WO2010110506A1 - Dh-type crystalline form of adefovir dipivoxil, preparing method thereof, and pharmaceutical composition for antiviral agent comprising the same - Google Patents
Dh-type crystalline form of adefovir dipivoxil, preparing method thereof, and pharmaceutical composition for antiviral agent comprising the same Download PDFInfo
- Publication number
- WO2010110506A1 WO2010110506A1 PCT/KR2009/002685 KR2009002685W WO2010110506A1 WO 2010110506 A1 WO2010110506 A1 WO 2010110506A1 KR 2009002685 W KR2009002685 W KR 2009002685W WO 2010110506 A1 WO2010110506 A1 WO 2010110506A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adefovir dipivoxil
- crystalline form
- type crystalline
- butyl alcohol
- solvent
- Prior art date
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention relates to a DH-type crystalline form of adefovir dipivoxil represented by Formula 1 below, a method of preparing the same, and a pharmaceutical composition for an antiviral agent comprising the same.
- Adefovir dipivoxil represented by the above Formula 1 has the chemical name of 9-[2-[bis(pivaloyloxy)methoxyphosphinylmethoxy]ethyl]adenine.
- Adefovir dipivoxil which is known effective for the treatment of patients with chronic hepatitis B virus (HBV) infection showing persistently elevated serum aminotransferase (ALT or AST) levels or abnormal histological activity, is commercially available as 'HepseraTM' (Glaxo Smith Kline, Inc.).
- Adefovir dipivoxil being an adenosine analog, serves as an acyclic nucleotide reverse transcriptase inhibitor.
- compositions comprising adefovir dipivoxil in an amorphous form and a crystalline form as active ingredients are disclosed in WO 00/35460. It discloses pharmaceutical compositions comprising a crystalline adefovir dipivoxil anhydride, a crystalline adefovir dipivoxil dihydrate, and an alkali excipient with improved stability.
- Korean Patent No. 0618663 discloses a crystalline adefovir dipivoxil having excellent storage stability, particularly, an anhydrous crystalline form (Form 1), a hydrated crystalline form (dihydrate, Form 2), a methanol solvate crystalline form (Form 3), a fumaric acid salt or complex (Form 4), and other acid addition salts or complexes.
- WO 99/4774 discloses pharmaceutical compositions comprising at least one crystalline adefovir dipivoxil, more specifically, including those in an anhydrous crystalline form, an anhydrous crystalline form, a solvate crystalline form, or a salt crystalline form of adefovir dipivoxil.
- Polymorphism of adefovir dipivoxil is caused by certain properties of some molecules and molecular complexes.
- a single molecule of adefovir dipivoxil may produce various solids having distinct physical properties such as melting point, X-ray diffraction pattern, and UV absorption fingerprint. Variations on the physical properties of the polymorphic products result from interaction between molecules (complexes) adjacent to bulk solids and orientation of the molecules. Thus, polymorphic products are considered as different solids having distinct physical properties although they have the same molecular formula.
- the present invention relates to a novel polymorphic adefovir dipivoxil.
- the present invention also relates to a method of preparing a novel polymorphic adefovir dipivoxil.
- the present invention also relates a pharmaceutical formulation including a novel polymorphic adefovir dipivoxil.
- the present invention also relates a novel polymorphic adefovir dipivoxil used for the treatment of chronic hepatitis B virus infection.
- a DH-type crystalline form of adefovir dipivoxil having a powder X-ray diffraction spectrum peak with a peak intensity being equal to or greater than 200 expressed in diffraction angles (2 ⁇ ) at 7.84, 8.49, 9.65, 12.43, 14.08, 14.31, 14.69, 15.5, 16.06, 17.14, 17.66, 18.35, 19.10, 19.45, 19.70, 20.34, 20.82, 21.82, 22.11, 22.86, 23.55, 24.46, 25.06, 26.45, 27.03, 27.66, 28.37, 29.09, and 29.77.
- a maximum endothermic peak of the DH-type crystalline form of adefovir dipivoxil in differential scanning calorimeter (DSC) thermogram is observed at 71.6°C.
- a method of preparing a DH-type crystalline form of adefovir dipivoxil comprising dissolving adefovir dipivoxil in n- butyl alcohol; and leaving the resulting solution at a temperature ranging from -10°C to 30°C to collect precipitated solid.
- novel polymorphic adefovir dipivoxil of DH-type crystalline form may be used to efficiently prepare antiviral agents due to its excellent chemical stability in moisturized conditions.
- FIG. 1 is a powder X-ray diffraction spectrum of A DH-type crystalline form of adefovir dipivoxil;
- FIG. 2 is a differential scanning calorimeter (DSC) thermogram of A DH-type crystalline form of adefovir dipivoxil;
- FIG. 3 is a thermal analyzer graph of A DH-type crystalline form of adefovir dipivoxil.
