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Novel Salts Of (1 S, 4 R) Cis 4 [2 Amino 6 (Cyclopropylamino) 9 H Purin 9 Yl] 2 Cyclopentene 1 Methanol

Abstract: The  present  invention  relates  to  novel  salts  of  (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1 -methanol of Formula I or solvates or hydrates thereof, wherein M represents hemimalonate, malonate, hemioxalate, oxalate, hydrobromide, dihydrobromide, hemimaleate, maleate.

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Patent Information

Application #
Filing Date
30 September 2009
Publication Number
13/2012
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

AUROBINDO PHARMA LTD
PLOT NO.2, MAITRIVIHAR, AMEERPET, HYDERABAD - 500 038

Inventors

1. BOBBALI NARSIHMA REDDY
AUROBINDO PHARMA LTD, PLOT NO.2, MAITRIVIHAR, AMEERPET, HYDERABAD - 500 038
2. VIPIN KUMAR KAUSHIK
AUROBINDO PHARMA LTD, PLOT NO.2, MAITRIVIHAR, AMEERPET, HYDERABAD - 500 038.
3. AMINUL ISLAM
AUROBINDO PHARMA LTD, PLOT NO.2, MAITRIVIHAR, AMEERPET, HYDERABAD - 500 038.
4. MEENAKSHISUNDERAM SIVAKUMARAN
AUROBINDO PHARMA LTD, PLOT NO.2, MAITRIVIHAR, AMEERPET, HYDERABAD - 500 038.

Specification

FIELD OF THE INVENTION The present invention relates to novel salts of (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1 -methanol of Formula I or solvates or hydrates thereof, wherein M represents hemimalonate, malonate, hemioxalate, oxalate, hydrobromide, dihydrobromide, hemimaleate, maleate. BACKGROUND OF THE INVENTION (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-l-methanol of Formula II is generally known as Abacavir. Abacavir is an antiviral drug, especially effective against HIV infections. US 5,034,394 discloses Abacavir and its pharmaceutically acceptable salts, base salts, e.g. derived from an appropriate base, such as alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) salts, ammonium and NW+4 (wherein W is C1-4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. EP 0 777 669 Bl discloses succinate salt of Abacavir. US 6,294,540 Bl discloses Abacavir hemisulfate, Abacavir glutarate, Abacavir hemisuberate, Abacavir adipate, Abacavir fumarate, Abacavir hemisebacate and Abacavir pimelate. We have now found novel salts of Abacavir or solvates or hydrates thereof, which are stable and can be used in medical therapy particularly for the treatment of retroviral infections and hepatitis B viral infections. OBJECTIVE The objective of the present invention is to provide novel salts of Abacavir or solvates or hydrates thereof. Yet another objective of the present invention is to provide novel salts of Abacavir or solvates or hydrates thereof, which are crystalline in nature. Yet another objective of the present invention is to provide novel salts of Abacavir or solvates or hydrates thereof, which are amorphous in nature. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 - Powder X-ray Diffraction (PXRD) of crystalline Abacavir malonate Figure 2 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir malonate Figure 3 - Powder X-ray Diffraction (PXRD) of amorphous Abacavir malonate Figure 4 - Powder X-ray diffraction (PXRD) of crystalline Abacavir maleate Figure 5 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir maleate Figure 6 - Powder X-ray diffraction (PXRD) of amorphous Abacavir maleate Figure 7 - Powder X-ray diffraction (PXRD) of crystalline Abacavir hemioxalate Figure 8 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir hemioxalate Figure 9 - Powder X-ray diffraction (PXRD) of crystalline Abacavir oxalate Figure 10 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir oxalate Figure 11 - Powder X-ray diffraction (PXRD) of crystalline Abacavir hydrobromide Figure 12 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir hydrobromide Figure 13 - Powder X-ray diffraction (PXRD) of crystalline Abacavir hydrobromide monohydrate Figure 14 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir hydrobromide monohydrate Figure 15 - Powder X-ray diffraction (PXRD) of crystalline Abacavir dihydrobromide Figure 16 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir dihydrobromide Figure 17 - Powder X-ray diffraction (PXRD) of crystalline Abacavir dihydrobromide monohydrate Figure 18 - Differential Scanning Calorimetry (DSC) of crystalline Abacavir dihydrobromide monohydrate SUMMARY OF THE INVENTION The present invention relates to novel salts of (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl] -2-cyclopentene-1 -methanol of Formula I or solvates or hydrates