist as two or more crystalline forms that have different arrangements or conformations of molecules in the crystal lattice. These different crystalline forms are known as "polymorphs" and are realized only in the crystalline state. While polymorphic forms have the same chemical composition, they differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. As such, these modifications may have different solid-state physical properties such as shape, colour, density, hardness, deformability, stability, dissolution properties, and the like. Pharmaceutical solids can exist in different crystal forms, such as crystalline, amorphous and also in solvated or hydrated states.
  • Solvates are crystalline solid adducts containing either stoichiometric or non-stoichiometric amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates. Polymorphism of an organic drug molecule and its consequences would be appreciated by one skilled in the pharmaceutical art.
  • This invention relates to new C, D, E,F,G,H and I crystalline monohydrate polymorphic of benidipine hydrochloride and processes for preparation thereof and pharmaceutical compositions of benidipine hydrochloride.
  • solid state study of an active pharmaceutical ingredient aims to widen the variety of crystalline forms that a formulation scientist has available for designing a pharmaceutical finished product with desired performance characteristics.
  • the new polymorphs may possess some properties can have a direct impact on the processability of drug substances and the
  • solid state form of an active pharmaceutical ingredient may affect its stability as in finished product.
  • the relative humidity and/or temperature of the environment may cause polymorphic transformation of API. Thence, stable polymorphs which cannot easily convert into the other forms in case of acquirement or lost of water, are always preferred.
  • the invention is also directed to methods of preparing the stable crystalline monohydrate polymorphic forms of benidipine hydrochloride. Optimization of process conditions to prepare stable crystalline monohydrate polymorphs of benidipine hydrochloride has been attempted.
  • the method comprises basically forming a solution of the benidipine hydrochloride by heating the suspension of benidipine hydrochloride or heating the suspension optionally by adding a second solvent to complete dissolution, and then cooling the solution after distilling off second solvent or after dissolution to facilitate precipitation of the polymorph.
  • specific anti solvent such as water is used to precipitate the desired polymorph from the solution.
  • Fig. 1 provides the X-ray diffractogram of crystalline C form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 2 provides the infrared spectrum (IR) of crystalline C form of
  • Fig. 3 provides the differential scanning calorimetry thermogram (DSC) crystalline C form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 4 provides the X-ray diffractogram of crystalline D form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 5 provides the infrared spectrum (IR) of crystalline D form of
  • Fig. 6 provides the differential scanning calorimetry thermogram (DSC) crystalline D form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 7 provides the X-ray diffractogram of crystalline E form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 8 provides the infrared spectrum (IR) of crystalline E form of
  • Fig. 9 provides the differential scanning calorimetry thermogram (DSC) crystalline E form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 10 provides the X-ray diffractogram of crystalline F form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 11 provides the infrared spectrum (IR) of crystalline F form of
  • Fig. 12 provides the differential scanning thermogram (DSC) crystalline F form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 13 provides the X-ray diffractogram of crystalline G form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 14 provides the infrared spectrum (IR) of crystalline G form of
  • Fig. 15 provides the differential scanning calorimetry thermogram (DSC) crystalline G form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 16 provides the X-ray diffractogram of crystalline H form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 17 provides the infrared spectrum (IR) of crystalline H form of