- Powder X-ray diffraction spectrum and differential scanning calorimeter (DSC) thermogram of powder of adefovir dipivoxil in a DH-type crystalline form according to the present invention are compared with those of adefovir dipivoxil in crystalline forms disclosed in Korean Patent No. 0618663, i.e., an anhydrous crystalline form (Form 1), a hydrated crystalline form (dihydrate, Form 2), and a methanol solvate crystalline form (Form 3), and the results are shown in Table 1 below.
- the X-ray diffraction (XRD) pattern of the powder of the DH-type crystalline form of adefovir dipivoxil according to the present invention is different from those of the conventional adefovir dipivoxil crystalline forms (Forms 1, 2, and 3).
- XRD X-ray diffraction
- the maximum endothermic peak of the powder of adefovir dipivoxil in the DH-type crystalline form according to the present invention in DSC thermogram is also different from those of adefovir dipivoxil in the conventional crystalline forms (Forms 1, 2, and 3).
- the DH-type crystalline form of adefovir dipivoxil of the present invention is a solvate crystalline form and comprises about 0.5 eq. of a crystalline solvent in a crystalline lattice structure.
- the crystalline solvent contained in the crystalline lattice structure may be a single solvent of n- butyl alcohol or a mixed solvent of n- butyl alcohol and an organic solvent.
- the DH-type crystalline form of adefovir dipivoxil of the present invention has excellent stability in moisture conditions.
- the DH-type crystalline form of adefovir dipivoxil ofo the present invention is a novel polymorphic material having physical and chemical properties distinct from those of the conventional amorphous or crystalline forms of adefovir dipivoxil.
- the present invention also relates to a method of preparing a DH-type crystalline form of adefovir dipivoxil.
- the method of preparing the DH-type crystalline form of adefovir dipivoxil includes: dissolving adefovir dipivoxil commonly used in the art, e.g., an amorphous form, a crystalline form, an anhydrous form, or a solvate form, or adefovir dipivoxil represented by Formula 1, in n- butyl alcohol; and crystallizing the solution to obtain a DH-type crystalline form of adefovir dipivoxil.
- Adefovir dipivoxil may be dissolved in n- butyl alcohol at a temperature ranging from 20°C to the reflux temperature of the solvent, and preferably 20°C to 150°C.
- Adefovir dipivoxil crystals may be precipitated at a temperature ranging from -30°C to 30°C, and preferably -10°C to 30°C.
- the crystalline solvent may be a single solvent of n- butyl alcohol, or a mixed solvent of n- butyl alcohol, as a main solvent, and an organic solvent commonly used in the art, as a co-solvent, in 10 to 50 vol%.
- n- butyl alcohol is used to dissolve adefovir dipivoxil used as a raw material.
- the precipitation may be performed in n- butyl alcohol.
- a co-solvent may further be added to the n- butyl alcohol.
- the amount of the crystalline solvent may be in the range of 1 to 20 mL/g, preferably 2 to 15 mL/g, based on 1 g of adefovir dipivoxil.
- the co-solvent added to the n- butyl alcohol may be a mixed solvent including at least one conventional organic solvent.
- the co-solvent may be selected from the group consisting of ketones, alcohols, ethers, amides, esters, hydrocarbons, chlorohydrocarbons, and nitriles.
- the ketones may include C 3 -C 7 ketone such as acetone and methyl ethyl ketone (MEK).
- the alcohols may include C 2 -C 7 saturated alcohol such as ethanol.
- the ethers may include C 2 -C 7 ether such as diethyl ether and tetrahydrofuran (THF).
- the amides may include N,N- dimethyl formamide (DMF), N,N- dimethyl acetamide (DMAC), and N,N' -dimethyl propyleneurea (DMPU).
- the esters may include C 3 -C 7 alkyl acetate such as methyl acetate.
- the hydrocarbons may include C 5 -C 10 hydrocarbon such as hexane or toluene.
- the chlorohydrocarbon may include chloroform, dichloromethane, 1,2-dichloroethane, and 1,1,1-trichloroethane.
- the nitriles may include C 3 -C 7 nitrile such as acetonitrile or propionyl nitrile.
- the present invention also relates to a pharmaceutical composition for an antiviral agent comprising a DH-type crystalline form of adefovir dipivoxil.
- An effective dose of the pharmaceutical composition, as an antiviral agent, for an adult may be in the range of 0.01 to 1000 mg/day.
- the daily dose may vary according to age, weight, and gender of a patient, route of administration, health condition, and seriousness of symptoms, and the pharmaceutical composition may be administered once or several times per day at regular intervals according to the advice of doctors and pharmacists.
- the pharmaceutical composition according to the present invention may further include supports, supplements, diluents, etc., which are commonly used in the art, in addition to the DH-type crystalline form of adefovir dipivoxil, as an active ingredient.
