EP2046342A2 - Crystalline form a of ibandronic acid and process for the preparation - Google Patents

Crystalline form a of ibandronic acid and process for the preparation

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Publication number
EP2046342A2
EP2046342A2 EP07813544A EP07813544A EP2046342A2 EP 2046342 A2 EP2046342 A2 EP 2046342A2 EP 07813544 A EP07813544 A EP 07813544A EP 07813544 A EP07813544 A EP 07813544A EP 2046342 A2 EP2046342 A2 EP 2046342A2
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European Patent Office
Prior art keywords
formula
acid
crystalline form
methyl
ibandronic
Prior art date
Legal status (The legal status 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 status listed.)
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EP07813544A
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German (de)
French (fr)
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EP2046342A4 (en
Inventor
Vijayabhaskar Bolugoddu
Jaydeepkumar Lilakar Dahyabhai
Rambabu Venkata Kammili
Yogesh Prakash More
Pallavi Thakur
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Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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Publication of EP2046342A2 publication Critical patent/EP2046342A2/en
Publication of EP2046342A4 publication Critical patent/EP2046342A4/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)

Definitions

  • the reaction medium containing the starting material and the solvent is made free of moisture suitably by using techniques such as treatment with hydrating agents like sodium sulfate, magnesium sulfate, molecular sieves and the like, azeotropic distillation of the reaction medium or other techniques known to one skilled in the art.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates crystalline Form A of Ibandronic acid having Formula (I) and a process for the preparation thereof.

Description

CRYSTALLINE FORM A OF IBANDRONIC ACID AND PROCESS FOR THE PREPARATION
FIELD
The present invention relates to a crystalline form of ibandronic acid and a process for the preparation thereof. The present invention also relates to crystalline Form A of ibandronic acid and a process for its preparation, and also a process for the preparation of substantially pure ibandronate sodium Form A.
BACKGROUND
Ibandronic acid is chemically named as 3-(Λ/-methyl-Λ/-pentyl) amino-1- hydroxypropane-1 ,1-diphosphonic acid (herein after referred to as "ibandronic acid") and has structural Formula I.
Formula I
Ibandronic acid is used as an intermediate for the preparation of ibandronate sodium. Ibandronate sodium is chemically named as 3-(Λ/-methyl-Λ/-pentyl) quine-1- hydroxypropane-1 ,1-diphosphonic acid, monosodium salt, monohydrate (hereinafter referred to as "ibandronate sodium") and has structural Formula II.
Formula Il
The monosodium salt of ibandronic acid is useful in the treatment of bone disorders such as hypocalcaemia of malignance, osteolysis, Paget's disease, osteoporosis and metastatic bone diseases and is available in the market under the trade name BONIVA as an ampoule with 1 ml concentrate for solution for infusion containing 1.125 mg of ibandronic acid monosodium salt monohydrate, corresponding to 1 mg of ibandronic acid in the form of tablets.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic representation of an embodiment of a process for the preparation of ibandronic acid and its salts.
Fig. 2 is an X-ray powder diffraction pattern of ibandronic acid Form A prepared as in Example 12.
Fig. 3 is quantification curve to show 2% of ibandronate sodium monohydrate Form A in ibandronate sodium monohydrate Form B.
Fig. 4 is an X-ray powder diffraction pattern of ibandronate sodium monohydrate Form B prepared as in Example 11.
Fig. 5 is quantification curve to show the percentage of Form A in ibandronate sodium monohydrate Form B prepared as in Example 11.
Fig. 6 is quantification curve to show 1 % of ibandronate sodium monohydrate Form B in Form A.
Fig. 7 is an X-ray powder diffraction pattern of ibandronate sodium monohydrate Form A prepared as in Example 13.
Fig. 8 is quantification curve to show the percentage of ibandronate sodium monohydrate Form B in Form A prepared as in Example 13.
Fig. 9 is an XRPD pattern of a combination of ibandronate sodium monohydrate Form A and Form B in a specific weight ratio of 45:55, prepared according to Example 15.
Fig. 10 is the schematic representation of the preparation of the compound of Formula I.
Fig. 11 is the schematic representation of the preparation of the compound of Formula II. Fig. 12 is the schematic representation of the preparation of the compound of Formula Vl.
Fig. 13 is an X-ray powder diffraction (XRPD) pattern of ibandronoic acid crystalline Form A.
Fig. 14 is an infrared (IR) absorption spectrum of ibandronic acid crystalline Form A.
DETAILED DESCRIPTION
The crystalline form of the present application is designated as crystalline Form A for convenience.
In one embodiment, the present invention provides a crystalline Form A of ibandronic acid having Formula I.
In an embodiment, the process for the preparation of ibandronic acid and its salts comprises: a) esterfication of valeric acid of Formula Ma, followed by condensation with methylamine to give N-methylpentanamide of Formula IVa.
Formula Ha Formula IVa b) reduction of N-methylpentanamide of Formula IVa with a suitable reducing agent to afford N-methyl pentylamine of Formula Va;
Formula Va c) condensation of N-methyl pentylamine of Formula Va with methyl acrylate to afford methyl 3-(N-methyl-N-pentylamino)propanoate of Formula Via followed by its hydrolysis to give its salt of Formula Vila;
Formula Via Formula Vila where X is an inorganic or organic acid, or an inorganic or organic cation. d) reaction of 3-(N-methyl-N-pentylamino) propanoic acid or its salt of Formula Vila with phosphonating agent in a suitable diluent to give ibandronic acid of Formula I, which can subsequently be converted into its salt of Formula IXa.
Formula IXa where X' is an inorganic or organic cation.
Step a) esterfication of valeric acid of Formula Ma.
Esterification can be carried out in the presence of an alcohol and a strong acid. Suitable alcohols which can be used include, but are not limited to methanol, ethanol, propanol, isobutyl alcohol, isopropanol, and the like to form the corresponding esters. Suitable strong acids which can be used include, but are not limited to sulfuric acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid and the like.
Suitable temperatures for conducting the reaction range from about -10 0C to about 50 0C, or from about 10 0C to about 30 0C.
In an embodiment, the alcohol used is methanol, and the corresponding ester formed is methyl pentanoate of Formula Ilia.
Formula Ilia Suitable solvents which can be used for the condensation of methylamine with the intermediate ester include, but are not limited to Ci-Cβ straight chain, branched, cyclic, or chlorinated hydrocarbons; aromatic hydrocarbons such as toluene, xylene; nitriles such as acetonitrile, propionitrile; ethers such as tetrahydrofuran and the like or mixtures thereof.
Suitably, methylamine is used in the form of its aqueous solution. The reaction can also be conducted without using any additional solvent and using the solution of methylamine as the solvent.
Suitable temperatures for conducting the reaction range from about -15 to about 50 °C, or about 10 to 40 0C, or about 25 to about 35 0C.
The intermediate compound of Formula IVa in step (b) may or may not be isolated. The same can be converted in situ, if desired, to the compound of Formula Va in step (b).