  • Fig. 18 provides the differential scanning calorimetry thermogram (DSC) crystalline H form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 19 provides the X-ray diffractogram of crystalline I form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 20 provides the infrared spectrum (IR) of crystalline I form of
  • Fig. 21 provides the differential scanning calorimetry thermogram (DSC) crystalline I form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.
  • Fig. 22 provides the X-ray diffractogram of crystalline C form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.
  • Fig. 23 provides the X-ray diffractogram of crystalline D form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.
  • Fig. 24 provides the X-ray diffractogram of crystalline E form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.
  • Fig. 25 provides the X-ray diffractogram of crystalline F form of benidipine hydrochloride monohydrate at accelerated storage conditions 40 °C, 75% relative humidity.
  • Fig. 26 provides the X-ray diffractogram of crystalline G form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.
  • Fig. 27 provides the X-ray diffractogram of crystalline H form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.
  • Fig. 28 provides the X-ray diffractogram of crystalline I form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.
  • Fig. 29 provides the Microscopic Images of crystalline C form of benidipine hydrochloride monohydrate.
  • Fig. 30 provides the Microscopic Images of crystalline D form of benidipine hydrochloride monohydrate.
  • Fig. 31 provides the Microscopic Images of crystalline E form of benidipine hydrochloride monohydrate.
  • Fig. 32 provides the Microscopic Images of crystalline F form of benidipine hydrochloride monohydrate.
  • Fig. 33 provides the Microscopic Images of crystalline G form of benidipine hydrochloride monohydrate.
  • Fig. 34 provides the Microscopic Images of crystalline H form of benidipine hydrochloride monohydrate.
  • Fig. 35 provides the Microscopic Images of crystalline I form of benidipine hydrochloride monohydrate.
  • the main objective of the present invention is to provide novel crystalline monohydrate forms of benidipine hydrochloride, which are described as C,
  • Another objective of the invention is to provide processes for the
  • step (c) Adding of a second solvent to the suspension in step (b) until complete dissolution.
  • step (d) Distilling off the second solvent added in step (c) from the solution.
  • step (e) After completion of the distillation, cooling the solution in step (d) to ambient temperature for crystallization.
  • step (f) Cooling down the mixture comprising benidipine hydrochloride crystals in step (e) to suitable temperature for further crystallization.
  • step (g) Stirring the cooled solution in step (f) for a suitable time to get better yield.
  • step (h) In case of no crystallization in step (g), a suitable amount of water is added into the mixture in step (g) and stirred for a suitable time for crystallization.
  • hydrochloride can be performed by any suitable method, including traditional solid-state techniques e.g., infra-red spectroscopy (IR), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD).
  • IR infra-red spectroscopy
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffraction
  • X-ray diffraction data are acquired using a Shimadzu X-ray diffractometer model 6100.
  • IR infrared
  • the infrared spectrum of form as neat has the characteristic absorptions at the following wavelengths in cm -1 .
  • DSC Differential scanning calorimetry
  • Shimadzu model DSC 60 Samples are analyzed inside crimped 40 ⁇ _ aluminium pans. The temperature range is 100 - 220 °C. Heating rate for all samples is 10 °C/min.
  • Karl Fischer titration is a classic titration method in analytical chemistry that uses coulometric or volumetric titration to determine trace amounts of water in a sample.
  • Karl Fischer Titration (KFT) method is used to determine the presence and amount of water of monohydrate forms, respectively novel crystalline monohydrate forms C, D, E, F, G, H and I of benidipine hydrochloride.
  • KFT method is used to follow the water content or moisture uptake potential of anhydrate forms of benidipine hydrochloride.
  • One embodiment of the present invention encompasses crystalline
  • a DSC thermogram of C form is substantially in accordance with Fig. 3, [0093] v) a DSC thermogram shown in Fig. 3, points with melting point: 183 °C for polymorph C of benidipine hydrochloride.