- the pharmaceutical composition may be formulated as various forms using methods commonly used in the art which are suitable for oral administration, buccal administration, rectum administration, parenteral administration (subcutaneous, intramuscular, and intravenous administrations), nasal inhalation, and eye drop.
- excipient used for the pharmaceutical composition of the present invention may include sweetening agents, binders, solubilizers, solubilizing agents, wetting agents, emulsifying agents, isotonic agents, absorbents, disintegrants, anti-oxidants, preservatives, lubricants, fillers, aromatics, etc.
- the excipient may be lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxyl methylcellulose, agar, water, ethanol, polyethylene glycol, polyvinyl pyrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla extract, etc.
- the diluent may be: a cellulose derivative such as powdered cellulose, noncrystalline cellulose, ultrafine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salt, and substitued and unsubstituted cellulose; starch; pregelatinized starch; an inorganic diluent such as calcium carbonate and dicalcium phosphate; and other diluents commonly used in the pharmaceutical formulations.
- the diluent may also be wax, sugar, sugar alcohol such as mannitol and sorbitol, an acrylate polymer and copolymer, pectin, dextrin, and gelatin.
- the excipient may also be acacia gum, pregelatinized starch, sodium alginate, glucose, other binders used for wet and dry granulations and purification under direct compression, sodium starch glycolate, cross povidone, low-substituted hydroxypropyl cellulose, etc.
- the excipient may also be a purified lubricant such as magnesium stearate, calcium stearate, and sodium stearyl fumarate; a seasoning; a sweetening agent; a preservative; a pharmaceutically acceptable dye; and a glidant such as silicon dioxide.
- the route of administration may vary according to features and seriousness of symptoms, but oral administration may be used.
- the pharmaceutical composition may be formulated using methods commonly used in the art in a unit dosage form.
- solid formulations such as tablets, powder, granules, aggregates, capsules, suppositories, sachets, troches, and lozenges, but also liquid formulations such as solutions, syrups, suspensions, and elixirs may be used.
- the capsules may be formed as gelatin capsules, or a solid composition may be contained in a conventional capsule.
- the tablets and powder may be coated. In addition, the tablets and powder may be enteric-coated.
- the coating of the enteric-coated powder may include cellulose acetate phthalate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a styrene-maleic acid copolymer, a methacrylic acid-methyl methacrylate copolymer, and analogs thereof. If desired, they may be used with a plasticizer and/or a bulking agent.
- the surface of the tablets may be coated or the tablets may include enteric-coated powder or granules.
- Example 1 Preparation of adefovir dipivoxil in an amorphous form
- amorphous form of adefovir dipivoxil a raw material to prepare adefovir dipivoxil in DH-type crystalline form, was prepared as follows.
- Example 2 5 g of the adefovir dipivoxil amorphous form prepared in Example 1 was added to 50 mL of anhydrous n- butyl alcohol, and the mixture was completely dissolved while heating at 40°C, and then floating materials were removed by filtration. The filtrate was crystallized at -10°C for 24 hours while stirring. A precipitated solid was collected by filtration and dried at 25°C for 48 hours to obtain 4.4 g of A DH-type crystalline form of adefovir dipivoxil (88%).
- adefovir dipivoxil produces mono(POM)PMEA, i.e., 9-(2-pivaloyloxymethoxyphosphinylmethoxyethyl)adenine in moisturized conditions since a pivalyloxymethoxy (POM) group is easily hydrolyzed [Korean Patent No. 0624214].
- adefovir dipivoxil in DH-type crystalline form adefovir dipivoxil in anhydrous crystalline form (Form 1)
- adefovir dipivoxil in hydrated crystalline form dihydrate, Form 2
- adefovir dipivoxil in methanol solvate crystalline form Form 3
- the reagents were stored in a dark and sealed container for 1, 2, and 4 months respectively at 40°C (relative humidity: 75%) and at 25°C (relative humidity: 60%) to obtain areas using area normalization.
- the area of adefovir dipivoxil (AD) and the area of mono(POM)PMEA produced by the hydrolysis of AD are shown in Tables 2a and 2b below.
- the DH-type crystalline form of adefovir dipivoxil according to the present invention has greater chemical stability in moisturized conditions than adefovir dipivoxil in crystalline forms (Forms 1, 2, and 3) disclosed in Korean Patent No. 0618663, thus being efficiently used for the formulation of pharmaceutical compositions.
- the DH-type crystalline form of adefovir dipivoxil of the present invention is efficiently used as an active pharmaceutical ingredient for the preparation of antiviral agents.
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Abstract
The present invention relates to a DH-type crystalline form of adefovir dipivoxil, a method of preparing the same, and a pharmaceutical composition for an antiviral agent comprising the same.
