FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
POLYMORPHIC FORMS OF AMLODIPINE BENZOATE AND PROCESS
FOR THE PREPARATION THEREOF
APPLICANT(S)
(a) Name: ALKEM LABORATORIES LIMITED
(b) Nationality: AN INDIAN COMPANY
(c) Address: ALKEM HOUSE, SENAPATI BAPAT MARG, LOWER
PAREL, MUMBAI - 400013
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES
THE INVENTION AND THE MANNER IN WHICH IT IS TO BE
PERFORMED:

FIELD OF INVENTION
The present invention relates to the polymorphic forms of Amlodipine benzoate and pharmaceutical compositions thereof. The present invention also relates to the processes for the preparation of Amlodipine benzoate. The present invention further relates to the manufacturing processes for the preparation of crystalline Amlodipine benzoate.
BACKGROUND OF THE INVENTION
Amlodipine benzoate, chemically known as 3-Ethyl-5-methyl (±)-2-[(2-ammoethoxy)memyl]-4-(2-cMorophenyl)-l,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenecarboxylate is benzoate salt of Amlodipine and is represented by the formula I.

Amlodipine benzoate is the active ingredient of the drug Katerzia® and intended for oral suspension. Amlodipine benzoate is a calcium channel blocker and is intended for the treatment of hypertension by reducing the blood pressure and thus reducing the risk of various cardiovascular events. Prior to Katrezia®, WO2005/089353 generically disclosed (S)-Amlodipine benzoate as the first intermediate salt during the preparation of (S)-Amlodipine maleate. Though, the PCT doesn't disclose specific preparation or isolation of (S)-Amlodipine benzoate.
CN110372575 discloses eutectic crystal of dihydropyridine calcium antagonist. The disclosed eutectic crystal has molecular formula: (C2oH25ClN205)-(C6H5COOH)-(Y)n, wherein Y is any one of water molecule, ethanol molecule or isopropanol molecule, is levamlodipine,
C6H5COOH is benzoic acid.

WO2018/067959 relates to the oral liquid formulation of Amlodipine benzoate, wherein the process for the preparation of oral liquid formulation comprises formation of Amlodipine benzoate in situ by reaction of more aqueous soluble Amlodipine salt (Amlodipine besylate or other Amlodipine salts) than Amlodipine benzoate, with a molar excess of sodium benzoate in the presence of at least one additional excipient.
A particular polymorphic form of a compound may have certain physical properties that differ from those of any other crystalline or amorphous forms and such properties may influence markedly the chemical and pharmaceutical processing of compound, particularly when the compound is prepared or used on a commercial scale. For example, each crystal form of a compound may show differences in physical properties such as crystalline size and shape, melting point, density, hygroscopicity, solubility, suspending properties and stability. In general, the more stable crystalline form is more suitable for formulation and processing on a commercial scale.
Amlodipine and its various pharmaceutically acceptable salts have been studied since decades. US4572909 disclosed Amlodipine and pharmaceutically acceptable salts such as, hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts. US4879303 & US6846931 disclosed Amlodipine besylate and Amlodipine pyroglutamate, respectively. Further, there are several prior-arts disclosing preparation of these salts, wherein the process comprises conversion of protected Amlodipine to Amlodipine free base followed by its conversion to desired salt.
Particularly, US20020143046, WO2005023769, CN102659673, CN105732482, CN103006648 and CN107445889 discloses conversion of Phthaloyl Amlodipine to Amlodipine free base followed by its conversion to desired salt, preferably in situ (without free base isolation). Wherein Phthaloyl amlodipine is preferably treated with aqueous solutions of primary amines in water immiscible solvents followed by treatment of the organic phase with suitable organic acids to give amlodipine in the form of a pharmaceutically acceptable salt. Generic

representation of conversion of Phthaloyl Amlodipine to Amlodipine Salt can be depicted as Scheme-1:

Though, none of these prior art explicitly discloses preparation of Amlodipine benzoate, WO2019/200143 discloses a process for conversion of Amlodipine salt (preferably besylate) having more aqueous solubility to Amlodipine benzoate in the presence of sodium benzoate by ultrasonic agitation. The process disclosed therein has one or more issues while scaling up, particularly ultrasonic agitation step. Further, the process comprise conversion of the first Amlodipine salt to final Amlodipine benzoate. Thus, the overall Amlodipine benzoate manufacturing process comprises an additional step of isolating the first Amlodipine salt. The inventors of the present invention have developed novel Amlodipine benzoate crystalline forms, possessing desirable processing properties. Also, the inventors of the present invention have addressed the need of developing an industrial viable process for the preparation of Amlodipine benzoate which can overcome the drawbacks associated with the known processes and result in the desired polymorph of Amlodipine benzoate with substantial purity and yield.
OBJECTIVE OF THE INVENTION
The primary objective of the present invention is to provide novel polymorphic forms of Amlodipine benzoate and pharmaceutical compositions thereof.
Another objective of the present invention is to provide an industrial viable process for the synthesis of Amlodipine benzoate.
Another objective of the present invention is to provide a process for the preparation of novel polymorphic forms of Amlodipine benzoate.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides a crystalline hydrate of Amlodipine benzoate.
In another general aspect, the present invention provides a crystalline dihydrate Form-I of Amlodipine benzoate characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.9,10.7 and
In another general aspect, the present invention provides a process for preparing crystalline hydrate Form-I of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine in methyl tert-butyl
ether to obtain Amlodipine free base;
b. contacting Amlodipine free base with benzoic acid in methyl tert-butyl ether;
and
c. isolating crystalline hydrate Form-I of Amlodipine benzoate.
In another general aspect, the present invention provides a process for preparing crystalline hydrate Form-I of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine to obtain amlodipine
free base;
b. contacting Amlodipine free base with benzoic acid in ethyl acetate and water;
and
c. isolating crystalline hydrate Form-I of Amlodipine benzoate.
In another general aspect, the present invention provides crystalline anhydrous form of Amlodipine benzoate.
In another general aspect, the present invention provides a crystalline Form-II of Amlodipine benzoate characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.4,6.0 and

