WO2012097764A1 - Metastable crystal forms of agomelatine - Google Patents

Metastable crystal forms of agomelatine Download PDF

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Publication number
WO2012097764A1
WO2012097764A1 PCT/CZ2012/000007 CZ2012000007W WO2012097764A1 WO 2012097764 A1 WO2012097764 A1 WO 2012097764A1 CZ 2012000007 W CZ2012000007 W CZ 2012000007W WO 2012097764 A1 WO2012097764 A1 WO 2012097764A1
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agomelatine
aliphatic
solvent
temperature
preparation
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PCT/CZ2012/000007
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English (en)
French (fr)
Inventor
Jindrich Richter
Ludek Ridvan
Jaroslav Rezac
Ondrej Dammer
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Zentiva, K.S.
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Publication of WO2012097764A1 publication Critical patent/WO2012097764A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • Metastable crystal forms of agomelatine Technical Field
  • the invention relates to metastable crystal forms of agomelatine, which can be used for obtaining polymorphously and chemically stable pharmaceutical compositions and for preparing pharmaceutical formulations containing said composition, and methods of their preparation.
  • Agomelatine is the first melatonergic antidepressant. It is an agonist of MT2 and MT] receptors and a 5-HT2 C antagonist.
  • agomelatine Several polymorphous forms of agomelatine are known.
  • Polymorph II has been described in the literature by means of a diffraction pattern obtained by the more usual X-ray powder diffraction method (XRPD), and is mentioned in, e.g., EP 1564202.
  • Polymorph III has been described in US 2006270876, polymorph IV in US 2006270875, polymorph V in US2006270877 and polymorph VI in US 2009069434.
  • thermodynamically less stable (metastable) polymorphs can, in case they can be successfully obtained in the pure form in a reproducible manner, under the conditions of use not undergoing change into other more stable forms, be more convenient for a certain technological application from the point of view of their properties than their most stable forms.
  • Diamond which is a thermodynamically less stable form of carbon than the much more readily available graphite, is probably the best known example.
  • metastable polymorph In the preparation of solid dosage forms a metastable polymorph may be more convenient than the thermodynamically stable form, e.g. in cases where the stable form exhibits lower solubility than required for the given use. Metastable forms usually offer higher solubility as well as dissolution speed, but at the same time it is much more difficult with them than with the thermodynamically stable form to meet the demanding requirements posed on all active ingredients for pharmaceutical use concerning their purity and stability.
  • the metastable polymorphous form often turns out to also be chemically less stable in stability tests, as compared to the most stable crystalline modification. Such behaviour is often observed especially in amorphous modifications.
  • agomelatine Nor has it been described for agomelatine whether, besides Form II, any other form can be obtained in a sufficiently stable form for pharmaceutical use.
  • the authors of the present invention have succeeded in solving the problem of obtaining a stable composition containing a metastable form of agomelatine by formulating this composition with the use of Form I obtained by a new method, or by using a new procedure of preparing an agomelatine composition producing new crystal forms of agomelatine.
  • the present invention consists in preparing solid metastable crystal forms of agomelatine, which can be used for obtaining a polymorphously stable solid pharmaceutical composition of agomelatine, comprising a metastable solid form of agomelatine, or comprising a mixture of more such metastable forms, and a pharmaceutical formulation containing said pharmaceutical composition. It is understood, under a polymorphously stable composition or dosage form, such a composition or dosage form, in which, during its shelf life, no change of its polymorphous composition, i.e. no transformation of agomelatine into other polymorphous forms than those that were present at the time of release of the drug for sale, nor any change of the quantitative representation of the individual solid forms, occurs.
  • the present invention further provides new crystal forms JRl , JR2, JR3 and JR4 of agomelatine and a method of preparing polymorphously stable metastable crystal forms of agomelatine, especially of crystal form I of agomelatine, characterized by typical reflections in the X-ray powder diffraction pattern presented in Table 1.