Step (b) reduction of N-methylpentanamide of Formula IVa.
The reducing agent which is to be used in this stage is to be selected carefully, as the product formed in this stage is highly volatile. Most of the reducing agents used in the art require the reaction to be conducted at very high temperatures of the range of more than 70 °C. It is desirable to select a reducing agent which can be used at lower temperatures of the range of below 50 0C to avoid degradation of the product due to high temperatures.
Suitable reducing agents which can be used at the desired temperature ranges include, but are not limited to, sodium bis(2-methoxyethoxy) aluminum hydride (Vitride), lithium aluminium hydride, sodium borohydride/acetic acid, diisobutyl aluminium hydride (DIBAL H) and the like. The reduction reaction is sensitive to moisture, hence the moisture content of the individual components and the reaction medium before adding the reducing agent should be less than 1% w/w.
The reaction medium containing the starting material and the solvent is made free of moisture suitably by using techniques such as treatment with hydrating agents like sodium sulfate, magnesium sulfate, molecular sieves and the like, azeotropic distillation of the reaction medium or other techniques known to one skilled in the art.
The molar ratio of the reducing agent to the starting N-methylpentanamide of Formula IVa is from about 0.5 to about 10, or from about 1.0 to about 5.0 moles.
Suitable solvents which can be used for the reaction include, but are not limited to Ci-Cβ straight chain or branched chain chlorohydrocarbons including dichloromethane, ethylene dichloride, chloroform, and carbon tetrachloride; chlorinated aromatics such as chlorobenzene, dichlorobenzene, and the like; hydrocarbons such as C1-C-6 straight chain, branched or cyclic hydrocarbons; aromatic hydrocarbons such as toluene, xylene; nitriles such as acetonitrile, propionitrile; ethers such as tetrahydrofuran and the like or mixtures thereof.
The intermediate compound of Formula Va in step (b) may or may not be isolated. The same can be converted in situ, if desired, to the compound of Formula Via in step c).
Step (c) condensation of N-methyl pentylamine of Formula Va.
Suitable solvents which can be used for the reaction include, but are not limited to, C1-C6 straight chain or branched chlorohydrocarbons, hydrocarbons, aromatic hydrocarbons such as toluene, xylene, and the like; nitriles such as acetonitrile, propionitrile and the like; polar solvents like water; or mixtures thereof.
The reaction may optionally be conducted in the absence of any additional solvent, when the reagent methyl acrylate acts the medium for reaction. Suitable temperatures for conducting the reaction can range from about -15 to 50 0C, or about 10 to 40 0C, or about 25 to 35 0C.
The intermediate compound of Formula Via may or may not be isolated and may be directly hydrolyzed in-situ if desired, to the compound of Formula Vila.
The hydrolysis can be done either in the acidic conditions or basic conditions using suitable acids or bases as required. Suitable acids which can be used for acidic hydrolysis include, but are not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, para-toluene sulfonic acid and the like; organic acids such as oxalic acid, acetic acid, tartaric acid, formic acid and the like.
Suitable bases which can be used for basic hydrolysis include, but are not limited to sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, sodium secondary butoxide, sodium tertiary butoxide and the like; alkali metal hydroxides comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate and the like; alkali metal hydrides comprises sodium hydride and the like.
The product can be isolated as the acid addition salt or as the base addition salt based on the reagent selected for hydrolysis. Optionally, the salt obtained can be further purified by recrystallization or slurry in a suitable solvent. Recrystallization involves providing a solution of the intermediate in a suitable solvent and then crystallizing the solid from the solution.
Suitable organic solvents which can be used for recrystallization or slurry include but are not limited to alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n- propanol, and the like; halogenated solvents such as dichloromethane, 1 ,2- dichloroethane, chloroform, carbon tetrachloride and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether.dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1 ,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof in various proportions.
The concentration of the intermediate in the solvent can range from 40 to 80% or more. For recrystallization, a solution can be prepared at an elevated temperature if desired to achieve a desired concentration. Any temperature is acceptable for the dissolution as long as a clear solution is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to room temperature for further processing if required or an elevated temperature may be used.
The compound obtained can be further dried suitably using a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35 0C to about 70 0C. The drying can be carried out for any desired time periods to achieve the desired product purity, times from about 1 to 20 hours, or longer, frequently being sufficient.
In an embodiment, the hydrolysis is carried out using hydrochloric acid and the acid addition salt formed is the hydrochloride salt of Formula Villa.
Formula Villa
The salt of Formula Villa obtained according to the process of the present invention is highly pure. It has a purity of not less than 95% and contains less than 1 % of the individual process related impurities. Step d) reaction of 3-(N-methyl-N-pentylamino) propanoic acid or its salt of Formula Vila.
Suitable phosphonating agents which can be used for the reaction include, but are not limited to, phosphorous acid in combination with any one of phosphorous trichloride, phosphorous pentachloride, phosphorous oxy trichloride, phosphorous tribromide, phosphorous pentabromide, phosphorous oxybromide and the like.
Diluent is an inert substance used to dilute the reaction medium. Suitable diluents which can be used include, but are not limited to, hydrocarbons such as Ci to Cβ straight chain, branched, or cyclic hydrocarbons; aromatic hydrocarbons such as N- pentane, n-hexane, n-heptane, cyclohexane, toluene, 4-chloro toluene, xylene, and the like; nitriles such as acetonitrile, propionitrile, and the like.
Suitably other diluents like chlorinated hydrocarbon solvents such as Ci to Ce straight chain or branched chain chlorohydrocarbons including dichloromethane, ethylene dichloride, chloroform, and carbon tetrachloride; chlorinated aromatics such as chlorobenzene, dichlorobenzene, and the like; ethers such as tetrahydrofuran; alkyl sulfonic acids such as methanesulfonic acid, toluene sulfonic acid, paraffin oil, pyridine, 2-methyl pyrrolidone, and the like can be used in combination with diluents such as methanesulfonic acid, triphenyl phosphine, pyridine, paraffin oil, morpholine and the like.
In an embodiment, the above mentioned diluents can also be used for preparation of other bis-phosphonic acid compounds like alendronic acid, risedronic acid, zoledronic acid, ibandronic acid, minodronic acid, neridronic acid, and olpadronic acid and the like.
Suitable temperatures for conducting the reaction range from about 20 to about 200 0C, or from about 20 to about 100 °C. In an embodiment, the diluent used for the preparation of ibandronic acid and its salts is a combination of chlorobenzene and methane sulfonic acid, and the phosphonating agent is a combination of phosphorus acid and phosphorous trichloride.
The reaction comprises taking a mixture of chlorobenzene and 3-(N-methyl-N- pentylamino) propanoic acid or its salt of Formula Vila, and adding phosphorous acid to it. Then phosphorous trichloride and methanesulfonic acid are added alternately in lots.
