WO2010110622A2 - Novel crystal forms of adefovir dipivoxil and processes for preparing the same - Google Patents

Novel crystal forms of adefovir dipivoxil and processes for preparing the same Download PDF

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WO2010110622A2
WO2010110622A2 PCT/KR2010/001867 KR2010001867W WO2010110622A2 WO 2010110622 A2 WO2010110622 A2 WO 2010110622A2 KR 2010001867 W KR2010001867 W KR 2010001867W WO 2010110622 A2 WO2010110622 A2 WO 2010110622A2
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adefovir dipivoxil
weight
crystalline
crystal
respect
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PCT/KR2010/001867
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French (fr)
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WO2010110622A9 (en
WO2010110622A3 (en
Inventor
Soo Jin Choi
Byung Goo Lee
Seong Soo Oh
Yong Tae Kim
Kwang Joo Kim
Hye Jin Kim
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Daewoong Pharmaceutical Co., Ltd.
Daewoong Bio Inc.
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Application filed by Daewoong Pharmaceutical Co., Ltd., Daewoong Bio Inc. filed Critical Daewoong Pharmaceutical Co., Ltd.
Priority to EP10756377.7A priority Critical patent/EP2411392B1/en
Priority to US13/256,197 priority patent/US9169257B2/en
Priority to RU2011143166/04A priority patent/RU2485121C1/en
Priority to CN201080013954.6A priority patent/CN102365283B/en
Priority to JP2012501942A priority patent/JP5642766B2/en
Publication of WO2010110622A2 publication Critical patent/WO2010110622A2/en
Publication of WO2010110622A9 publication Critical patent/WO2010110622A9/en
Publication of WO2010110622A3 publication Critical patent/WO2010110622A3/en

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention relates to novel crystal forms of a nucleotide analog of 9-[2-[phosphonomethoxy]ethyl]adenine bis-pivaloyloxymethyl ester (“Adefovir dipivoxil”) and processes for the preparation thereof.
  • Adefovir dipivoxil is an antiviral nucleotide analog, showing excellent effect as a therapeutic agent for HIV infection and hepatitis B virus (HBV) infection.
  • the antiviral activity of said compound is shown in the references (for example, see US Patent Nos. 4,724,233 and 4,808,716; EP Patent No. 0 481 214; Benzaria et al., “Nucleosides and Nucleotide” 14(3-5):563-565, 1995; and Starrett et al., J. Med. Chem. 37:1857-1864, 1994).
  • Adefovir dipivoxil was first disclosed in EP Patent No. 0 481 214 and may exist in amorphous or crystalline forms.
  • the amorphous form of adefovir dipivoxil can be obtained by eluting from a silica gel column using a mixture of methanol (about 4%) and methylene chloride (about 96%), and precipitating by rotary evaporation under reduced pressure at about 35°C (see J. Med. Chem., 19:1857-1864, 1994).
  • the purification and preparation of an amorphous form have the disadvantages that the procedures are not suitable for application to mass production and the amorphous form must be protected from heat, light, oxygen and moisture.
  • adefovir dipivoxil was prepared and used.
  • WO04/043972 discloses a spray-drying process wherein directly prepared or commercially available adefovir dipivoxil is dissolved in an organic solvent and sprayed as micro droplets of drug solution under a high-temperature stream, and thus obtained droplets are immediately dried to give crystals.
  • this method has the disadvantage of using a spray-dryer device that is not suitable for mass production.
  • 6,451,340 discloses a method of preparing Form 2 (2 hydrate) by diluting adefovir dipivoxil solution containing 0.2% or less of water and 50% or more of 1-methylpyrrolidinone with acetone, adding n-butyl ether to produce a crystal, cooling to give Form 1, contacting said Form 1 with air having 75% or more of relative humidity or crystallizing it from a solvent containing 2-5% of water.
  • this method uses a dangerous and explosive organic solvent such as n-butyl ether as the crystallizing solvent.
  • Polymorphism is generally considered to mean separate solids having the same molecular formula but different physical properties in melting point, solubility, density, etc.
  • the differences in physical properties of polymorphs come from the alignments of adjacent molecules (complexes) and interactions between molecules in a bulk solid.
  • polymorphs having the same molecular formula are unique solids in that it is not clear whether one polymorph has more advantageous physical properties than another.
  • One of the most important physical properties of a pharmacological polymorph is water solubility, particularly solubility in the gastric juice of a patient. For example, when absorption through the intestinal tract is slow, it is desirable that the drug which is unstable under the circumstance of the stomach or intestine of a patient is slowly dissolved and not to be accumulated under this harmful circumstance.
  • Such crystal compounds may have different fluidity, elastic deformability, dissolution rate in a pharmaceutical preparation, stability, efficacy, etc.
  • a crystal form that is more stable, easier to handle and has a high dissolution rate is required in the art. That is, discovery of a novel crystal form of a drug would enable a skilled artisan in the field of formulation to design a pharmaceutical formulation of a drug having the desired release profile or other characteristics.
  • Another object of the present invention is to provide processes for the preparation of the novel crystal forms of adefovir dipivoxil.
  • novel crystal forms provided by the present invention may be more specifically defined as follows.
  • Crystal forms are generally decided by thermodynamic characteristics such as solubility and dynamic characteristics such as several operation factors.
  • the crystallization mechanism is decided by the operation factors, and the mechanism has influence on the formation of crystal core, growth of crystal and deformation of crystal form to give the desired crystal.
  • analysis of the crystallization mechanism for control of the crystal form is indispensable and should be necessarily carried out in the research of crystal forms.
  • Various methods for forming over-saturation have been studied to develop an efficient method.
  • the starting material of adefovir dipivoxil used for preparing the novel crystal forms according to the present invention may be obtained by the art-known processes, e.g., the processes from US Patent No. 5,663,159 or J. Med. Chem., (1994) 19:1857-1864.
  • the present invention sets no special limit on the process of preparing the starting material of adefovir dipivoxil.
  • the present invention provides various novel crystal forms of adefovir dipivoxil and processes for preparing them. According to the present invention, the following advantages are given in this field.
  • various crystal forms provided by the present invention have the effect of broadening the spectrum of selection of the base material in preparing pharmaceutical compositions.