In another general aspect, the present invention provides a process for preparing crystalline Form-II of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine in methyl tert-butyl
ether to obtain Amlodipine free base;
b. removing water from the organic layer;
c. contacting Amlodipine free base with benzoic acid in methyl tert-butyl ether;
and
d. isolating crystalline Form-II of Amlodipine benzoate.
In another general aspect, the present invention provides a crystalline Form-Ill of Amlodipine benzoate characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.1 and 5.6±0.2° 20.
In another general aspect, the present invention provides a process for preparing crystalline Form-Ill of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine in a solvent, selected
from the group comprising of hydrocarbon solvents, halogenated solvents or
mixture thereof to obtain Amlodipine free base;
b. contacting Amlodipine free base with benzoic acid in a solvent, selected from
the group comprising of hydrocarbon solvents, halogenated solvents or
mixture thereof; and
c. isolating crystalline Form-Ill of Amlodipine benzoate.
In another general aspect, the present invention provides a crystalline monohydrate Form-IV of Amlodipine benzoate characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.71 and 7.93±0.2° 29.
In another general aspect, the present invention provides a process for preparing crystalline monohydrate Form-IV of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine to obtain amlodipine
free base;
b. contacting Amlodipine free base with benzoic acid in a Ethyl acetate; and
c. isolating crystalline monohydrate Form-IV of Amlodipine benzoate.

In another general aspect, the present invention provides a process for preparing Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine in a solvent to
obtain Amlodipine free base;
b. contacting Amlodipine free base with benzoic acid in a solvent; and
c. isolating Amlodipine benzoate.
In another general aspect, the present invention provides an amorphous Amlodipine benzoate.
In another general aspect, the present invention provides a pharmaceutical composition containing a hydrate, crystalline form or amorphous form of Amlodipine benzoate.
DEFINITIONS
As used herein, the term "ambient temperature" refers to a temperature ranging from about 15°C to 35°C, preferably the ambient temperature refers to a temperature from about 20°C to 30°C, more preferably to a temperature of 25°C. The terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited.
The term "optionally" or "optional" is taken to mean that the event or circumstance describes in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
As used herein, the term "hydrate" refers to the crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of water incorporated within the crystal structure. Hydrates can be defined based on the moles of water incorporated within the crystal structure one mole of Amlodipine benzoate. "Monohydrate" stands for one mole of water with respect to one mole of Amlodipine benzoate;

"dihydrate" stands for two moles of water with respect to one mole of Amlodipine benzoate; and similarly "hemihydrate" and "sesquihydrate" stands for half and 1.5 moles of water with respect to one mole of Amlodipine benzoate. The same can be indicated as percentage (%) weight of water with respect to weight of Amlodipine benzoate. The percentage (%) weight of water can be obtained by various analytical tools; preferably, Karl-Fischer titration and Thermal Gravimetric Analysis.
As used herein, the term "anhydrous" refers to the crystalline or amorphous solid adducts containing undetectable bound water, incorporated within the crystal structure.
As used herein, the term "remove water" or "removing water" stands for removing or separating trace amount of water from a mixture of organic solution with water by the means of distillation, physical adsorption or chemical methods.
As used herein, the term "azeotropically" or "azeotropic distillation" stands for the process to break azeotrope and to separate two close-boiling components, facilitated by dean-stark apparatus.
As used herein, the term "contacting" includes mixing, adding, slurrying, stirring or a combination thereof.
As used herein, the term "about" are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The term "substantially the same" with reference to analytical characterization such as X-ray powder diffraction (XRPD) peak positions or TGA thermogram endothermic / exothermic peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak position (2 theta) will show some inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as

variability due to degree of crystallinity, preferred orientation, prepared sample
surface and other factors known to those skilled in the art and should be taken as
quantitative measure only.
ABBREVIATIONS
XRPD X-Ray Powder Diffraction
TGA Thermal Gravimetric Analysis
DSC Differential Scanning Calorimetry
KF Karl Fischer Titration
HPLC High Performance Liquid Chromatography
BRIEF DESCRIPTION OF FIGURES
Fig. 1 represents an X-ray powder diffraction (XRPD) pattern of the crystalline hydrate Form-I of Amlodipine benzoate prepared as per Example 1;
Fig. 2 represents a thermal gravimetric analysis (TGA) of the crystalline hydrate Form-I of Amlodipine benzoate of the present invention;
Fig. 3 represents differential scanning calorimetry (DSC) of the crystalline hydrate Form-I of Amlodipine benzoate of the present invention;
Fig. 4 represents an X-ray powder diffraction (XRPD) pattern of the crystalline Form-II of Amlodipine benzoate prepared as per Example 2;
Fig. 5 represents a thermal gravimetric analysis (TGA) of the crystalline Form-II of Amlodipine benzoate of the present invention;
Fig. 6 represents differential scanning calorimetry (DSC) of the crystalline Form-II of Amlodipine benzoate of the present invention;
Fig. 7 represents an X-ray powder diffraction (XRPD) pattern of the crystalline Form-Ill of Amlodipine benzoate prepared as per Example 3;