The alternate addition in lots of phosphorus trichloride and methanesulfonic acid helps in eliminating their reacting with each other to form methanesulfonyl chloride, and hence the phosphorus trichloride added reacts with 3-(N-methyl-N-pentylamino) propanoic acid for the required product.
The mole ratio of methanesulfonic acid to the starting material 3-(N-methyl-N- pentylamino) propanoic acid or its salt of Formula Vila may range from about 0.8 to 1 moles per mole of the starting material. It is important to maintain the mole ratio within the said limits as a mole ratio less than or more than the given range effects the yield of the product since the excess of methanesulfonic acid if present in the reaction medium reacts with the phosphorus trichloride making it unavailable for the desired reaction.
The product ibandronic acid which is formed in insoluble in chlorobenzene and hence separates as a gum when it is formed in the reaction medium, suitably methanesulfonic acid is added slowly to the reaction medium such that the exothermicity caused during the addition can be controlled and the product formed is dissolved.
The ibandronic acid formed in the reaction mixture is then directly converted to its base addition salts by adding the required moles of base to the reaction medium containing ibandronic acid. The reaction medium containing the ibandronic acid is highly acidic, hence pH is suitably adjusted to 1.0 to 1.8 using a suitable base to form the required salt. Ibandronic acid is capable of forming either mono or dibasic salts. Hence depending on the pH to which the reaction medium is adjusted, mono basic or dibasic salts are formed. The pH of the reaction medium is important since it determines the nature of the salt. When a mono basic salt is proposed to be formed, the pH of the reaction medium containing ibandronic acid is adjusted to about 1.0 to about 1.8; and when a dibasic salt is proposed to be formed the pH of the reaction medium is adjusted to about 3.0 to about 5.0.
Suitable bases which can be used for salt formation include, but are not limited to alkali metal alkoxides such as potassium alkoxide, sodium methoxide; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate; amines such as tertiarybutylamine, dicyclohexylamine and the like. In an embodiment, the base used is sodium hydroxide and the salt formed is ibandronate sodium.
lbandronate sodium thus formed may optionally be further purified by recrystallization or slurry in a suitable solvent. Recrystallization involves providing a solution of ibandronate sodium in a suitable solvent and then crystallizing the solid from the solution.
Suitable organic solvents which can be used for recrystallization or slurry include but are not limited to alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n- propanol, and the like; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like or mixtures thereof in various proportions, or their mixtures with water.
The concentration of ibandronate sodium in the solvent can range from about 0.1 to about 10 g/ml or more. For recrystallization, a solution can be prepared at an elevated temperature if desired to achieve a desired concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the ibandronate sodium is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to room temperature for further processing if required or an elevated temperature may be used. A higher temperature will allow the precipitation from solutions with higher concentrations of ibandronate sodium resulting in better economies of manufacture.
The compound obtained can be further dried suitably using a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35 °C to about 70 °C. The drying can be carried out for any desired time periods to achieve the desired product purity, times from about 1 to 20 hours, or longer, frequently being sufficient.
In another embodiment, the present invention provides a process for the preparation of crystalline Form A of ibandronic acid, comprising the steps of: i) reacting N-methyl-N-pentyl amine propionic acid of Formula IV
FORMULA IV with phosphorous acid and phosphorous pentachloride in the presence of a suitable organic solvent ii) isolating using a suitable organic solvent to afford the compound of
Formula I; iii) purifying the compound of Formula I using a suitable organic solvent(s) to afford the pure compound of Formula I; and iv) recovering the desired crystalline Form A of ibandronic acid from step (iii). Steps (i) and (ii) - reaction of the compound of Formula IV with phosphorous acid and phosphorous trichloride followed by isolating the compound to afford the compound of Formula I.
Suitable organic solvents for isolation include but are not limited to: alcohols such as methanol, ethanol, and isopropanol, butanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n- propyl acetate, n-butyl acetate, tertiary-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N, N- dimethylacetamide (DMA) and the like; or mixtures thereof. In an embodiment of the present invention, the organic solvent is chlorobenzene as solvent.
The reaction temperature for conversion of the compound of Formula IV to the compound of Formula I in step (i) can range from about 0 0C to about 60 0C, or up to the reflux temperature of the solvent used.
Step (iii) purification of the compound of Formula I.
Organic solvents used for purification include but are not limited to any solvent or mixture of solvents in which ibandronic acid is soluble, for example alcohols such as methanol, ethanol, and isopropanol, butanol and the like.
Step (iv) recovering the desired crystalline Form A of ibandronic acid.
Step (iv) can be carried out by using techniques, such as centrifugation, decantation, gravity filtration, vacuum filtration or other techniques known to one skilled in the art for the separation of solids. The wet solid isolated in step (iii) may be dried by using techniques, such as for example fluid bed drying (FBD), aerial drying, oven drying or other techniques known to one skilled in the art. The drying can be conducted at temperatures of about 0 0C to about 30 0C or about 25 0C to about 30 °C with or without application of a vacuum. Drying can be carried out under inert conditions.
In another embodiment, the present invention provides an improved process for the preparation of substantially pure crystalline Form A of ibandronic acid comprising the step of recrystallisation of crude ibandronic acid using suitable organic solvent(s) for example alcohols such as methanol, ethanol, and isopropanol, butanol and the like or mixtures thereof to afford the desired substantially pure crystalline Form A Ibandronic acid.
As used herein "substantially pure" it is meant that crystalline Form A prepared in accordance with the present invention has a purity of more than about 95% or more than about 99% by HPLC, and contains less than about 0.5%, or less than about 0.1 % by weight of related impurities as characterized by a high performance liquid chromatography ("HPLC").
In an embodiment, the process for the preparation of substantially pure ibandronate sodium monohydrate crystalline Form A, substantially pure ibandronate sodium monohydrate crystalline Form B and a mixture of Form A and Form B comprises: a) providing a solution of ibandronate sodium; b) adding an antisolvent to the solution obtained in step a); c) isolating the separated solid.
Step a) providing a solution of ibandronate sodium.
The solution of ibandronate sodium may be obtained by dissolving the ibandronate sodium in a suitable solvent, or such a solution may be obtained directly from a reaction in which ibandronate sodium is formed. When the solution is prepared by dissolving ibandronate sodium in a suitable solvent, any form of ibandronate sodium such as the crystalline or amorphous form, including any salts, solvates and hydrates may be utilized for preparing the solution.
Suitable solvents useful in the preparation of the monohydrate of ibandronate sodium include water alone or in combination with an organic solvent, such as for example ketones like acetone, propanone; acetonitrile, and the like; and mixtures thereof. The quantity of solvent used for dissolution is critical in determining the final polymorphic form obtained from the process. When the quantity of solvent is less than 1.6 times to the weight of ibandronate sodium taken, the resulting polymorphic form is ibandronate sodium monohydrate Form A, and when the quantity is more than about 1.6 or more than about 2.0 times, the resulting polymorphic form is ibandronate sodium polymorphic Form B.
