Claims:WE CLAIM,
1. A Meglumine salt of Telmisartan in the form of amorphous or crystalline or mixture of amorphous and crystalline.
2. A Meglumine salt of Telmisartan according to claim 1 having DSC peaks as shown in Figure 7 or Figure 25.
3. A Meglumine salt of Telmisartan according to claim 1 having PXRD peaks as shown in Figure 12.
4. A Meglumine salt of Telmisartan according to claim 1 having FTIR peaks as shown in Figure 14.
5. A Meglumine salt of Telmisartan according to claim 1 having drug release profile as shown in Figure 2 or Figure 3 or Figure 4 or Figure 5.
6. A process for the preparation of a Meglumine salt of Telmisartan according to any one of claims 1-6 wherein the process comprises steps of,
(a) Melting Meglumine at 130°C;
(b) Addition of Telmisartan to the molten mass of Meglumine obtained in step (a) and thereby dissolving Telmisartan;
(c) The resultant clear molten liquid containing Meglumine and Telmisartan in a china dish was immediately cooled at -80ºC and thereby solidifying Meglumine salt of Telmisartan.
7. A pharmaceutical composition comprising a Meglumine salt of Telmisartan according to any one of claims 1-5 or prepared according to the process claimed in claim 6 and one or more pharmaceutically acceptable excipients. , Description:FIELD OF THE INVENTION
The present invention relates, in general, to a pharmaceutical field and more precisely it relates to a crystal modification of the commercially available drug Telmisartan having improved dissolution, stability and bioavailability. The present invention also provides a facile method for preparing such crystal modification of Telmisartan.

BACKGROUND OF THE INVENTION
Telmisartan is an Angiotensin II receptor blocker (ARB) used for the treatment of hypertension and cardiovascular reduction in patients where Angiotensin Converting Enzyme (ACE) inhibitors prove ineffective. It is a white crystalline powder having poor water solubility along with pH dependent solubility where high solubility is achieved at pH < 3 or pH > 9. It exhibits high permeability, but due to its pH dependent solubility, the bioavailability is limited to 40-42% and is therefore classified as Biopharmaceutical Class II drug (Archives of Pharmacal Research, 2011, 34, 463-468).

Telmisartan exhibits polymorphism that manifests in three polymorphic states. Two are anhydrous forms (Form A and Form B) whereas, the third form (Form C) is a solvate. Form A has a needle like crystal habit and is the stable form having a melting point of 270°C. Form A is practically insoluble in water. Form B is the metastable form having a higher aqueous solubility than the former form with a melting point of 180°C. But this form is not a stable form and easily gets converted to Form A. Form C is the solvated form and has a polyhederal geometry. It is formed in formic acid-water mixtures. However, as soon as it is filtered out of the mother liquor, it gets converted to Form A (Journal of Pharmaceutical Sciences, 2000, 89, 1465-1479).

The commercially available Telmisartan is of Form A in the form of long needles with an electrostatic charge that is known to cause problems in production of pharmaceutical dosage forms. Difficulties in filtration, washing, isolation and drying are commonly encountered with Form A of Telmisartan due to its needle shape and electrostatic charge. WO 2007/147889 describes methods to prepare salts of Telmisartan with ammonium, choline, tert-butyl amine, arginine, meglumine, ethanolamine, piperazine, diehtylamine, sulphuric acid, maleic acid, tartaric acid, citric acid, fumaric acid, oxalic acid, benzenesulphonic acid, naphthalene-2-sulphonic acid, tris-(hydroxymethyl) amine and new polymorphic forms of Telmisartan that exhibited different crystal shape than needles (of Form A) with desirable properties. The patent describes preparation of Telmisartan salts by refluxing its solution prepared in organic or inorganic base with polar solvent followed by cooling at -10ºC, filtration and drying in a vacuum dryer. The shape of the Telmisartan salts obtained by the researchers was reported to be ‘round’. WO 2007/147889 also discloses preparation of Telmisartan granulates by dissolving it with a basic agent in an appropriate solvent followed by spray drying followed by mixing it with other excipients of tablet formulation. However, the prior art work does not provide any teaching or suggestion that the modified forms prepared therein have any influence on dissolution and bioavailability of Telmisartan.