Fig. 8 represents a thermal gravimetric analysis (TGA) of the crystalline Form-Ill of Amlodipine benzoate of the present invention;
Fig. 9 represents differential scanning calorimetry (DSC) of the crystalline Form-Ill of Amlodipine benzoate of the present invention.
Fig. 10 represents an X-ray powder diffraction (XRPD) pattern of the crystalline monohydrate Form-IV of Amlodipine benzoate prepared as per Example 4; Fig. 11 represents an X-ray powder diffraction (XRPD) pattern of the amorphous Amlodipine benzoate prepared as per Example 5;
DETAILED DESCRIPTION OF THE INVENTION
In one general aspect, the present invention provides crystalline hydrate of Amlodipine benzoate. The crystalline hydrate of present invention contains from about 1.5% to about 12.7% w/w of water by Karl-Fischer titration.
In one another aspect, the present invention provides a crystalline hydrate Form-I of Amlodipine benzoate. The crystalline hydrate Form-I of Amlodipine benzoate contains about 6.3% w/w of water by Karl-Fischer titration. The crystalline hydrate Form-I of Amlodipine benzoate according to the present invention is a di-hydrate of Amlodipine benzoate.
The crystalline dihydrate Form-I of Amlodipine benzoate is characterized by at least one of the following:
a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.9,10.7
and 13.7±0.2° 20 and an X-ray powder diffraction (XRPD) pattern substantially
the same as depicted in Fig. 1;
b. by a weight loss of about 5.6% as measured by thermal gravimetric analysis
(TGA) and a thermal gravimetric thermogram substantially the same as depicted in
Fig. 2; or

c. by DSC endotherm with onset temperature at 87.24°C and a DSC pattern substantially the same as depicted in Fig. 3.
The crystalline dihydrate Form-I of Amlodipine benzoate can be further characterized by an X-ray diffraction (XRPD) pattern comprising peaks at about 9.7,15.7,19.2,22.0, 24.9 and 25.6±0.2° 20.
In one another aspect, the present invention provides a process for preparing crystalline hydrate Form-I of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine; optionally in
methyl tert-butyl ether to obtain Amlodipine free base;
b. contacting Amlodipine tree base with benzoic acid in methyl tert-butyl
ether; and
c. isolating crystalline hydrate Form-I of Amlodipine benzoate.
Step (a) may be carried out at ambient temperatures to 70°C for the time sufficient to obtain Amlodipine free base. Preferably the step (a) may be carried out at the temperature ranging from 20°C to 60°C for the time sufficient to obtain Amlodipine free base. Step (a) may further involve extraction of Amlodipine free base using the solvent of step (a) or organic solvent selected from ethyl acetate or dichloromethane followed by optional separation of organic layer from the reaction mixture and washing thereof with brine or water.
Step (a) may further comprise isolation of Amlodipine free base from the reaction mixture as solid before contacting the same with benzoic acid. Alternatively, Amlodipine free base is not isolated from the reaction mixture of Step (a) and the reaction mixture is directly contacted with benzoic acid.
Step (b) may be carried out at 0°C to 5 0°C for the time sufficient to obtain crystalline hydrate Form-I of Amlodipine benzoate. Preferably the step (b) may be carried out at 10°C to ambient temperature for the time sufficient to obtain crystalline hydrate Form-I of Amlodipine benzoate.

Step (c), wherein the crystalline hydrate Form-I of Amlodipine benzoate may be isolated by methods such as precipitation, cooling, filtration, centrifugation or combinations thereof. The crystalline hydrate Form-I may optionally be washed with methyl tert-butyl ether.
Thus obtained crystalline hydrate Form-I is dried by the methods such as vacuum drying, air drying, heat drying, freeze drying or supercritical drying. Any of the mentioned methods may also be used in combination to ensure removal of unbound solvent or water. Preferably the crystalline hydrate Form-I of Amlodipine benzoate is dried by air, heat and/or vacuum drying methods. A suitable drying temperature is, for example, from 35°C to 100°C, preferably from 40°C to70°C. As may be recognized, the drying time will be dependent upon, amongst other things, the amount of material to be dried, and the particular drying method used. Generally a drying time of 20 minutes to 25 hours, preferably 2 hours to 10 hours is sufficient. Conveniently the drying is performed by heating under vacuum and optionally under inert atmosphere, for example by passing a stream of warm inert gas such as nitrogen over or through material.
In one another aspect, the present invention provides a crystalline anhydrous form of Amlodipine benzoate. The crystalline anhydrous form of Amlodipine benzoate contains less than 1% w/w of water by Karl-Fischer titration.
In one another aspect, the present invention provides a crystalline Form-II of Amlodipine benzoate. The crystalline Form-II of Amlodipine benzoate contains about 0.21% w/w of water by Karl-Fischer titration.
The crystalline Form-II of Amlodipine benzoate is characterized by at least one of the following:
a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.4, 6.0 and 12.1±0.2° 29 and an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 4;