  • water is used as the crystallizing solvent for preparing the crystal forms of adefovir dipivoxil in the present invention, whereby the organic solvents having some pharmaceutical restrictions remain in a less amount than in the prior arts. Furthermore, according to the present invention the production cost is reduced and its preparation including mass production becomes simple.
  • the crystal forms of the present invention have a high recovery yield, excellent dissolution rate and storage stability.
  • Figure 1 represents the XRD results of known forms of crystalline adefovir dipivoxil [(a) Form 1, (b) Form 2, (c) Form 3, (d) Form 4 (Forms 1 ⁇ 4 are disclosed in US Patent No. 6,451,340), (e) Form of WO04/043972].
  • Figure 2 represents the X-ray diffraction spectrum of Form A of crystalline adefovir dipivoxil obtained in Example 1.
  • Figure 3 represents the X-ray diffraction spectrum of Form C of crystalline adefovir dipivoxil obtained in Example 4.
  • Figure 4 represents the X-ray diffraction spectrum of Form D of crystalline adefovir dipivoxil obtained in Example 5.
  • Figure 5 represents the X-ray diffraction spectrum of Form E of crystalline adefovir dipivoxil obtained in Example 7.
  • Figure 6 represents the X-ray diffraction spectrum of Form F of crystalline adefovir dipivoxil obtained in Example 9.
  • Figure 7 represents the X-ray diffraction spectrum of Form G of crystalline adefovir dipivoxil obtained in Example 10.
  • Figure 8 represents the X-ray diffraction spectrum of Form B of crystalline adefovir dipivoxil obtained in Example 11.
  • Figure 9 represents the DSC endothermic curve of Form A of crystalline adefovir dipivoxil obtained in Example 3.
  • Figure 10 represents the DSC endothermic curve of Form B of crystalline adefovir dipivoxil obtained in Example 11.
  • the kinds of novel crystals are decided by the ratio of solute (adefovir dipivoxil): good solvent: crystallization solvent, solubility condition, crystallization temperature, etc, which are explained in detail below.
  • acetone is used as the good solvent in the amount of 2 to 7 times by weight, preferably 4 to 6 times by weight with respect to the weight of adefovir dipivoxil, which is the minimum amount to dissolve adefovir dipivoxil.
  • adefovir dipivoxil is dissolved at 10 to 40°C, preferably 20 to 30°C
  • water is added to the above solution as a solvent for crystallizing adefovir dipivoxil.
  • the amount of water is 20 to 40 times by weight, preferably 25 to 30 times by weight with respect to the weight of adefovir dipivoxil.
  • the crystallization solvent is added to form crystals and the thus-obtained mixture is stirred for 4 to 30 h, preferably 5 to 20 h while maintaining the temperature range of 0 to 30°C, preferably 5 to 25°C to assist the formation and growth of the crystal core.
  • the mixture is filtered, and the collected crystal is dried under reduced pressure at 35°C or lower to give Form A of crystalline adefovir dipivoxil.
  • Form A is determined to have a moisture content of 6.5% to 7.1% by Karl Fisher titration. If the stirring temperature is high, the yield may be reduced. Thus, the temperature and time of stirring may play an important role in obtaining the desired high yield and purity of Form A of crystalline adefovir dipivoxil.
  • the good solvent acetone is used in the amount of 2 to 7 times by weight, preferably 2 to 4 times by weight with respect to the weight of adefovir dipivoxil to dissolve adefovir dipivoxil at 10 to 40°C, preferably 20 to 30°C.
  • water is added to the above solution as a crystallization solvent in the amount of 7 to 13 times by weight, preferably 9 to 11 times by weight with respect to the weight of adefovir dipivoxil.
  • the thus-obtained mixture is not stirred but is allowed to stand while being maintained at a constant cooling temperature range of 0 to 10°C, preferably 5 to 10°C for 5 to 30 h, preferably 5 to 20 h to induce the growth of crystal.
  • the mixture is filtered, and the collected crystal is dried under reduced pressure at 35°C or lower. After drying, Form C is determined to have a moisture content of 6.5% to 7.1% by Karl Fisher titration.
  • Form A is prepared by using 1-methylpyrrolidinone or ethanol as the good solvent and water as the crystallization solvent.
  • 1-methylpyrrolidinone is used as the good solvent to dissolve adefovir dipivoxil, it is used in the amount of 2 to 5 times by weight, preferably 3 to 4 times by weight with respect to the weight of adefovir dipivoxil.
  • ethanol is used as the good solvent, it is used in the amount of 5 to 15 times by weight, preferably 8 to 12 times by weight with respect to the weight of adefovir dipivoxil.
  • the thus-obtained solution is allowed to stand while maintaining the temperature at 10 to 40°C, preferably 20 to 30°C to dissolve adefovir dipivoxil.
  • water is added to the above solution as a crystallization solvent in the amount of 10 to 30 times by weight, preferably 15 to 20 times by weight with respect to the weight of adefovir dipivoxil.
  • the mixture is stirred for 3 to 10 h, preferably 4 to 5 h while maintaining at a constant cooling temperature of 0 to 10°C, preferably 5 to 10°C.
  • the mixture is filtered, and the collected crystal is dried under reduced pressure at 30°C or lower to give Form A of crystalline adefovir dipivoxil.
  • the moisture content after drying is 6.5% to 7.1% by Karl Fisher titration.
  • the crystal forms of adefovir dipivoxil can be prepared by mixing crystallization solvents such as n-heptane or cyclohexane with the adefovir dipivoxil solution in the good solvents such as chloroform, ethyl acetate, acetonitrile or isopropyl alcohol.
  • crystallization solvents such as n-heptane or cyclohexane
  • good solvents such as chloroform, ethyl acetate, acetonitrile or isopropyl alcohol.
  • adefovir dipivoxil is dissolved in the good solvent chloroform in the amount of 1 to 5 times by weight, preferably 2 to 4 times by weight with respect to the weight of adefovir dipivoxil at a temperature of 30 to 50°C, preferably 35 to 45°C.
  • This solution is cooled to 10 to 30°C, preferably 20 to 25°C, and n-heptane is added to crystallize.