Salts of Telmisartan and Meglumine were prepared by co-grinding where the salt formation was confirmed by characteristic absorption bands at (1550-1600) and ~1380 cm-1 due to asymmetric and symmetric vibration absorption band of carboxylate ion. The samples prepared by hard milling (vibratory mill) were converted to salt in a better way than those prepared by soft milling (roll mill). Zhong et al. discloses that the co-ground samples obtained from vibratory mill were able to release ~90% of drug in 5 min in intestinal fluid, whereas, the samples prepared by soft milling though initially exhibited high dissolution, gradually decreased in solubility as the base was digested by the buffer and drug precipitated in the medium itself (Drug Development and Industrial Pharmacy, 2014, 40, 1660-1669). This work though highlights the enhanced dissolution of Telmisartan in intestinal fluid, it does not reveal the resultant effect on bioavailability. Further, soft milling was observed not to aid in enhancing the dissolution of Telmisartan in intestinal fluid. It remains to be seen if the crystals produced by hard milling would remain stable or not.

Alatas et al. formulated co-crystals of Telmisartan with Oxalic acid using solvent evaporation and solvent drop grinding techniques (International Journal of Pharmacy and Pharmaceutical Sciences, 2015, 7, 423-426). The co-crystals prepared by both techniques were found to be identical in shape and characteristics having an enhanced dissolution profile in pH 7.5 compared to the pure drug. However, even with an enhanced solubility profile, co-crystals of Telmisartan and Oxalic acid were able to release only 55.7% of drug in 60 minutes in phosphate buffer pH 7.5.

The prior art suggests the use of Telmisartan and Meglumine in tablet formulations for complying with the pharmacopeial requirement of more than 85% release in 45 minutes in phosphate buffer pH 7.4. Briefly, Meglumine is dissolved in water and Telmisartan is added to it. Many times sodium hydroxide is also added to the Meglumine solution to enhance the alkalinity of the solution for enhancing the solubility of Telmisartan. This Telmisartan-Meglumine solution is then sprayed on mannitol in a spray dryer to obtain granules for compression into tablets (Journal of Pharmaceutical Investigation, 2017, 47, 163-171).

It is important to note that the commercially available Telmisartan is of form A, which is practically insoluble in water. Therefore, currently, the tablet formulations contain Meglumine and sodium hydroxide in order to make it soluble in water. In addition, the recommended dissolution fluid is phosphate buffer pH 7.4 that would further help in solubilizing Telmisartan. It is worth mentioning that the compendia require evaluating the release of Telmisartan in phosphate buffer pH 7.4. However, in practice, the commercial uncoated tablet would first encounter acidic pH in the stomach. Therefore, it seems essential to evaluate the release of Telmisartan from uncoated tablets in acidic pH too.

Hence, in light of these facts it was envisaged to probe the impact of co-processing Meglumine with Telmisartan using various methods so as to enhance its dissolution in both acidic and alkaline media. Further, different Telmisartan : Meglumine ratios were tried for investigating the role of Meglumine in influencing the dissolution rate of Telmisartan.

OBJECTS OF THE INVENTION
It is therefore one of the principle object of the present invention to provide physical modification of Telmisartan having improved stability, dissolution and pharmacokinetic profile which is to be used for the preparation of solid pharmaceutical oral dosage forms on industrial scale thus overcoming the problem of the poor solubility of Telmisartan under physiological conditions.

It is one of the further object of the present invention to provide a facile method for preparing such a physical modification having improved stability, dissolution and pharmacokinetic profile.

It is one of the further object of the present invention to provide pharmaceutical composition comprising physical modification of Telmisartan according to the present invention and process for the preparation thereof.
It is one of the further object of the present invention to use physical modification of Telmisartan according to the present invention in method of treating diseases/disorders related to Angiotensin II receptor.

It is one of the further object of the present invention to provide method of treating diseases/disorders related to Angiotensin II receptor which comprises administration of an effective amount of the physical modification of Telmisartan according to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows Photomicrographs of: A: Commercial sample of Telmisartan powder; B: Commercial sample of Meglumine; C: Physical mixture (1:2.5) of Telmisartan and Meglumine; D: Co-ground sample of Telmisartan and Meglumine (1:2.5); E: Product obtained after spray drying of Telmisartan-Meglumine (1:2.5) dissolved in water; F: Product obtained from Telmisartan- Meglumine melt cooled at room temperature: G: Product obtained from Telmisartan- Meglumine Melt Quenched Formulation (-80ºC).

Figure 2 shows Percentage Telmisartan released in Phosphate Buffer pH 7.4 from formulations prepared by different processes.

Figure 3 shows Percentage Telmisartan released in 0.1 N HCl from formulations prepared by different processes.

Figure 4 shows Release of Telmisartan in Phosphate Buffer pH 7.4 from Melt Quenched Formulations containing different ratios of Telmisartan and Meglumine.

Figure 5 shows Telmisartan released in 0.1N HCl from Melt Quenched Formulations containing different ratios of Telmisartan and Meglumine.

Figure 6 shows DSC thermographs of (a) Telmisartan, (b) Meglumine, (c) Meglumine heated to 150°C, (d) Meglumine cooled from (c) run and reheated.

