FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION: "Novel polymorph of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-
amine"

2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field of invention:
This invention relates to novel crystalline form of Valsartan, designated as Form C and its solvates thereof, processes for their preparation, pharmaceutical compositions containing said polymorphs and their use in medicine.
Background of the invention:
(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine commonly known as Valsartan has the following structure (Formula I):

_

Valsartan is a member of the class of agents termed angiotensin-II receptor antagonists having effective anti-hypertensive activity with an excellent profile of safety and tolerability. Activation of angiotensin (AT) receptors in the outer membrane of vascular smooth muscle cells of the heart and arteries causes the tissues to constrict. AT-I receptors are activated by an octa-peptide, angiotensin-II. Angiotensin-II helps to maintain constant blood pressure despite fluctuations in a person's state of hydration, sodium intake and other physiological variables. Angiotensin-II also performs the regulatory tasks of inhibiting excretion of sodium by the kidneys, inhibiting nor-ephedrin reuptake and stimulating aldosterone biosynthesis. By inhibiting angiotensin-II binding to AT receptors, valsartan disrupts the vasoconstriction mediated by AT receptors.
Valsartan is therefore a non-peptide angiotensin-II antagonist, inhibits the actions of angiotensin-II on its receptors, thus preventing the increase of blood pressure produced by the hormone-receptor interactions. Hence it is used in the treatment of cardiovascular complaints such as hypertension and heart failure. Comparative trial studies have shown that valsartan is equally effective as angiotensin-converting enzyme (ACE) inhibitors,
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calcium-channel blockers and a-blockers, and is generally better tolerated. Valsartan is marketed as the free acid under the name trade name DIOVAN, however, its combination with diuretics, such as hydrochlorothiazide have specific advantage as anti-hypertensive agent.
The synthesis of Valsartan and its intermediates was reported in patent (US patent no. 5,399,578) and Bioorganic & Medicinal Chemistry Letters, vol. 4, pp 29-34, 1994. However this patent fails to disclose any crystalline forms of Valsartan.
The present invention relates to the solid state physical properties of Valsartan. These properties can be influenced by controlling the conditions under which Valsartan is obtained in solid form. Solid state physical properties include, for example, the flowability/fluidity of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product/composition. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous/lipid fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state properties of a compound may also affect its behavior on compaction and its storage stability. The physical characteristics of a compound are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to different thermal behavior from that of the amorphous material or another polymorphic form.
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Thermal properties of a pharmaceutical compound is measured in the laboratory by using techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetric (DSC) and can be used as a basic tool to distinguish some polymorphic forms from others. A particular polymorphic form will give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state C NMR spectroscopy and infrared spectrophotometry.
A crystalline form of a substance has well-defined crystal lattices and distinct spectral characteristics when subjected to X-Ray crystallography; however, an amorphous form will exhibit a "smearing" of some of those properties due to the lack of a specific crystal order. An amorphous substance will produce a near featureless PXRD pattern although the diffraction pattern of a crystalline form of the same substance may have many well-resolved reflections. Generally, molecular interactions caused by tight crystal packing make a substance more thermally stable and less soluble than the substance in an amorphous state. Although thermal stability is a desirable characteristic of a pharmaceutical compound, it is often the case that increased, rather than decreased, solubility is desired. The rate of dissolution of an active ingredient in a patient's gastric fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. Increased solubility of a pharmaceutical agent in aqueous fluids, therefore, can increase bioavailability. The effect that the solid-state has on bioavailability may be so significant that a crystalline form of a drug cannot be considered bioequivalent to the amorphous form.
In US patent No. 5399578 example 16, the Valsartan obtained from ethyl acetate indicated to have a melting intervals ranging from 105 to 115 °C. In the Merck index, Valsartan is described as crystals from di-isopropyl ether having a melting point of 116 to 117 °C. However, in our hands the product obtained from diisopropyl ether was a sticky solid which upon drying yielded Valsartan having a melting range of 70 to 79 °C and was characterized to be amorphous.
