Novel HPMC phthalate succinate polymers and process for synthesising thereof

Abstract

The present invention provides a novel hydroxypropyl methylcellulose (HPMC) phthalate succinate polymer(s) and a process to prepare the same. The said polymers have a good film forming properties, tensile strength and pH sensitive values thus finding wide applications in the pharmaceuticals industry.

Description

[0001] NOVEL HPMC PHTHALATE SUCCINATE POLYMERS AND PROCESS FOR SYNTHESISING THEREOF

[0002] PRIORITY:

[0003] This application claims the benefit of Indian application number 202441044307 dated 7thJune 2024 entitled, ‘NOVEL HPMC PHTHALATE SUCCINATE POLYMERS AND PROCESS FOR SYNTHESISING THEREOF’, the contents of which are incorporated herein by reference.

[0004] TECHNICAL FIELD OF THE INVENTION

[0005] The present invention relates to a novel hydroxypropyl methylcellulose (HPMC) phthalate succinate polymer(s). In particular, it relates to a process for producing HPMC phthalate succinate polymer(s) using HPMC, phthalic anhydride and succinate anhydride. The said polymers have good film forming properties, tensile strength and pH sensitive values thus finding a wide range of applications in the pharmaceutical industry.

[0006] BACKGROUND OF THE INVENTION

[0007] Among the predictable sources of failure of drug candidates, two important sources are lack of efficacy, PK / bioavailability (Meanwell et al., “Improving drug candidates by design: A focus on physicochemical properties as a means of improving compound disposition and safety”, Chem. Res. Toxicol 2011, 24, 1420-1456). Molecular obesity to drive potency during initial drug discovery kills the dmg products at later stages because of poor solubility (Michael et al., “Molecular obesity, potency and other addiction in drug discovery”, Med. Chem. Commun -2011, 2, 349-355).

[0008] The overall lipophilicity of the drugs is a major cause of solubility problems, their bioavailability and efficacy. Because of this, administration of large amounts of the dmg or multiple dosage units is necessary to achieve the required efficacy even using solubility enhancement techniques (Babu et al. “Evolution of Solid Dispersion Technology: Solubility Enhancement using Hydroxypropyl Methylcellulose Acetate Succinate: Myth or Reality? ” , Assay and Drug Development Technologies 2022, 20, 149-163).

[0009] Many techniques are in practice to improve the aqueous solubility of drugs such as particle size reduction, solid dispersion and employing drug nanoparticles.

[0010] Cellulose is a very abundantly occurring material from natural sources. Its use as firewood is as old as the history of prehistoric humans. Use of Cellulose other than firewood has evidence of as old as 4500 B.C. The modem history of cellulose chemistry began in 1837 when Anselme Payen isolated uniform chemical substance from plants and the material was named as “Cellulose” by French Academy in year 1839 (Brongniart et al. C.R. (1839) Seances Acad. Sci 8, 51-51). However, the concept of cellulose as a linear macromolecule consisting of anhydro glucose units evolved in 1920’s. Eventually many derivatives of cellulosic polymer have been synthesized over the century and they have been exploited for variety of uses based on their characteristics viz., Hydroxypropyl Cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0011] Several polymeric excipients have been approved by the United States Pharmacopeia (USP) which can be exploited for making amorphous dmg products by solid dispersion technology including polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), HPMC, HPMCP, and HPMCAS.

[0012] The following polymers are known in the pharmaceuticals industry.

[0013] Cellulose (Three reactive Hydroxyl groups (at 2, 3 and 6thposition)), HPC ( Hydroxy propyl group substituted through an ether linkage at the reactive hydroxyl presents on anhydroglucose monomer and on the newly formed hydroxyl group of the substituent), HPMC ( Hydroxy propyl group and methyl groups are substituted through ether linkage at the reactive hydroxyl present on anhydroglucose monomer and on the newly formed hydroxyl group of the substitutent), HPMCP Phthalic acid ester of HPMC), HPMCAS (-Cellulose derivative-Two ethers: Methoxy (MeO) and Hydroxy propoxy (HPO)-Two ester: Acetate (Ac) & Succinate (Su)).