Figure 7 shows DSC thermographs of (a) Physical Mixture; (b) Physical Mixture heated to 150°C; (c) Physical Mixture cooled from (b) and reheated; (d) Co-Ground; (e) Spray Dried; (f) Melt-Normal Cooled; (g) Melt-Quench Formulation.

Figure 8 shows DSC thermographs of Melt Quenched Formulation samples prepared by using different ratios of Telmisartan and Meglumine.

Figure 9 shows DSC thermograph of Telmisartan- Meglumine salt prepared by solvent evaporation as mentioned in WO 2007/147889.

Figure 10 shows X-ray Diffraction Patternof Telmisartan.

Figure 11 shows X-ray Diffraction Pattern of Meglumine.

Figure 12 shows X-ray Diffraction Pattern of Melt Quenched Formulation.

Figure 13 shows X-ray Diffraction Pattern of Telmisartan- Meglumine salt as provided in WO 2007/147889.

Figure 14 shows FT-IR spectra of (a) Telmisartan, (b) Meglumine, (c) Physical Mixture, (d) Melt Normal Cooled, (e) Melt Quenched Formulation.

Figure 15 shows DSC thermographs of Melt Quenched Formulation crystals after a; one day, b; 30 days, c; 60 days, d; 90 days of storage at 40°C temperature and relative humidity of 75± 5%.

Figure 16 shows Photomicrographs obtained during Hot Stage Microscopy of MQC sample from ambient to 300°C temperature at different temperatures.
Figure 17 shows Kinetic profile of pure drug, Brand X, Brand Y and MQF.

Figure 18 shows Kinetic profile of pure drug, marketed formulation and MQF.

DETAILED DESCRIPTION OF THE INVENTION
Polymorphic Form A is the commercially available form of Telmisartan. The DSC thermograph of the procured sample confirmed the commercial sample to belong to Form A as a melting peak was obtained at 270°C (Figure 6a). Further the crystals were needle like in shape (Figure 1a) and both these studies confirmed that the commercial sample was of form A.

Subjecting the commercial drug powder to dissolution studies in 0.1N HCl revealed that its dissolution was incomplete with only 52.68±3.44% (Figure 3) Telmisartan dissolution in 2 hours. In the official media (phosphate buffer pH 7.4) the dissolution was further compromised as only 6.17 ± 0.31% of Telmisartan dissolved after 2 hours (Figure 2).

Indian marketed tablets of Telmisartan (X) contain an alkalizing agent like Meglumine, Magnesium oxide, Magnesium dioxide, Di-potassium hydrogen phosphate or Sodium hydroxide. Subjecting the marketed tablet to the official dissolution medium (phosphate buffer pH 7.4), more than 85% of the dose dissolved in 15 minutes (Figure 2). But when the marketed tablet was subjected to dissolution in acidic media of 0.1N HCl, the dissolution progressed slowly and it took nearly one hour to dissolve 85% of the drug (Figure 3).

Although, the marketed dosage form complies with the official limit (Q-point of more than 85% in 45 minutes) in phosphate buffer pH 7.4 (official media), but the same cannot be held true in acidic medium of 0.1N HCl where the dissolution was significantly slower. This phenomenon gains importance as the tablet would be initially subjected to acidic conditions of stomach, and the tablet should dissolve faster in the gastric conditions because it is an immediate release uncoated tablet.

BEST MODE OF CARRYING OUT THE INVENTION

EXAMPLE-1: PROCESSING TECHNIQUES FOR PREPARING ALTERNATE FORMS CONTAINING TELMISARTAN AND MEGLUMINE
Telmisartan was processed with Meglumine in a constant ratio of 1:2.5 by employing different techniques mentioned below to understand the effect of different processes on crystal modification of the drug.

PHYSICAL MIXING
Telmisartan and Meglumine were intimately mixed in the predetermined ratio for 10 minutes.

CO-GRINDING
Telmisartan and Meglumine mixture was milled in a ball mill for 15 minutes at room temperature. Stainless steel milling jar (250 ml) containing appropriate mass of balls (15 mm) was used. One gram of the mixture was milled in jar with a ball/sample weight ratio of 30:1. The rotating speed was set at 200 rpm.

SPRAY DRYING
In this process, Meglumine was added to water along with Telmisartan. This mixture was stirred to dissolve both solids and was sprayed from spray dryer at rate of 1 ml per minute with inlet temperature of 70°C and outlet temperature of 50°C and aspirator rate of 50%.

MELTING NORMAL COOLING
In this process, known quantity of Meglumine was melted at 130 °C and into the same molten mass, Telmisartan was added and allowed to solubilize by stirring with a glass rod. The melt was allowed to cool and solidify at 25°C (room temperature).