b. by a weight loss of about less than 1% as measured by thermal gravimetric
analysis (TGA) and a thermal gravimetric thermogram substantially the same as
depicted in Fig. 5; or
c. by DSC endotherm with onset temperature at 136.86°C and a DSC pattern
substantially the same as depicted in Fig. 6.
The crystalline Form-II of Amlodipine benzoate can be further characterized by an X-ray diffraction (XRPD) pattern comprising peaks at about 8.5,11.9, 19.9, 20.5, 20.9,22.3,23.0 and 23.8±0.2° 20.
In one another aspect, the present invention provides a process for preparing crystalline Form-II of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine in methyl tert-butyl
ether to obtain Amlodipine free base;
b. removing water from the organic layer;
c. contacting Amlodipine free base with benzoic acid in methyl tert-butyl ether;
and
d. isolating crystalline Form-II of Amlodipine benzoate.
Step (a) may be carried out at ambient temperatures to 70°C for the time sufficient to obtain Amlodipine free base. Preferably the step (a) may be carried out at the temperature ranging from 20 to 60°C for the time sufficient to obtain Amlodipine free base. Step (a) may further involve extraction of Amlodipine free base using the solvent of step (a) or organic solvent selected from ethyl acetate or dichloromethane followed by optional separation of organic layer from the reaction mixture and washing thereof with brine or water.
Step (b), wherein calculated amount of water may be removed by either of the methods known to the skilled practitioner, such as distillation, physical adsorption (molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate), chemical water removal or combination thereof. Preferably, the water is removed by distillation. More preferably, by carrying out azeotropic distillation using dean-stark apparatus.

Step (b) may further comprise isolation of Amlodipine free base from the reaction mixture as solid before contacting the same with benzoic acid. Alternatively, Amlodipine free base is not isolated from the reaction mixture of Step (b) and the reaction mixture is directly contacted with benzoic acid.
Step (c) may be carried out at 0°C to 50°C for the time sufficient to obtain crystalline Form-II of Amlodipine benzoate. Preferably the step c) may be carried out at 10°C to ambient temperature for the time sufficient to obtain crystalline Form-II of Amlodipine benzoate.
Step (d), wherein the crystalline Form-II of Amlodipine benzoate may be isolated by methods such as precipitation, cooling, filtration, centrifugation or combination thereof. The crystalline Form-II may optionally be washed with methyl tert-butyl ether.
Thus obtained crystalline Form-II is dried by the methods such as vacuum drying, air drying, heat drying, freeze drying or supercritical drying. Any of the mentioned methods may also be used in combination to ensure removal of unbound solvent or water. Preferably the crystalline Form-II of Amlodipine benzoate is dried by air, heat and/or vacuum drying methods. A suitable drying temperature is, for example, from 35°C to 100°C, preferably from 40°C to70°C. As may be recognized, the drying time will be dependent upon, amongst other things, the amount of material to be dried, and the particular drying method used. Generally a drying time of 20 minutes to 25 hours, preferably 2 hours to 10 hours is sufficient. Conveniently the drying is performed by heating under vacuum and optionally under inert atmosphere, for example by passing a stream of warm inert gas such as nitrogen over or through material.
In one another aspect, the present invention provides a crystalline Form-Ill of Amlodipine benzoate. The crystalline Form-Ill of Amlodipine benzoate contains about 0.15% w/w of water. The crystalline Form-Ill of Amlodipine benzoate is characterized by at least one of the following:

a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.1 and
5.6±0.2° 20 and an X-ray powder diffraction (XRPD) pattern substantially the same
as depicted in Fig. 7; or
b. by DSC endotherm with onset temperature at 125.96°C and a DSC pattern
substantially the same as depicted in Fig. 9.
The crystalline Form-Ill of Amlodipine benzoate can be further characterized by an X-ray diffraction (XRPD) pattern comprising peaks at about 11.4,12.3,12.8,15.5, 19.7,23.8, 24.0 and 24.3±0.2° 26.
In one another aspect, the present invention provides a process for preparing crystalline Form-Ill of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine in a solvent selected
from the group comprising of hydrocarbon solvents, halogenated solvents or
mixture thereof to obtain Amlodipine free base;
b. contacting Amlodipine free base with benzoic acid in a solvent selected from
the group comprising of hydrocarbon solvents, halogenated solvents or
mixture thereof; and
c. isolating crystalline Form-Ill of Amlodipine benzoate.
Steps (a) and (b), wherein the solvent may be selected from the group comprising toluene, xylene, dichloromethane or mixture thereof. Preferably, the solvent may be selected from toluene or dichloromethane. More preferably, the solvent is toluene.
Step (a) may be carried out at ambient temperatures to 120°C for the time sufficient to obtain Amlodipine free base. Preferably the step (a) may be carried out at the temperature ranging from 20°C to 60°C for the time sufficient to obtain Amlodipine free base. Step (a) may further involve extraction of Amlodipine free base using the solvent of step (a) or organic solvent selected from ethyl acetate or dichloromethane followed by optional separation of organic layer from the reaction mixture and washing thereof with brine or water.