[0014] Patents namely US2013019579A1, US9447089, US10646481, US10646481, U10206877, US10905694B2, US10206877, US20170027910A1 discloses HPMCAS, HPMCAS, HPMCAS, HPMCAS+SLS, HPMC, HPC, HPMCAS & HPMC, HPMCAS as polymers used for the solid dispersion technique respectively.

[0015] Many poorly soluble new chemical entities (NCE) viz., Telaprevir, Vemurafenib, Ivacaftor, Enzalutamide have been formulated as solid dispersions using Hydroxy Propyl Methyl Cellulose Acetate Succinate (HPMCAS) and all are protected by multiple patents.. Considering the fact, most of the HPMCAS polymer-based solid dispersions are protected by patents, there is a need for the industry to understand “Solubility Enhancement Using Hydroxypropyl Methylcellulose Acetate Succinate: Myth or Reality?” In the review article, the author(s) concluded that HPMCP showed a concentration enhancement similar to HPMCAS. There are unmet needs in the industry for alternate polymers as the existing polymers are either patent protected or the polymer HPMCAS could not enhance the concentration at a lower polymer ratio.

[0016] Cellulose is natural polysaccharide, structurally, the simplest molecule consists of monosaccharide repeating units of glucose, connected through (1-4) glycosidic bonds. The repeating unit consists of hydroxyl groups as the only functional group. There are three Hydroxyl groups on anhydroglucose have different acidity, accessibility for reaction and hence different probabilities for being substituted. Chemical modification can change the character of the polysaccharides rendering them hydrophobic or hydrophilic based on the new group (s) introduced.

[0017] Chemical modification of cellulose results in incorporation of new groups. Each of the three available hydroxyl groups per glucose monomer unit is substituted by methyl- or a hydroxypropyl or remain unsubstituted in hydroxypropyl methyl cellulose. Methyl and hydroxypropyl groups are attached to the anhydroglucose unit by ether linkage (methoxy, hydroxy propoxy) in hydroxypropyl methyl cellulose.

[0018] HPMCAS is a HPMC derivative, where acetate and succinate groups are attached by ester linkage (Acetate, Succinate). Acetate groups in HPMCAS postulated to facilitate hydrophobic drug molecular dispersion. Hydroxyl groups facilitates hydration of resulting solid dispersions in solution. Ionized carboxylic acid groups from succinic acid stabilizes colloidal stability in vivo. High Tg of the HPMCAS polymer stabilizes amorphous solid dispersion at a temperature of 40°C and humidity at 75% RH. Drug diffusion is the rate-limiting step for crystallization. Below Tg of SDDs, the mobility of drug is poor and hence inhibits its ability to migrate, phase separate and the crystallization.

[0019] Therefore, while considering the above mentioned problems, there is a need in the art to develop an alternate polymer that is novel and has improved hydrophobic and hydrophilic properties.

[0020] The present invention provides a novel polymer which provides a better hydrophobic molecular dispersion with additional colloidal stability in vivo. The invention also provides a process to prepare the novel polymer.

[0021] OBJECT OF THE INVENTION

[0022] The main object of the present invention is to provide a novel polymer that has wide applications in the pharmaceutical industry.

[0023] One of the objects of the present invention is to provide a process for preparing the novel polymer at mild reaction conditions, using cheaper reagents and green solvents which makes feasible at large scale industrial production.

[0024] Another object of the present invention is to provide a novel polymer which has an improved hydrophobic molecular dispersion and which can provide additional colloidal stability in vivo.

[0025] Yet another object of the present invention is to provide a process for preparing the novel polymer, wherein acetyl functional group of HPMCAS is replaced with other hydrophobic functional group (phthalic group) which have better Tg and good hydrophobic drug molecular dispersion property.

[0026] Another object of the present invention is to provide the characterisation of said prepared novel polymer. Yet another object of the present invention is to provide a novel polymer which has an improved film forming nature, tensile strength and pH sensitive values.