Description
The present invention relates to a DH-type crystalline form of adefovir dipivoxil represented by Formula 1 below, a method of preparing the same, and a pharmaceutical composition for an antiviral agent comprising the same.
Formula 1
Adefovir dipivoxil represented by the above Formula 1 has the chemical name of 9-[2-[bis(pivaloyloxy)methoxyphosphinylmethoxy]ethyl]adenine. Adefovir dipivoxil, which is known effective for the treatment of patients with chronic hepatitis B virus (HBV) infection showing persistently elevated serum aminotransferase (ALT or AST) levels or abnormal histological activity, is commercially available as 'Hepsera™' (Glaxo Smith Kline, Inc.). Adefovir dipivoxil, being an adenosine analog, serves as an acyclic nucleotide reverse transcriptase inhibitor. It interferes with an RNA-dependent DNA polymerase of HBV to inhibit the replication of HBV, thereby showing strong in vivo antiviral activity [Starrett, J.E et al. J. Med. Chem. 1994, 37, 1857].
A method of preparing adefovir dipivoxil is disclosed in U.S. Patent No. 5,663,159, and J. Med. Chem. 1994, 37, 1857, etc.
Pharmaceutical compositions comprising adefovir dipivoxil in an amorphous form and a crystalline form as active ingredients are disclosed in WO 00/35460. It discloses pharmaceutical compositions comprising a crystalline adefovir dipivoxil anhydride, a crystalline adefovir dipivoxil dihydrate, and an alkali excipient with improved stability.
Korean Patent No. 0618663 discloses a crystalline adefovir dipivoxil having excellent storage stability, particularly, an anhydrous crystalline form (Form 1), a hydrated crystalline form (dihydrate, Form 2), a methanol solvate crystalline form (Form 3), a fumaric acid salt or complex (Form 4), and other acid addition salts or complexes.
In addition, WO 99/4774 discloses pharmaceutical compositions comprising at least one crystalline adefovir dipivoxil, more specifically, including those in an anhydrous crystalline form, an anhydrous crystalline form, a solvate crystalline form, or a salt crystalline form of adefovir dipivoxil.
Polymorphism of adefovir dipivoxil is caused by certain properties of some molecules and molecular complexes. A single molecule of adefovir dipivoxil may produce various solids having distinct physical properties such as melting point, X-ray diffraction pattern, and UV absorption fingerprint. Variations on the physical properties of the polymorphic products result from interaction between molecules (complexes) adjacent to bulk solids and orientation of the molecules. Thus, polymorphic products are considered as different solids having distinct physical properties although they have the same molecular formula.
In general, the development of a novel polymorphic drug broadens the range of pharmaceutical formulations having different properties. Thus, a novel polymorphic drug is efficiently used for various pharmaceutical formulations.
The present invention relates to a novel polymorphic adefovir dipivoxil.
The present invention also relates to a method of preparing a novel polymorphic adefovir dipivoxil.
The present invention also relates a pharmaceutical formulation including a novel polymorphic adefovir dipivoxil.
The present invention also relates a novel polymorphic adefovir dipivoxil used for the treatment of chronic hepatitis B virus infection.
According to an aspect of the present invention, there is provided a DH-type crystalline form of adefovir dipivoxil having a powder X-ray diffraction spectrum peak with a peak intensity being equal to or greater than 200 expressed in diffraction angles (2θ) at 7.84, 8.49, 9.65, 12.43, 14.08, 14.31, 14.69, 15.5, 16.06, 17.14, 17.66, 18.35, 19.10, 19.45, 19.70, 20.34, 20.82, 21.82, 22.11, 22.86, 23.55, 24.46, 25.06, 26.45, 27.03, 27.66, 28.37, 29.09, and 29.77.
A maximum endothermic peak of the DH-type crystalline form of adefovir dipivoxil in differential scanning calorimeter (DSC) thermogram is observed at 71.6℃.
According to another aspect of the present invention, there is provided a method of preparing a DH-type crystalline form of adefovir dipivoxil, the method comprising dissolving adefovir dipivoxil in n-butyl alcohol; and leaving the resulting solution at a temperature ranging from -10℃ to 30℃ to collect precipitated solid.
The novel polymorphic adefovir dipivoxil of DH-type crystalline form may be used to efficiently prepare antiviral agents due to its excellent chemical stability in moisturized conditions.
The above and other features and advantages of the present invention will become more apparent by describing in detail exemplary embodiments thereof with reference to the attached drawings in which:
FIG. 1 is a powder X-ray diffraction spectrum of A DH-type crystalline form of adefovir dipivoxil;
FIG. 2 is a differential scanning calorimeter (DSC) thermogram of A DH-type crystalline form of adefovir dipivoxil; and
FIG. 3 is a thermal analyzer graph of A DH-type crystalline form of adefovir dipivoxil.
Hereinafter, the present invention will now be described more fully with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown.