Any temperature below 200 °C may be used for dissolution as long as a clear solution is obtained.
The solution can be maintained at this temperature for about 1 minute to any desired time. The solution can optionally be filtered by passing through paper, glass fiber, or other membrane material or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The concentration of the solution can be about 0.1 g/ml to about 20 g/ml of the solvent, or it may range form 1 g/ml to 5 g/ml.
Step b) adding an antisolvent to the solution obtained in step a).
A solvent or a mixture of solvents may be added to the solution obtained in step a) to initialize crystallization. Suitable solvents which can be used as anti-solvents include, but are not limited to water, ketonic solvents like acetone, ethyl methyl ketone, and the like or mixtures thereof. The temperature for addition of the anti-solvent may range from about 40 °C to about 70 °C or from about 50 °C to about 60 °C.
The crystallization may be performed with stirring until the desired crystal yield has been obtained. The crystallization step may further include facilitative measures known to one skilled in the art. For example, crystallization step may further include cooling the solution. The maintenance time during crystallization can range from about 1 to about 20 hours. There is no disadvantage to further extending the crystallization period for getting polymorphic Form A, other than an increased processing expense, and an appropriate time for a given batch size can be determined with little effort by one skilled in the art.
The cooling of the solution may be achieved by simple radiation cooling under atmospheric conditions, accompanied by stirring, or through the use of controlled cooling mechanisms such as for example circulation of cooling media in jacket vessels and the like. Such techniques for rapid and gradual cooling are well known to a person skilled in the art and are all included herein without limitation.
Step c) recovering the separated solid.
Recovery can be performed by any means including, but not limited to, filtration, centrifugation, and decanting. The crystalline form may be recovered from any composition containing the crystalline form and the solvent or solvents including but not limited to a suspension, solution, slurry, and emulsion.
The obtained compound can be further dried under ambient or reduced pressure. For example, drying can be performed under reduced pressure or under atmospheric pressure at a temperature of at about 40 0C to 60 0C, or about 70 0C to 80 0C, or higher. Drying can be performed until a desired residual solvent content has been obtained, such as for a duration of about 2 hours to 24 hours, or about 3 to 6 hours. Yet another aspect of the present invention provides a mixture of ibandronate sodium monohydrate polymorphs Form A and Form B in any desired ratio of either form to the other and a process for its preparation comprising physically mixing the crystalline forms in any desired ratio.
Physical mixing of the crystalline forms comprises taking the required weights of Form A and Form B to prepare the mixture into a round bottom flask and mixing it by rotating the flask containing it. Other techniques of mixing well known to a person skilled in the art can be used to prepare the mixture.
Thus, according to this aspect Form A of ibandronate sodium monohydrate is mixed with Form B in any ratio from about 0.1 to 99% w/w with respect to the other form. Any form of mixing may be utilized to ensure complete homogeneity of one form in the other. Such forms of mixing could include trituration, blending using different blenders and the like and are within the scope of understanding of a person skilled in the art of processing pharmaceutical powders. The individual crystalline forms or the final mixture may also be subjected to pulverization to reduce the particle size. The particle size and distribution to be used will be determined by the composition into which the mixture is to be incorporated, rates of dissolution and the like and will be within the scope of understanding of a pharmaceutical scientist.
In an embodiment, the mixture is a 45 + 5 to 45 + 5 mixture of Form A to Form B, and the mixing is done by stirring the required weights of Form A and Form B in a flask at an RPM of about 25 to about 30.
In another embodiment, present invention provides an improved process for the synthesis of ibandronate sodium of Formula II,
comprising the steps of reacting 3-(N-methyl-N-pentylamino) propanoic acid hydrochloride of Formula III
FORMULA III
with phosphoric acid, phosphorous trichloride in the presence of suitable diluents and suitable organic solvent to give ibandronic acid of Formula I1
FORMULA I which is subsequently converted into the sodium salt of Formula II.
Suitable diluents that may be used for the reaction includes but are not limited to: methane sulfonic acid, paraffin oil, pyridine, 2-methyl pyrrolidone, and the like; or mixtures thereof, or their combination with water in various proportions. In one embodiment of the present invention the diluent is methane sulfonic acid. Suitable organic solvents used for isolation include but are not limited to: alcohols such as methanol, ethanol, and isopropanol, butanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, tertiary-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N1N- dimethylacetamide (DMA) and the like; or mixtures thereof, or their combination with water in various proportions.
In another embodiment of the present invention, there is provided an improved process for the preparation of N-methyl pentylamine, having Formula Vl,
'NHCH3
Formula Vl which process comprises the step of reducing N-methylpentanamide, having Formula V
Formula V using suitable reducing agent in the presence of suitable organic solvent to afford N- methyl pentylamine of Formula Vl.
Suitable reducing agents include but are not limited to lithium aluminium hydride, Diisobutylaluminium hydride (DIBAL-H), Sodium Dihydro-bis-(2-Methoxyethoxy) Aluminate (vitride), Sodium borohydride in combination with acetic acid, sodium cyano borohydride and the like. In an embodiment of the present invention the reducing agent is vitride. Suitable organic solvents include but are not limited to ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1 ,4- dioxane, and the like; hydrocarbons such as C~ι-C6 straight chain, branched or cyclic hydrocarbons and the like; aromatic hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures thereof.
Temperatures for conversion of compound of Formula V to the compound of Formula Vl can range from about 0 0C to about 90 0C.
Still another aspect of the present invention provides crystalline Form A of ibandronic acid, and a process for its preparation.
The crystalline Form A of ibandronic acid has an XRD pattern substantially in accordance with Figure 4, which was measured on a Bruker Axe, D8 Advance Powder X-ray Diffractometer with a Cu K alpha-1 radiation source. The crystalline Form A of ibandronic acid obtained by the above process is characterized by an X-ray powder diffraction pattern using Cu K α-1 radiation with peaks at approximately: 5, 5.9, 7.3, 8.2, 11 , 12.2, 13.9, 14.6, 18.7, 21.2, 22.8, 24.6, 30.7, ± 0.2 degrees 2 theta.
The infrared (IR) spectra of crystalline Form A of ibandronic acid combination of ibandronic acid with pharmaceutically acceptable carriers has been recorded on a Perkin Elmer System Spectrum 1 model spectrophotometer, between 450 cm-1 and 4000 cm-1 , with a resolution of 4 cm-1 in a potassium bromide pellet, the test compound being at the concentration of 1% by mass.
The crystalline form A ibandronic acid is characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 523.13, 576.98, 672.03, 663.29, 641.13, 933.64, 1054.19, 1152.13, 1381.93, 1473.01 , 1641.95, 2309.79, 2759.58, 2873.35, 2937.52, 2960.91 , and 3089.95 ± 5 cm-1. Crystalline Form A ibandronic acid is also characterized by its infrared absorption spectrum in potassium bromide substantially in accordance with the spectrum of Fig. 14. The process for its preparation comprises purification of the crude acid obtained according to the process of the present invention or any processes described in the prior art. The purification involves recrystallization in organic solvents. Organic solvents which can be used include but are not limited to any solvent or mixture of solvents in which ibandronic acid is soluble, for example alcohols such as methanol, ethanol, and isopropanol, butanol and the like or mixtures thereof.
lbandronate salts prepared according to the process of the present invention have a D90 less than about 200 μm.