MELT QUENCH FORMULATION (MQF)
In this process, known quantity of Meglumine was melted at 130°C and Telmisartan added to the molten mass where it dissolved immediately. The resultant clear molten liquid containing Meglumine and Telmisartan in a china dish was immediately cooled at -80ºC. The entire mass immediately solidified as a brittle white powder.

EXAMPLE-2: ANALYTICAL TECHNIQUES
HPLC ANALYSIS
The mobile phase consisted of a mixture of 50mM ammonium acetate adjusted to pH 3.8: ACN: methanol in ratio of 20:50:30 v/v. The mobile phase was pre filtered through 0.45µm polytetrafluoroethylene (PTFE) filter and sonicated for 15 minutes. The analysis was carried out under isocratic conditions at flow rate of 1ml/min at 25°C using a 250 x 4.6mm, 5µm, C18 column. Precisely, 5 mg of Telmisartan was weighted accurately and added to volumetric flask of 25 ml capacity. The volume was made up to the mark with methanol to obtain a final concentration of 200µg/ml. From this stock, serial dilutions were made by diluting it with mobile phase to obtain solutions of Telmisartan ranging from 1-1280 ng/ml. The final dilutions were filtered through 0.45µm membrane filter and analyzed on HPLC (Primade, Hitachi, Japan) in triplicate at 296 nm with run time of 8 min using UV detector. The HPLC system was operated with a Chromatography Data Station Software- Primade System Manager, Version 1.0. A Rheodyne 7725i (Thermo Fisher TM, US) injector with 20µl loop was used for sample injection.

DISSOLUTION ANALYSIS
The dissolution of Telmisartan from powders obtained by the different processing techniques were evaluated in both dissolution media i.e. 0.1N HCl as well as phosphate buffer pH 7.4 using USP dissolution apparatus 2 at a temperature of 37 ± 0.5 °C at 100 rpm.

IN VITRO DRUG RELEASE STUDIES
Although, pharmacopoeia suggests phosphate buffer pH 7.4 to be used for evaluating the release profile of Telmisartan from tablets, Telmisartan itself is not soluble in pH 7.4. The marketed formulations use different alkalizers, like Meglumine, magnesium oxide, etc. in the formulation so as to aid solubilization of the drug in phosphate buffer pH 7.4. The higher dissolution of Telmisartan from marketed tablets in pH 7.4 cannot be ascribed to alteration of media pH (due to the presence of alkalizers in the formulation) because no change in media pH was observed. However, in case of magnesium oxide, an alkaline surface was maintained owing to its inorganic nature, which did not allow it to dissolve in the dissolution medium (Tran et al., 2008)

Further, in the official media, no significant differences in Telmisartan dissolution profiles were observed for various formulations prepared by different processes and more than 80% of the drug within 45 minutes was released in official media (phosphate buffer pH 7.4). The only exception was physical mixture of Telmisartan and Meglumine that did not release more than 10% of Telmisartan (Figure 2). This strengthens the hypothesis, that unprocessed Meglumine does not have any effect on solubility and dissolution rate of Telmisartan. Hence, certain amount of co-processing of Meglumine and Telmisartan seems imperative for improving release profile of Telmisartan from its formulations. It is important to take into consideration that under practical situation the uncoated tablet is bound to face the gastric conditions first in the stomach. Hence, it seems reasonable to evaluate the release of Telmisartan in 0.1N HCl (Figure 3).

Under acidic conditions, the release rate of pure Telmisartan was improved as expected by its pH dependent solubility, but it was not more than 55%. Further, as observed in phosphate buffer, in acidic conditions too, physical mixture did not exhibit a marked effect on dissolution profile of Telmisartan. The dissolution profiles of processed formulations could be ranked for Telmisartan dissolution in acidic medium in the order: Spray Dried < Co-Ground < Fluidized Bed Dried = Marketed (X) tablet = Melt-Normal Cooled < MQF.

Since the MQF sample was found to exhibit excellent release rate, hence different ratios of Telmisartan and Meglumine ranging from 1:0.625 to 1:5 (Telmisartan : Meglumine) were evaluated. The release rate of Telmisartan from powders obtained by employing different ratios of Telmisartan and Meglumine was found to follow the order 1:5>1:2.5=1:1.25=1:0.625>Marketed Tablet (X) in phosphate buffer pH 7.4. This suggests overwhelming influence of melt quench technique on increasing the dissolution rate of Telmisartan.

The release rate was found to follow the order 1:5=1:2.5>1:1.25>1:0.625=Marketed Tablet (X) in 0.1N HCl. It is evident from Figures 4 and 5 that Telmisartan: Meglumine ratio of 1:5 and 1:2.5 when processed by melt quench technique exhibited best dissolution (>85%) in both phosphate buffer pH 7.4 and 0.1N HCl.