thereof, wherein M represents hemimalonate, malonate, hemioxalate, oxalate, hydrobromide, dihydrobromide, hemimaleate, maleate. In another embodiment the present invention also relates to the novel salts of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-l-methanol or solvates or hydrates thereof, which are crystalline. In another embodiment the present invention also relates to the novel salts of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-l-methanol or solvates or hydrates thereof, which are amorphous. In another embodiment the present invention also relates to the process for preparing novel salts of (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol or solvates or hydrates thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel salts of Abacavir of Formula I or solvates or hydrates thereof, wherein M represents hemimalonate, malonate, hemioxalate, oxalate, hydrobromide, dihydrobromide, hemimaleate, maleate. Another aspect of the present invention relates to novel salt of Abacavir malonate of Formula III or solvates or hydrates thereof, wherein X represents 54 or 1 In an aspect of the present invention, crystalline Abacavir malonate having Powder X-ray diffraction °20 values at 9.47, 13.2, 14.2, 15.6, 17.5, 18.5, 21.6, 22.5, 23.1, 25.2, 26.1, 27.0, 28.6 ±0.2. In an aspect of the present invention, crystalline Abacavir malonate has Differencial scanning calorimetry (DSC) endothermic peak at 153.3°C. Yet another aspect of the present invention relates to a process to prepare crystalline form of Abacavir malonate salt, comprising: i) treating Abacavir with malonic acid in a solvent; ii) isolating Abacavir malonate salt, wherein Abacavir is a free base or a salt other than malonate; salt is isolated as hemi-malonoate or malonoate; the solvent is selected from polar solvents, non-polar solvents or mixtures thereof. Another aspect of the present invention relates to Abacavir malonate in amorphous form. Yet another aspect of the present invention relates to a process to prepare amorphous form of Abacavir malonate salt, comprising: i) treating Abacavir with malonic acid in a solvent; ii) removing the solvent; and iii) isolating the Abacavir malonate salt, wherein Abacavir is a free base or a salt other than malonate; salt is isolated as hemi-malonoate or malonoate; the solvent is selected from polar solvents, non-polar solvents or mixtures thereof. The removal of solvent is carried out using distillation, spray-drying, freeze-drying or lyophilization. Another aspect of the present invention relates to novel salt of Abacavir oxalate of Formula IV or solvates or hydrates thereof, wherein X represents Vi or 1. In an aspect of the present invention, crystalline Abacavir hemioxalate having Powder X-ray diffraction °20 values at 9.4, 12.1, 12.5, 16.9, 17.1, 18.1, 18.6, 18.9, 19.9, 21.3, 21.8, 22.5, 23.4, 23.8, 28.4, 33.9, 36.1 ±0.2. In an aspect of the present invention, crystalline Abacavir hemioxalate has DSC endothermic peaks at 164.3°C and 221.4°C. In an aspect of the present invention, Abacavir oxalate in crystalline form, having Powder X-ray diffraction °28 values at 6.4,9.1,17.1,23.4,27.5 ±0.2. In an aspect of the present invention, Abacavir oxalate in crystalline form, having DSC endothermic peaks at 82.5°C, 148.6°C and 165.6°C. Yet another aspect of the present invention relates to a process to prepare crystalline form of Abacavir oxalate, comprising: i) treating Abacavir with oxalic acid in a solvent; ii) isolating Abacavir oxalate salt, wherein Abacavir is free base or a salt other than oxalate; salt is isolated as hemi-oxalate or oxalate salt; the solvent is selected from polar solvents, non-polar solvents or mixtures thereof. Another aspect of the present invention relates to novel salt of Abacavir maleate of Formula V, or solvates or hydrates thereof, wherein X represents Vz or 1. In an aspect of the present invention, crystalline Abacavir maleate having Powder X-ray diffraction °20 values at 10.2, 12.0, 12.6, 14.3, 15.8, 16.4, 17.6, 18.4, 19.2, 20.5, 21.2, 22.5,23.0, 24.2,25.7,26.5,27.4,27.7, 28.5 ±0.2. In an aspect of the present invention, crystalline Abacavir maleate has DSC endothermic peak at 141.0°C. Yet another aspect of the present invention relates to a process to prepare crystalline form of Abacavir maleate, comprising: i) treating Abacavir with maleic acid in a solvent; ii) isolating Abacavir maleate salt, wherein Abacavir is a free base or a salt other than maleate; salt is isolated as hemi-maleate or