[0027] SUMMARY OF THE INVENTION

[0028] In an aspect of the present invention, there is provided a novel polymer represented by compound of formula (I): In another aspect of the present invention, there is provided a process for synthesising the novel polymer represented by compound of formula (I), the process comprising: a) preparing a mixture comprising a polymer, a base, and an acid and heating the mixture at a temperature in the range of 75°C to 90°C to obtain a solution; b) contacting the solution obtained from step (a) with an anhydride compound at a temperature in the range of 75°C to 90°C for a time period ranging from 2 hrs to 5 hrs to obtain a polymer of compound of formula (I);

[0029] Wherein the synthesised polymer is having glass transition temperature in the range of 138.4°C to 156.8°C;

[0030] Wherein said polymer has a film forming nature, and wherein said polymer films have remained intact at 0.1N HO and pH 4.5 acetate buffer; has solubility at pH 6.8 phosphate buffer.

[0031] In one aspect of the present invention, there is provided a process for preparing the novel polymer of compound of formula (I) at mild reaction conditions, using cheaper reagents and green solvents which makes feasible at large scale industrial production.

[0032] In another aspect of the present invention, there is provided a novel polymer of compound of formula (I) which has an improved hydrophobic molecular dispersion and which can provide additional colloidal stability in vivo.

[0033] In another aspect of the present invention, there is provided a process for preparing the novel polymer of compound of formula (I), wherein acetyl functional group of HPMCAS is replaced with other hydrophobic functional group (phthalic group) which have better Tg and good hydrophobic dmg molecular dispersion property.

[0034] In another aspect of the present invention, there is provided the characterisation of said prepared novel polymer of compound of formula (I).

[0035] In another aspect of the present invention, there is provided a novel polymer of compound of formula (I), which has an improved film forming nature, tensile strength and pH sensitive values.

[0036] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 shows FT-IR spectrum of HPMC

[0038] Figure 2 depicts FT-IR spectrum of HPMC succinate

[0039] Figure 3 illustrates FT-IR spectrum of HPMC phthalate succinate 41 [phthalic anhydride: Succinic anhydride (1:0.25)]

[0040] Figure 4 shows FT-IR spectrum of HPMC phthalate succinate 73 [Phthalic anhydride: Succinic anhydride (1:0.43) Figure 5 depicts FT-IR spectrum of HPMC phthalate succinate 32 [Phthalic anhydride: Succinic anhydride (1:0.66)]

[0041] Figure 6 shows 'H-NMR spectrum of HPMC succinate

[0042] Figure 7 shows13C-NMR spectrum of HPMC succinate

[0043] Figure 8 illustrates 'H-NMR spectmm of HPMC phthalate succinate 41 [Phthalic anhydride: Succinic anhydride (1:0.25)]

[0044] Figure 9 shows13C-NMR spectrum of HPMC phthalate succinate 41 [Phthalic anhydride: Succinic anhydride (1:0.25)]

[0045] Figure 10 depicts 'H-NMR spectrum of HPMC phthalate succinate 73 [Phthalic anhydride: Succinic anhydride (1:0.43)]

[0046] Figure 11 shows13C-NMR spectrum of HPMC phthalate succinate 73 [Phthalic anhydride: Succinic anhydride (1:0.43)]

[0047] Figure 12 shows 'H-NMR spectrum of HPMC phthalate succinate 32 [Phthalic anhydride: Succinic anhydride (1:0.66)]

[0048] Figure 13 depicts13C-NMR spectrum of HPMC phthalate succinate 32 [Phthalic anhydride: Succinic anhydride (1:0.66)]

[0049] Figure 14 shows PXRD chromatogram of HPMC

[0050] Figure 15 shows PXRD chromatogram of HPMC succinate

[0051] Figure 16 illustrates PXRD chromatogram of HPMC phthalate succinate 41

[0052] Figure 17 shows PXRD chromatogram of HPMC phthalate succinate 73

[0053] Figure 18 depicts PXRD chromatogram of HPMC phthalate succinate 32

[0054] Figure 19 shows SEM of HPMC phthalate succinate 32

[0055] Figure 20 shows SEM of HPMC phthalate succinate 73

[0056] DESCRIPTION OF THE INVENTION

[0057] In the present invention, different terms are used to describe the invention. The definitions of the terms are as follows.