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It is further substantiated by findings of Marti et al (WO 02/06253, page 2, paragraph 1) that the X-ray diffraction pattern of valsartan free acid obtained from prior process consists essentially of a very broad, diffused X-ray reflection; and therefore designated as almost amorphous under X-Ray.
Subsequently, WO03/089417 disclosed new crystalline forms of Valsartan designated as 'Form I' and 'Form II' and their preparation methods.
Yet another patent application WO04/083192 disclosed new crystalline forms of Valsartan designated as 'Form I to Form XI and methods for their preparation. This patent also discloses pure amorphous form (of Valsartan having DSC thermogram, lacking melting point above 1 J in the temperature region of 80 to 100 degree Celsius) on a DSC thermogram and a process for the preparation of the same. The patent also talks about interconversion of one Form to another form or vice versa.
It has been observed that the process of refluxing valsartan in solvents like toluene led to partial or complete racemization of valsartan under the experimental conditions, thereby contaminates valsartan with the unwanted isomer. Valsartan is not stable to higher temperature operations and therefore these processes are not suitable for preparation of valsartan in its enantiomeric crystalline forms.
Thus it is clear from the foregoing discussion, it would be desirable to have valsartan in a stable crystalline form having improved bulk handling and dissolution properties and this becomes the object of the present invention
Summary of the invention:
In one aspect, the present invention relates to a new crystalline form of Valsartan which is hereinafter designated as Form C and its solvates thereof. More particularly, the present invention relates to a novel crystalline form of Valsartan denoted as Form C as characterized by a powder X-ray diffraction pattern with peaks at about 13.85 5.256, 7.443, 20.316, 24.017, 25.11, 12.800, 11.733, 9.662, 15.684, and 17.023 + 0.30 degrees 2
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theta angles. The 'Form C valsartan of the present invention is also characterized by a DSC thermogram having a melting interval having maxima between 106 to 113 °C. The Valsartan 'Form C of the present invention has a crystal content of at least 20 %, preferably 50% and more preferably over 70 % having characteristic peak at 7.443, 13.851, 12.800, 11.733, 14.683, 24.01 and 25.11 ± 0.30 degrees 2 theta angle on a PXRD diagram and a DSC thermogram having an endotherm at 106 to 113 °C.
In a further aspect, the present invention relates to a process for preparing Valsartan in crystalline 'Form C which includes the steps of suspending amorphous or partially crystalline valsartan in a hydrocarbon solvent especially toluene at a temperature where valsartan is stable to racemization; agitating the suspension for a period of 24 hours to 7 days; filtering the crystals in the suspension to isolate Valsartan 'Form C of the present invention.
In another aspect, the present invention relates to the use of new polymorph 'Form C of Valsartan and their solvates thereof for producing an anti-hypertensive/cardiovascular effect in mammals, including human patients for treating hypertension. Valsartan 'Form C and its solvates thereof can be formulated into a variety of compositions for administration to humans and mammals. Pharmaceutical compositions of the present invention contain Valsartan 'Form C and its solvates thereof, optionally as mixtures with other crystalline forms and/or other active ingredients such as hydrochlorothiazide. In addition to the active ingredient (s), the pharmaceutical compositions of the present invention can contain one or more commonly used pharmaceutical excipients. Excipients are added to the composition for a variety of purposes.
Brief description of the accompanying Drawings
Figure 1 represents Powder X-Ray diffraction pattern (PXRD) of 'Form C of Valsartan prepared as in example 1.
Figure 2 represents Differential Scanning Calorimeter record of 'Form C of Valsartan prepared as in example 1.
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Detailed description of the invention:
As used herein, the phrase "Valsartan 'Form C", where 'C is Roman numerals/letters refers to a crystalline form of Valsartan that one of skill in the art can identify as a distinct entity distinguishable from other crystalline forms of Valsartan based on the characterization provided herein. As used herein, the phrase having "at least one characteristic of 'Form C refers to a crystalline form of Valsartan that possesses one of the PXRD peaks or endotherms of a DSC thermogram provided herein. For example, a single or a combination of PXRD peaks which is not found in another crystalline form of Valsartan is enough to show at least one of the characteristics of Form 'C. A single or a combination of endotherms of a DSC thermogram may also serve the same purpose.