Step (a) may further comprise isolation of Amlodipine free base from the reaction mixture as solid before contacting the same with benzoic acid. Alternatively, Amlodipine free base is not isolated from the reaction mixture of Step (a) and the reaction mixture is directly contacted with benzoic acid.
Step (b) may be carried out at 0°C to 50°C for the time sufficient to obtain crystalline Form-Ill of Amlodipine benzoate. Preferably the step (b) may be carried out at 10°C to ambient temperature for the time sufficient to obtain crystalline Form-Ill of Amlodipine benzoate.
Step (c), wherein the crystalline Form-Ill of Amlodipine benzoate may be isolated by methods such as precipitation, cooling, filtration, centrifugation or combination thereof. The crystalline Form-Ill may optionally be washed with the solvent selected from toluene, xylene, dichloromethane or mixture thereof. Thus obtained crystalline Form-Ill is dried by the methods such as vacuum drying, air drying, heat drying, freeze drying or supercritical drying. Any of the mentioned methods may also be used in combination to ensure removal of unbound solvent or water. Preferably, the crystalline Form-Ill of Amlodipine benzoate is dried by air, heat and/or vacuum drying methods. A suitable drying temperature is, for example, from 35°C to 100°C, preferably from 40°C to70°C. As may be recognized, the drying time will be dependent upon, amongst other things, the amount of material to be dried, and the particular drying method used. Generally a drying time of 20 minutes to 25 hours, preferably 2 hours to 10 hours is sufficient. Conveniently the drying is performed by heating under vacuum and optionally under inert atmosphere, for example by passing a stream of warm inert gas such as nitrogen over or through material.
In one another aspect, the present invention provides a crystalline monohydrate Form-IV of Amlodipine benzoate. The crystalline Form-IV of Amlodipine benzoate contains about 0.15% w/w of water.
The crystalline monohydrate Form-IV of Amlodipine benzoate is characterized by X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.1 and

and an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 10;
The crystalline monohydrate Form-IV of Amlodipine benzoate can be further characterized by an X-ray diffraction (XRPD) pattern comprising peaks at about 4.1,5.6,11.4,12.3,12.8,15.5,19.7,23.8, 24.0 and 24.3±0.2°2θ.
In one another aspect, the present invention provides a process for preparing crystalline Form-IV of Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine to obtain
Amlodipine free base;
b. contacting Amlodipine free base with benzoic acid in a ethyl acetate; and
c. isolating crystalline monohydrate Form-IV of Amlodipine benzoate.
In one another aspect, the present invention provides a process for preparing Amlodipine benzoate, comprising:
a. contacting phthaloyl amlodipine with monomethyl amine optionally in a
solvent to obtain Amlodipine free base;
b. contacting Amlodipine free base with benzoic acid in a solvent; and
c. isolating Amlodipine benzoate.
Steps (a) and (b), wherein the solvent comprises water, methanol, ethanol, diethyl-ether, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, heptane, xylene, toluene or mixture thereof. Preferably, the solvent may be selected from ethanol, methyl tert-butyl ether, toluene or mixture thereof. More preferably, the solvent may be selected from methyl tert-butyl ether, ethyl acetate or toluene.
Step (a) may be carried out at ambient temperatures to 70°C for the time sufficient to obtain Amlodipine free base. Preferably the step (a) may be carried out at the temperature ranging from 20°C to 60°C for the time sufficient to obtain Amlodipine free base. Step (a) may further involve extraction of Amlodipine free base using the organic solvent of step (a) or organic solvent selected from ethyl acetate or

dichloromethane followed by optional separation of organic layer from the reaction mixture and washing thereof with brine or water.
Step (a), may further comprise removal of calculated amount of water from the organic layer by either of the methods known to the skilled practitioner, such as distillation, physical adsorption (molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate), chemical water removal or combination thereof. Preferably, the water may be removed by distillation. More preferably, by carrying out azeotropic distillation using dean-stark apparatus.
Step (a) may further comprise isolation of Amlodipine free base from the reaction mixture as solid before contacting the same with benzoic acid. Alternatively, Amlodipine free base is not isolated from the reaction mixture of Step (a) and the reaction mixture is directly contacted with benzoic acid.
Step (b) may be carried out at 0°C to 50°C for the time sufficient to obtain Amlodipine benzoate. Preferably the step (b) may be carried out at 10°C to ambient temperature for the time sufficient to obtain Amlodipine benzoate.
Step (c), wherein Amlodipine benzoate may be isolated by methods such as precipitation, cooling, filtration, centrifugation or combination thereof. The isolated Amlodipine benzoate may optionally be washed with a solvent selected from the group comprising of water, methanol, ethanol, diethyl-ether, methyl tert-butyl ether, ethyl acetate, 1,4-dioxane, dichloromethane, heptane, xylene, toluene or mixture thereof.
Thus obtained Amlodipine benzoate is dried by the methods such as vacuum drying, air drying, heat drying, freeze drying or supercritical drying. Any of the mentioned methods may also be used in combination to ensure removal of unbound solvent or water. Preferably Amlodipine benzoate is dried by air, heat and/or vacuum drying methods. A suitable drying temperature is, for example, from 35°C to 100°C, preferably from 40°C to70°C. As may be recognized, the drying time will be dependent upon, amongst other things, the amount of material to be dried, and the