However, the marketed tablet (X) formulation exhibited greater than 85% dissolution of Telmisartan only in phosphate buffer pH7.4 and not in 0.1N HCl.

DIFFERENTIAL SCANNING CALORIMETRY (DSC) ANALYSIS
Thermal analysis was carried out using a Differential Scanning Calorimeter (DSC EVO 131, Setaram, France). Sample of 5-10 mg was sealed hermetically in an aluminium pan with a pin hole in its cap and heated over the range of 40-340°C unless specified in an atmosphere of nitrogen at a flow rate of 30 ml/min at a constant heating rate of 10°C/minute.

The DSC profiles of commercial samples of Telmisartan, Meglumine, and those obtained by subjecting them to different heating conditions are depicted in Figure 6. The thermographs obtained by subjecting the different formulations to DSC analysis are depicted in Figure 7. The peak temperatures and ?H values obtained from DSC analysis have been summarized in Table 1.

Table 1: Relative Temperature range and magnitude of heat exchange observed during DSC analysis of different formulations containing 1:2.5 ratio of Telmisartan and Meglumine
Sample Temperature Range
130°C Temperature Range 180°C Temperature Range
270°C
Peak Temp(°C) Expected ?H (J/g) ?H
(J/g) Peak Temp
(°C) ?H
(J/g) Peak Temp
(°C) ?H
(J/g)
Telmisartan - - - - - 269.8±
1.3 104.05±
0.65
Meglumine 131.13±
1.13 - 312.5±
2.35 - - - -
Physical Mixture 129.7±
0.26 214 216.1±
3.15 - - - -
Co-Ground 126.1 214 149.4 173 2.359 - -
Spray Dried 117.2 214 199.1 181.6 7.4 - -
Melt Normal Cooled 131.1 214 217.6 182.6 6.95 - -
Melt Quench Cooled 124.5±
0.7 214 144.4±
1.65 178.3 18.0±
0.8 - -
Note: Avg ± SD for the samples carried out in triplicates

It is evident in Figures 6 and 7, that there are three major zones of interest in all the thermographs. The first ranges around 130°C, second at 180°C, and third at 270°C. In the DSC thermograph of Telmisartan (Figure 6a) only a single peak at 270°C was observed, which corresponds to the melting point of Telmisartan. Meglumine on the other hand gave a sharp melting endotherm at 130°C (Figure 6b). Meglumine degraded above 250°C. Meglumine sample gave a single melting endotherm when it was heated to 150°C (Figure 6c). This sample was allowed to cool in the DSC pan itself to 40°C and again subjected to DSC analysis. It was observed that Meglumine recrystallized at 80°C and the same endothermic transition at 130°C was observed even during its second heating phase (Figure 6d).

In the physical mixture, a single peak at 130°C corresponding to melting of Meglumine was observed. However, no peak of Telmisartan was observed (Figure 7a). This might be due to solubilization of Telmisartan in molten Meglumine. Moreover, Meglumine also exhibits degradation peaks above 250°C. Therefore, the melting peak of Telmisartan was not observed clearly in this mixture. It is important to note that Telmisartan possesses a higher melting point of 270°C than Meglumine (130°C). The absence of characteristic melting peak of Telmisartan in the presence of Meglumine indicated some interaction between Telmisartan form A (commercial form) and molten Meglumine.

In the other mechanically processed mixtures, it was observed that the peak of Meglumine started to become smaller with significant reduction of ?H (of transition at 130°C) than the expected value of 214 J/g calculated theoretically from the fraction of Meglumine present in the mixture (Table 1). This brings us to the conclusion that all the processes contributed to an interaction of Meglumine and Telmisartan which could have played a role in stabilizing a new form of Telmisartan. Moreover, in all cases (Figure 7c-7g), a small peak at 180°C was observed which varied in its intensity and ?H value depending upon the type of process. The observed characteristic melting peak of Telmisartan form B (180°C) or Telmisartan-Meglumine salt in the presence of molten Meglumine (130°C) indicates that Telmisartan form B or Telmisartan-Meglumine salt was produced during heating of Telmisartan-Meglumine mixture.
Another interesting observation was made in the relationship of peaks at 130°C and 180°C in the compositions prepared after mechanical processes. As ?H at 180°C increased, the ?H pertaining to melting of Meglumine (130°C) reduced gradually for all processed mixtures.