The D-io, D50 and D90 values are useful ways for indicating a particle size distribution. Dgo refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D50 and Di0 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining Di0, D50 and D90 include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern, Worcestershire, United Kingdom) equipment.
Ibandronic acid and its pharmaceutically acceptable salts prepared according to the present invention have a mean particle size of less than about 100 μm, D10 less than 20 μm or less than 50 μm, D50 less than 50 μm or less than 100 μm, and D90 less than 100 μm or less than 200 μm. There is no specific lower limit for any of the D values.
The processes of present invention are simple, cost effective, ecofriendly, reproducible, scalable, robust to produce the desired crystalline Form A of ibandronic acid, which is free flowing and directly compressible into stable formulations. Still more another aspect of the present invention provides a pharmaceutical composition comprising pure ibandronic acid or its pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers, excipients or diluents.
The pharmaceutical composition may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
In the compositions of present invention ibandronic acid or its pharmaceutically acceptable salts is a useful active ingredient in the range of 0.5 mg to 500 mg, or 1 mg to 250 mg, per dosage form unit.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLE 1 : PREPARATION OF IBANDRONIC ACID CRYSTALLINE FORM A
N-methyl-N-pentyl propionic acid of Formula IV (50 g) was charged into a 4-neck round bottom flask containing chlorobenzene (350 ml), and phosphorous acid and heated to about 80 0C to about 85 0C. Phosphorous trichloride (52 ml) was added slowly over a period of about 20-30 minutes and the reaction mass was stirred for about 4 to about 5 hours to a temperature of about 85 0C to about 90 0C. The reaction mass was cooled to about 60 0C -65 0C followed and water (250 ml) was slowly added over a period of about 30 to about 45 minutes. The separated solid was filtered through celite and the organic and aqueous layers were separated.
The filtrate was charged into a clean and dry round bottom flask followed by heating to about 95 0C to about 100 0C for about 16 to about 17 hours. The resultant filtrate was distilled completely under vacuum. The obtained residue was cooled to about 25 0C to about 30 0C followed by addition of isopropyl alcohol (100 ml) and the resultant suspension was stirred over a period of about 10 to about 12 hours. The separated solid was filtered and the solid was washed with isopropyl alcohol (10 ml). The solid obtained was dried at about 50 0C to about 55 °C under vacuum over a period of about 8 to aboutiO hours to afford 10.3 g of a crude form of title compound.
To the above-obtained crude compound methanol (70 ml) was charged followed by stirring for about 1 to about 2 hours. The solid was filtered and dried at about 25 0C to about 35 0C under vacuum for about 6 to about 7 hours to afford 2.4 g of crystalline Form A of ibandronic acid, with a purity by HPLC 95.36% and having the X-ray powder diffraction pattern of Fig. 13 with peaks approximately at: 5, 5.9, 7.3, 8.2, 10.9, 12.2, 13.9, 4.6, 18.7, 21.2, 22.8, 24.6, 30.7, ± 0.2 degrees 2 theta.
The crystalline form A of ibandronic acid is characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 523.13, 576.98, 672.03, 663.29, 641.13, 933.64, 1054.19, 1152.13, 1381.93, 1473.01 , 1641.95, 2309.79, 2759.58, 2873.35, 2937.52, 2960.91 , and 3089.95 ± 5 cm-1. Crystalline Form A ibandronic acid is also characterized by its infrared absorption spectrum in potassium bromide substantially in accordance with the spectrum of Fig. 14.
EXAMPLE -2: PROCESS FOR THE PREPARATION OF IBANDRONATE SODIUM (FORMULA II)
3-(N-methyl-N-pentylamino) propanoic acid hydrochloride of Formula III (20 mg) was charged into a round bottom flask containing chlorobenzene (140 ml) and phosphorous acid (15.6 g). The contents were heated to about 75 0C to about 80 0C and phosphorous trichloride (20.8 ml) was added slowly for about 20 to about 30 minutes, followed by addition of methane sulfonic acid (10 ml) for a period of about 20 to about 30 minutes. The reaction mass was stirred for about 3 to about 4 hours at a temperature of about 90 0C to about 100 0C followed by cooling to about 50 0C to about 60 0C. Water (100 ml) was added slowly over a period of about 15 to about 20 minutes followed and the reaction mass was filtered through celite. The organic layer and aqueous layer were separated. The separated aqueous layer was charged in to the fresh round bottom flask and heated to about 95 0C to about 100 0C for about 16 to about 18 hours followed by cooling to about 0 0C to about 10 0C. Sodium hydroxide (9.4 g) was added slowly followed by addition of methanol (280 ml) and stirred for about 4 to about 5 hours. The separated solid was filtered and the solid was kept for sucking for about 15 to about 30 minutes.
The above-obtained wet solid (28 g) was charged into a round bottom flask containing water (56 ml) and heated to about 60 0C to about 70 0C and maintained for about 30 to about 45 minutes followed by cooling the reaction mass to about 25 0C to about 30 0C. Methanol (112 ml) was added in to the reaction mass and stirred for about 30 to about 45 minutes. The separated solid was filtered and the solid was washed with methanol (20 ml) and kept for sucking for about 30 to about 45 minutes. The filtered solid was charged into a round bottom flask containing water (50 ml) and the contents were heated to about 65 0C to about 70 0C for about 45 to about 60 minutes. Acetone (200 ml) was added into the reaction mass and stirred for about 20 to about 30 minutes. The separated solid was filtered and the solid was washed with acetone (50 ml) and kept for sucking for about 30 to about 45 minutes. The solid obtained was dried to about 45 0C to about 50 0C for about 3 to about 4 hours to afford 16 gm of title compound as a solid with purity by HPLC 99.76%.
EXAMPLE 3: PREPARATION OF N-METHYLPENTYLAMINE (FORMULA VI)
N-methylpentanamide of Formula V (40 g) was charged into a round bottom flask containing toluene (200 ml) followed by stirring for about 5 to about 10 minutes. The aqueous layer and toluene layer were separated and kept aside. Sodium Dihydro-bis- (2-Methoxyethoxy) Aluminate (vitride) (210 ml) and toluene (200 ml) were charged into a clean and dry round bottom flask followed by stirring for about 5 to about 10 minutes. The above-obtained N-methylpentanamide dissolved in toluene was added drop wise slowly over about 45 to about 60 minutes at a temperature of about 25 °C to about 30 0C. The resultant reaction mass was stirred for about 7 to about 8 hours at about 25 0C to about 30 0C followed by cooling to about 5 0C to about 10 0C. Sodium potassium tartarate (120 g) was dissolved in water (800 ml) and added drop wise slowly over a period of about 30 to about 45 minutes at about 0 0C to about 10 0C followed by stirring for about 10 to about 15 minutes. The organic and aqueous layers were separated and the aqueous layer was extracted with toluene (120 ml) followed by separation of the organic and the aqueous layers. Both the organic layers were combined and the total organic layer was washed with water (2x80 ml) followed by separation of the organic and the aqueous layers.