maleate; the solvent is selected from polar solvents, non-polar solvents or mixtures thereof. In an aspect of the present invention Abacavir maleate is in amorphous form. Yet another aspect of the present invention relates to a process to prepare amorphous form of Abacavir maleate salt, comprising: i) treating Abacavir with maleic acid in a solvent; ii) removing the solvent; and iii) isolating Abacavir maleate salt, wherein Abacavir is a free base or a salt other than maleate; salt is isolated as hemi-maleate or maleate; the solvent is selected from polar solvents, non-polar solvents or mixtures thereof. The removal of solvent can be carried out using distillation, spray-drying, freeze-drying or lyophilization. Another aspect of the present invention relates to novel salt of Abacavir hydrobromide of Formula VI, or solvates or hydrates thereof, wherein X represents 1 or 2. In an aspect of the present invention, crystalline Abacavir hydrobromide having Powder X-ray diffraction °2θ values at 6.9, 11.8, 15.7, 16.3, 18.4, 18.6, 19.1, 21.0, 21.6, 22.4, 22.8, 23.1, 23.5, 23.9, 25.0, 25.6, 26.5, 27.1 ±0.2. In an aspect of the present invention, crystalline Abacavir hydrobromide has DSC endothermic peaks at 67.2°C, 150.5°C and exothermic peak at 155.8°C. In an aspect of the present invention, crystalline Abacavir di-hydrobromide having Powder X-ray diffraction °20 values at 7.6, 15.1, 18.0, 18.3,20.8, 21.2, 25.1, 26.3,29.3 ±0.2. In an aspect of the present invention, crystalline Abacavir di-hydrobromide has DSC endothermic peak at 185.2°C and exothermic peaks at 204.6°C and 235.2°C. Yet another aspect of the present invention relates to a process to prepare crystalline form of Abacavir hydrobromide, comprising: i) treating Abacavir with hydrobromic acid in a solvent; ii) isolating Abacavir hydrobromide salt, wherein Abacavir is a free base or a salt other than hydrobromide; salt is isolated as hydrobromide or dihydrobromide salt; the solvent is selected from polar solvents, non-polar solvents or mixtures thereof. In an aspect of the present invention, crystalline Abacavir hydrobromide monohydrate having Powder X-ray diffraction °20 values at 7.5, 9.2, 11.8, 13.4, 14.3, 16.3, 17.7, 18.6, 19.1, 19.6, 21.3, 21.6, 22.3, 23.0, 23.7, 24.1, 25.1, 25.8, 26.0, 26.5, 26.8, 28.0, 29.9, 30.5, 31.1, 31.6, 32.4, 36.5, 36.9 ±0.2. In an aspect of the present invention, crystalline Abacavir hydrobromide monohydrate has DSC endothermic peaks at 94.1°C, 133.0°C and exothermic peak at 153.8°C, 247.1°C. In an aspect of the present invention, crystalline Abacavir dihydrobromide monohydrate having Powder X-ray diffraction °29 values at 7.1, 14.2, 18.8, 21.4, 21.7, 23.3,24.8,25.7, 26.8,27.9, 31.3 ±0.2. In an aspect of the present invention, crystalline Abacavir dihydrobromide monohydrate has DSC endothermic peaks at 142.0°C and exothermic peak at 151.6°C, 190.1°C,237.1°C. Another embodiment of the present invention, the novel salts of the present invention are stable and non-hygroscopic. The polar solvent is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, butanol, ethylacetate, methylacetate, acetonitrile, acetone. The non-polar solvent is selected from the group consisting of methyl t-butyl ether, tetrahydrofuran, diisopropyl ether, toluene, hexanes, heptanes. Abacavir is prepared by using processes reported in literature. In another embodiment of the invention there are provided the compounds according to the invention for use in medical therapy particularly for the treatment of retroviral infections and hepatitis B viral infections. Examples of retroviral infections which may be treated or prevented in accordance with the invention include human retroviral infections such as human immunodeficiency virus (HIV), HIV-1, HIV-2 and human T-cell lymphotropic virus (HLTV), e.g. HTLV-I or HTLV-II infections. The compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), AIDS-related neurological conditions, such as multiple sclerosis or tropical paraparesis, anti-HIV antibody-positive and HIV-positive conditions and thrombocytopenic purpura. The compounds may also be used in the treatment or prevention of psoriasis. The compounds of the invention may be administered alone or in combination with other therapeutic agents suitable in the treatment of HIV infections, such as Nucleoside Reverse Transciptase Inhibitors (NRTIs) for example zidovudine, zalcitabine, lamivudine, didanosine, stavudine, 5-chloro-2',3'-dideoxy-3'-fluorouridine, adefovir and (2R,5S)-5-fluoro-1 -[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, lovaride; non-NRTIs for example nevirapine, delavuridine, a-APA, HBY-1293 and efavirenz; HIV protease inhibitors for example saquinavir, indinavir, nelfinavir, ritonavir and VX-478, immune modulators for example interleukin II, erythyropoetin, tucaresol, and interferons for example a-interferon. In addition the compound of the invention may be administered in combination with other therapeutic agents suitable in the treatment of HBV infections for example lamivudine, emtricitabine, immune modulators, and interferons. Such combinations may be administered together or sequentially providing that any duration between the administration of each therapeutic agent does not diminish their additive effect. In view of their useful pharmacological properties, the compounds according to the present invention may be formulated into various pharmaceutical forms for administration purposes. While it is possible for the compound of the present invention to be administered as the raw chemical, it is preferable and advantageous to present the compound of the invention as a pharmaceutical formulation, and represents a further embodiment of the invention. The pharmaceutical formulation comprises the compounds of the invention as active ingredient optionally together with one or more pharmaceutically acceptable carrier(s) therefore and optionally other therapeutic agents. The carrier(s) must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients and the active ingredient of the formulation and not deleterious to the recipients thereof. The compounds according to the invention may be administered by any route appropriate to the condition to be treated, suitable routes including, but not limited to, oral, rectal, nasal, topical (including, but not limited to, transdermal, buccal and sublingual), vaginal and parenteral (including, but not limited to, subcutaneous, intramuscular, intravenous, intradermal, intraarticular, intrathecal and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. For each of the above-indicated utilities and indications the amount required of the individual active ingredient will depend upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician. In general, however, for each of these utilities and indications, a suitable, effective dose will be in the range of 1 to 1000 mg per day. The dose may if desired be presented as two, three, four or more sub-doses administered at appropriate intervals throughout the day. The formulations can be presented in any dosage form, including unit dosage form and may be prepared by any of the methods well known in the art. To prepare the pharmaceutical compositions of this invention, an effective amount of the compound of the present invention, as the active ingredient is optionally combined with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an emulsion. The active ingredient may also be presented as a bolus or paste or may be contained within liposomes. A tablet formulation can be prepared by any process known in the art, including wet granulation, dry granulation/compaction or direct compression or moulding. Compressed tablets may be prepared by compressing in a suitable machine the pharmaceutical composition comprising active ingredient optionally with one or more pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carrier(s) include diluents, binders, disintegrant, lubricant, glidant, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide modified or controlled release of the active ingredient therein, using various techniques for controlled release or modified release well known in the art. A capsule may be made by filling a loose or compressed powder, pellets, granules, mini-tablets, tablets, microsphere or the like or combinations thereof, optionally with one or more pharmaceutically acceptable carriers using appropriate capsule filling machine. Examples of pharmaceutically acceptable carriers include binders, glidants, lubricants, diluents, disintegrants, and surface active or dispersing agents. Capsules may also be formulated to provide slow or controlled release of the active ingredient. This can be achieved by using various techniques for controlled release or modified release well known in the art. For buccal administration the formulation may take the form of tablets or lozenges formulated in conventional manner. Diluents, also termed "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, cellulose derivatives, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, starch