  • the amount of n-heptane is 1 to 5 times by weight, preferably 2 to 3 times by weight with respect to the weight of adefovir dipivoxil.
  • the mixture is stirred for 4 to 20 h, preferably 5 to 10 h while maintaining the temperature of -10 to 30°C, preferably -5 to 25°C to assist the formation and growth of the crystal core.
  • the mixture is filtered, and the collected crystal is dried to give Form D of crystalline adefovir dipivoxil.
  • the good solvent ethyl acetate is used in the amount of 0.5 to 2 times by weight, preferably 0.5 to 1 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40°C, preferably 20 to 30°C to prepare a solution containing adefovir dipivoxil in high content. Then, this solution is added to n-heptane at the temperature of -20 to 20°C, preferably -5 to 5°C to crystallize. The amount of n-heptane is 10 to 100 times by weight, preferably 20 to 50 times by weight with respect to the weight of adefovir dipivoxil.
  • the mixture is stirred for 4 to 20 h, preferably 5 to 10 h while maintaining the temperature of -20 to 20°C, preferably -5 to 5°C to assist the formation and growth of the crystal core.
  • the mixture is filtered, and the collected crystal is dried to give Form D of crystalline adefovir dipivoxil.
  • the good solvent isopropyl alcohol is used in the amount of 5 to 20 times by weight, preferably 10 to 15 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40°C, preferably 20 to 30°C to prepare a solution of adefovir dipivoxil. Then, cyclohexane is added to this solution at the temperature of 10 to 40°C, preferably 20 to 30°C to crystallize. The amount of cyclohexane is 10 to 40 times by weight, preferably 20 to 30 times by weight with respect to the weight of adefovir dipivoxil.
  • the mixture is stirred for 10 to 40 h, preferably 15 to 25 h while maintaining the temperature of -20 to 20°C, preferably 0 to 10°C to assist the growth of the crystal core.
  • the mixture is filtered, and the collected crystal is dried to give Form F of crystalline adefovir dipivoxil.
  • the good solvent chloroform is used in the amount of 1 to 5 times by weight, preferably 2 to 3 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40°C, preferably 20 to 30°C to prepare a solution of adefovir dipivoxil. Then, n-hexane is added to this solution at the temperature of 10 to 40°C, preferably 20 to 30°C to crystallize. The amount of n-hexane is 5 to 30 times by weight, preferably 5 to 10 times by weight with respect to the weight of adefovir dipivoxil.
  • the mixture is stirred for 1 to 10 h, preferably 2 to 5 h while maintaining the temperature of 10 to 40°C, preferably 20 to 30°C to assist the growth of the crystal core.
  • the mixture is filtered, and the collected crystal is dried to give Form G of crystalline adefovir dipivoxil.
  • Form A of crystalline adefovir dipivoxil is prepared and filtered.
  • the collected crystal is dried under reduced pressure at the temperature of 35 to 45°C to give Form B of crystalline adefovir dipivoxil.
  • the moisture content after drying is 0.01% to 0.5% by Karl Fisher titration.
  • the good solvent methyl acetate or acetonitrile is used in the amount of 3 to 40 times by weight, preferably 3 to 15 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40°C, preferably 20 to 30°C to dissolve adefovir dipivoxil.
  • the good solvent used is removed by evaporation under reduced pressure at the same temperature to give Form E of crystalline adefovir dipivoxil.
  • Adefovir dipivoxil (0.3g) prepared according to Example 9 of US Patent No. 5,663,159 and 1-methylpyrrolidinone (1.00g) were mixed in the weight ratio of 1:3.33, and adefovir dipivoxil was thoroughly dissolved at 30°C. To this solution was added water controlled to 25°C in advance until a crystal was formed. The amount of water added was 5.00g. The solution was cooled using a refrigerator controlled to 5°C. The thus-cooled solution was stirred for about 4.5 h and the slurry was filtered to separate a crystal. The crystal obtained from filtration was washed with water and filtered again. The crystal was dried under reduced pressure at 25 to 30°C to give 0.3g (recovery yield: 93%) of Form A (moisture content by Karl Fisher titration: 6.7%).
  • Example 2 The same procedure as Example 1 was carried out to give 0.31g (recovery yield: 96%) of Form A (moisture content by Karl Fisher titration: 7.1%) except that adefovir dipivoxil (0.3g) prepared according to Example 9 of US Patent No. 5,663,159 and ethanol (3.31g) were mixed in the weight ratio of 1:11.03.
  • Adefovir dipivoxil (3.94kg) prepared according to Example 9 of US Patent No. 5,663,159 and acetone (14.15kg) were mixed in the weight ratio of 1:3.59, and adefovir dipivoxil was thoroughly dissolved at 30°C.
  • water 141.5kg
  • the crystal was separated by filtration and washed with water. The crystal was dried under reduced pressure at 25 to 30°C to give 3.83kg (recovery yield: 91%) of Form A (moisture content by Karl Fisher titration: 6.9%).
  • Adefovir dipivoxil (0.301g) prepared according to Example 9 of US Patent No. 5,663,159 and acetone (1.30g) were mixed in the weight ratio of 1:4.32, and adefovir dipivoxil was thoroughly dissolved at 30°C.
  • water in the amount of twice the amount of acetone solvent, i.e., 2.60g.
  • the mixture was allowed to stand at 6.4°C for about 17 h to induce the growth of crystal.
  • the crystal was separated by filtration and dried under reduced pressure at 25 to 30°C for 24 h to give 0.29g (recovery yield: 90%) of Form C (moisture content by Karl Fisher titration: 6.5%).
  • Adefovir dipivoxil (1.00g) prepared according to Example 9 of US Patent No. 5,663,159 and chloroform (3g) were mixed in the weight ratio of 1:3.00, and adefovir dipivoxil was thoroughly dissolved at 45°C.
  • the resulting solution was cooled to 25°C, and n-heptane (2.7g) controlled to 25°C in advance was added thereto.
  • the mixture was cooled using a refrigerator controlled to 0°C and stirred for about 5 h.
  • the crystal was separated by filtration and washed with n-heptane.
  • the crystal was dried under reduced pressure at 25 to 30°C for 24 h to give 0.89g (recovery yield: 89%) of Form D.