Purity by Gas chromatography of the title compound is 76.792%.
EXAMPLE 4 - PREPARATION OF METHYL PENTANOATE (FORMULA Ilia):
100 g of valeric acid and 400 ml of methanol were taken into a round bottom flask and stirring given. 104 ml of sulfuric acid was added to the mixture slowly at about 30 °C. The reaction mass was maintained at about 26 °C for about 1 hour. 300 ml of water was added to the reaction mass and stirred for about 10 minutes. 200 ml of dichloromethane was added to it and stirred for another about 15 minutes. The organic layer was separated and the aqueous layer was extracted into 300 ml of dichloromethane. The combined organic layer was distilled atmospherically at about 55 °C to get the product in the form of a residue. Purity by GC: 97.34%.
EXAMPLE 5 - PREPARATION OF N-METHYL PENTANAMIDE (FORMULA IVa)
100 g of crude methyl pentanoate obtained by a process similar to one described in Example 4, and 400 ml of methylamine were taken into a round bottom flask and stirring given at 27 0C. The reaction mass was maintained at about 27 °C for about 5 hours. 300 ml of water was added to the reaction mass and stirred for 15 minutes. 200 ml of dichloromethane was added to it and stirred for 5 minutes. The organic layer was separated and aqueous layer was extracted into 300 ml of dichloromethane. The combined organic layer was distilled atmospherically at a temperature of 49 0C to get a residue.
Purity by GC: 97.8%.
EXAMPLE 6 - PREPARATION OF N-METHYL PENTYLAMINE (FORMULA Va):
50 g of N-methyl pentanamide obtained as per the process given in Example 5 and 250 ml of toluene was taken into a round bottom flask and stirring given at about 28 0C. The organic layer was dried over sodium sulfate. A solution of 262.5 ml of vitride in 250 ml of toluene was taken into a separate round bottom flask and stirred for about 5 minutes. The solution of N-methyl pentanamide in toluene prepared above was added to the mixture of vitride in toluene at about 28 °C. The reaction mass was maintained at about 28 0C for about 5 hours and then cooled to about 4 0C. A solution of 150 g of sodium potassium tartarate in 1000 ml of water was added to the above reaction mass slowly. The reaction mass temperature was raised to about 27 °C. The organic layer was separated and the aqueous layer was extracted into 50 ml of toluene. The combined organic layer was washed with 200 ml of water in two equal lots. Purity by GC: 90.67%.
EXAMPLE 7 - PREPARATION OF N-METHYL PENTYLAMINE (FORMULA Va)
250 ml of 1 ,4-dioxane was added to 70 g of n-methyl pentanamide prepared by a process similar to one described in Example 5 and cooled to about 10 °C. 20 g of sodium borohydride was added to the reaction mass under stirring. Then a mixture of 35 ml of acetic acid and 70 ml of 1 ,4-dioxane was added to the reaction mass at about 10 °C. The contents were heated to about 90 0C and maintained for about 3 hours. Reaction completion was confirmed by thin layer chromatography and the reaction mass was cooled to about 10 °C. 500 ml water of was added to the reaction mass slowly and then pH was adjusted to 0.4 with 75 ml of 36% aqueous hydrochloric acid at about 10 °C. The aqueous reaction mass was washed with 400 ml of dichloromethane in four equal lots to remove impurities. The pH was then adjusted to 12.2 with 50% aqueous sodium hydroxide solution. The reaction mass was extracted with 1000 ml of dichloromethane in five equal lots and the organic layer was progressed to the next step.
EXAMPLE 8 - PREPARATION OF 3-(N-METHYL-N-PENTYLAMINO) PROPANOATE (FORMULA VIa)
The organic layer obtained by a process similar to one described in Example 6 was taken (containing 21 g of N-methylpentylamine). 69 ml of methyl acrylate was added to it and maintained at about 28 °C for about 15 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the organic layer was proceeded to the next stage. Purity by GC: 92.45%.
EXAMPLE 9 - PREPARATION OF 3-(N-METHYL-N-PENTYLAMINO) PROPANOIC ACID HYDROCHLORIDE (FORMULA VIIa):
40 g of 3-(N-methyl-N-pentylamino) propanoate prepared as per the process given in Example 8 and 90ml of 4 normal hydrochloric acid solution were taken into a round bottom flask and stirred for about 10 minutes. The aqueous layer was separated and the organic layer was extracted into 23 ml of acidic water. The combined aqueous layer was taken into another round bottom flask and heated to about 80 0C. The reaction mass was maintained at about 80 °C for about 11 hours. The reaction mass was then taken into a Bucchi Rotavapor flask and distilled off under a vacuum of 33 mm/Hg at about 82 °C. The remaining residue was cooled to about 30 0C and 150 ml of ethyl acetate was added. The mixture was further cooled to about 5 °C and maintained for about one hour. The separated solid was filtered and washed with 20 ml of ethyl acetate. The wet material was dried at about 34 0C for about 4 hours to yield 15 g of the title compound.
EXAMPLE 10 - PREPARATION OF 3-(N-METHYL-N-PENTYLAMINO) PROPANOIC ACID HYDROCHLORIDE (FORMULA VIIIa):
50 g of crude 3-(N-methyl-N-pentylamino) propanoic acid hydrochloride and 150 ml of acetone was taken into a round bottom flask and heated to about 50 0C. The reaction mixture was maintained at about 50 °C for one hour. The mixture was then cooled to about 30 0C and 300 ml of ethyl acetate was added to it. The mixture was stirred at about 30 °C for about 40 minutes. The separated solid was filtered and washed with 20 ml of ethyl acetate. The wet solid was dried at about 54 °C for about 6 hours to yield 47.5 g of the title compound.
Purity by GC: 99.8%. EXAMPLE 11 - PREPARATION OF IBANDRONATE SODIUM BY USING CYCLOHEXANE AS DILUENT:
10 g of 3-(N-methyl-N-pentylamino) propanoic acid hydrochloride was charged into a round bottom flask containing 70 ml of cyclohexane. 8.5 g of phosphorous acid was charged to the reaction mass and then heated to about 5 0C. 12.5 ml of phosphorous trichloride was added slowly. The reaction mass was stirred for about 6 hours and then cooled to about 28 °C. 70 ml of water was added slowly and the contents were heated to about 75 0C. The reaction mass was stirred for about 35 minutes and then filtered through a flux calcined diatomaceous earth (Hyflow) bed. The aqueous layer was then separated from the filtrate and heated to 95 °C in another flask. The aqueous layer was stirred at same temperature for about 23 hours and then cooled to about 8 0C. 140 ml of methanol was added and the contents were stirred for about 20 minutes. 2.5 g of sodium hydroxide was charged and the mixture was stirred for about 7 hours at about 4 0C. Another 2.5 g of sodium hydroxide were charged and stirred for about 5 hours at about 5 0C. The separated solid was filtered and washed with 20 ml of methanol. The solid was dried at about 55 °C for about 8 hours to afford 8.5 g of the title compound as crystalline solid.