derivatives, pre-gelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and sugars. The amount of diluents in the formulation can range from about 20 to about 90% by weight of the total formulation. Binders refers to substances that has binding properties, thus serve as the "adhesive" in the formulation. Binders according to the present invention can be selected from the group comprising, but not limited to, water-soluble polymer, water insoluble polymer, gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; waxes, gelling agents, polysaccharides or the like. Preferably can be water soluble polymers for example hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, povidone, starch and its derivatives, cellulose derivatives, methyl cellulose or the like. The amount of binder in the formulation can range from, but not limited to, about 1 to about 10% by weight of the total formulation. Glidants refers to material that prevents caking and improves the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidants include colloidal silicon dioxide and talc. The amount of glidant in the formulation can range from about 0.01% to about 5% by weight of the total formulation. Lubricants are substances added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; sodium stearyl fumarate; high melting point waxes such as glyceryl behenate; and water soluble lubricants such as boric acid sodium chloride, sodium benzoate, sodium acetate, sodium chloride sodium oleate, polyethylene glycols and d'1-leucine. The amount of lubricant in the formulation can range from about 0.1 to about 10% by weight of the tablet formulation. Disintegrant refers to materials added to the formulation to help it break apart (disintegrate) and release the drug. Suitable disintegrants include starches; modified starches such as sodium starch glycolate; natural and synthetic gums such as locust bean, karaya, guar gum, tragacanth and agar; cellulose derivatives such as methylcellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked polymers such as sodium croscarmellose, crospovidone; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the formulation. Formulations of the present invention suitable for parenteral administration may be presented in the form of parenteral solutions, suspension, liposomes, nanosomes, emulsions or the like. The parenteral solutions may be prepared by dissolving active ingredient in pharmaceutically acceptable carriers/solvents including aqueous or non¬aqueous carriers optionally along with other ingredients including but not limited to, buffering agent, isotonicity agent, suspending agent, preservatives, stabilizing agent, viscosity modifier or combinations thereof. Injectable solutions, for example, may be prepared in which the carrier comprises sterile water, saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing non-aqueous carrier may be formulated in oil for prolonged action. Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a liquid solvent to form a homogeneous solution of the solute in the solvent. The extent of the solubility of a substance in a specific solvent is measured as the saturation concentration where adding more solute does not increase the concentration of the solution. The saturation solubility of the compounds according to the present invention is measured in various solvent systems including simulated gastric fluid, pH 4.5 buffer, pH 6.8 buffer solution and pH 7.2 buffer solution. The compounds according to the present invention show better solubility as compared to abacavir sulphate in all solvent systems. Table-1: Comparison of saturation solubility of Abacavir malonate with Abacavir sulphate (marketed salt) POWDER X-RAY DIFFRACTION (PXRD) The X-ray powder diffractogram is obtained using a Seifert, XRD 3003 TT system. The X-ray generator was operated at 40 kv and 30 mA, using the Kal radiation source. It is scanned in the diffraction range of 3° to 40° 29 at a scan rate of 0.03° 20 per second. DIFFERENCIAL SCANNING CALORIMETRY (DSC) The thermal behavior of Abacavir salts is examined by DSC, using Mettler Toledo -instrument Model DSC8216, caliberated with Indium and Zinc. The sample is heated in a pierced aluminium pan under nitrogen atmosphere at a rate of 10°C/min over a temperature range of 30°C to 200°C. The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. EXAMPLE-1 PREPARATION OF (lS,4R)-4-[2-AMINO-6-(CYCLOPROPYLAMINO)-9H-PURIN-9-YLJ-2-CYCLOPENTENE-1-METHANOL (ABACAVIR