[0058] The term ‘polymer’ or ‘compound of formula (I)’ as used herein refers to HPMC phthalate succinate polymer(s) which is obtained by using HPMC, phthalate anhydride and succinate anhydride used in appropriate ratio at suitable reaction conditions. The terms ‘polymer’, ‘compound of formula (I)’ can be used interchangeably in the specification. The compound of formula (I) can represented as:

[0059]

[0060] The pharmaceutical compositions containing the novel polymer of the compound of formula (I) are suitable for use with a biologically active compound desired to be administered to a patient in need of the active agent. The compositions may contain one or more active agents. The pharmaceutical compositions are particularly suitable for low-solubility active agents. The active agent does not need to be a low-solubility active agent in order to benefit from the disclosed compositions, although low-solubility active agents represent a preferred class for use with some embodiments of the compositions.

[0061] In one embodiment, the active agent is a small molecule. In another embodiment, the active agent is a biological active agent. In still another embodiment, the active agent is a mixture of a small molecule and a biological active agent.

[0062] An active agent, as used herein, is a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical, or other compound that may be administered to the subject.

[0063] Examples of classes of active agents include, but are not limited to, antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, triglyceride-reducing agents, anti- atherosclerotic agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's disease agents, antibiotics, anti-depressants, antiviral agents, glycogen phosphorylase inhibitors, and cholesteryl ester transfer protein inhibitors.

[0064] Amorphous means non-crystalline, having no or substantially no molecular lattice structure.

[0065] A dispersion is a system in which particles are distributed throughout a different composition. A solid dispersion is a system in which particles of at least one solid component are dispersed throughout another solid component. A molecular dispersion is a system in which at least one component is homogeneously or substantially homogeneously dispersed on a molecular level throughout another component. A molecular dispersion is also known as a solid solution.

[0066] An excipient is a physiologically inert substance that is used as an additive in a pharmaceutical composition. As used herein, an excipient may be incorporated within particles of a pharmaceutical composition, or it may be physically mixed with particles of a pharmaceutical composition. An excipient can be used, for example, to dilute an active agent and / or to modify properties of a pharmaceutical composition.

[0067] The active agent and the novel polymer of the compound of formula (I) may be combined in any suitable manner, including by blending or mixing (e.g., by wet or dry granulation), coating active agent particles partially or fully with the polymer, coating a tablet comprising the active agent with the polymer, co-administration (i.e., administering the two components separately, but within the same general timeframe). In a preferred embodiment, the active agent and polymer are combined to form a solid amorphous dispersion.

[0068] In one embodiment, the composition is in the form of a solid dispersion comprising the active agent and the novel polymer of the compound of formula (I), wherein at least 90 wt % of the active agent in the dispersion is non-crystalline. The relative amounts of active agent and novel polymer of the compound of formula (I) in the dispersion may range from 0.01 wt % to 99 wt % active agent, and from 1 wt % to 99.99 wt % novel polymer of the compound of formula (I).

[0069] In one embodiment, at least 90 wt % of the active agent present in the dispersion is amorphous. By “amorphous” is meant that the active agent is non-crystalline as determined by differential scanning calorimetry, powder X-ray diffraction (PXRD), by solid state nuclear magnetic resonance (NMR), or by any other known quantitative measurement.

[0070] The solid dispersions of the present invention may be formed by any method known in the art, including milling, extrusion, precipitation, or solvent addition followed by solvent removal. For example, active agent and the novel polymer of the compound of formula (I) may be processed by heat, mechanical mixing and extrusion using, for example, a twin-screw extruder. The product may then be milled to the desired particle size. In another example, the active agent and novel polymer of the compound of formula (I) are dissolved in a solvent in which both materials are soluble. The dispersions may then be formed from the solution by any known process, including precipitation in a miscible non-solvent, emulsifying in an immiscible non-solvent, or by forming droplets followed by removal of the solvent by evaporation.

[0071] In another embodiment, the solid dispersion may be formed as a coating on an appropriate substrate. For example, the solid dispersion may be coated onto multiparticulates having diameters ranging from 50 pm to 5,000 pm. In another example, the solid dispersion may be coated onto a tablet or capsule. In still another embodiment, the solid dispersion may be formed into a layer that is incorporated into a tablet.