Powder X-ray diffraction spectrum and differential scanning calorimeter (DSC) thermogram of powder of adefovir dipivoxil in a DH-type crystalline form according to the present invention are compared with those of adefovir dipivoxil in crystalline forms disclosed in Korean Patent No. 0618663, i.e., an anhydrous crystalline form (Form 1), a hydrated crystalline form (dihydrate, Form 2), and a methanol solvate crystalline form (Form 3), and the results are shown in Table 1 below.
Table 1
 |
As a result of the comparison, the X-ray diffraction (XRD) pattern of the powder of the DH-type crystalline form of adefovir dipivoxil according to the present invention is different from those of the conventional adefovir dipivoxil crystalline forms (Forms 1, 2, and 3). Thus, a novel polymorphic structure of the DH-type crystalline form of adefovir dipivoxil is identified.
In addition, while a maximum endothermic peak of the powder of the DH-type crystalline form of adefovir dipivoxil according to the present invention in the DSC thermogram is observed at 71.6℃, maximum endothermic peaks of the anhydrous crystalline form (Form 1), the hydrated crystalline form (dihydrate, Form 2), and the methanol solvate crystalline form (Form 3) of the adefovir dipivoxil are respectively observed at 102℃, 73℃, and 85℃. Thus, the maximum endothermic peak of the powder of adefovir dipivoxil in the DH-type crystalline form according to the present invention in DSC thermogram is also different from those of adefovir dipivoxil in the conventional crystalline forms (Forms 1, 2, and 3).
In addition, as a result of analyses using a thermal analyzer and a nuclear magnetic resonance (NMR) spectrum, the DH-type crystalline form of adefovir dipivoxil of the present invention is a solvate crystalline form and comprises about 0.5 eq. of a crystalline solvent in a crystalline lattice structure. The crystalline solvent contained in the crystalline lattice structure may be a single solvent of n-butyl alcohol or a mixed solvent of n-butyl alcohol and an organic solvent.
In addition, The DH-type crystalline form of adefovir dipivoxil of the present invention has excellent stability in moisture conditions.
According to the results described above, the DH-type crystalline form of adefovir dipivoxil ofo the present invention is a novel polymorphic material having physical and chemical properties distinct from those of the conventional amorphous or crystalline forms of adefovir dipivoxil.
The present invention also relates to a method of preparing a DH-type crystalline form of adefovir dipivoxil.
The method of preparing the DH-type crystalline form of adefovir dipivoxil includes: dissolving adefovir dipivoxil commonly used in the art, e.g., an amorphous form, a crystalline form, an anhydrous form, or a solvate form, or adefovir dipivoxil represented by Formula 1, in n-butyl alcohol; and crystallizing the solution to obtain a DH-type crystalline form of adefovir dipivoxil.
Adefovir dipivoxil may be dissolved in n-butyl alcohol at a temperature ranging from 20℃ to the reflux temperature of the solvent, and preferably 20℃ to 150℃. Adefovir dipivoxil crystals may be precipitated at a temperature ranging from -30℃ to 30℃, and preferably -10℃ to 30℃.
The crystalline solvent may be a single solvent of n-butyl alcohol, or a mixed solvent of n-butyl alcohol, as a main solvent, and an organic solvent commonly used in the art, as a co-solvent, in 10 to 50 vol%. In particular, n-butyl alcohol is used to dissolve adefovir dipivoxil used as a raw material. The precipitation may be performed in n-butyl alcohol. If desired, a co-solvent may further be added to the n-butyl alcohol. The amount of the crystalline solvent may be in the range of 1 to 20 mL/g, preferably 2 to 15 mL/g, based on 1 g of adefovir dipivoxil. The co-solvent added to the n-butyl alcohol may be a mixed solvent including at least one conventional organic solvent. The co-solvent may be selected from the group consisting of ketones, alcohols, ethers, amides, esters, hydrocarbons, chlorohydrocarbons, and nitriles. The ketones may include C3-C7 ketone such as acetone and methyl ethyl ketone (MEK). The alcohols may include C2-C7 saturated alcohol such as ethanol. The ethers may include C2-C7 ether such as diethyl ether and tetrahydrofuran (THF). The amides may include N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMAC), and N,N'-dimethyl propyleneurea (DMPU). The esters may include C3-C7 alkyl acetate such as methyl acetate. The hydrocarbons may include C5-C10 hydrocarbon such as hexane or toluene. The chlorohydrocarbon may include chloroform, dichloromethane, 1,2-dichloroethane, and 1,1,1-trichloroethane. The nitriles may include C3-C7 nitrile such as acetonitrile or propionyl nitrile.
The present invention also relates to a pharmaceutical composition for an antiviral agent comprising a DH-type crystalline form of adefovir dipivoxil.