  • a second embodiment of the present invention encompasses crystalline monohydrate E form characterized by a data selected from a group consisting of:
  • step (b) If the suspension dissolves in step (b), second solvent is not added at this step.
  • step (d) Cooling down the mixture comprising benidipine hydrochloride crystals in step (c) to suitable temperature for crystallization.
  • step (e) Stirring the cooled solution in step (d) for a suitable time to get better yield.
  • step (f) In case of no crystallization in step (e), a suitable amount of water is added into the mixture in step (e) and stirred for a suitable time for crystallization.
  • Another embodiment the present invention encompasses crystalline
  • a IR spectrum of F form is substantially in accordance with Fig. 1 1
  • a DSC thermogram of F form is substantially in accordance with Fig.
  • One embodiment the present invention encompasses crystalline
  • monohydrate G form characterized by a data selected from a group consisting of: [0116] i) a X-ray powder diffraction pattern of G form as depicted in Fig. 13.
  • a IR spectrum of G form is substantially in accordance with Fig. 14, [0119] iv) a DSC thermogram of G form substantially in accordance with Fig. 15, [0120] v) a DSC thermogram shown in Fig. 15 points with melting point: 183 °C for G form of benidipine hydrochloride.
  • Another embodiment the present invention encompasses crystalline
  • iii)a IR spectrum of H form is substantially in accordance with Fig. 17, [0125] iv) a DSC thermogram of H form is substantially in accordance with Fig.
  • Another embodiment the present invention encompasses crystalline
  • a DSC thermogram of I form is substantially in accordance with Fig. 21 , [0132] v) a DSC thermogram shown in Fig. 21 , points with melting point: 179 °C for I form of benidipine hydrochloride. [0133] In a third aspect of the present invention, Form D of benidipine
  • hydrochloride is obtained by a process which is different from process A and B.
  • Process to prepare form D defined as process C, comprises following steps:
  • step (b) Heating the suspension in step (a) up to a suitable temperature and stirring for a suitable time.
  • step (c) Cooling down the suspension of benidipine hydrochloride in step (b) to ambient temperature.
  • step (d) Further stirring the cooled suspension in step (c) for 1 to 4 hours.
  • Another embodiment the present invention encompasses crystalline
  • Benidipine hydrochloride in step (a) is anhydrate polymorph form of
  • suitable solvent in step (a) is water or 1-butanol.
  • suitable solvent in step (a) is selected from the group of consisting of methyl ethyl ketone, water, acetic acid or methyl ethyl ketone/water mixture.
  • Preparation of monohydrate forms of benidipine hydrochloride comprises a conversion reaction from anhydrate form of benidipine hydrochloride to monohydrate forms.
  • Disruption of the crystalline structure of anhydrate benidipine hydrochloride encompasses a range of dissolution processes from complete dissolution to only slight dissolution. Degree of dissolution can be modified by selection of the appropriate solvent and/or by selection of process temperature within the specified allowable temperature ranges.
  • Second solvent which is added in step (c) to dissolve benidipine
  • hydrochloride is:
  • -aliphatic alcohol preferably, methanol or ethanol, for process A.
  • -ketone such as, methyl ethyl ketone or acetone, for process B.
  • Suitable temperature in step (b) ranges from 80 to 100 °C, for process A, B and C.
  • Cooling temperature range in step (f) for process A and in step (d) for process B changes from 0 to -5 °C and the time for crystallization ends up changes from 1 to 7 hours, preferably 3 hours, and most preferably 2 hours, for both of process A and B.
  • Suitable time for stirring in step (f) for process A, step (e) for process B and step (b) for process C changes from 30 minutes to 5 hours.
  • Suitable time for drying in step (j) for process A, step (h) for process B and step (f) for process C changes from 1 to 12 hours.
  • the present invention also provides optimized processes A and B for preparation of highly purified crystalline monohydrate forms of benidipine hydrochloride, namely C, D, E, F, G, H and I forms.