In one aspect, this invention provides novel Valsartan in a specific and distinguishable crystalline form that is denoted as 'Valsartan Form C". The character of this new form is identified and confirmed by PXRD patterns and Differential Scanning Calorimeter thermogram (also referred as DSC) obtained from a sample thereof which are provided as FIGS. 1 to 4 respectively. The PXRD pattern shows at least one characteristic peak at about 13.851 + 0.2 degrees2 theta. More particularly the PXRD pattern shows characteristic peaks at 13.85 5.256, 7.443, 20.316, 24.017, 25.11, 12.800, 11.733, 9.662, 15.684, and 17.023 + 0.30 degrees 2 theta angles.
Furthermore, DSC shows a characteristic endotherm at about 106 to 113 °C for Form C. The differential enthalpy analysis (DSC) of the 'Form C was carried out using a TA Q100 instrument with a standard open pan arrangement, calibrated by reference to indium. For the calorimetric analysis 2.0 mg of Form C was used, as obtained in EXAMPLE 2, in a crimped and pierced aluminum cup and scanned in a temperature range from 0 to 160 degree C with a rate of heating of 5 deg. C./minute.
The PXRD pattern was measured on a SIEMAN D500 40KV/30mA powder X-Ray Diffractometer with a solid state detector. Copper radiation of 1.5406 A0 wavelength was
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used. The crystalline 'Form C of Valsartan has X-ray powder diffraction pattern as substantially as shown in the Figure 1 and the characteristic peaks with their 2 theta value and corresponding d spacing and relative intensity in percentage are listed in the table given below.

2-theta values in degrees D spacing Percentage relative intensity
5.256 16.8009 68.1
7.443 11.868 40.6
9.662 9.147 26.5
11.783 7.536 27.0
12.8001 6.9102 34.8
13.851 6.388 34.8
14.683 6.028 24.1
15.684 5.646 36.3
17.023 5.2044 33.9
20.316 4.367 39.9
24.017 3.702 27.6
25.111 3.543 28.2
In one embodiment, the present invention provides a process for preparing Valsartan in a crystalline form that denoted as 'Form C having at least one characteristic listed above. The process includes the steps of providing a suspension of Valsartan in an organic solvent selected from toluene, hexane, cyclohexane or the like, subjecting it to agitation at a temperature starting from 0 degree to 60 degrees for longer duration till the required crystallinity is obtained and isolating the crystals formed in the suspension. Further, the process optionally includes the steps of reducing the temperature of the Valsartan suspension and maintaining the suspension at reduced temperature for a holding time.
In a preferred embodiment of the present invention, Valsartan is suspended in the solvent especially toluene at a temperature of 20 to 35°C to form a fine suspension in said solvent followed by maintaining the mass under constant stirring for about 24 hours to 7
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days. The amorphous or partially crystalline (partially crystalline is referred to a sample of Valsartan having amorphous Form as well as crystalline forms). Alternately, the sample of Valsartan can be subjected to shearing in the said solvents for a longer period of time. It has been found that when the shearing speed is increased, the conversion to crystalline 'Form C is faster and normally with in a period of 24 hours, about 60% of amorphous valsartan converts to stable crystals of 'Form C. The suspension may be further cooled to a temperature of -5 to +5°C to obtain pure 'Form C of Valsartan. The 'Form C crystals can then be separated from the mixture by conventional means such as filtration, centrifugation etc. and can be optionally dried at ambient or elevated temperatures.
The hydrocarbon solvent (toluene) is used in about 5 to 30 volumes relative to the weight of Valsartan used and preferably the volume of solvent is 10 to 15 times that of vaslartan. The starting valsartan is preferably stirred in the said solvents for about 50 to 150 hours, and more preferably about 72 to 125 hours. The 'Form C crystals of valsartan is stable to the experimental conditions.