An effective dose of the pharmaceutical composition, as an antiviral agent, for an adult may be in the range of 0.01 to 1000 mg/day. However, the daily dose may vary according to age, weight, and gender of a patient, route of administration, health condition, and seriousness of symptoms, and the pharmaceutical composition may be administered once or several times per day at regular intervals according to the advice of doctors and pharmacists.
The pharmaceutical composition according to the present invention may further include supports, supplements, diluents, etc., which are commonly used in the art, in addition to the DH-type crystalline form of adefovir dipivoxil, as an active ingredient. The pharmaceutical composition may be formulated as various forms using methods commonly used in the art which are suitable for oral administration, buccal administration, rectum administration, parenteral administration (subcutaneous, intramuscular, and intravenous administrations), nasal inhalation, and eye drop.
Examples of the excipient used for the pharmaceutical composition of the present invention may include sweetening agents, binders, solubilizers, solubilizing agents, wetting agents, emulsifying agents, isotonic agents, absorbents, disintegrants, anti-oxidants, preservatives, lubricants, fillers, aromatics, etc. For example, the excipient may be lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxyl methylcellulose, agar, water, ethanol, polyethylene glycol, polyvinyl pyrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla extract, etc.
In addition, the diluent may be: a cellulose derivative such as powdered cellulose, noncrystalline cellulose, ultrafine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salt, and substitued and unsubstituted cellulose; starch; pregelatinized starch; an inorganic diluent such as calcium carbonate and dicalcium phosphate; and other diluents commonly used in the pharmaceutical formulations. The diluent may also be wax, sugar, sugar alcohol such as mannitol and sorbitol, an acrylate polymer and copolymer, pectin, dextrin, and gelatin.
The excipient may also be acacia gum, pregelatinized starch, sodium alginate, glucose, other binders used for wet and dry granulations and purification under direct compression, sodium starch glycolate, cross povidone, low-substituted hydroxypropyl cellulose, etc. In addition, the excipient may also be a purified lubricant such as magnesium stearate, calcium stearate, and sodium stearyl fumarate; a seasoning; a sweetening agent; a preservative; a pharmaceutically acceptable dye; and a glidant such as silicon dioxide.
The route of administration may vary according to features and seriousness of symptoms, but oral administration may be used. The pharmaceutical composition may be formulated using methods commonly used in the art in a unit dosage form. For the oral administration, not only solid formulations such as tablets, powder, granules, aggregates, capsules, suppositories, sachets, troches, and lozenges, but also liquid formulations such as solutions, syrups, suspensions, and elixirs may be used. The capsules may be formed as gelatin capsules, or a solid composition may be contained in a conventional capsule. The tablets and powder may be coated. In addition, the tablets and powder may be enteric-coated. The coating of the enteric-coated powder may include cellulose acetate phthalate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a styrene-maleic acid copolymer, a methacrylic acid-methyl methacrylate copolymer, and analogs thereof. If desired, they may be used with a plasticizer and/or a bulking agent. The surface of the tablets may be coated or the tablets may include enteric-coated powder or granules.
The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Examples
Example 1. Preparation of adefovir dipivoxil in an amorphous form
An amorphous form of adefovir dipivoxil, a raw material to prepare adefovir dipivoxil in DH-type crystalline form, was prepared as follows.
30 g (0.11 mol) of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) was dissolved in 240 mL of dimethyl formamide (DMF), 42.4 g of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) was added thereto, and the mixture was stirred. 82.8 g of chloromethyl pivalate was added thereto, and the mixture was stirred at 25℃ for 24 hours. After confirming the termination of reaction via thin layer chromatography (TLC), 240 mL of water was added thereto, and the mixture was stirred for about 10 minutes. The mixture was subjected to extraction three times, each time with 500 mL of toluene, dried using sodium sulfate, and concentrated under reduced pressure to obtain 41.3 g of an amorphous form of adefovir dipivoxil (yield: 75%).
Purity: 99.5 % (HPLC); 1H NMR (CDCl3, ppm) 8.32 (s, 1H), 7.91 (s, 1H), 6.14 (s, 2H, NH2), 5.64 (m, 4H), 4.38 (t, 2H, J = 4.8 ㎐), 3.93 (t, 2H, J = 4.8 ㎐), 3.84 (d, 2H, J = 7.5 ㎐), 1.19 (s, 18H, CH3)
Example 2. Preparation of adefovir dipivoxil in DH-type crystalline form
5 g of the adefovir dipivoxil amorphous form prepared in Example 1 was added to 50 mL of anhydrous n-butyl alcohol, and the mixture was completely dissolved while heating at 40℃, and then floating materials were removed by filtration. The filtrate was crystallized at -10℃ for 24 hours while stirring. A precipitated solid was collected by filtration and dried at 25℃ for 48 hours to obtain 4.4 g of A DH-type crystalline form of adefovir dipivoxil (88%).