  • the crystalline monohydrate forms of benidipine hydrochloride are obtained with a purity of over 99.9%. Also, the said process avoids multiple recrystallization cycles which are not only cause loss off the compound by recrystallization but also need a great amount of solvent which is not favourable in environmental aspect.
  • Another aspect of the invention relates to the preparation of stable
  • Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g, identity, purity, strength etc. until drug expiry.
  • Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the API.
  • the changes in solid state form of the API may be result from the conditions of product manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and compressing. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of API.
  • a solvent e.g., wet granulation, polymorphs in solution, and polymorphs in suspension
  • crystalline stability of API has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of API should be used in pharmaceutical formulations.
  • the crystalline stability referred to here is the stability of a polymorphic form of API with respect to polymorph transformations, hydration or dehydration, salt disproportionation, crystallization, or amorphization through time under the conditions 25 °C, 60% RH and 40 °C, 75% RH for 6 months after preparation.
  • X-Ray diffractograms of presented monohydrate forms under the conditions at 40 °C, 75% RH are given in Fig 22, Fig 23, Fig 24, Fig 25, Fig 26, Fig 27 and Fig 28, X-Ray diffractograms (Fig 22 to Fig 28) clearly show that 2-theta and intensity values of characteristic peaks did not changed when exposed to accelerated stability conditions in described monohydrate forms.
  • samples of obtained crystalline monohydrate forms are stored for 6 months in stability chambers under following conditions of 25°C 60% RH and 40°C 75% RH to test stability of novel crystalline monohydrate forms of benidipine hydrochloride.
  • moisture-powder interaction is a major factor in formulation, processing, and performance of solid dosage forms.
  • the amount of moisture adsorbed by drugs and excipients affects the flow of the powder, compression characteristics, and hardness of granules and tablets. Differences in powder flow can affect content uniformity in solid processing either in the mixing process or during transfer to other processing equipment such as tablet process.
  • anhydrate form of benidipine hydrochloride are shown in Table 2. Samples of anhydrate form of benidipine hydrochloride are stored in flasks those open to air at the conditions 25 °C 60% RH and 40 °C 75% RH for determination of the moisture uptake potential of anhydrate form of benidipine hydrochloride. According to Table 2, moisture amount of anhydrate form samples of benidipine hydrochloride is changed from 0.31 % to 1.02% at long term stability conditions, 25 °C 60% RH and to 1.10% at accelerated stability conditions, 40 °C 75% RH after 42 days. According to Japan Pharmacopoeia, moisture amount of anhydrate form of benidipine hydrochloride should be less than 0.5%.
  • Yet another objective of the present invention is to provide pharmaceutical compositions containing the novel benidipine hydrochloride monohydrate polymorphs C, D, E, F, G, H and I.
  • polymorphic forms of benidipine hydrochloride may include fillers, binders, disintegrants, glidants, lubricants, flavourings.
  • Fillers fill out the size of a composition, making it practical to produce and convenient for the consumer to use.
  • Suitable filler/diluent includes, but are not limited, to calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (e.g.
  • methylcellulose polymers such as, e.g., Methocel A®, Methocel A4C®, Methocel A 15C®, Metocel A4M®), hydroxyethylcellulose, hydroxypropylcellulose,
  • L-hydroxypropylycellulose low substituted
  • HPMC hydroxypropyl methylcellulose
  • Methocel E®, F and K Metolose SH® of Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 15,000 and 100,000 cps grades of Methocel K®; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH®
  • sodium carboxymethylcellulose e.g. Methocel E®, F and K, Metolose SH® of Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 15,000 and 100,000 cps grades of Methocel K®; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH®
  • sodium carboxymethylcellulose e.g. Methocel E®, F and K, Metolose SH® of Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 1
  • carboxymethylene carboxymethylhydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, sucrose, sugar, xylitol, and erythritol.