In an alternate embodiment of the present invention the amorphous, or partially crystalline or any crystalline form of Valsartan can be converted to crystalline 'Form C by way of the present process. More preferably an amorphous form of Valsartan is converted to a stable crystalline form (Form C) by using the process of the present invention.
In another aspect, according to the present invention, Valsartan 'Form C and its solvates thereof are useful for treating patients with hypertension and for producing an anti-hypertensive/cardiovascular effect in mammals, including human patients. Valsartan 'Form C can be formulated into a variety of compositions for administration to humans and mammals for treatment of above diseases.
Pharmaceutical compositions of the present invention contain Valsartan 'Form C and its solvates thereof, optionally as mixture with other crystalline forms and/or other active
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ingredients such as hydrochlorothiazide. In addition to the active ingredient (s), the pharmaceutical compositions of the present invention can contain one or more commonly used pharmaceutical excipients. Excipients are added to the composition for a variety of purposes.
Valsartan 'Form C can be administered for treatment of hypertension by any means that delivers the active pharmaceutical ingredient (s) to the site of the body where competitive inhibition of an AT-I receptor exerts a therapeutic effect on the patient. For example, administration can be oral, buccal, parenteral (including subcutaneous, intramuscular, and intravenous) rectal, inhalant and ophthalmic. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. Valsartan 'Form C can be conveniently administered to a patient in oral unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs. The active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
Accordingly, Valsartan 'Form C can be milled into a powder and be used in a pharmaceutical product/composition or physically modified such as by granulation to produce larger granules. Valsartan 'Form C can also be used to prepare a liquid pharmaceutical composition by dissolving or dispersing or suspending/emulsifying it in a pharmaceutically acceptable liquid medium such as water, glycerin, vegetable oil and the like as discussed in greater detail below.
When a dosage form such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure from a punch and dye.
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Solid and liquid compositions can also be dyed using any pharmaceutical^ acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, Valsartan 'Form C and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. Liquid pharmaceutical compositions can contain emulsifying/suspending agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
Selection of particular excipients and the amounts to use can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field. The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
A comparative study related to improved efficacy of the present polymorphic form i.e., 'Form C with respect to the existing polymorphs is to be studied and compiled. The proposed comparative study includes the percentage crystallinity studies, stability studies, physico-mechanical property studies (for example grinding and compression effects), solubility studies, intrinsic dissolution studies etc.
The following non-limiting examples are provided to further illustrate the invention with specific embodiments stipulated in the present invention.
Examples
Example 1: Valsartan 'Form C
In a reaction vessel, 100 gm Valsartan (prepared as per method given in US patent 5399578) was dissolved in 1000 ml toluene at about 30°C. The mixture was stirred for about 72 hours, the white crystals obtained was filtered on a crucible and dried under
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vacuum at 50°C. The solid obtained shows a PXRD pattern of 'Form C as in Fig. 1 and a DSC thermogram of Fig. 2. Purity 99.8%, yield 98.0%.
Example 2: Valsartan 'Form C
In a reaction vessel, 100 gm Valsartan (prepared as per method given in US patent
5399578) was dissolved in 1200 ml toluene at about 45°C. The mixture was stirred for
about 50 hours and cooled to a temperature of 0 °C. The white crystals obtained was
filtered on a crucible and dried under vacuum at 30°C. The solid obtained shows a PXRD
pattern of' Form C as in Fig. 1 and a DSC thermogram of Fig. 2. Purity 99.8% and yield
98%.
Example 3: Valsartan 'Form C
In a reaction vessel, 100 gm Valsartan (prepared as per method given in US patent 5399578) was dissolved in 2000 ml toluene at about 30°C. The mixture was stirred for about 100 hours the white crystals obtained was filtered on a crucible and dried under vacuum at 30°C. The solid obtained shows a PXRD pattern of 'Form C as in Fig. 1 and a DSC thermogram of Fig. 2. Purity 99.8% and yield 99%.

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