BASE) Cyclopropylamine (147.20 g, 2.582 mol) was added to a suspension of (lS,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-l-methanolhydrochloride (150 g, 0.497 mol) in ethanol (absolute alcohol, 1500 ml) at 25-30°C and reaction mass was heated to reflux at 74-78°C for ~6 hrs to complete the reaction. Thereafter, the reaction mass was concentrated at 40-50°C under reduced pressure (700-50 mm of Hg) to remove the solvents completely. Obtained concentrated mass was diluted with DM water (450 ml) & ethyl acetate (1500 ml) at 25-45°C and pH was adjusted to 7.5-8.0 with 10% w/v aqueous sodium hydroxide solution maintaining temperature 40-45 °C. Organic layer was separated and aqueous layer, saturated with sodium chloride (150g) was re-extracted with preheated ethyl acetate (1 x 900 ml, 1 x 450 ml, 40-45°C). Combined organic layer was treated with carbon enoanticromos and concentrated at 40-50°C under reduced pressure (200-50 mm of Hg) to yield a foamy solid i.e. (lS,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl] -2-cyclo-pentene-1 -methanol (Abacavir base). EXAMPLE-2 PREPARATION OF (lS,4R)-4-[2-AMINO-(6-CYCLOPROPYLAMINO)-9H-PURIN-9-YL1-2-CYCLOPENTENE-1-METHANOL (ABACAVIR BASE) Abacavir hemisulfate (300 g, 0.453 mol) was suspended in mixture of ethyl acetate (3000 ml) and DM water (900 ml) at 25-30°C. The contents were heated to 40-45°C and pH of the suspension was adjusted to 6.0-6.1 with 20% w/w aqueous sodium hydroxide solution (-250 ml). Thereafter, organic layer was separated and aqueous layer was re-extracted with ethyl acetate (1 x 600 ml) at 40-45°C. Carbon enoanticromos (15 g) was added to the combined organic layer and contents were stirred for ~1 h at 40-45°C. Carbon was removed through hyflo and residue was washed with pre-heated ethyl acetate (2 x 100 ml,40-45°C), Concentrated the filtrate at 50-60°C under reduced pressure (150-50 mm Hg) to obtain a foamy oily mass. Thereafter, acetone (1000 ml) was added to the concentrated mass and stirred for -30 min at 0-5°C. Product was filtered, washed with acetone (2 x 100 ml) under nitrogen atmosphere and dried at 40-50°C under reduced pressure (10-50 mm Hg) to a constant weight. Yield: 200 g (78% of Theory) Chromatographic Purity (by HPLC) : 99.86% Chiral Purity (by HPLC) : 99.93% Assay (by HPLC, % w/w) : 99.4 EXAMPLES PREPARATION OF (lS,4R)-4-[2-AMINO-6-CHLORO-9H-PURIN-9-YL]-2-CYCLOPENTENE-1-METHANOL (CHLOROPURINE BASE) (1 S,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1 -methanol hydrochloride (50 g, 0.1656 moles) was suspended in DM water (400 ml, 25-30°C) and contents were further cooled to 10-15°C. Thereafter, pH of reaction mixture was adjusted to 7.0-7.5 with -10% w/w aqueous ammonia solution (25 ml) slowly in a period of-60 min at 10-15°C. Product was filtered, washed with pre-cooled DM water (100 ml) and dried at 40-50°C/~10mmHg to at constant weight. Yield: 38 g Chromatographic Purity (by HPLC): 98.55% EXAMPLE-4 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR MALONATE Malonic acid (14.2 g, 0.136 mole) dissolved in 150 ml of ethanol was added to a suspension of Abacavir base (30 g, 0.105 mole) in 300 ml of ethanol in a period of -15 min at 25-30°C. The contents were heated to 60-70°C and stirred for -30 min to obtain a clear solution. Thereafter, obtained solution was cooled to 40-45°C. Precipitated product was further cooled to 5-10°C and stirred for -2 h. Product was filtered, washed with pre-cooled ethanol (1 x 30 ml, 5-10°C) and dried under reduced pressure (10- 50mm Hg) to obtain Abacavir malonate. Yield : 36 g (88% of theory). Chromatographic Purity (by HPLC) : 99.88% Chiral Purity (by HPLC) : 99.95% Assay(by HPLC, %w/w) : 99.9 Water content (By KF) : 0.14% w/w SOR: [ά]D25 (C=0.5 in Methanol, on anhydrous basis) = -33.5° Malonic acid content (on as is basis): 26.70% w/w (Theoretical value-26.67%w/w) 'H-NMR (300MHZ) in DMSO-d6: ct(ppm): 7.64-7.62 (1H, d, N=CH); 7.50 (1H, S, NH); 6.12-6.11 (1H, d, CH=CH); 5.97 (2H, S, NH2); 5.88-5.86 (1H, dd, CH-CH); 5.40-5.37 (1H, d, CHN); 3.46-3.44 (2H, d, OCH2); 3.20-3.19 (2H, d, CH2, Malonate Salt); 3.02 (1H, S, CH-NH); 2.87 (1H, S, CHCH20); 2.62-2.58 (1H, m, CH2, Cyclopentene); 1.61-1.56 (1H, m, CH2, Cyclopentene); 0.69-0.59 (4H, m, 2CH2, Cyclopropyl). Melting range: 148°C -150°C DSC: Onset-152.34°C Peak- 153.34°C EXAMPLE-5 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR MALONATE Malonic acid (2.36 g, 0.0227 moles) dissolved in 30 ml of methanol was added to a suspension of Abacavir base (5 g, 0.0175 mole) in 30 