  • Adefovir dipivoxil (3.8g) prepared according to Example 9 of US Patent No. 5,663,159 and ethyl acetate (2.7g) were mixed in the weight ratio of 1:0.71, and adefovir dipivoxil was thoroughly dissolved at 30°C to make a solution of high concentration.
  • the resulting solution was added to n-heptane (82g) maintained at 0°C, and the mixture was allowed to crystallize for about 6 h.
  • the thus-formed crystal was separated by filtration, washed with n-heptane and filtered again.
  • the crystal was dried under reduced pressure at 25 to 30°C for 24 h to give 3.7g (recovery yield: 97%) of Form D.
  • Adefovir dipivoxil (0.5016g) prepared according to Example 9 of US Patent No. 5,663,159 and isopropyl alcohol (6.11g) were mixed in the weight ratio of 1:12.2, and adefovir dipivoxil was thoroughly dissolved at 30°C. To this solution was added cyclohexane in the amount of about twice the amount of isopropyl alcohol solvent, i.e., 12.83g. Then, the mixture was stirred at 6.4°C for about 20 h to induce the growth of crystal.
  • Adefovir dipivoxil (0.50g) prepared according to Example 9 of US Patent No. 5,663,159 and chloroform (1.50g) were mixed in the weight ratio of 1:3, and adefovir dipivoxil was thoroughly dissolved at 30°C.
  • Form A of adefovir dipivoxil (3.83kg), which was prepared according to the same procedure as in Example 3 and collected by filtration, was dried under reduced pressure at 35 to 45°C to give 3.54kg (recovery yield: 99%) of Form B of crystalline adefovir dipivoxil (moisture content by Karl Fisher titration: 0.2%).
  • Adefovir dipivoxil prepared in the examples were analyzed by X-ray diffraction analytical devices [instruments: M18XHF-SRA (Mac Science, Japan) and Powder XRD (Bruker AXS, Germany)], and the results are represented in Figures 2, 3, 4, 5, 6, 7 and 8.
  • Form A prepared by Example 3 was treated with various drying temperatures and drying times under the vacuum condition of 0.1 ⁇ 1.0 Torr, and the resulting transformation of the crystal form is represented in Table 1.
  • novel Forms A and B of Examples 3 and 11 of the present invention, and 50 mg of the authentic adefovir dipivosil (purity: 99.5%) were precisely weighed into a 50 mL volumetric flask and dissolved in diluent. After making up to the mark, they were used as sample solution and standard solution, respectively. Analysis was carried out according to the following conditions, so that the contents of the novel Forms A and B, and the amounts of decomposition products of adefovir dipivoxil formed were calculated by the peak areas. The changes in the contents of novel crystal forms and the amounts of decomposition products were measured under 5°C and accelerated condition over 6 months. The results are shown in the following Tables 2 and 3.
  • Mobile phase mixing condition was operated as follows: For 19 min, mobile phase A was changed from 100% to 0%, and mobile phase B was changed from 0% to 100%. After elution with mobile phase B 100% till 36 min, the elution was changed from mobile phase A 0% to 100% till 46 min.
  • Buffer 9.2g of K 2 HPO 4 and 47.2g of KH 2 PO 4 were dissolved in 2 L of purified water
  • novel Forms A and B maintained the content of 98.85% ⁇ 100.48% and the total amount of decomposition product of 0.25% ⁇ 0.66%, thereby exhibiting highly excellent stability.
  • each formulation was manufactured by the technique disclosed in Example 1 of WO00/35460. Dissolution rates were compared in 0.01N HCl solution, pH 1.2 buffer solution (NaCl 20g + 37% HCl 68 ⁇ 70mL + distilled water 9L), pH 4.0 buffer solution (sodium acetate 7.38g + acetic acid 25mL + distilled water 9L), pH 6.0 buffer solution (KH 2 PO 4 68g + NaOH + distilled water 10L) and pH 7 distilled water. Experiments were repeated 3 times for each case, and the average values are represented in Table 4.

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Abstract

The present invention relates to novel Forms A, B, C, D, E, F and G of crystalline 9-[2-[phosphonomethoxy]ethyl]adenine bis-pivaloyloxymethyl ester, i.e., adefovir dipivoxil, and processes for preparing them. According to the present invention, said novel crystal forms having a high purity can be obtained by a simple method and in a high yield.

Description

NOVEL CRYSTAL FORMS OF ADEFOVIR DIPIVOXIL AND PROCESSES FOR PREPARING THE SAME
The present invention relates to novel crystal forms of a nucleotide analog of 9-[2-[phosphonomethoxy]ethyl]adenine bis-pivaloyloxymethyl ester (“Adefovir dipivoxil”) and processes for the preparation thereof.
Adefovir dipivoxil is an antiviral nucleotide analog, showing excellent effect as a therapeutic agent for HIV infection and hepatitis B virus (HBV) infection. The antiviral activity of said compound is shown in the references (for example, see US Patent Nos. 4,724,233 and 4,808,716; EP Patent No. 0 481 214; Benzaria et al., “Nucleosides and Nucleotide” 14(3-5):563-565, 1995; and Starrett et al., J. Med. Chem. 37:1857-1864, 1994).
The chemical structure of adefovir dipivoxil is seen in the following formula 1:
Figure PCTKR2010001867-appb-I000001
Adefovir dipivoxil was first disclosed in EP Patent No. 0 481 214 and may exist in amorphous or crystalline forms. The amorphous form of adefovir dipivoxil can be obtained by eluting from a silica gel column using a mixture of methanol (about 4%) and methylene chloride (about 96%), and precipitating by rotary evaporation under reduced pressure at about 35℃ (see J. Med. Chem., 19:1857-1864, 1994). However, the purification and preparation of an amorphous form have the disadvantages that the procedures are not suitable for application to mass production and the amorphous form must be protected from heat, light, oxygen and moisture. Thus, as an alternative method, the crystal forms of adefovir dipivoxil were prepared and used. As an example thereof, WO04/043972 discloses a spray-drying process wherein directly prepared or commercially available adefovir dipivoxil is dissolved in an organic solvent and sprayed as micro droplets of drug solution under a high-temperature stream, and thus obtained droplets are immediately dried to give crystals. However, this method has the disadvantage of using a spray-dryer device that is not suitable for mass production. On the other hand, US Patent No. 6,451,340 discloses a method of preparing Form 2 (2 hydrate) by diluting adefovir dipivoxil solution containing 0.2% or less of water and 50% or more of 1-methylpyrrolidinone with acetone, adding n-butyl ether to produce a crystal, cooling to give Form 1, contacting said Form 1 with air having 75% or more of relative humidity or crystallizing it from a solvent containing 2-5% of water. However, this method uses a dangerous and explosive organic solvent such as n-butyl ether as the crystallizing solvent.