  • Table 1 Typical reflections of the X-ray powder diffraction pattern of Polymorph I of agomelatine in accordance with the invention
  • Another aspect of the invention provides a method of preparing crystal form I of agomelatine with the chemical and polymorphous purities and stability allowing obtaining of a polymorphousiy stable composition of agomelatine based on Form I and a method of preparing a polymorphousiy stable solid dosage form of agomelatine in accordance with the invention, based on a metastable solid form or a mixture of metastable solid forms of agomelatine.
  • the first one consists in slow cooling of a hot saturated solution of agomelatine in a suitable solvent under elimination of stirring or the presence of other shocks or vibrations of the whole crystallization apparatus.
  • a hot solution is meant to include a solution at a temperature of at least 60°C. Crystallization of Form I from the obtained supersaturated solution occurs spontaneously or by seeding with Form I after cooling of the solution.
  • Suitable solvents for this embodiment of the invention include aromatic hydrocarbons with six to ten carbon atoms and their mixtures, e.g.
  • toluene ethyl benzene, cumene, tetralin or xylenes.
  • Toluene is an especially preferable solvent for this embodiment.
  • Spontaneous cooling of the hot solution is an advantageous way of slow cooling.
  • the second variant of the method according to the invention involves a very quick reduction of solubility of agomelatine, caused by a quick decreasing of the temperature of the solution of agomelatine in the first solvent accompanied, by a further reduction of solubility of agomelatine due to mixing of the first solvent with a worse solvent, i.e. "precipitant".
  • the first solvent of agomelatine refers to a solvent in which solubility of agomelatine of at least 1 kg per 10 L of the solvent can be achieved at temperatures above 50°C; the worse solvent meaning a solvent in which solubility of agomelatine at temperatures lower than 30°C is less than 1 kg per 100 L of the solvent.
  • Examples of the first solvents of agomelatine suitable for this variant of the method of the invention include aromatic hydrocarbons with six to ten carbon atoms or their mixtures, e.g. toluene, ethyl benzene, cumene, tetralin or xylenes; aliphatic or cyclic esters with three to seven carbon atoms, e.g.
  • cyclic ethers or acetals with three to six carbon atoms such as tetrahydrofuran, methyl tetrahydrofuran, dioxolane or dioxane; aliphatic or cycloaliphatic C3-C 10 ether-alcohols such as 2-methoxyethanol, diethylene glycol, triethylene glycol or tetrahydrofurfuryl alcohol and their methyl or ethyl ethers and acetates; polyethylene glycol with a relative molecular weight up to 6000, halogen derivatives with two to seven carbon atoms and one to three halogen atoms such as 1 ,2-dichloroethane, 1 , 1 , 1 -trichloroethan
  • dimethyl sulfoxide dimethyl sulfone, sulfolane, tetramethylurea, formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.
  • solvents for agomelatine include water, C3-C25 liquid aliphatic and alicyclic hydrocarbons and their mixtures, such as e.g.
  • MTBE methyl tert-butyl ether
  • the first and the other solvent mutually form a homogeneous mixture in at least such a proportion of both constituents in which they are used in carrying out the method of preparation of Polymorph I according to the invention.
  • a polar solvent miscible with water in a broad range of composition e.g. a lower aliphatic alcohol, an ether alcohol or ketone, water can conveniently be used as the precipitant.
  • an aromatic hydrocarbon is used to dissolve agomelatine
  • a precipitant selected from the group consisting of aliphatic and alicyclic hydrocarbons and mixtures thereof or from the group consisting of aliphatic ethers, or a mixed precipitant constituted by a mixture of two precipitants selected from the above-mentioned groups to achieve a sufficiently fast reduction of solubility leading to the production of polymorphously pure Form I.
  • the solution of agomelatine in the first solution is prepared at a temperature exceeding 60°C and sprayed into the precipitant at this temperature is such a way that the temperature of the crystallization mixture during the precipitation never exceeds 25°C, more preferably in such a way that the temperature during the crystallization do not exceed 5°C.
  • a suitable crystallization regime may be set and controlled by the amount and pre-cooling temperature of the precipitant, intensity of the cooling and stirring during the crystallization as well as the concentration, temperature and rate of addition of the solution of agomelatine.