ml of methanol in a period of -15 min at 25-30°C and stirred to obtain a clear solution. Thereafter, obtained solution was cooled to 0-5 °C and stirred for ~3 h. Product was filtered, washed with pre-cooled methanol (5ml, 5-10°C) and dried Under reduced pressure (~20mm Hg) to obtain crystalline form of Abacavir malonate. EXAMPLE-6 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR MALONATE Malonic acid (2.36 g, 0.0227 moles) dissolved in 45 ml of isopropyl alcohol was added to a suspension of Abacavir base (5 g, 0.0175 mole) in 30 ml isopropyl alcohol in a period of ~15min at 25-30°C and further heated to 45-50°C. Thereafter, obtained suspension was cooled to 25-30°C and stirred for ~2 h. Product was filtered, washed with isopropyl alcohol (5ml) and dried under reduced pressure (~20mm Hg) to obtain crystalline form of Abacavir malonate. EXAMPLE-7 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR MALONATE Malonic acid (2.36 g, 0.0227 moles) dissolved in 70 ml of tetrahydofuran was added to a suspension of Abacavir base (5 g, 0.0175 mole) in 30 ml tetrahydofuran in a period of ~15min at 25-30°C and further heated to 45-50°C to obtain a clear solution. Thereafter, obtained solution was cooled to 25-30°C and stirred for ~3 h. Product was filtered, washed with tetrahydofuran (10ml) and dried under reduced pressure (~20mm Hg) to obtain crystalline form of Abacavir malonate. EXAMPLE-8 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR MALONATE Malonic acid (2.36 g, 0.0227 moles) dissolved in 100 ml of acetonitrile was added to a suspension of Abacavir base (5 g, 0.0175 mole) in 50 ml acetonitrile in a period of ~15min at 25-30°C and further heated to 50-55°C. Thereafter, obtained suspension was cooled to 25-30°C and stirred for ~3 h. Product was filtered, washed with acetonitrile (10ml) and dried under reduced pressure (~20mm Hg) to obtain crystalline form of Abacavir malonate. EXAMPLE-9 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR MALONATE Abacavir malonate (3.0g, 0.0076moles) suspended in 18 ml of methanol was heated to 45-50°C to obtain a clear solution. Thereafter, 72ml of methyl-tert-butyl ether was added to the obtained clear solution in a period of-15 min & stirred for ~1 hr at this temperature to precipitate the product. Thereafter, obtained suspension was cooled to 25-30°C and stirred for ~2 h. Product was filtered, washed with methanol: methyl-tert-butyl ether (1:4; 10ml) and dried under reduced pressure (~20mm Hg) to obtain crystalline form of Abacavir malonate. EXAMPLE-10 PREPARATION OF AMORPHOUS FORM OF ABACAVIR MALONATE Abacavir malonate (5.0g, 0.0128moles), suspended in 50 ml of DM water was stirred 25-30°C to obtain a clear solution and treated with carbon. Thereafter, obtained filtrate was lyophilized at 25-30°C under reduced pressure (50-100 milli torr. of Hg) to obtain Amorphous Abacavir malonate. EXAMPLE-11 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR HEMIOXALATE Oxalic acid dihydrate (13.88 g, 0.110 mole) was added to suspension of Abacavir base (30 g, 0.105mole) in 450 ml of 20%v/v aqueous ethanol at 25-30°C. Thereafter, the suspension was heated to 70-7 5 °C and stirred for ~15 min to obtain a clear solution and then the solution was cooled to 25-3 0°C to precipitate the product, which was further cooled to 0-5 °C and stirred for ~2 h. Product was filtered, washed with ethanol (absolute alcohol, 30 ml, 0-5°C) and dried at 40-50°C under reduced pressure (10-50 mm Hg). Yield : 22.5 g (65% of theory). Chromatographic Purity (by HPLC) : 99.84% Chiral Purity (by HPLC) : 99.99% Assay (by HPLC, %w/w) : 99.1 Water content (By KF) : 0.24% w/w SOR: [ά]D25 (C=0.5 in methanol, on anhydrous basis) = -37.9° Oxalic acid content (on as is basis): 13.93% w/w (Theoretical value=13.60%w/w) !H-NMR (300MHz) in DMSO-d6: cc(ppm) 7.79 (1H,S, NH);7.68-7.67 (1H, d, N=CH); 6.13-6.11 (1H, d, CH=CH); 5.88-5.86 (1H, t, CH=CH); 5.40 (1H, S, CH-N); 6.15 & 4.98 (4H, broad peak, NH2, 2 x COOH, OH); 3.46-3.44 (2H, d, OCH2); 3.03 (1H, S, CH-NH), 2.87 (1H, S, CHCH20); 2.63-256 [1H, m, CH2(cyclopentene)]; 1.61-1.55 [1H, m, CH2 (cyclopentene)]; 0.71-0.61 (4H, m, 2CH2, cyclopropyl). Melting range : Decomposed at 213°C DSC: Onset- 216.42°C Peak-221.41°C EXAMPLE-12 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR HEMIOXALATE Abacavir hemioxalate (3 g, 0.0045moles) was suspended in 60 ml of 20%v/v aqueous methanol at 25-30°C. Thereafter, the suspension was heated to 60-65°C and stirred for -15 min to obtain a clear solution. Obtained