To gain a better understanding of different events occurring in DSC pan, MQF samples prepared by using different ratios of Telmisartan and Meglumine (1:0.625, 1:1.25 and 1:2.5) were subjected to DSC analysis at a scanning rate of 2°C/min (Figure 8). Firstly, it was observed that with increasing amount of Telmisartan and decreasing amount of Meglumine in the samples, the peak at 180°C shifted towards 200°C. Secondly, in these samples, the intensity of endotherm at 130°C was observed to decrease and was completely removed in sample of 1: 0.625 ratio.

WO 2007/147889 reports melting of amorphous Telmisartan-Meglumine salt near 90°C and that of crystalline Telmisartan-Meglumine salt to be near 200°C. Hence, the observed shifting of melting point from 200°C in the samples containing lower amount of Meglumine to 180°C in samples containing higher amount of Meglumine could be due to the effect of molten Meglumine present in the DSC crucible. The samples containing higher amount of Meglumine would contain larger amount of molten Meglumine which will dissolve the Telmisartan- Meglumine salt to greater extent thus lowering the melting point to greater extent. However, when Meglumine is present in lower amount, the Telmisartan-Meglumine salt would not get easily dissolved in molten milieu and the melting point will not be lowered to a great extent.

In addition, thermographs in Figure 8 show two distinct closely spaced thermal events between 110°C to 125°C. The first event was a small endotherm in the temperature range of 100°C-120°C. The second event was the occurrence of an exotherm in the temperature range of 120°C-125°C. WO 2007/147889 does not report any such peak at these temperatures. The observed events indicate melting of amorphous Telmisartan-Meglumine salt (reported melting point 90°C) in the form of first endotherm, its transition to crystalline Telmisartan-Meglumine salt in the form of subsequent exotherm (reported temperature of 120°C) and the final melting of this crystalline Telmisartan-Meglumine salt at 200°C.
As a corollary, subjecting amorphous Telmisartan-Meglumine salt to temperatures ranging from 80°C to 120°C is very likely to result in its transformation to crystalline Telmisartan-Meglumine salt. This is quite likely to happen in wet granulation processes, fluidized bed processing, tray drying etc.

FTIR-ATR ANALYSIS
The spectrum of Telmisartan, Meglumine, Physical mixture and its Melt Quench Cooled form was recorded on FTIR-ATR spectrophotometer (Alfa, Bruker, Berlin, Germany). The ATR spectra were obtained in region of 4000 cm-1 to 500 cm-1.

To understand the interaction between Telmisartan and Meglumine, FTIR analysis of Telmisartan, Meglumine, their physical mixture and melt-normal cooled and MQF sample was carried out. The ATR spectra of Telmisartan depicted peak at 747 cm-1 pertaining to Ortho substituted out of plane bending of aromatic ring, whereas the band at 860 cm-1 represented para substituted out of plane bending of aromatic ring. The stretching of carbonyl group (-C=O) was depicted by band at 1684 cm-1, whereas, the aromatic -C=C- stretch was represented by peaks in range of 1453 to 1411 cm-1.

The ATR spectra of Meglumine is presented in Figure 14 along with the ATR spectra of Telmisartan, Telmisartan-Meglumine physical mixture and MQF sample. ATR spectra of physical mixture of Telmisartan and Meglumine depicted cumulative peaks of both compounds and no additional peaks were observed. But in MQF sample, the peak representing out of plane bending of Meta substituted aromatic ring of Telmisartan was reduced at 747 cm-1. Further, new peaks were also observed in range from 1600 cm-1 to 1500 cm-1 which correspond to formation of salt between Telmisartan and Meglumine where the peak at 1540 cm-1 represents the asymmetric CO2 bending and peak at 1396 cm-1 can be ascribed to symmetric CO2 bending. Similar FTIR spectra were reported by Zhong et al. (Drug Development and Industrial Pharmacy, 40, 2014, 1660-1669) after co-grinding Telmisartan and Meglumine for obtaining their amorphous salt. However, the XRD spectra of the co-ground sample exhibited a halo pattern. This essentially might be due to the excess mechanical stress exerted over the sample in the vibration mill. It is worth noting that the SEM analysis of the co-ground samples reported by Zhong et al. (Drug Development and Industrial Pharmacy, 2014, 40, 1660-1669) were of spherical shape and are similar to the structure of MQF sample obtained by the inventors.

EVALUATION OF FLOW PROPERTIES
The melt quenched crystals were evaluated for their flow and compressibility properties to evaluate the feasibility of using the powder for direct compression into tablets. Therefore, bulk density, tapped density, Carr’s index, Hausner’s ratio, and angle of repose of the crystals were determined.