  • Decreasing the temperature difference of the precipitating and precipitated solution in carrying out the method according to the invention also supports formation of other metastable forms of agomelatine than Form I.
  • the use of a mixture of water and ice represents a preferable embodiment for preparation of polymorphously pure Form I.
  • An especially advantageous embodiment of this method is represented by the use of finely crushed ice or artificially prepared ice in a fine crystal form.
  • this method of crystallization of Form I of agomelatine may serve as a convenient method of purification of agomelatine from organic impurities determinable by the HPLC method, but is not generally suitable as the final step of manufacture of a pharmaceutically active substance intended for us ein the production of therapeutic formulations.
  • the variant of the method according to the invention using crystallization of Form I of agomelatine by quick mixing of a solution of agomelatine in the first solvent with water, has generally proved to be less efficient in reducing the content of organic impurities.
  • this method provides agomelatine with a low content of residual solvents, fully complying with ICH regulations.
  • This variant of crystallization can especially conveniently be used as the final purification step providing, optionally in combination with preceding crystallization of Form I from a nonaqueous environment, agomelatine in crystal form I complying with all the above-mentioned requirements for an active pharmaceutical ingredient.
  • agomelatine in crystal form I complying with all the above-mentioned requirements for an active pharmaceutical ingredient.
  • Agomelatine in long-term polymorphously stable Form I obtained by the method according to the invention was subsequently used for the preparation of pharmaceutical compositions, which were tested for polymorphous and chemical stability.
  • other possibilities of preparation of compositions containing metastable solid forms of agomelatine were examined and their stability was tested in parallel with the compositions based on pure Form I.
  • polymorphously stable compositions containing metastable forms of agomelatine can also be prepared on the basis of some other, new metastable forms of agomelatine or their mixtures with Form I. In the crystallization experiments with agomelatine it has been possible to obtain and characterize several new metastable forms of agomelatine.
  • Form JR1 characterized by typical XRPD reflections presented in Table 2, was obtained by re-fusing agomelatine in boiling water and slow cooling of the resulting emulsion. Quick cooling provided Form JR2 in a similar way.
  • Form JR3 was obtained by crystallization from aqueous acetic acid while crystallization from anhydrous acetic acid provided a mixture of Forms I and JR1 .
  • Table 2 Typical reflections of X-ray power pattern of Form JR1 of agomelatine
  • a composition according to the invention, based on a metastable crystal form of agomelatine, can be obtained by methods that limit or rule out the use of solvents and of temperatures of the processed material above 60°C. Suitable methods include direct compression and processes using dry granulation, e.g. compaction.
  • Direct compression means a manufacturing method in which agomelatine, prepared in a polymorphously metastable crystal form or as a polymorphous mixture of metastable crystal forms, is homogenized with at least one solid excipient in one or several production steps and the resulting mixture is used for the production of tablets.
  • Compaction means a production method in which agomelatine produced in a polymorphously metastable crystal form or as a polymorphous mixture of metastable crystal forms is homogenized with at least one solid excipient in one or more manufacturing steps and . subsequently a strip of compact mass is produced by the action of pressure in a compactor, which is then ground in a sieving device to a defined particle size determined by the sieve mesh.
  • the resulting granulate can either be used for the production of solid dosage forms, e.g. tablets, capsules or sachets, either directly or after admixing of one or more excipients. Tablets are a preferred dosage form.
  • a composition based on a polymorphously stable mixture of metastable crystal forms of agomelatine can also be prepared in such a way that a mixture of metastable crystal forms with at least one solid excipient is produced directly during the process of preparation of the composition. This could be achieved e.g. by quick drying of a solution of agomelatine dissolved together with a soluble polymeric excipient in an organic solvent in the presence of at least one solid excipient insoluble in the given solvent.
  • Other excipients can be optimally added to the obtained solid mixture and preparation of the final form may be carried out, e.g. tabletting, filling of capsules, coating of tablets, and the like.