  • starches or modified starches including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch
  • magnesium carbonate magnesium oxide
  • maltitol maltodextrins
  • maltose maltose
  • sorbitol sucrose
  • sugar xylitol
  • erythritol erythritol
  • a binder is used to impart cohesive qualities to the solid dosage form and thus ensure that a tablet remains intact after compression.
  • binders include, but not limited to, microcrystalline cellulose,
  • hydroxymethyl cellulose hydroxypropylcellulose
  • starch including corn starch and pregelatinized starch
  • sugars including sucrose, glucose, dextrose, lactose, and sorbitol
  • waxes polyethylene glycol
  • natural and synthetic gums e.g. acacia, tragacanth sodium alginate, celluloses, and Veegum
  • synthetic polymers such as
  • polymetacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxy ethyl cellulose, polyethylene oxide, mixtures thereof and the like.
  • a disintegrant is a substance which helps the composition break up once ingested. Disintegrants are, but not limited to, cross linked
  • polyvinylpyrolidone crospovidone, polyplyplasdone XL®, kollidon CL®
  • starches such as maize starch and dried sodium starch glycolate
  • gums such as alginic acid, sodium alginate, guar gum
  • croscarmellose sodium cellulose products
  • microcrystalline cellulose and its salts microfine cellulose, low-substituted hydroxypropylcellulose, mixtures thereof and the like.
  • Glidants improve the flowability of the composition.
  • the composition may also comprise a glidant.
  • Glidants are, but not limited to, colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, mixtures thereof and the like.
  • Lubricants prevent composition ingredients from clumping together and from sticking to the tablet punches or capsule filling machine and improve flowability of the composition mixture.
  • Lubricants are, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.
  • Flavourings are, but not limited to, cinnamon oil, essence of apple,
  • additives can be chosen and used by the artisan having regard to the particular desired properties of the solid dosage form.
  • hydrochloride respectively C, D, E, F, G, H and I can be administered alone or in combination with other pharmaceutically active compounds.
  • Suitable pharmaceutical compositions include, but are not limited to,
  • capsules Tablets, tablets, granules, powders and unit dose pockets.
  • Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (50 ml_) at room temperature and the suspension heated up to 95 - 100 °C. At this temperature, methanol (35 ml_) was added by 5 ml_ portions until complete dissolution. After complete dissolution, methanol was distilled off from the solution. After all methanol distilled off, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (50 ml_).
  • Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (50 ml_) at room temperature and the suspension heated up to 95 - 100 °C. At this temperature, ethanol (23 ml_) was added by small portions until complete dissolution. After complete dissolution, ethanol was distilled off from the solution. After all ethanol distilled off, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (50 mL).
  • Benidipine HCI (5.0 g, 9.2 mmol, anhydrate form) was suspended in water (50 mL) at room temperature and the suspension heated up to 95 - 100 °C. After stirring 30 min at this temperature, heating stopped and the mixture was allowed to cool to ambient temperature. The suspension was stirred further at room temperature for 2 - 3 h. Then, the product crystals were filtered and washed with water (70 - 80 mL). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI monohydrate (4.5 g, 90%; 99.93% purity by HPLC; 3.36% water content; 186 °C DSC peak) as a slightly yellowish powder.
  • Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (50 ml_) at room temperature and the suspension heated up to 90 - 100 °C. At this temperature, methyl ethyl ketone (16 ml_) was added by 2 ml_ portions until complete dissolution. After complete dissolution, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (25 ml_).
  • Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (20 mL) at room temperature and the suspension heated up to 90 - 100 °C. At this temperature, acetone (35 mL) was added by 5 mL portions until complete dissolution. After complete dissolution, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (25 mL).