Polymorphism is generally considered to mean separate solids having the same molecular formula but different physical properties in melting point, solubility, density, etc. The differences in physical properties of polymorphs come from the alignments of adjacent molecules (complexes) and interactions between molecules in a bulk solid. Thus, polymorphs having the same molecular formula are unique solids in that it is not clear whether one polymorph has more advantageous physical properties than another. One of the most important physical properties of a pharmacological polymorph is water solubility, particularly solubility in the gastric juice of a patient. For example, when absorption through the intestinal tract is slow, it is desirable that the drug which is unstable under the circumstance of the stomach or intestine of a patient is slowly dissolved and not to be accumulated under this harmful circumstance. Such crystal compounds may have different fluidity, elastic deformability, dissolution rate in a pharmaceutical preparation, stability, efficacy, etc. Thus, a crystal form that is more stable, easier to handle and has a high dissolution rate is required in the art. That is, discovery of a novel crystal form of a drug would enable a skilled artisan in the field of formulation to design a pharmaceutical formulation of a drug having the desired release profile or other characteristics.
Therefore, the present inventors tried to provide a variety of novel crystal forms of adefovir dipivoxil to broaden the range of choice in preparing a pharmaceutical composition as well as to resolve the problems of the prior art in preparing the novel crystal forms.
Thus, it is one object of the present invention to provide novel crystal forms of adefovir dipivoxil.
Another object of the present invention is to provide processes for the preparation of the novel crystal forms of adefovir dipivoxil.
As a result of extensive researches for achieving the above objectives, the present inventors successfully developed novel Forms A, B, C, D, E, F and G of crystalline adefovir dipivoxil.
The novel crystal forms provided by the present invention may be more specifically defined as follows.
The XRD pattern of Form A represents the characteristic peaks at 2θ = 12.9, 25.9 and 28.1. Specifically, Form A represents the powder XRD pattern of 2θ = 4.4, 8.7, 12.9, 17.2, 19.8, 21.6, 25.9, 28.1 and 30.38 ± 0.3o.
The XRD pattern of Form B represents the characteristic peaks at 2θ = 7.3, 16.3, 17.2 and 22.2. Specifically, Form B represents the powder XRD pattern of 2θ = 6.4, 7.3, 8.6, 9.7, 12.6, 13.5, 16.3, 17.2, 19.5, 20.8, 22.2 and 26.0 ± 0.3o.
The XRD pattern of Form C represents the characteristic peaks at 2θ = 8.1, 8.8, 9.5, 24.5, 25.3 and 32.9. Specifically, Form C represents the powder XRD pattern of 2θ = 8.1, 8.8, 9.5, 15.4, 17.2, 17.6, 19.7, 21.8, 24.5, 25.3, 26.8, 28.9 and 32.9 ± 0.3o.
The XRD pattern of Form D represents the characteristic peaks at 2θ = 3.8 and 13.0. Specifically, Form D represents the powder XRD pattern of 2θ = 3.8, 7.2, 10.4, 12.4, 13.0, 15.9, 17.5, 21.0 and 23.3 ± 0.3o.
The XRD pattern of Form E represents the characteristic peaks at 2θ = 3.4. Specifically, Form E represents the powder XRD pattern of 2θ = 3.4, 6.9, 11.8, 12.7, 15.7, 17.2, 20.7, 21.5, 22.5 and 23.3 ± 0.3o.
The XRD pattern of Form F represents the characteristic peaks at 2θ = 5.6. Specifically, Form F represents the powder XRD pattern of 2θ = 5.6, 6.9, 11.8, 12.7, 15.7, 17.2, 20.7, 21.5, 22.5 and 23.3 ± 0.2o.
The XRD pattern of Form G has the feature of lacking the peak at 2θ = 11.8, which is the characteristic peak of the Form 1 of US Patent No. 6,451,340. Specifically, Form G represents the powder XRD pattern of 2θ = 6.9, 12.7, 15.7, 17.2, 20.7, 21.5, 22.5 and 23.3 ± 0.2o.
Crystal forms are generally decided by thermodynamic characteristics such as solubility and dynamic characteristics such as several operation factors. The crystallization mechanism is decided by the operation factors, and the mechanism has influence on the formation of crystal core, growth of crystal and deformation of crystal form to give the desired crystal. Thus, analysis of the crystallization mechanism for control of the crystal form is indispensable and should be necessarily carried out in the research of crystal forms. Various methods for forming over-saturation have been studied to develop an efficient method.
It has been determined through substantial studies that the change of over-saturation according to the concentration and temperature in various solvents is the most important factor for the preparation of crystal forms of adefovir dipivoxil. The parameters having the greatest influence on the crystal form of particles when the crystal is precipitated by the core formation from the saturated solution are temperature and solvent. Various off-line methods such as X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC), microscopic examination, etc. are used to examine the crystal forms obtained by the crystal-forming processes.
The starting material of adefovir dipivoxil used for preparing the novel crystal forms according to the present invention may be obtained by the art-known processes, e.g., the processes from US Patent No. 5,663,159 or J. Med. Chem., (1994) 19:1857-1864. However, the present invention sets no special limit on the process of preparing the starting material of adefovir dipivoxil.
As explained above, the present invention provides various novel crystal forms of adefovir dipivoxil and processes for preparing them. According to the present invention, the following advantages are given in this field.
First, various crystal forms provided by the present invention have the effect of broadening the spectrum of selection of the base material in preparing pharmaceutical compositions.