  • a composition in the form of tablets can be prepared, e.g., by spraying of an ethanolic solution of agomelatine and povidone onto a mixture of lactose, microcrystalline cellulose and crospovidone in a process of fluid granulation, drying of the granulate, addition of other excipients in the dry state and tabletting.
  • polymorphous stability of the prepared composition can help to maintain polymorphous stability of the composition according to the invention even under inconvenient conditions, such as distribution in countries with wet and hot climate. It may be preferable for polymorphous stability of the prepared composition to use a material that prevents access of air humidity for the production of a pharmaceutical formulation containing the composition according to the invention, or to pack the drug in an environment of dry air or an inert gas. These measures may be further combines with the use of a dessicant.
  • a preferable embodiment of such a pharmaceutical formulation containing the composition according to the invention in the form of, e.g., tablets or capsules is represented by, e.g., a blister pack made of aluminium foil or a glass vial with a plastic cap that contains a suitable desiccant, absorbing moisture diffusing inside through the cap or during opening of the vial.
  • Fig. 1 X-ray powder diffraction pattern of crystal form JR1 of agomelatine.
  • Fig. 2 Comparison of X-ray powder diffraction patterns of crystal forms JR4, JR2, 1, II and JR 1
  • Fig. 3 X-ray powder diffraction pattern of crystal form JR3 of agomelatine.
  • the primary optics programmable divergence slits with the irradiated sample area of 10 mm
  • 0.02 rad Soller slits and a 1 ⁇ 4° anti-dispersion slit were used.
  • the X 'Celerator detector with the maximum opening of the detection slit, 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.
  • the mixture was stirred for 1 h and then the precipitated product was isolated by filtration.
  • Microcrystalline cellulose (65.7 g), lactose monohydrate (198.8 g) and crospovidone (8 g) were charged into a fluid granulator. This mixture of three excipients was heated up in the granulator to 27°C by the flow of input air (at 55°C).
  • spraying of the fluidizing mixture of the excipients with the ethanolic solution of agomelatine and povidone K30 was started using a peristaltic pump and a nozzle connected to pressurized air at the pressure of 250 kPa (2.5 bar). The spraying process took 60 min. Then, the resulting granulate was dried by the flow of input air (having the temperature of 55°C throughout the spraying and drying periods) for 20 min until the granulate temperature of 34°C was obtained.
  • the temperature of the product in the granulator ranged from 27°C to 31 °C during the spraying and from 3 1 °C to 34°C during the drying.
  • the dried granulate was sieved through a sieve with the mesh size of 0.8 mm.
  • the humidity of the granulate measured as the drying loss at 105°C, 10 min, was 1 .4%.
  • Further excipients colloidal silicon dioxide (3.2 g) and crospovidone (1 1 .4 g) were added by sieving to the granulate (33 1 .9 g).
  • the mixture was homogenized for 12 min.
  • sieved stearic acid glidant 5.6 g was added to the mixture and the mixture was homogenized for 3 min.
  • the humidity of the tabletting matter measured as the drying loss at 105°C, 10 min, was 1 .7%.
  • the tabletting matter produced in the above mentioned way was used for the production of oblong-shaped cores with the weight of 129.2 mg (122- 1 34 mg specification), hardness of 99 N (at least 40 N specification), disintegration of 3 min (max. 15 min specification), dimensions of 9 x 4.5 mm (length x width).
  • These cores were then coated with a pre-prepared coating suspension on the basis of hydroxypropyl methyl cellulose.
  • the suspension was prepared by dissolving hydroxypropyl methyl cellulose (61 .2 g) in hot (80°C) water (300 g) under intensive stirring ( 1 5 min), after the dissolution polyethylene glycol (14.7 g) was added under intensive stirring (5 min) until dissolution.
  • titanium dioxide (7.8 g), talc ( 1 5.6 g) and yellow ferric oxide (3 g) were suspended in water (100 g, laboratory temperature). Then, both parts of the suspension were mixed and water was added (200 g, laboratory temperature). The cores were put into the drum of a coating device, heated up by the flow of input air (at 60°C) to the output air temperature of 50°C; immediately after that spraying with the coating suspension was started using a peristaltic pump and a nozzle connected to pressurized air at the pressure of 100- 125 kPa ( 1 - 1 .25 bar).