[0072] The novel polymer(s) represented by the compound of formula (I) are useful in component of controlled release or sustained release dosage forms and also as an enteric coating agents.

[0073] The term ‘mixture’ as used herein refers to a combination of two or more substances in which the identities are retained and are mixed in the form of solutions, suspensions and colloids. In the present invention, the mixture is obtained by adding a polymer, a base, and an acid in an appropriate proportion. The term ‘solution’ as used herein refers to a special type of homogeneous mixture composed of two or more substances. In such a mixture, a solute is a substance (s) that is dissolved in another substance, known as a solvent. In the present invention, the solution may be clear or turbid solution.

[0074] One of the embodiments of the present invention provides a process for synthesising the polymer of compound of formula (I), the process comprising: c) preparing a mixture comprising a polymer, a base, and an acid and heating the mixture at a temperature in the range of 75°C to 90°C to obtain a solution; d) contacting the solution obtained from step (a) with an anhydride compound at a temperature in the range of 75°C to 90°C for a time period ranging from 2 hrs to 5 hrs to obtain the polymer of compound of formula (I);

[0075] Wherein the synthesised polymer has a glass transition temperature (Tg) in the range of 138.4°C to 156.8°C;

[0076] Wherein said polymer has film forming nature, and wherein said polymer films have remained intact at 0.1N HO and pH 4.5 acetate buffer; solubility at pH 6.8 phosphate buffer.

[0077] In another embodiment of the present invention, there is provided a process for synthesising the polymer of compound of formula (I), wherein the polymer is selected from the group comprisingHydroxy propyl cellulose, Hydroxypropyl methylcellulose (HPMC), Hypromellose phthalate (HPMCP), Hydroxypropyl methylcellulose succinate and hydroxypropyl methylcellulose acetate succinate (HPMCAS) and combinations thereof.

[0078] In another embodiment of the present invention, there is provided a process for synthesising the polymer represented by compound of formula (I), wherein the base is an organic and / or inorganic base.

[0079] In another embodiment of the present invention, there is provided a process for synthesising the polymer represented by compound of formula (I), wherein the organic base is selected from the group comprising sodium alkoxide, potassium alkoxide, butyl lithium, pyridine, quinoline, 4- dimethylaminopyridine, an organic amine, and combinations thereof.

[0080] In yet another embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the organic base is sodium alkoxide.

[0081] In yet most preferred embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the sodium alkoxide is sodium acetate.

[0082] In another embodiment of the present invention, there is provided a process for synthesising the polymer represented by compound of formula (I), wherein the inorganic base is selected from the group comprising sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof.

[0083] In another embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the acid is an organic and / or inorganic acid.

[0084] In yet another embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein said acid is an organic acid.

[0085] In yet another embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the organic acid is selected from a group comprising acetic acid, trifluoroacetic acid, formic acid, salicylic acid, citric acid, tartaric acid, oxalic acid, gallic acid, lactic acid, oxalic acid and combinations thereof.

[0086] In yet most preferred embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the organic acid is an acetic acid.

[0087] In another embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the solution is obtained by heating the mixture at 85°C.

[0088] In another embodiment of the present invention, there is provided a process for synthesising the polymer represented by compound of formula (I), wherein contacting the solution with an anhydride compound at a temperature 85°C for a time period of 3 hrs to obtain the polymer compound of formula (I).

[0089] In another embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the anhydride compound is selected from acetic anhydride, succinic anhydride, phthalic anhydride, ethanoic anhydride, 2- methylpropionic anhydride, hexanoic anhydride, maleic anhydride and combinations thereof.

[0090] In a most preferred embodiment of the present invention, there is provided a process for synthesising polymer represented by compound of formula (I), wherein the anhydride compound is succinic anhydride and / or phthalic anhydride.