Purity: 99.9 % (HPLC); 1H NMR (CDCl3, ppm) 8.33 (1H, s), 7.94 (1H, s), 6.02 (2H, br), 5.61-5.69 (4H, m), 4.39 (2H, t), 3.94 (2H, t), 3.85 (2H, d), 1.20 (18H, s), 3.65 (1H, t), 1.56 (1H, quintet), 1.39 (1H, sextet), 0.93 (1.5H, t).
In an NMR spectrum, the peak of a crystalline solvent (n-butyl alcohol) was observed at δ3.65, 1.56, 139, and 0.93 ppm. As a result of calculating the integrated peak area, the amount of the crystalline solvent contained in the crystalline lattice structure was about 0.5 eq. It was identified that weight of adefovir dipivoxil was decreased by 7.4% according to the thermal analysis(TGA).
Powder X-ray diffraction spectrum, differential scanning calorimeter (DSC) thermogram, and thermal analysis of The DH-type crystalline form of adefovir dipivoxil prepared in Example 2 were measured, and the results are respectively shown in FIGS. 1, 2, and 3.
Example 3. Preparation of adefovir dipivoxil in DH-type crystalline form
10 g of adefovir dipivoxil in amorphous form prepared according to Example 1 was added to 100 mL of anhydrous n-butyl alcohol, and the mixture was completely dissolved while heating at 40℃, and then floating materials were removed by filtration. 200 mL of n-hexane was added twice to the filtrate at 10 minute intervals at -5℃ and the mixture was stirred at the same temperature for 24 hours to crystallize the filtrate. A precipitated solid was collected by filtration and dried at 25℃ for 48 hours to obtain 4.5 g of A DH-type crystalline form of adefovir dipivoxil (yield: 90%, HPLC purity: 99.9%).
NMR spectrum, powder X-ray diffraction spectrum, DSC thermogram, and thermal analyzer of the prepared adefovir dipivoxil DH-type crystalline form were measured. It was identified that the results are identical to those obtained in Example 2.
Example 4. Stability of adefovir dipivoxil DH-type crystalline form
In general, adefovir dipivoxil produces mono(POM)PMEA, i.e., 9-(2-pivaloyloxymethoxyphosphinylmethoxyethyl)adenine in moisturized conditions since a pivalyloxymethoxy (POM) group is easily hydrolyzed [Korean Patent No. 0624214]. Thus, in order to identify chemical stability of adefovir dipivoxil in DH-type crystalline form according to the present invention in moisturized conditions, experiments were performed as follows.
[Experiment]
Reagents: adefovir dipivoxil in DH-type crystalline form, adefovir dipivoxil in anhydrous crystalline form (Form 1), adefovir dipivoxil in hydrated crystalline form (dihydrate, Form 2), and adefovir dipivoxil in methanol solvate crystalline form (Form 3)
Conditions: the reagents were stored in a dark and sealed container for 1, 2, and 4 months respectively at 40℃ (relative humidity: 75%) and at 25℃ (relative humidity: 60%) to obtain areas using area normalization. The area of adefovir dipivoxil (AD) and the area of mono(POM)PMEA produced by the hydrolysis of AD are shown in Tables 2a and 2b below.
[HPLC analysis conditions]
Detect: UV absorbance (at 260 nm)
Column: column filled with octyl silylated silica gel (4.6 mm x 250 mm, 5 ㎛)
Mobile phase: 0.05M diammonium hydrogen phosphate (pH 6 adjusted using phosphoric acid) / acetonitrile = 35 / 65 (v/v)
Flow rate: 1.2 mL/min
Table 2
 |
Referring to Tables 2a and 2b, the DH-type crystalline form of adefovir dipivoxil according to the present invention has greater chemical stability in moisturized conditions than adefovir dipivoxil in crystalline forms (Forms 1, 2, and 3) disclosed in Korean Patent No. 0618663, thus being efficiently used for the formulation of pharmaceutical compositions.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the following claims.
The DH-type crystalline form of adefovir dipivoxil of the present invention is efficiently used as an active pharmaceutical ingredient for the preparation of antiviral agents.
Claims (10)
- A DH-type crystalline form of adefovir dipivoxil represented by Formula 1 below,Formula 1
having a powder X-ray diffraction spectrum peak with a peak intensity being equal to or greater than 200 expressed in diffraction angles (2θ) at 7.84, 8.49, 9.65, 12.43, 14.08, 14.31, 14.69, 15.5, 16.06, 17.14, 17.66, 18.35, 19.10, 19.45, 19.70, 20.34, 20.82, 21.82, 22.11, 22.86, 23.55, 24.46, 25.06. 26.45, 27.03, 27.66, 28.37, 29.09, and 29.77. - The DH-type crystalline form of adefovir dipivoxil of claim 1, wherein the maximum endothermic peak in differential scanning calorimeter (DSC) thermogram is present at 71.6℃.