  • the input air temperature was maintained at 60 °C throughout the spraying period (60 min) and in the range of 45°C to 55°C throughout the drying period ( 10 min).
  • the final average weight of the coated tablets was 1 30.7 mg ( 126- 138 mg specification), the hardness 1 02 N (at least 40 N specification), disintegration 5 min (max. 30 min specification).
  • a mixture of Polymorph 1 and Polymorph JR1 was detected in the coated tablets.
  • the homogenized mixture was granulated in a compactor at the pressure of 4.5 MPa (45 bar), the granulate was sieved through a sieve with the mesh size of 0.8 mm.
  • the humidity of the granulate measured as a drying loss at 105 °C, 10 min, was 2.3 %.
  • Sieved (mesh size 0.8 mm) colloidal silicon dioxide (4.8 g) and crospovidone (3 1 .4 g) were added to the granulate (91 7.8 g). The mixture was stirred for 12 min. Then, sieved (mesh size 0.8 mm) stearic acid ( 1 5.2 g) and magnesium stearate (6.3 g) were added. The mixture was stirred for 3 min.
  • the humidity of the resulting tabletting matter measured as the drying loss at 105 °C, 10 min, was 2.3 %.
  • the resulting tabletting matter was used for the production of oblong-shaped cores with the weight of 1 34.8 mg ( 124- 1 36 mg specification), hardness of 69 N (at least 40 N specification), disintegration of 5 min (max. 15 min specification), dimensions of 9 x 4.5 mm (length x width). These cores were then coated with a pre-prepared coating suspension on the basis of hydroxypropyl methyl cellulose prepared in advance.
  • the suspension was prepared by dissolution of hydroxypropyl methyl cellulose (61 .2 g) in hot (80°C) water (300 g) under intensive stirring ( 1 5 min); after the dissolution polyethylene glycol (14.7 g) was added under intensive stirring (5 min) until dissolution.
  • titanium dioxide (7.8 g), talc ( 1 5.6 g) and yellow ferric oxide (3 g) were suspended in water ( 1 00 g, laboratory temperature). Then, both parts of the suspension were mixed and water was added (200 g, laboratory temperature).
  • the cores were put in the drum of a coating device, heated up by the flow of input air (at 60°C) to the output air temperature of 50°C, immediately after that spraying with the coating suspension was started using a peristaltic pump and a nozzle connected to pressurized air at the pressure of 1 00- 125 kPa ( 1 - 1 .25 bar).
  • the input air temperature was maintained at 60 °C throughout the spraying period (60 min) at 60 °C and in the range of 45°C to 55°C throughout the drying period (1 0 min).
  • the final average weight of the coated tablets was 137.4 mg ( 128- 140 mg specification), the hardness 97 N (at least 40 N specification), disintegration 9 min (max. 30 min specification). Polymorph I was detected In the coated tablets.

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CZ20110032A CZ303787B6 (cs) 2011-01-21 2011-01-21 Metastabilní krystalové formy agomelatinu a jejich farmaceutické kompozice
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2743255A1 (en) 2012-12-17 2014-06-18 Dr. Reddy's Laboratories Ltd. Cocrystal of agomelatine with phosphoric acid
EP3087977A4 (en) * 2013-12-23 2017-08-02 Tianjin Taipu Pharmaceutical Science & Technology Development Co., Ltd. Stable crystal i-form agomelatine tablet and preparation method thereof

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Cited By (2)

* Cited by examiner, † Cited by third party
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EP2743255A1 (en) 2012-12-17 2014-06-18 Dr. Reddy's Laboratories Ltd. Cocrystal of agomelatine with phosphoric acid
EP3087977A4 (en) * 2013-12-23 2017-08-02 Tianjin Taipu Pharmaceutical Science & Technology Development Co., Ltd. Stable crystal i-form agomelatine tablet and preparation method thereof

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