Second, water is used as the crystallizing solvent for preparing the crystal forms of adefovir dipivoxil in the present invention, whereby the organic solvents having some pharmaceutical restrictions remain in a less amount than in the prior arts. Furthermore, according to the present invention the production cost is reduced and its preparation including mass production becomes simple.
Third, the crystal forms of the present invention have a high recovery yield, excellent dissolution rate and storage stability.
Figure 1 represents the XRD results of known forms of crystalline adefovir dipivoxil [(a) Form 1, (b) Form 2, (c) Form 3, (d) Form 4 (Forms 1~4 are disclosed in US Patent No. 6,451,340), (e) Form of WO04/043972].
Figure 2 represents the X-ray diffraction spectrum of Form A of crystalline adefovir dipivoxil obtained in Example 1.
Figure 3 represents the X-ray diffraction spectrum of Form C of crystalline adefovir dipivoxil obtained in Example 4.
Figure 4 represents the X-ray diffraction spectrum of Form D of crystalline adefovir dipivoxil obtained in Example 5.
Figure 5 represents the X-ray diffraction spectrum of Form E of crystalline adefovir dipivoxil obtained in Example 7.
Figure 6 represents the X-ray diffraction spectrum of Form F of crystalline adefovir dipivoxil obtained in Example 9.
Figure 7 represents the X-ray diffraction spectrum of Form G of crystalline adefovir dipivoxil obtained in Example 10.
Figure 8 represents the X-ray diffraction spectrum of Form B of crystalline adefovir dipivoxil obtained in Example 11.
Figure 9 represents the DSC endothermic curve of Form A of crystalline adefovir dipivoxil obtained in Example 3.
Figure 10 represents the DSC endothermic curve of Form B of crystalline adefovir dipivoxil obtained in Example 11.
In the processes for preparing the novel crystal forms according to the present invention, the kinds of novel crystals are decided by the ratio of solute (adefovir dipivoxil): good solvent: crystallization solvent, solubility condition, crystallization temperature, etc, which are explained in detail below.
1) Case of using water as the crystallization solvent
In an embodiment of the present invention, acetone is used as the good solvent in the amount of 2 to 7 times by weight, preferably 4 to 6 times by weight with respect to the weight of adefovir dipivoxil, which is the minimum amount to dissolve adefovir dipivoxil. After adefovir dipivoxil is dissolved at 10 to 40℃, preferably 20 to 30℃, water is added to the above solution as a solvent for crystallizing adefovir dipivoxil. The amount of water is 20 to 40 times by weight, preferably 25 to 30 times by weight with respect to the weight of adefovir dipivoxil. The crystallization solvent is added to form crystals and the thus-obtained mixture is stirred for 4 to 30 h, preferably 5 to 20 h while maintaining the temperature range of 0 to 30℃, preferably 5 to 25℃ to assist the formation and growth of the crystal core. The mixture is filtered, and the collected crystal is dried under reduced pressure at 35℃ or lower to give Form A of crystalline adefovir dipivoxil. After drying, Form A is determined to have a moisture content of 6.5% to 7.1% by Karl Fisher titration. If the stirring temperature is high, the yield may be reduced. Thus, the temperature and time of stirring may play an important role in obtaining the desired high yield and purity of Form A of crystalline adefovir dipivoxil.
In another embodiment of the present invention, the good solvent acetone is used in the amount of 2 to 7 times by weight, preferably 2 to 4 times by weight with respect to the weight of adefovir dipivoxil to dissolve adefovir dipivoxil at 10 to 40℃, preferably 20 to 30℃. Then, water is added to the above solution as a crystallization solvent in the amount of 7 to 13 times by weight, preferably 9 to 11 times by weight with respect to the weight of adefovir dipivoxil. The thus-obtained mixture is not stirred but is allowed to stand while being maintained at a constant cooling temperature range of 0 to 10℃, preferably 5 to 10℃ for 5 to 30 h, preferably 5 to 20 h to induce the growth of crystal. The mixture is filtered, and the collected crystal is dried under reduced pressure at 35℃ or lower. After drying, Form C is determined to have a moisture content of 6.5% to 7.1% by Karl Fisher titration.
In another embodiment of the present invention, Form A is prepared by using 1-methylpyrrolidinone or ethanol as the good solvent and water as the crystallization solvent. In the case that 1-methylpyrrolidinone is used as the good solvent to dissolve adefovir dipivoxil, it is used in the amount of 2 to 5 times by weight, preferably 3 to 4 times by weight with respect to the weight of adefovir dipivoxil. In the case that ethanol is used as the good solvent, it is used in the amount of 5 to 15 times by weight, preferably 8 to 12 times by weight with respect to the weight of adefovir dipivoxil. The thus-obtained solution is allowed to stand while maintaining the temperature at 10 to 40℃, preferably 20 to 30℃ to dissolve adefovir dipivoxil. Then, water is added to the above solution as a crystallization solvent in the amount of 10 to 30 times by weight, preferably 15 to 20 times by weight with respect to the weight of adefovir dipivoxil. In order to induce the growth of crystal, the mixture is stirred for 3 to 10 h, preferably 4 to 5 h while maintaining at a constant cooling temperature of 0 to 10℃, preferably 5 to 10℃. The mixture is filtered, and the collected crystal is dried under reduced pressure at 30℃ or lower to give Form A of crystalline adefovir dipivoxil. In the case that crystallization is performed using water as the crystallization solvent, the moisture content after drying is 6.5% to 7.1% by Karl Fisher titration.
2) The case of using organic solvents as the good solvent and the crystallization solvent
The crystal forms of adefovir dipivoxil can be prepared by mixing crystallization solvents such as n-heptane or cyclohexane with the adefovir dipivoxil solution in the good solvents such as chloroform, ethyl acetate, acetonitrile or isopropyl alcohol.
In an embodiment of the present invention, adefovir dipivoxil is dissolved in the good solvent chloroform in the amount of 1 to 5 times by weight, preferably 2 to 4 times by weight with respect to the weight of adefovir dipivoxil at a temperature of 30 to 50℃, preferably 35 to 45℃. This solution is cooled to 10 to 30℃, preferably 20 to 25℃, and n-heptane is added to crystallize. The amount of n-heptane is 1 to 5 times by weight, preferably 2 to 3 times by weight with respect to the weight of adefovir dipivoxil. After crystallizing, the mixture is stirred for 4 to 20 h, preferably 5 to 10 h while maintaining the temperature of -10 to 30℃, preferably -5 to 25℃ to assist the formation and growth of the crystal core. The mixture is filtered, and the collected crystal is dried to give Form D of crystalline adefovir dipivoxil.