particular drying method used. Generally a drying time of 20 minutes to 25 hours, preferably 2 hours to 10 hours is sufficient. Conveniently the drying is performed by heating under vacuum and optionally under inert atmosphere, for example by passing a stream of warm inert gas such as nitrogen over or through material.
In another general aspect, the present invention provides a crystalline form of Amlodipine benzoate having a purity by HPLC of >99%. In particular, a purity by HPLC of >99.5%, more particularly, a purity by HPLC of >99.8%, most particularly, a purity by HPLC of >99.9%.Pharmaceutical Compositions:
Also provided herein is a pharmaceutical composition comprising Amlodipine Benzoate in an amorphous form or crystalline Form 1, Form -II, Form -III, Form-IV or a acceptable hydrate or solvate thereof, as an active pharmaceutical ingredient, in combination with one or more pharmaceutically acceptable carriers or excipients. The choice of excipient, to a large extent, depends on factors, such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.
The pharmaceutical composition described herein is preferably an Amlodipine Oral Liquid Formulation. The oral liquids pharmaceutical composition may include, but are not limited to, solutions (both aqueous and nonaqueous), suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. It is envisioned that solution/suspensions are also included where certain components described herein are in a solution while other components are in a suspension. In some embodiments, the oral liquid formulation is a suspension.
INSTRUMENTS
XRPD: X-ray diffraction data is obtained using a Bruker AXS D8 advance (or) equivalent X-ray Diffractometer, CuKa radiation, wavelength 1.54 A.
TGA: TGA measurement is performed using a TGA55; TRIOS software V4.3.1.39215, temperature range 30°C-300°C and 10°C/min.

DSC: DSC measurement is performed using DSC25; TRIOS software V4.3.1.39215, temperature range 25°C-300°C and 5°C/min.
KF: KF results is obtained using Metrohm; 870KF Titrino plus.
EXAMPLES
Example-1: Process of Crystalline hydrate Form-I of Amlodipine benzoate
Phthaloyl amlodipine (25.0 g, 1 equivalent) was treated with aqueous monomethyl amine solution (Aqueous 40%, 75 ml, 3.0 volumes) at 30°C-50° C in methyl tert-butyl ether (250 ml, 10.0 volume). After completion of reaction, organic layer was separated and aqueous layer back extracted with methyl tert-butyl ether (50 ml X 2 times). Washed the combined methyl tert-butyl ether layer with water (50 ml X 2 times). Distilled out approximately 2.0 volume of methyl tert-butyl ether (50 ml) at atmospheric pressure, cooled the reaction mass to 10°C-30 °C and added methyl tert-butyl ether (75 ml, 3.0 volume) to the reaction mass. Added slowly benzoic acid solution (5.09 g, 0.9 equivalent) dissolved in methyl tert-butyl ether (75 ml, 5.0 volume) at 10°C-30°C. Maintained the reaction mass for 1.0-2.0 hour at 20°C-30°C, filtered the reaction mass and washed with methyl tert-butyl ether (50 ml, 2.0 volume). Dried the product at 50°C-65°C for 8.0 hours in vacuum tray dryer. Output: 21.9 g; yield: 83.42%; HPLC purity: 99.79%; Water content by KF: 6.31% w/w;XRPD peaks: 4.91,9,78,10.76,11.04,11.43,12.61,13.19,13.69,14.42.15.75, 16.58, 17.54, 18.50, 19.19. 19.74, 20.61, 21.24, 21.57, 22.03. 22.96, 23.35, 23.74, 23.96, 24.97. 25.59. 26.81, 27.02, 27.53, 28.62, 29.59, 30.12, 30.62, 31.16, 31.91, 33.48,34.45,34.73,35.36,35.98,36.48,37.55,38.94,39.25,39.72±0.2° 29 (Fig. 1); TGA: 5.68 weight percentage loss (Fig. 2); DSC: Endotherm with onset temperature 87.24°C (Fig. 3)
Example-la: Process of crystalline dihydrate Form I of Amlodipine benzoate
Phthaloyl amlodipine (301.5 gm, 1 equivalent) was treated with aqueous monomethyl amine solution (Aqueous 40%, 1200 ml, 4.0 volumes) at 30°C-37°C and maintained for 12 hours. Added aqueous monomethyl amine solution (Aqueous

40%, 150 ml, 0.5 volumes) at 30°C-37°C, stirred for 12 and then stirred for 8 hours at 40°C-46 ° C. After completion of reaction, added water (600 ml, 2 volume) into the reaction mass, stirred the reaction mass at 0°C-10 °C for 2 hours and filtered. The isolated solid was washed with water (1200 ml, 4 volume). The isolated wet solid was partitioned between ethyl acetate (2400 ml, 8 volume) and water (300 ml,
1 volume) followed by layer separation. The ethyl acetate layer was cooled to 0°C
-10°C, added water (60 ml, 0.2 volume) and benzoic acid (67.0 gm, 0.98 equivalent)
dissolved in the ethyl acetate (600 ml, 2 volume). The wet solid was filtered after
12 hours of maintenance at 0°C -10 °C. The Amlodipine benzoate dihydrate was
obtained after drying the wet solid at 30°C -42 °C for 8 hours.
Output- 257 gm, yield-81.43%; HPLC purity: 99.87%.; Water content: 6.36%
XRD: 5.01, 9.87, 10.85, 11.13, 11.56, 12.71,13.28, 13.71, 14.52,15.91, 16., 17.63, 18.60, 19.29, 19.84, 20.71, 21.37, 21.66, 22.14, 23.01, 23.49, 24.09, 25.09, 25.70, 26.63, 26.90, 27.13, 27.63, 28.41, 28.72, 29.69, 30.25, 30.70, 31.26, 32.02, 32.67, 33.11, 33.58, 34.02, 34.69, 34.85,35.47,36.08, 37.63,38.01, 38.98.
Exaraple-2: Process of Crystalline Form-H of Amlodipine benzoate
Phthaloyl amlodipine (50g, 1.0 equivalent) was treated with aqueous monomethyl amine solution (Aqueous 40%, 200 ml, 4.0 volume) at 30°C -50°C in methyl tert-butyl ether (500ml, 10.0 volume). After completion of reaction, organic layer was separated and aqueous layer back extracted with methyl tert-butyl ether (100 ml X
2 times). Washed the combined methyl tert-butyl ether layer was washed water (100
ml X 2 times). Added methyl tert-butyl ether (100 ml, 2.0 volume) in to the organic
layer and filtered through celite bed. Distilled out approximately 2.0 volume of
methyl tert-butyl ether (100 ml) at atmospheric pressure and then equipped Dean-
Stark apparatus for removal of water azeotropically. After completion of azeotropic
distillation, cooled the reaction mass to 10°C -30 °C and added methyl tert-butyl
ether (350 ml, 7.0 volume) to the reaction mass. Added slowly benzoic acid solution
(10.18 g, 0.9 equivalent) dissolved in methyl tert-butyl ether (250 ml, 5.0 volume)
at 10°C -30°C slowly. Maintained the reaction mass for 1.0-2.0 hour at 20°C -30