EXAMPLE 12- PREPARATION OF IBANDRONATE SODIUM BY USING ANISOLE AS DILUENT:
10 g of 3-(N-methyl-N-pentylamino) propanoic acid hydrochloride was charged into a round bottom flask containing 70 ml of anisole. 8.5 g of phosphorous acid was charged to the reaction mass and then heated to about 84 °C. 12.5 ml of phosphorous trichloride was added slowly at about 85 0C. The reaction mass was heated to about 95 0C and maintained for about 3 hours. It was then cooled to about 61 0C and 70 ml of water was added at about 61 °C. The contents were heated again to about 78 °C and stirred for about 15 minutes. The reaction mass was cooled to about 27 0C and filtered through a flux calcined diatomaceous earth (Hyflow) bed. The aqueous layer was separated from the filtrate and heated to about 95 0C in another flask. The aqueous layer was stirred at about 95 °C for about 19 hours and then cooled to about 5 0C. 140 ml of methanol was then added and the contents were stirred for about 20 minutes. 2.5 g of sodium hydroxide was charged and stirred for about 5 hours and 25 minutes at about 3 0C. Another 1.0 g of sodium hydroxide was added and stirred for about 4 hours and 20 minutes at about 3 0C. The separated solid was filtered and washed with 20 ml of methanol. The solid was dried at about 55 0C for about 6 hours to afford 7.0 g of the title compound as crystalline solid.
EXAMPLE 13 - PREPARATION OF IBANDRONATE SODIUM BY USING 4- CHLOROTOLUENE AS DILUENT:
7.0 g of 3-(N-methyl-N-pentylamino) propanoic acid hydrochloride was charged into a round bottom flask containing 50 ml of 4-chlorotoluene and then heated to about 80 °C. 10 ml of phosphorous trichloride was added slowly at about 84 °C and stirred for about 1 hour 35 minutes. It was then cooled to about 45 °C and 9.8 g of phosphorous acid was charged to the reaction mass. The reaction mass was heated to about 95 0C and stirred for about 2 hours 30 minutes at about 97 0C. The reaction mass was cooled to about 64 °C and 50 ml of water was added slowly at about 64 °C. The contents were heated again to about 75 °C and stirred for about 15 minutes. The reaction mass was filtered through a flux calcined diatomaceous earth (Hyflow) bed and aqueous layer separated from the filtrate was heated to about 95 °C in another flask. The aqueous layer was stirred at about 95 °C for about 19 hours and then cooled to about 5 0C. 100 ml of ethanol was added and the contents were stirred for about 20 minutes. 5.8 g of sodium hydroxide was added and stirred for about 8 hours at about 4 °C. The solid was separated, filtered and washed with 50 ml of ethanol. The solid was dried at about 54 0C for about 6 hours 30 minutes to afford 4.8 g of the title compound as crystalline solid.
EXAMPLE 14 - PREPARATION OF IBANDRONATE SODIUM MONOHYDRATE FORM B USING MIXTURE OF CHLOROBENZENE AND METHANE SULFONIC ACID AS DILUENT:
50 g of 3-(N-methyl-N-pentylamino) propanoic acid hydrochloride, 350 ml of chlorobenzene, and 39 g of phosphorous acid were taken into a round bottom and stirring given. The reaction mass was heated to about 80 °C, and 41.6 ml of phosphorous trichloride was added to it at about 80 to 83 °C. Immediately after the addition of phosphorous trichloride, 10 ml of methanesulfonic acid was added to the reaction mass slowly. After addition of the methanesulfonic acid was completed, another 10.4 ml of phosphorous trichloride was added to the reaction mass. Another 40 ml of methanesulfonic acid was added to the reaction mass slowly. The reaction mass was then heated to about 96 0C and maintained for about 3 hours. The reaction mass was then cooled to about 63 °C and 250 ml of water was added to it slowly. The reaction mass was then filtered and the layers separated. The aqueous layer was taken into another round bottom flask and stirred. The aqueous layer was heated to about 99 0C and maintained for about 14 hours. The aqueous layer was then cooled to about 5 0C and pH of the aqueous layer was adjusted to 1.8 using 48% aqueous sodium hydroxide solution. 700 ml of methanol was added to the aqueous layer and maintained at about 5 0C for about 4 hours 25 minutes. The separated solid was filtered and washed with 10 ml of methanol. The wet solid was taken into another round bottom flask and 220 ml of water was added to it. The mixture was heated to about 80 °C and checked for clear dissolution. Once clear dissolution was obtained, the mixture was cooled to about 30 0C and 560 ml of methanol was added to it. The mixture was maintained at about 30 0C for about 1 hour. The separated solid was filtered and the solid was washed with 50 ml of methanol. The wet compound was again taken into another round bottom flask and 168 ml of water was added to it. The mixture was heated to about 70 °C and about 80 ml of water was distilled off. Then the reaction mass was again heated to about 76 0C and 84 ml of water was added to it. After a clear dissolution was obtained, the reaction mass was cooled to about 30 0C and 500 ml of acetone was added to it. The reaction mass was stirred at about 30 0C for about 1 hour. The separated solid was filtered and washed with 50 ml of acetone. The wet solid was taken into another round bottom flask and 272 ml of water was added t it. The mixture was heated to about 77 0C and checked for clear dissolution. After clear dissolution was obtained, the solution was cooled to about 30 °C and 816 ml of acetone was added to it and stirred for about 10 minutes. The separated solid was filtered and washed with 50 ml of acetone. The wet solid was dried at about 55 °C for about 16 hours to yield 51.7 g of the title compound. Purity by HPLC: 99.8%.
EXAMPLE 15 - PREPARATION OF SUBSTANTIALLY PURE IBANDRONATE SODIUM MONOHYDRATE CRYSTALLINE FORM A:
50 g of ibandronate sodium was taken and 61.6 ml of water was added to it. The mixture was heated to about 90 °C and checked for clear dissolution. After a clear dissolution was obtained, the solution was filtered under hot condition and the filtrate was cooled to about 50 0C. A mixture of 250 ml of acetone and 50 ml of water was added to the above solution at about 50 0C. The reaction mass was then cooled to about 30 0C and maintained for about 6 hours. The separated solid was filtered and washed with 83.3 ml of acetone. The wet solid was dried at about 60 0C for about 12 hours to yield 47.5 g of the title compound.