solution was cooled to 25-30°C. Precipitated product was further cooled to 0-5°C and stirred for -2 h. Product was filtered, washed with pre-cooled methanol (6 ml, 0-5°C) and dried at 40-50°C under reduced pressure (20mm Hg) to obtain crystalline form of Abacavir hemioxalate. EXAMPLE-13 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR HEMIOXALATE Abacavir hemioxalate (2 g, 0.003moles) was suspended in 50 ml of 20%v/v aqueous isopropyl alcohol at 25-30°C. Thereafter, the suspension was heated to 70-78°C and stirred for -15 min to obtain a clear solution. Obtained solution was cooled to 25-30°C. Precipitated product was further cooled to 0-5°C and stirred for -2 h. Product was filtered, washed with pre-cooled isopropyl alcohol (4 ml, 0-5°C) and dried at 40-50°C under reduced pressure (20mm Hg) to obtain crystalline form of Abacavir hemioxalate EXAMPLE-14 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR MONOOXALATE (1:1) Oxalic acid dihydrate (13.88 g, 0.110 moles) was added to a suspension of Abacavir base (15 g, 0.052 moles) in 225 ml of 20% v/v aqueous ethanol at 25-30°C. The contents were heated to 70-75 °C and stirred for ~15 min to obtain a clear solution. Thereafter, obtained clear solution was cooled slowly to 0-5 °C and stirred for -2 h atthis temperature. Product was filtered, washed with pre-cooled ethanol (30 ml, 0-5°C) and dried at 40-50°C under reduced pressure (10-50 mm Hg). Yield : 13.5 g (68% of theory). Chromatographic Purity (by HPLC) . 99.46% Chiral Purity (by HPLC) : 99.96% Assay (by HPLC, %w/w) : 94.7 Water content (By KF) : 0.58% w/w SOR: [ά]D25 (C=0.5 in methanol, on anhydrous basis): -25.1° Oxalic acid content (on as is basis): 26.32% w/w (Theoretical value-23.94%w/w) DSC: Triplet: 1) Onset: 68.97°C and Peak: 82.56°C 2) Onset: 145.10°C and Peak: 148.67°C 3) Onset: 159.46°C and Peak: 165.62 °C Melting range. 154°C-157°C *H-NMR (300MHz) in DMSO-d6 : g(ppm): 7.79 (1H,S, NH);7.71-7.69 (1H, d, N=CH); 6.13-6.11 (1H, d, CH=CH); 5.88-5.86 (1H, t, CH=CH);5.40 (1H, S, CH-N);4.07 (4H, broad peak, NH2, 2 x COOH, OH); 3.45-3.44 (2H, d, OCH2); 3.00 (1H, S, CH-NH), 2.87 (1H, S, CHCH20); 2.63-256 [1H, m, CH2 (cyclopentene)]; 1.61-1.57 [1H, m, CH2 (cyclopentene)]; 0.73-0.63 (4H, m, 2CH2, cyclopropyl). EXAMPLE-15 PREPARATION OF CRYSTALLINE FORM OF ABACAVIR HYDROBROMIDE 48% w/w aqueous hydrobromic acid (3.1 g, 0.0184 mole,) was added to a suspension of Abacavir base (5 g, 0.0175 mole) in 60 ml of ethanol in a period of-15 min at 25-30°C and stirred for ~30 min to obtain a clear solution. Reaction mass was concentrated at 40-50°C under reduced pressure (200-50 mm Hg) to obtain oily mass. Thereafter, tetrahydrofuran (60 ml) was added to concentrated mass and stirred for ~30 min at 25-30°C. Precipitated product was cooled to 0-5°C and stirred for ~3 h to complete the precipitation. Product was filtered, washed with pre-cooled tetrahydrofuran (lx 15 ml, 0-5°C) and dried at 40-50°C under reduced pressure (10-50 mm Hg). Yield: 5.25 g (82% theory) Chromatographic Purity (by HPLC) : 99.88% Chiral Purity (by HPLC) : 99.93% Assay (by HPLC, %w/w) : 97.9 Water content (By KF) : 0.59% w/w SOR: [ά]D25 (C=0.5 in methanol, on anhydrous basis) = -21.2° HBr content (on as is basis): 22.06% w/w (Theoretical value=22.07%w/w) Melting range: Decomposed at 138°C DSC: Triplet: 1) Onset: 48.74°C and Peak: 67.29°C 2) Onset: 143.41°C and Peak: 150.58°C 3) Onset: 153.53°C and Peak: 155.84 °C H-NMR (300MHz) in DMSO-d6 :

Documents

Application Documents

# Name Date
1 2385-che-2009 form-2 30-09-2009.pdf 2009-09-30
2 2385-che-2009 form-1 30-09-2009.pdf 2009-09-30
3 2385-che-2009 description (provisional) 30-09-2009.pdf 2009-09-30
4 2385-che-2009 correspondence others 30-09-2009.pdf 2009-09-30
5 2385-CHE-2009 FORM-1 10-12-2009.pdf 2009-12-10
6 2385-CHE-2009 FORM-5 29-09-2010.pdf 2010-09-29
7 2385-CHE-2009 FORM-2 29-09-2010.pdf 2010-09-29
8 2385-CHE-2009 FORM-1 29-09-2010.pdf 2010-09-29
9 2385-CHE-2009 DRAWINGS 29-09-2010.pdf 2010-09-29
10 2385-CHE-2009 DESCRIPTION(COMPLETE) 29-09-2010.pdf 2010-09-29
11 2385-CHE-2009 CORRESPONDENCE 29-09-2010.pdf 2010-09-29
12 2385-CHE-2009 CLAIMS 29-09-2010.pdf 2010-09-29
13 2385-CHE-2009 ABSTRACT 29-09-2010.pdf 2010-09-29
14 2385-che-2009 form-1 11-10-2010.pdf 2010-10-11
15 2385-che-2009 form-3 02-11-2010.pdf 2010-11-02
16 2385-CHE-2009 FORM-3 13-05-2011.pdf 2011-05-13
17 2385-CHE-2009 CORRESPONDENCE OTHERS 13-05-2011.pdf 2011-05-13
18 2385-che-2009 form-1 10-12-209.pdf 2011-09-04
19 2385-CHE-2009 ABSTRACT.jpg 2012-03-01