The MQF crystals exhibited excellent flow and compressibility along with an ideal bulk density as summarized in the Table 2, exhibiting their worthiness for a directly compressible tablet.
Table 2: Flow properties of Melt Quenched Crystals
Flow Property Value Remarks
Bulk Density 0.625 ± 0.052g/ml Ideal tableting density
Tapped Density 0.810 ± 0.011g/ml -
Hausner’s Ratio 1.296 Passable Compressibility
Carr’s Compressibility Index 22.8 Passable Compressibility
Angle of Repose 30.1 ± 1.3° Excellent Flow Behavior

STABILITY STUDIES
Stability studies were carried out to evaluate the stability of the metastable form in the prepared formulation as metastable forms are known to get converted to the stable forms at higher temperature or under influence of humidity. Stability studies were carried out at 40°C temperature and 75±5% RH for 3 months using Environmental Chamber (Allyone, Mumbai, India). The samples were evaluated after 1, 2 and 3 months storage for their dissolution profile and thermal attributes.

The stability studies carried out over a period of three months did not indicate any change in thermographic attributes for Meglumine (130°C) or Telmisartan-Meglumine crystalline salt form (Figure 15). Also, in vitro release studies did not depict any change in release kinetics in 0.1N HCl or phosphate buffer pH 7.4 on evaluation of the same sample after 30 days, 60 days and 90 days of storage at 40°C temperature and relative humidity of 75±5%.
HOT STAGE MICROSCOPY
Hot stage microscopy was carried out for MQF samples to evaluate the changes occurring in the crystal lattice during the course of DSC. The samples were loaded on the slide and set under the microscope and temperature was raised from ambient to 300°C at a heating rate of 2°C per minute.

HOT STAGE PHOTOMICROGRAPHY
The structural changes occurring in the MQF sample were evaluated under hot stage microscopy. MQF initially exhibited a round shape crystalline structure with striations on its surface. Upon heating, the first microscopic change was observed above 80°C where the surface of the crystal started to smoothen. But on subsequent heating, above 100°C, several small crystals started to nucleate over the surface of large crystals till temperature reached 120°C, corresponding to the temperature where the newly observed endotherm ended and the exotherm started to appear in DSC analysis (Figures 16A-16C). The cracks on crystal surfaces started to get filled above temperature of 90°C subsequently followed by blackening of crystals after 120°C (Figure 16G-16N) giving it an opaque appearance which subsided after 200°C and transformed into needle type structure. This structure is characteristic of Form A of Telmisartan. These needle shaped crystals melted at a temperature of 270°C (Figure 16S and 16T).

MICROSCOPIC EXAMINATION
Polymorphic Form A of Telmisartan exhibited a needle like structure (Figure 1A), while Meglumine also existed in a thin rod shape (Figure 1B). A physical mixture of both does not exhibit any change in structure (Figure 1C). However, subjecting crystals to co-grinding (Figure 1D) and spray drying processes (Figure 1E), a platy habit was observed. The product of melt normal cooled crystals had a mixture of rhombohedral, needle and platy like crystal habit (Figure 1F). The MQF had a rhombohedral geometry (Figure 1G).

X-RAY DIFFRACTION ANALYSIS
The XRD patterns of Telmisartan (Figure 10), Meglumine (Figure 11), MQF prepared by using 1:2.5 ratio of Telmisartan-Meglumine (Figure 12) and peak assignments (Table 3) shows that the MQF sample was amorphous Telmisartan:Meglumine salt. Although, the XRD does not give a halo pattern as peculiar for any amorphous sample, but the peaks observed in the XRD of MQF were majorly similar to that of Meglumine, and no peaks having a similar pattern as reported for Telmisartan-Meglumine salt disclosed in WO 2007/147889 were present. Therefore, the prepared MQF sample can be confirmed to be an amorphous salt of Telmisartan and Meglumine.
Table 3: XRD Peaks of different samples
Pure DrugTelmisartan Meglumine Telmisartan-Meglumine Salt (Prior art form) Melt Quench
Telmisartan Form A Telmisartan-Meglumine Salt (Present invention) Meglumine
6.8 NP 6.9 6.8 NP NP
NP 8.9 NP NP NP 8.9
NP 9.1 NP NP NP NP
NP 12.5 NP NP NP 12.5
14.3 NP NP NP NP NP
15.1 NP 15.5 NP NP NP
NP 17.4 NP NP NP 17.4
NP 18.0 17.9 NP NP NP
19.1 NP NP NP NP NP
NP 19.7 NP NP NP 19.8
NP 22.1 22.1 NP NP 21.8
22.4 NP NP NP NP NP
23.9 24.2 23.4 NP NP NP
NP 27.1 NP NP NP 26.4
NP =Not present

EXAMPLE-3: PHARMACOKINETIC STUDY
Pharmacokinetic studies were carried out using Wistar rats after oral administration of pure drug, Indian marketed (X) tablets, Innovator marketed tablets (Y) and Melt-Quenched formulation (MQF). Dose equivalent to 4mg/kg (crushed tablets or MQF powder) was administered to rats and blood samples (250µl) were withdrawn from retro orbital vein at predetermined time intervals, the blood samples were withdrawn in K2 EDTA lined Eppendorf tubes of 0.5 ml capacity, and centrifuged at 6000 rpm for 15 minutes to separate plasma from blood. Plasma (100µl) was separated from the supernatant and frozen until analysis.