°C, filtered the reaction mass and washed with methyl tert-butyl ether (50 ml, 2.0 volume). Dried the product at 50°C -65 °C for 8.0 hours in VTD.
Output: 35.0g; yield: 71.06%; HPLC purity: 99.91%; Water content by KF: 0.21% w/w; XRPD peaks: 4.39, 6.02, 8.49, 11.14, 11.97. 12.19, 13.43, 14.03, 15.52, 15.27, 15.89, 16.66, 17.07, 17.68, 19.89, 20.50. 20.92. 22.31. 23.03, 23.89. 24.72, 25.33, 26.24, 26.62, 27.32, 27.75, 28.54, 29.25, 30.14, 32.39, 32.85, 34.02, 35.49 ±0.2° 20 (Fig. 4); TGA: 0.741 weight percentage loss (Fig. 5); DSC: Endotherm with onset temperature 136.86°C (Fig. 6)
ExampIe-3: Process of crystalline Form-III of Amlodipine benzoate
Phthaloyl amlodipine (20g, 1 equivalent) was treated with aqueous monomethyl amine solution (Aqueous 40%, 80 ml, 4.0 volume) at 30°C -50 °C in toluene (100 ml, 5.0 volume). After completion of reaction, organic layer was separated and aqueous layer back extracted with toluene (20 ml X 2 times). Washed the combined toluene layer with water (40 ml X 3 times). Distilled out approximately 1.0 volume of toluene (20 ml) under vacuum below 40°C. Cooled the reaction mass to 10°C -3 0°C and added toluene (180ml, 9.0 volume) to the reaction mass. Added slowly benzoic acid solution (4.07 g, 0.9 mole eq.) dissolved toluene (100 ml, 5.0 volume) at 10°C -30°C. Maintained the reaction mass for 1.0-2.0 hour at 10°C -30°C, filtered the reaction mass and washed with toluene (20 ml, 1.0 volume). Dried the product at 50°C -65°C for 8.0 hours in VTD.
Output: 16.0g; yield: 81.21%; HPLC purity: 99.79%; Water Content by KF: 0.15% w/w; XRPD peaks: 4.09, 5.60, 7.29, 8.17,10.47,11.41.12.17,12.38.12.83.14.09, 14.65, 15.58. 16.29, 16.83, 17.82, 18.27, 18.69, 19.75. 20.55, 20.81, 21.17, 21.97, 22.27, 22.64, 23.80. 24.08. 24.34. 25.39, 25.99, 26.52, 27.12, 27.94, 28.26, 29.20, 31.24, 32.24, 33.06, 33.63, 34.52,35.06,36.08, 37.74±0.2° 20 (Fig. 7); TGA: 2.803 weight percentage loss (Fig.8); DSC: Endotherm with onset temperature 125.96°C (Fig. 9).