[0091] The details of the present invention are provided in the examples given below to illustrate the invention only and therefore they should not be construed to limit the scope of invention. EXAMPLES

[0092] 1. Synthesis of HPMC succinate

[0093] 250 mL clean, dry, round bottom flask set up with magnetic stirrer and thermometer. Round Bottom Flask (RBF) charged with 1 g of HPMC and 0.9 g of sodium acetate in 12.50 mL of acetic acid with stirring at 200 rpm at 85°C (Observation: Clear solution obtained). Charge RBF with 1.10 g of succinic anhydride with stirring at 200 rpm for 3 hours at 85°C (Observation: Clear solution obtained). After cooling the reaction to room temperature, add 5.75 mL of Deionized water (Observation: Suspension obtained). Pour reaction mixture into 200 mL of Deionized water dropwise (Observation: Gummy solid). Gummy solid dissolved in 10 mL Tetrahydrofuran at 40°C, then dropwise into 100 mL of water. White gummy solid obtained dried under suction with nitrogen gas flushing.

[0094] Reaction scheme:

[0095] 2. Synthesis of HPMC Phthalate Succinate

[0096] The synthesis was carried out as follows. Suitable clean, dry, round bottom flask set up with magnetic stirrer and thermometer. Round Bottom Flask (RBF) charged with 26 g of HPMC E5, required quantity of sodium acetate in 340 mL of acetic acid with stirring at 200 rpm at 85°C until clear solution obtained. Charge RBF with suitable quantity of succinic anhydride and Phthalic anhydride with stirring at 200 rpm at 85°C for 3 hours / until clear solution obtained. After cooling the reaction to room temperature add sufficient quantity of deionized water. Pour reaction mixture into more quantity of deionized water to precipitate. Filter the precipitate and dissolve in 300 mL of Tetrahydrofuran at 40°C. Precipitate the solution by adding to water, filter and dry the polymer under suction with nitrogen gas flushing.

[0097] Number of reactants and quantity used in the synthesis of HPMC Phthalate Succinate was provided in below table 1.

[0098] Table 1 : Amount of reactants used in the synthesis of HPMC Phthalate Succinate

[0099] Reaction scheme:

[0100] HPMC Phthalate Succinate Synthesis:

[0101] 3. Characterisation of synthesised polymer

[0102] Melting points were determined using DSC (Mettler Toledo). Infrared (IR) and proton nuclear magnetic resonance (1H-NMR) spectra were recorded for the compounds using Shimadzu IRTracer-100 and Bruker 500 MHz-Advance III instrument respectively.

[0103] The synthesised novel polymer(s) structure was characterized by FT-IR, 1H(13C)-NMR and XRD spectroscopic methods. In addition, their thermal degradation was examined by DTA / TGA. a. FT-IR Analysis:

[0104] • HPMC

[0105] Wave Number: Interpretation

[0106] 3550 cm'1: Broad peak representing “-OH” group stretching; 2900 cm'1: Axial deformation of -C- H bonds in aliphatic chains (-CH3) arising from the substitution of hydroxyl groups by methoxy and hydroxypropyl; 1650 cm'1: Axial deformation of carbonyl group in glucose; cm'1: Axial deformation of C-O-C bonds of cellulose ethers

[0107] • HPMC Succinate Wave Number: Interpretation; 3550 cm'1: Broad peak representing “-OH” group stretching (Intensity reduced because of esterification); 2900 cm'1: Axial deformation of -C-H bonds in aliphatic chains (-CH3) arising from substitution of hydroxyl groups by methoxy and hydroxypropyl; 1765 cm'1: -C=O stretch of ester (This is absent in HPMC); 1650 cm'1: Axial deformation of carbonyl group in glucose; 1300-1000 cm'1: -C-0 stretch (Change can be clearly seen with respect to HPMC)

[0108] • HPMC Phthalate Succinate

[0109] Wave Number: Interpretation; 3550 cm'1: Broad peak representing “-OH” group stretching (Intensity reduced because of esterification); 2900 cm'1: Axial deformation of -C-H bonds in aliphatic chains (-CH3) arising from substitution of hydroxyl groups by methoxyl and hydroxypropyl; 1765 cm'1: -C=O stretch of ester (This is absent in HPMC); 1650 cm'1: Axial deformation of carbonyl group in glucose; 1300-1000 cm'1: -C-0 stretch (Change can be clearly seen with respect to HPMC) b. 'll (13C)-NMR Analysis:

[0110] Chemical shift values of the1H(13C)-NMR spectra of synthesized polymer(s) were recorded in DMSO solvent medium.