EXAMPLE 16 - PREPARATION OF IBANDRONATE SODIUM MONOHYDRATE CRYSTALLINE FORM A:
15 g of ibandronate sodium was taken and 18.5 ml of water was added to it. The mixture was heated to about 90 °C and checked for clear dissolution. After a clear dissolution was obtained, the solution was filtered and the filtrate was cooled to about 60 °C. A mixture of 51.8 ml of acetone and 29 ml of water was taken into another round bottom flask and heated to about 50 0C. The above acetone water mixture was added to the filtrate obtained above. The reaction mixture was cooled to about 30 0C and maintained for about one hour. The separated solid was filtered and the solid was washed with 50 ml of a 1 :1 mixture of acetone and water. The wet solid was dried at about 60 °C for about 21 hours to yield 4.1 g of the title compound. EXAMPLE 17 - PREPARATION OF 45:65 MIXTURE OF IBANDRONATE SODIUM MONOHYDRATE FORM A AND FORM B:
27.5 g of ibandronate sodium Form A and 25 g of ibandronate sodium Form B were taken into a bucchi rota vapor flask and stirred at an RPM of about 30. The sample was maintained under rotation for about 8 to 10 hours to afford 52.5 g of the desired combination of ibandronate sodium polymorphs Form A to Form B in a weight to weight ratio of about 45% w/w to about 55% w/w.

Claims

We claim:
1. A crystalline Form A of ibandronic acid.
2. The crystalline Form A of claim 1 , characterized by the X-ray powder diffraction pattern having peak locations substantially in accordance with Fig. 13.
3. The crystalline Form A of claim 1 , characterized by an X-ray powder diffraction pattern using Cu K α-1 radiation with peaks at approximately: 5, 5.9, 7.3, 8.2, 11 , 12.2, 13.9, 14.6, 18.7, 21.2, 22.8, 24.6, 30.7, ± 0.2 degrees 2 theta.
4. The crystalline form A of claim 1 , characterized by an infrared absorption spectrum having peaks locations substantially in accordance with Fig. 14.
5. The crystalline form A of claim 1 , characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 523.13, 576.98, 672.03, 663.29, 641.13, 933.64, 1054.19, 1152.13, 1381.93, 1473.01 , 1641.95, 2309.79, 2759.58, 2873.35, 2937.52, 2960.91 , and 3089.95 ± 5 cm-1.
6. Crystalline Form A of ibandronate sodium monohydrate containing less than about 2% of crystalline Form B of ibandronate sodium monohydrate.
7. Crystalline Form A of ibandronate sodium monohydrate containing less than about 1 % of crystalline Form B of ibandronate sodium monohydrate.
8. A process for the preparation of crystalline Form A of ibandronic acid, comprising the steps of:
(a) reacting N-methyl-N-pentyl amine propionic acid of Formula IV with phosphorous acid and phosphorous pentachloride in the presence of chlorobenzene and methane sulfonic acid;
(b) isolating using an organic solvent; (c) purifying using an organic solvent; and
(d) recovering the desired crystalline Form A of ibandronic acid.
9. A process for the preparation of substantially pure crystalline Form A of ibandronic, comprising the step of recrystallisation of crude ibandronic acid using an organic solvent.
10. A process for the preparation of ibandronate sodium of Formula II, comprising:
(a) reacting 3-(N-methyl-N-pentylamino) propanoic acid hydrochloride of Formula III with phosphoric acid, phosphorous trichloride, together with a diluent and an organic solvent; and
(b) converting to the sodium salt of Formula II.
11. The process of claim 10, wherein said diluent is mixture of chlorobenzene and methane sulfonic acid.
12. A process for the preparation of N-methyl pentylamine of Formula Vl comprising reducing N-methylpentanamide of Formula V with a reducing agent in the presence of an organic solvent.
13. The process of claim 12, wherein said reducing agent is vitride.
14. A process for preparing ibandronic acid comprising reacting a compound of Formula.
with a suitable reducing agent to give the compound of Formula
15. The process of claim 14, wherein the reducing agent is selected from a group consisting of sodium bis(2-methoxyethoxy) aluminum hydride, lithium aluminium hydride, sodium borohydride/acetic acid, and diisobutyl aluminium hydride (DIBAL H).
16. The process according to claim 14, wherein the reducing agent used is sodium bis(2-methoxyethoxy) aluminum hydride.
17. The process according to claim 15, wherein the reducing agent used is sodium bis(2-methoxyethoxy) aluminum hydride.
18. The process of claim 14, wherein the compound having Formula IVa is prepared by esterification of the compound of Formula
followed by condensation with methylamine.
19. The process of claim 14 further comprises reacting the compound of Formula with methylacrylate to give the compound of Formula
which upon hydrolysis followed by reaction with a phosphonating agent in a suitable diluent gives ibandronic acid.
20. A process of claim 18, wherein the esterification is carried out in the presence of an inorganic acid.
21. The process of claim 20, wherein the inorganic acid is sulfuric acid.
22. A process of claim 19, further comprising converting ibandronic acid to its pharmaceutically acceptable salt.
23. The process of claim 9, wherein the alcoholic solvent is methanol.
24. A process for the preparation of ibandronic acid and its salts comprises: a) esterfication of valeric acid of Formula Ma, followed by condensation with methylamine to give N-methylpentanamide of Formula IVa.
Formula Ma Formula IVa b) reduction of N-methylpentanamide of Formula IVa with a suitable reducing agent to afford N-methyl pentylamine of Formula Va;
Formula Va c) condensation of N-methyl pentylamine of Formula Va with methyl acrylate to afford methyl 3-(N-methyl-N-pentylamino)propanoate of Formula Via followed by its hydrolysis to give its salt of Formula Vila;
Formula Via
where X is an inorganic or organic acid, or an inorganic or organic cation. d) reaction of 3-(N-methyl-N-pentylamino) propanoic acid or its salt of Formula Vila with phosphonating agent in a suitable diluent to give ibandronic acid of Formula I.
25. The process of claim 24, wherein said ibandronic acid of Formula I is subsequently be converted into its salt of Formula IXa.
Formula IXa where X' is an inorganic or organic cation.
26. The process of claim 24 wherein in step (a) said alcohol is methanol, and the corresponding ester formed is methyl pentanoate of Formula HIa.
Formula HIa
27. The process of claim 24, wherein said hydrolysis is carried out using hydrochloric acid and the acid addition salt formed is the hydrochloride salt of Formula Villa.
Formula Villa
28. A pharmaceutical composition comprising pure ibandronic acid or its pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers, excipients or diluents.
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WO2012007021A1 (en) * 2010-07-14 2012-01-19 Pharmathen S.A. Process for the preparation of 3-(n-methyl-n-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid salt or derivatives thereof
TR201200588A2 (en) * 2012-01-18 2012-07-23 Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇ Processes for preparing sodium ibandronate monohydrate polymorphs and mixtures with polymorphs.

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