In another embodiment of the present invention, the good solvent ethyl acetate is used in the amount of 0.5 to 2 times by weight, preferably 0.5 to 1 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40℃, preferably 20 to 30℃ to prepare a solution containing adefovir dipivoxil in high content. Then, this solution is added to n-heptane at the temperature of -20 to 20℃, preferably -5 to 5℃ to crystallize. The amount of n-heptane is 10 to 100 times by weight, preferably 20 to 50 times by weight with respect to the weight of adefovir dipivoxil. After crystallizing, the mixture is stirred for 4 to 20 h, preferably 5 to 10 h while maintaining the temperature of -20 to 20℃, preferably -5 to 5℃ to assist the formation and growth of the crystal core. The mixture is filtered, and the collected crystal is dried to give Form D of crystalline adefovir dipivoxil.
In another embodiment of the present invention, the good solvent isopropyl alcohol is used in the amount of 5 to 20 times by weight, preferably 10 to 15 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40℃, preferably 20 to 30℃ to prepare a solution of adefovir dipivoxil. Then, cyclohexane is added to this solution at the temperature of 10 to 40℃, preferably 20 to 30℃ to crystallize. The amount of cyclohexane is 10 to 40 times by weight, preferably 20 to 30 times by weight with respect to the weight of adefovir dipivoxil. After crystallizing, the mixture is stirred for 10 to 40 h, preferably 15 to 25 h while maintaining the temperature of -20 to 20℃, preferably 0 to 10℃ to assist the growth of the crystal core. The mixture is filtered, and the collected crystal is dried to give Form F of crystalline adefovir dipivoxil.
In another embodiment of the present invention, the good solvent chloroform is used in the amount of 1 to 5 times by weight, preferably 2 to 3 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40℃, preferably 20 to 30℃ to prepare a solution of adefovir dipivoxil. Then, n-hexane is added to this solution at the temperature of 10 to 40℃, preferably 20 to 30℃ to crystallize. The amount of n-hexane is 5 to 30 times by weight, preferably 5 to 10 times by weight with respect to the weight of adefovir dipivoxil. After crystallizing, the mixture is stirred for 1 to 10 h, preferably 2 to 5 h while maintaining the temperature of 10 to 40℃, preferably 20 to 30℃ to assist the growth of the crystal core. The mixture is filtered, and the collected crystal is dried to give Form G of crystalline adefovir dipivoxil.
3) Preparation of Form B of crystalline adefovir dipivoxil
In another embodiment of the present invention, Form A of crystalline adefovir dipivoxil is prepared and filtered. The collected crystal is dried under reduced pressure at the temperature of 35 to 45℃ to give Form B of crystalline adefovir dipivoxil. The moisture content after drying is 0.01% to 0.5% by Karl Fisher titration.
4) Preparation of Form E of crystalline adefovir dipivoxil
In another embodiment of the present invention, the good solvent methyl acetate or acetonitrile is used in the amount of 3 to 40 times by weight, preferably 3 to 15 times by weight with respect to the weight of adefovir dipivoxil at 10 to 40℃, preferably 20 to 30℃ to dissolve adefovir dipivoxil. The good solvent used is removed by evaporation under reduced pressure at the same temperature to give Form E of crystalline adefovir dipivoxil.
The present invention will be more specifically explained by the following examples. However, it should be understood that the examples are provided for the purpose of illustration only, and the scope of the present invention is not confined thereto.
Example 1: Preparation of Form A
Adefovir dipivoxil (0.3g) prepared according to Example 9 of US Patent No. 5,663,159 and 1-methylpyrrolidinone (1.00g) were mixed in the weight ratio of 1:3.33, and adefovir dipivoxil was thoroughly dissolved at 30℃. To this solution was added water controlled to 25℃ in advance until a crystal was formed. The amount of water added was 5.00g. The solution was cooled using a refrigerator controlled to 5℃. The thus-cooled solution was stirred for about 4.5 h and the slurry was filtered to separate a crystal. The crystal obtained from filtration was washed with water and filtered again. The crystal was dried under reduced pressure at 25 to 30℃ to give 0.3g (recovery yield: 93%) of Form A (moisture content by Karl Fisher titration: 6.7%).
Example 2: Preparation of Form A
The same procedure as Example 1 was carried out to give 0.31g (recovery yield: 96%) of Form A (moisture content by Karl Fisher titration: 7.1%) except that adefovir dipivoxil (0.3g) prepared according to Example 9 of US Patent No. 5,663,159 and ethanol (3.31g) were mixed in the weight ratio of 1:11.03.
Example 3: Preparation of Form A
Adefovir dipivoxil (3.94kg) prepared according to Example 9 of US Patent No. 5,663,159 and acetone (14.15kg) were mixed in the weight ratio of 1:3.59, and adefovir dipivoxil was thoroughly dissolved at 30℃. To this solution was added water (141.5kg) controlled to 25℃ in advance, and the mixture was stirred for about 10 h at 20 to 25℃. The crystal was separated by filtration and washed with water. The crystal was dried under reduced pressure at 25 to 30℃ to give 3.83kg (recovery yield: 91%) of Form A (moisture content by Karl Fisher titration: 6.9%).
Example 4: Preparation of Form C
Adefovir dipivoxil (0.301g) prepared according to Example 9 of US Patent No. 5,663,159 and acetone (1.30g) were mixed in the weight ratio of 1:4.32, and adefovir dipivoxil was thoroughly dissolved at 30℃. To this solution was added water in the amount of twice the amount of acetone solvent, i.e., 2.60g. The mixture was allowed to stand at 6.4℃ for about 17 h to induce the growth of crystal. The crystal was separated by filtration and dried under reduced pressure at 25 to 30℃ for 24 h to give 0.29g (recovery yield: 90%) of Form C (moisture content by Karl Fisher titration: 6.5%).