[0111] Theoretical possibility:

[0112] • HPMC Succinate

[0113] 'H-NMR: 0.5 Protons at 1.7 to 2.1 ppm related HPMC Succinate;

[0114] 13C-NMR: Two peaks in the region of 160-220 ppm detected are related to carbonyl carbons of succinate functional group.

[0115] • HPMC Phthalate Succinate 41 [Phthalic anhydride: Succinic anhydride (1:0.25)

[0116] Tl-NMR: 3.38 protons at 1.7 to 2.1 ppm related to succinate; 4 protons at 7.50 to 8.01 ppm related to Phthalate; 1 proton at 13 ppm related to phthalate; According to results ration between phthalate to succinate is 1: 0.35 (1.3892 / 4 = 0.3473). Results are close to the reaction ratios.

[0117] 13C-NMR: Three peaks in the region of 160-220 ppm detected are related to carbonyl carbons of succinate and phthalate functional groups; Three peaks in the region of 140-120 ppm detected are related to aromatic carbon present in phthalate group

[0118] • HPMC Phthalate Succinate 73 [Phthalic anhydride: Succinic anhydride (1:0.43) 'H-NMR: 3 protons at 1.7 to 2.1 ppm related to succinate; 4 protons at 7.50 to 8.01 ppm related to Phthalate; 1 proton at 13 ppm related to phthalate

[0119] According to results ration between phthalate to succinate is 1: 0.75 (3.0036 / 4 = 0.7509).

[0120] 13C-NMR: Three peaks in the region of 160-220 ppm detected are related to carbonyl carbons of succinate and phthalate functional groups; Three peaks in the region of 140-120 ppm detected are related to aromatic carbon present in phthalate group

[0121] • HPMC Phthalate Succinate 32 [Phthalic anhydride: Succinic anhydride (1:0.66)]

[0122] 'H-NMR: 0.5 protons at 1.7 to 2.1 ppm related to succinate; 4 protons at 7.50 to 8.01 ppm related to Phthalate; 1 proton at 13 ppm related to phthalate;

[0123] According to results ration between phthalate to succinate is 1: 0.13 (0.5253 / 4 = 0.1313).

[0124] 13C-NMR: Three peaks in the region of 160-220 ppm detected are related to carbonyl carbons of succinate and phthalate functional groups; Three peaks in the region of 140-120 ppm detected are related to aromatic carbon present in phthalate group. c. PXRD Analysis:

[0125] Morphological characterization of HPMC and newly synthesized polymers were characterized by powder X-ray diffraction using Bruker D8 advance. As shown in Fig. X, except for HPMC Phthalate Succinate 73, all other polymers including HPMC exhibit amorphous form which lack long range crystallographic order. d. Morphology Investigation (SEM):

[0126] SEM is generally used to explore the morphology of the materials which provides a high- resolution, three-dimensional visualization for in-depth examination and characterization of micro and nanoscale polymer surfaces and internal structures. e. DSC / TGA:

[0127] For examining the thermal stability of cellulose and HPMC by TGA and DSC. The amounts of mass losses and Tg are given Table. As can be seen from the thermograms, mass losses occur in two stages. A maximum initial loss of 3% at 30°- 80°C attributed to the solvent (tetrahydro furan). From 80° C to 160° the newly synthesized polymers are stable. In the second stage, thermal decomposition occurs at approximately 160°C- 280°C an average loss of around 50% has occurred. This stage could be attributed to the oxidative decomposition of cellulose ethers, involving intramolecular dehydration and demethylation process. The experiment stopped at 300°C, considering the obvious third stage of mass loss because of excess carbon and ash residues. f. Glass Transition Temperatures (Tg):

[0128] The glass-transition temperature (Tg) is the temperature at which molecular mobility begins to take place, below which molecular mobility is frozen and the elastomer becomes rigid and glassy. The Tg of the elastomer depends on the chemical structure of the elastomer.

[0129] The Tg of synthesised polymer was provided below table.