Abstract

La présente invention concerne de nouvelles formes cristallines de monohydrate de Benidipine HCl, la forme C, forme D, forme E, forme F, forme G, forme H et la forme I, des compositions comprenant ces formes solides cristallines, et des procédés de préparation de ces formes solides cristallines.
PCT/IB2017/055586 2017-09-15 2017-09-15 Formes solides cristallines de benidipine hcl et leurs procédés de préparation WO2019053491A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2017/055586 WO2019053491A1 (fr) 2017-09-15 2017-09-15 Formes solides cristallines de benidipine hcl et leurs procédés de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2017/055586 WO2019053491A1 (fr) 2017-09-15 2017-09-15 Formes solides cristallines de benidipine hcl et leurs procédés de préparation

Publications (1)

Publication Number Publication Date
WO2019053491A1 true WO2019053491A1 (fr) 2019-03-21

Family

ID=59955599

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/055586 WO2019053491A1 (fr) 2017-09-15 2017-09-15 Formes solides cristallines de benidipine hcl et leurs procédés de préparation

Country Status (1)

Country Link
WO (1) WO2019053491A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0106275B1 (fr) 1982-10-15 1991-03-13 Kyowa Hakko Kogyo Co., Ltd. Dérivés de 1,4-dihydropyridine
EP0063365B2 (fr) 1981-04-17 1994-06-15 Kyowa Hakko Kogyo Co., Ltd. Dérivés de 1,4-dihydropyridine et les compositions pharmaceutiques les contenant
JP3763538B1 (ja) 2005-06-28 2006-04-05 ダイト株式会社 高純度塩酸ベニジピンの工業的製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0063365B2 (fr) 1981-04-17 1994-06-15 Kyowa Hakko Kogyo Co., Ltd. Dérivés de 1,4-dihydropyridine et les compositions pharmaceutiques les contenant
EP0106275B1 (fr) 1982-10-15 1991-03-13 Kyowa Hakko Kogyo Co., Ltd. Dérivés de 1,4-dihydropyridine
JP3763538B1 (ja) 2005-06-28 2006-04-05 ダイト株式会社 高純度塩酸ベニジピンの工業的製造方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1 January 2003 (2003-01-01), H.SHOUICHI ET AL.: "Characterization of monohydrate form of benidipine hydrochloride and comparison of dissolution behaviors of its anhydrate and monohydrate form", XP002778197, Database accession no. 2003:863323 *
H. SHOUICHI ET AL.: "Characterzation of monohydrate form of benidipine hydrochloride and omparison of dissolution behaviors of its anhydrate and monohydrate form", YAKUZAIGAKU, vol. 63, no. 3, 1 January 2003 (2003-01-01), pages 158 - 164 *
SHOICHI ET AL.: "Characterization of Monohydrate Form of Benidipine Hydrochloride and Comparison of Dissolution Behaviours of Its Anhydrate and Monohyrate Form", JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, 2003

Similar Documents

Publication Publication Date Title
US9309201B2 (en) Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV
EP1615645B2 (fr) Forme cristalline iii de chlorhydrate de moxifloxacine anhydre et procede de preparation de cette derniere
US9856270B2 (en) Dolutegravir salts
JP6185490B2 (ja) ３−（４−ニトロ−１−オキソイソインドリン−２−イル）ピペリジン−２，６−ジオンの固体形態
US11518753B2 (en) Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione dihydrate, compositions and methods of use thereof
US10919873B2 (en) Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione monohydrate, compositions and methods of use thereof
US20170226119A1 (en) Solid salt form of alpha-6-mpeg6-o-hydroxycodone as opioid agonists and uses thereof
TWI385148B (zh) 右旋酮洛芬氨丁三醇之多晶型物，其製法及含有其之組成物
US10487069B2 (en) Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione hemihydrate, compositions and methods of use thereof
WO2019053491A1 (fr) Formes solides cristallines de benidipine hcl et leurs procédés de préparation
US20200283381A1 (en) Solid state forms of elafibranor
EP3587421A1 (fr) Formes cristallines de (s)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo [1,5-alpha]pyrazin-1-yl-n-(pyridin-2-yl)benzamide
EP2945948B1 (fr) Forme cristalline ii de chlorhydrate d'anagrélide monohydraté
KR101423630B1 (ko) 비칼루타미드와 니코틴아미드의 공결정
EP2604596A1 (fr) Polymorphes d'imatinib
EP2064206A2 (fr) Formes cristallines d'hydrochlorure de tiagabine et procèdès pour la préparation d'hydrochlorure de tiagabine amorphe
WO2006009549A1 (fr) Nouvelles formes cristallines de compositions de matière comprenant les éléments gallium, azote et oxygène
WO2023283080A1 (fr) Formes à l'état solide de 4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxyméthyl]-n-méthylpyridine-2-carboxamide et leur sel
WO2018162394A1 (fr) Formes cristallines du chlorhydrate de vinpocétine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17772118

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17772118

Country of ref document: EP

Kind code of ref document: A1