- The DH-type crystalline form of adefovir dipivoxil of claim 1, wherein the amount of a crystalline solvent in a crystalline lattice structure is about 0.5 eq.
- The DH-type crystalline form of adefovir dipivoxil of claim 3, wherein the crystalline solvent is a single solvent of n-butyl alcohol, or a mixed solvent of n-butyl alcohol and a co-solvent selected from the group consisting of C3-C7 ketone, C2-C7 saturated alcohol, C2-C7 ether, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMAC), N,N'-dimethyl propyleneurea (DMPU), C3-C7 alkyl acetate, C5-C10 hydrocarbon, C1-C4 chlorohydrocarbon, and C3-C7 nitrile in 10 to 50 vol%.
- A method of preparing A DH-type crystalline form of adefovir dipivoxil according to any one of claims 1 to 4 comprising:dissolving adefovir dipivoxil in n-butyl alcohol; andplacing the resulting solution at a temperature ranging from -10℃ to 30℃ to collect a precipitated solid.
- The method of claim 5, wherein the n-butyl alcohol is a single solvent of n-butyl alcohol, or a mixed solvent of n-butyl alcohol and a co-solvent selected from the group consisting of C3-C7 ketone, C2-C7 saturated alcohol, C2-C7 ether, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMAC), N,N'-dimethyl propyleneurea (DMPU), C3-C7 alkyl acetate, C5-C10 hydrocarbon, C1-C4 chlorohydrocarbon, and C3-C7 nitrile in 10 to 50 vol%.
- The method of claim 5, wherein the adefovir dipivoxil dissolved in the n-butyl alcohol is in a form selected from the group consisting of an amorphous form, a crystalline form, an anhydrous form, and a solvate form.
- The method of claim 5, wherein the resulting solution was placed in a condition comprising a single solvent selected from the group consisting of C3-C7 ketone, C2-C7 alcohol, C2-C7 ether, C3-C7 ester, and C3-C7 amide, or a mixture thereof.
- The method of claim 5, wherein the dissolving adefovir dipivoxil in n-butyl alcohol is performed at a temperature ranging from 20℃ to 150℃.
- A pharmaceutical composition for an antiviral agent comprising a DH-type crystalline form of adefovir dipivoxil according to any one of claims 1 to 4.
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| KR1020090026612A KR101088020B1 (en) | 2009-03-27 | 2009-03-27 | Adefovir dipivoxil DH-type crystalline form, preparing method thereof, and pharmaceutical composition for antivirus agent containing them |
| KR10-2009-0026612 | 2009-03-27 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120238753A1 (en) * | 2011-03-14 | 2012-09-20 | Vellenki Siva Rama Prasad | Process for the preparation of adefovir dipivoxil |
| CN106188140A (en) * | 2016-06-25 | 2016-12-07 | 河南康达制药有限公司 | A kind of synthesis technique of adefovir ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020045599A1 (en) * | 1997-07-25 | 2002-04-18 | Gilead Sciences, Inc. | Nucleotide analog compositions |
| US20060025384A1 (en) * | 2002-11-12 | 2006-02-02 | Guocheng Wang | New crystal form of adefovir dipivoxil and its composition |
| CN1935818A (en) * | 2006-09-22 | 2007-03-28 | 闫敬武 | Adefovir dipivoxil novel crystallinestate, crystalline state composition, and itspreparing method and use |
| CN1995048A (en) * | 2006-12-14 | 2007-07-11 | 浙江车头制药有限公司 | Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof |
-
2009
- 2009-03-27 KR KR1020090026612A patent/KR101088020B1/en active IP Right Grant
- 2009-05-21 WO PCT/KR2009/002685 patent/WO2010110506A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020045599A1 (en) * | 1997-07-25 | 2002-04-18 | Gilead Sciences, Inc. | Nucleotide analog compositions |
| US20060025384A1 (en) * | 2002-11-12 | 2006-02-02 | Guocheng Wang | New crystal form of adefovir dipivoxil and its composition |
| CN1935818A (en) * | 2006-09-22 | 2007-03-28 | 闫敬武 | Adefovir dipivoxil novel crystallinestate, crystalline state composition, and itspreparing method and use |
| CN1995048A (en) * | 2006-12-14 | 2007-07-11 | 浙江车头制药有限公司 | Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120238753A1 (en) * | 2011-03-14 | 2012-09-20 | Vellenki Siva Rama Prasad | Process for the preparation of adefovir dipivoxil |
| CN106188140A (en) * | 2016-06-25 | 2016-12-07 | 河南康达制药有限公司 | A kind of synthesis technique of adefovir ester |
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| KR20100108113A (en) | 2010-10-06 |
| KR101088020B1 (en) | 2011-11-30 |
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