Example-4: Process of crystalline monohydrate Form IV of Amlodipine benzoate
Phthaloyl amlodipine (151.0 gm, 1 equivalent) was treated with aqueous monomethyl amine solution (Aqueous 40%, 600 ml, 4.0 volumes) at 25°C -35 ° C and maintained for 23 hours. After completion of reaction, added water (300 ml, 2 volume) into the reaction mass and filtered the solid after maintaining the reaction mass at 0°C -10°C for 2 hours. The isolated solid was washed with water (600 ml, 4 volume). The isolated wet solid (20gm equivalent) was dissolved in ethyl acetate (200 ml, 10 volume) and cooled to 0°C -10 °C followed by addition of benzoic acid (4.1 gm, 0.90 equivalent) dissolved in the ethyl acetate (40 ml, 2 volume). The wet solid was isolated after filtration followed by ethyl acetate washing (40 ml, 2 volume). The Amlodipine benzoate monohydrate was obtained after drying the wet solid at 30°C -42 °C for 8 hours.
Output-16.1 gm, yield-81.76%; HPLC purity: 99.56%; Water content: 3.33%;
XRD peaks: 6.71, 7.93, 11.08, 12.19, 12.46, 12.77, 13.37, 14.32, 15.65, 17.034, 17.08, 18.12, 18.60, 19.13, 19.82, 19.37, 20.06, 21.06, 21.71, 22.20, 22.62, 23.37, 24.00, 24.31, 25.06, 25.85, 26.23, 26.84, 27.44, 27.66, 28.80, 29.31, 29.81, 30.33, 31.32, 32.11, 32.62, 33.69, 35.37,36.40, 37.65,38.00, 38.72, 39.26.
ExampIe-5: Process for preparation of Amlodipine benzoate amorphous form.
Phthaloyl amlodipine (l00g, 1.0 equivalent) was treated with aqueous monomethyl amine solution (Aqueous 40%, 400 ml, 4.0 volume) at 30°C -50 °C in methyl tert-butyl ether (1000ml, 10.0 volume) for 8-10 hours. After completion of reaction, organic layer was separated and aqueous layer back extracted with methyl tert-butyl ether (200 ml X 2 times). Washed the combined methyl tert-butyl ether layer was washed water (200 ml X 4 times). Added methyl tert-butyl ether (200 ml, 2.0 volume) in to the organic layer and filtered through Cellite bed. Distilled out approximately 2.0 volume of methyl tert-butyl ether (200 ml) at atmospheric pressure. Take 50g equivalent reaction mass for further experimentation. Cooled the reaction mass to 10°C -30 °C and added methyl tert-butyl ether (350 ml, 7.0 volume) to the reaction mass. Added slowly benzoic acid solution (10.18 g, 0.9 equivalent) dissolved in methyl tert-butyl ether (250 ml, 5.0 volume) at 10°C -30 oC slowly. Maintained the reaction mass for 1.0-2.0 hour at 20-30 °C, filtered the reaction mass and washed with methyl tert-butyl ether (50 ml X 2 times, 2.0 volume). Dried the product at 60°C -65 °C for 8.0 hours in VTD.
Output: 38.0g; yield: 77.14%; HPLC purity: 99.69%; XRPD: Amorphous

We Claim:
1. A crystalline hydrate of Amlodipine benzoate.
2. The crystalline hydrate of Amlodipine benzoate as claimed in Claim 1 is a crystalline dihydrate Form-I of Amlodipine benzoate characterized by at least one of the following:
i. comprising about 6.3% w/w of water; ii. an X-ray powder diffraction (XRPD) pattern comprising peaks at about
4.9,10.7andl3.7±0.2°2θ; iii. an X-ray powder diffraction (XRPD) pattern further comprising peaks at
about 9.7,15.7,19.2,22.0,24.9 and 25.6±0.2° 2θ; or iv. an X-ray powder diffraction (XRPD) pattern substantially the same as
depicted in Fig. 1.
3. A process for the preparation of crystalline dihydrate Form-I as claimed in claim
2, of comprising:
a) contacting phthaloyl amlodipine with monomethyl amine optionally in methyl tert-butyl ether to obtain Amlodipine free base;
b) contacting Amlodipine free base with benzoic acid in methyl tert-butyl ether; and
c) isolating crystalline hydrate Form-I of Amlodipine benzoate.
4. The crystalline hydrate of Amlodipine benzoate as claimed in Claim 1 is a
crystalline monohydrate Form-IV of Amlodipine benzoate characterized by at
least one of the following:
i. comprising about 3.33% w/w of water; ii. an X-ray powder diffraction (XRPD) pattern comprising peaks at about
7.93and l3.37±0.2°2θ; iii. an X-ray powder diffraction (XRPD) pattern further comprising peaks at
about 7.93,11.08,12.77,20.06,25.85 and 28.8±0.2° 2θ; or iv. a4n X-ray powder diffraction (XRPD) pattern substantially the same as
depicted in Fig. 10.
5. A crystalline anhydrous form of Amlodipine benzoate.

6. The crystalline anhydrous form of Amlodipine benzoate as claimed in claim 5,
is a crystalline Form-II of Amlodipine benzoate characterized by at least one of
the following:
i. comprising less thanl% w/w of water; ii. an X-ray powder diffraction (XRPD) pattern comprising peaks at about
4.4, 6.0 and 12.1±0.2° 2θ; iii. an X-ray powder diffraction (XRPD) pattern further comprising peaks at
about 8.5,11.9,19.9,20.5,20.9, 22.3, 23.0 and 23.8±0.2° 2θ; iv. an X-ray powder diffraction (XRPD) pattern substantially the same as
depicted in Fig. 4.
7. The crystalline anhydrous form of Amlodipine benzoate as claimed in Claim 5
is crystalline Form-Ill of Amlodipine benzoate characterized by at least one of
the following:
i. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.1
and5.6±O.2°2θ; ii. an X-ray powder diffraction (XRPD) pattern further comprising peaks at
about 11.4,12.3,12.8,15.5,19.7,23.8,24.0 and 24.3±0.2° 2θ; or iii. an X-ray powder diffraction (XRPD) pattern substantially the same as
depicted in Fig. 7.
8. A process for the preparation of Amlodipine benzoate comprising:
a) contacting phthaloyl amlodipine with monomethyl amine in a solvent to obtain Amlodipine free base;
b) contacting Amlodipine free base with benzoic acid in a solvent; and
c) isolating Amlodipine benzoate.

9. An amorphous form of Amlodipine benzoate.
10. A Pharmaceutical composition comprising Amlodipine Benzoate in an amorphous form or crystalline Form 1, Form -II, Form -III, Form-IV or a acceptable hydrate or solvate thereof as claimed in Claims 1-9.