Analysis of plasma samples was done after thawing them to room temperature. Acetonitrile (0.4ml) was added to the Eppendorf tubes to precipitate plasma proteins and also to extract the drug into the organic phase. The organic layer was transferred to a clean glass tube of 5 ml capacity and evaporated to dryness. Mobile phase (100µl) was added to the glass tube to reconstitute the drug and it was injected for HPLC for analysis, using a validated method.

To evaluate the effect of faster release in 0.1N HCl, the formulation with fastest release (MQF) was evaluated in Wistar rats. Pure drug and Indian marketed formulation (Brand X) and Innovator product (Brand Y) were also evaluated and their pharmacokinetic profile was obtained (Figure 17 and 18). As clearly observed, marketed formulation (X) had a significantly higher CMAX than that exhibited by the pure drug powder. Moreover, the absorption phase observed in case of pure drug was prolonged due to incomplete absorption from the GI tract. The AUC of Brand X was nearly double than that obtained from the pure drug along with a faster rate of absorption (Table 4). The results of pure drug are similar to those obtained by earlier researchers.

Further, comparing in vivo profile of marketed formulation (X) with MQF sample, it was observed that the later system exhibited faster release rate and a higher CMAX in a shorter duration of time. However, when comparing the release profile of MQF sample with that of innovator marketed system (Brand Y), a faster absorption phase of MQF with TMAX at 1 h was observed while innovator product (Y) exhibited TMAX at 2 h. The CMAX and AUC were found to be similar for MQF and Brand Y.
Table 2: Kinetic Parameters of pure drug, Marketed formulation and Melt-Quench Cooled crystals
Formulation KE
(h-1) THALF (h) AUC0- 8
(ng ml-1h-1) TMAX (h) CMAX
(ng ml-1) Relative Bioavailability@ Relative Bioavailability#
Pure Drug
(4 mg/Kg) 0.051 13.67 2016.97 3.33 358.33 ± 42.57 1 0.15
Brand X
(4 mg/Kg) 0.051 13.68 4716.73 2.00 1030.70 ±159.11 2.33 0.36
Brand Y
(2 mg/Kg) 0.062 11.14 7721.67 2.00 1405.49 ± 313.7 7.65 1.17
Brand Y
(4 mg/Kg) 0.053 13.08 13232.22 2.00 2529.89 ± 564.6 6.56 1

MQF
(2 mg/Kg) 0.062 11.14 8310.04 1.0 1585.42 ± 260.5 8.24 1.26
MQF
(4 mg/Kg) 0.048 14.33 14174.15 1.00 2853.75 ± 468.9 7.03 1.07
@ Relative to Pure Drug; # Relative to Innovator Tablet 4 mg/Kg

The results of the present investigation revealed a facile method to prepare amorphous salt of Telmisartan and Meglumine having melting point of 180°C and exhibiting polyhedral crystal habit. This form of Telmisartan was not found to interact with molten Meglumine as opposed to that observed for Form A. The prepared form of Telmisartan (MQF) exhibited highest dissolution rate in 0.1N HCl and phosphate buffer pH 7.4 as compared to Form A (commercial form), marketed tablet and other forms prepared by solid manipulation. Further, it exhibited short TMAX along with approximately 7-fold and 3-fold higher bioavailability, respectively, to pure drug powder and marketed formulation (Brand X). The salt form of Telmisartan was highly stable and did not convert to Form A after storage for 3 months at 40°C and 75% RH.

PHARMACEUTICAL COMPOSITIONS
The polymorphic form of Telmisartan-Meglumine can also be formulated in the form of pharmaceutical composition. The pharmaceutical composition of the present invention comprises the physical form of Telmisartan-Meglumine prepared according to the present invention and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are those known to a person skilled in the art.

The pharmaceutical composition of the present invention can be in the form of pharmaceutically acceptable dosage forms including solid, liquid, parenteral etc. The polymorphic form of the present invention can be formulated in any dosage form known to the person skilled in the art using pharmaceutically acceptable excipients suitable for preparing that particular dosage forms. The processes for preparing suitable dosage form of the polymorphic form of the present invention can be any process that is known to the person skilled in the art.

It should be understood that various changes and modifications to the presently preferred embodiments and examples described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.