[0130] * We could not determine

[0131] 4. Film forming nature and solubility of the polymer at different pH conditions:

[0132] HPMCAS and novel polymers synthesized are cast as fdms by dissolving them in

[0133] Dichloromethane (DCM) and ethanol mixture.

[0134] The above-prepared films were evaluated for solubility at different pH conditions (0.1 N HO, pH

[0135] 4.5 Acetate buffer, pH 6.8 Phosphate buffer).

[0136] X = Not dissolved

[0137] Rate of solubility of polymers qualitatively can be grades as follows.

[0138] HPMC Succinate, HPMC Phthalate Succinate 41 > HPMC Phthalate Succinate 32 > HPMC Phthalate Succinate 73.

[0139] Polymer films have remained intact at 0.1N HO and pH 4.5 Acetate buffer (except of HPMC succinate), however were dissolved at pH 6.8 Phosphate buffer, meaning the polymers can be used for enteric drug delivery systems or targeted drug delivery systems. Another advantage is the novel polymers need less solvent to dissolve in comparison with the HPMCAS for same polymer quantity.

[0140] HPMC ester polymers have been synthesized as an alternative to HPMCAS polymer and are characterized by IR and NMR spectroscopy. Glass transition temperature has been determined by DSC. Based on solubility and film forming properties of the polymers, it is anticipated wide range of applications viz., as film formers, pH dependent drug delivery and in the preparation of solid dispersions etc.

[0141] The number given at the end of the polymer name represents the ratio of Phthalate anhydride and Succinate anhydride ratio used in the synthesis of novel polymer. For example, in HPMC Phthalate Succinate 41, the ratio of Phthalate anhydride and Succinate anhydride used during synthesis were at 4:1 molar ratio respectively.

Claims

We Claim:

1. A polymer represented by compound of formula (I)2. A process for synthesising polymer represented by compound of formula (I) as claimed in claim 1, wherein the process comprises: a) preparing a mixture comprising a polymer, a base, and an acid and heating the mixture at a temperature in the range of 75°C to 90°C to obtain a solution; b) contacting the solution obtained from step (a) with an anhydride compound at a temperature in the range of 75°C to 90°C for a time period ranging from 2hrs to 5 hrs to obtain polymer of compound of formula (I);Wherein the synthesised polymer is having glass transition temperature (Tg) in the range of 138.4°C to 156.8°C;Wherein said polymer has film forming nature, and wherein said polymer films have remained intact at 0. IN HO and pH 4.5 Acetate buffer; solubility at pH 6.8 Phosphate buffer.

3. The process as claimed in claim 2, wherein polymer is selected from Hydroxypropyl Cellulose (HPC), Hydroxypropyl Methylcellulose (HPMC), Hypromellose Phthalate (HPMCP), Hydroxypropyl Cellulose Succinate and Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) and combinations thereof.

4. The process as claimed in claim 2, wherein base is organic and / or inorganic base.

5. The process as claimed in claim 4, wherein organic base is selected from sodium alkoxide, potassium alkoxide, butyl lithium, pyridine, quinoline, 4- dimethylaminopyridine or an organic amine; preferably sodium alkoxide; wherein sodium alkoxide is sodium acetate.

6. The process as claimed in claim 2, wherein, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof.

7. The process as claimed in claim 8, wherein acid is selected from acetic acid, trifluoroacetic acid, formic acid, salicylic acid, citric acid, tartaric acid, oxalic acid, gallic acid, lactic acid, oxalic acid and combinations thereof; preferably acetic acid.

8. The process as claimed in claim 2, wherein contacting the solution with the anhydride compound at a temperature 85°C for a time period of 3 hrs to obtain polymer of compound of formula (I).

9. The process as claimed in claim 2, wherein the anhydride compound is selected from acetic anhydride, succinic anhydride, phthalic anhydride, ethanoic anhydride, 2- methylpropionic anhydride, hexanoic anhydride and combinations thereof; preferably succinic anhydride and / or phthalic anhydride; wherein the ratio of Phthalate anhydride and Succinate anhydride used during synthesis is at 4: 1 molar ratio respectively.

10. A polymer represented by compound of formula (I) is HPMC Phthalate Succinate.

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