Example 5: Preparation of Form D
Adefovir dipivoxil (1.00g) prepared according to Example 9 of US Patent No. 5,663,159 and chloroform (3g) were mixed in the weight ratio of 1:3.00, and adefovir dipivoxil was thoroughly dissolved at 45℃. The resulting solution was cooled to 25℃, and n-heptane (2.7g) controlled to 25℃ in advance was added thereto. The mixture was cooled using a refrigerator controlled to 0℃ and stirred for about 5 h. The crystal was separated by filtration and washed with n-heptane. The crystal was dried under reduced pressure at 25 to 30℃ for 24 h to give 0.89g (recovery yield: 89%) of Form D.
Example 6: Preparation of Form D
Adefovir dipivoxil (3.8g) prepared according to Example 9 of US Patent No. 5,663,159 and ethyl acetate (2.7g) were mixed in the weight ratio of 1:0.71, and adefovir dipivoxil was thoroughly dissolved at 30℃ to make a solution of high concentration. The resulting solution was added to n-heptane (82g) maintained at 0℃, and the mixture was allowed to crystallize for about 6 h. The thus-formed crystal was separated by filtration, washed with n-heptane and filtered again. The crystal was dried under reduced pressure at 25 to 30℃ for 24 h to give 3.7g (recovery yield: 97%) of Form D.
Example 7: Preparation of Form E
Adefovir dipivoxil (0.2g) prepared according to Example 9 of US Patent No. 5,663,159 and methyl acetate (2.8g) were mixed in the weight ratio of 1:14, and adefovir dipivoxil was thoroughly dissolved at 25℃. From the resulting solution, the solvent was evaporated under reduced pressure at the same temperature to give 0.18g (recovery yield: 90%) of Form E which additionally has the peak at 2θ=3.4° compared with Form 1 of US Patent No. 6,451,340.
Example 8: Preparation of Form E
The same procedure as in Example 7 was carried out except that adefovir dipivoxil (0.2g) prepared according to Example 9 of US Patent No. 5,663,159 and acetonitrile (0.8g) were mixed in the weight ratio of 1:4. As a result, 0.18g (recovery yield: 90%) of Form E which additionally has the peak at 2θ=3.4° compared with Form 1 of US Patent No. 6,451,340 was obtained.
Example 9: Preparation of Form F
Adefovir dipivoxil (0.5016g) prepared according to Example 9 of US Patent No. 5,663,159 and isopropyl alcohol (6.11g) were mixed in the weight ratio of 1:12.2, and adefovir dipivoxil was thoroughly dissolved at 30℃. To this solution was added cyclohexane in the amount of about twice the amount of isopropyl alcohol solvent, i.e., 12.83g. Then, the mixture was stirred at 6.4℃ for about 20 h to induce the growth of crystal. The crystal was separated by filtration, washed with cyclohexane, filtered again and dried under reduced pressure at 25 to 30℃ for 24 h to give 0.45g (recovery yield: 90%) of Form F which additionally has the peak at 2θ=5.6° compared with Form 1 of US Patent No. 6,451,340.
Example 10: Preparation of Form G
Adefovir dipivoxil (0.50g) prepared according to Example 9 of US Patent No. 5,663,159 and chloroform (1.50g) were mixed in the weight ratio of 1:3, and adefovir dipivoxil was thoroughly dissolved at 30℃. To this solution was added n-hexane (3.03g) controlled to the same temperature in advance. Then, the mixture was stirred for about 4 h, the crystal was separated by filtration using an aspirator and dried at 25 to 30℃ for 24 h to give 0.42g (recovery yield: 84%) of Form G which lacks the peak at 2θ=11.8° compared with the Form 1 of US Patent No. 6,451,340.
Example 11: Preparation of Form B
Form A of adefovir dipivoxil (3.83kg), which was prepared according to the same procedure as in Example 3 and collected by filtration, was dried under reduced pressure at 35 to 45℃ to give 3.54kg (recovery yield: 99%) of Form B of crystalline adefovir dipivoxil (moisture content by Karl Fisher titration: 0.2%).
Experiment 1: X-ray Diffraction Spectrum
Adefovir dipivoxil prepared in the examples were analyzed by X-ray diffraction analytical devices [instruments: M18XHF-SRA (Mac Science, Japan) and Powder XRD (Bruker AXS, Germany)], and the results are represented in Figures 2, 3, 4, 5, 6, 7 and 8.
Experiment 2: Differential Scanning Calorimeter; DSC
The crystal forms of adefovir dipivoxil prepared in Examples 3 and 11 were analyzed by differential scanning calorimeter [instrument: DSC822e, Mettler Toledo], and the results are represented in Figures 9 and 10.
Experiment 3: Drying Temperature Conditions for the Preparation of Forms A and B
Form A prepared by Example 3 was treated with various drying temperatures and drying times under the vacuum condition of 0.1 ~ 1.0 Torr, and the resulting transformation of the crystal form is represented in Table 1.
Table 1
Figure PCTKR2010001867-appb-T000001
As shown in Table 1, when Form A of crystalline adefovir dipivoxil prepared according to Example 3 was vacuum dried at 25℃, it was not transformed to other crystal forms, and maintained the water content corresponding to 2 hydrate as Form A. However when dried at 35 to 45 ℃, it was found to be transformed from Form A to Form B. On the other hand, Form I was not transformed to Form B even when dried at the above-mentioned temperature.
Experiment 4: Stability Test
The novel Forms A and B of Examples 3 and 11 of the present invention, and 50 mg of the authentic adefovir dipivosil (purity: 99.5%) were precisely weighed into a 50 mL volumetric flask and dissolved in diluent. After making up to the mark, they were used as sample solution and standard solution, respectively. Analysis was carried out according to the following conditions, so that the contents of the novel Forms A and B, and the amounts of decomposition products of adefovir dipivoxil formed were calculated by the peak areas. The changes in the contents of novel crystal forms and the amounts of decomposition products were measured under 5℃ and accelerated condition over 6 months. The results are shown in the following Tables 2 and 3.
Analytical conditions
Instrument: Waters HPLC model 2695
Column: Allech Mixed Mode Anion exchange C8, 7um 100A pore size, 250mm × 4.6mm
Analytical conditions
Mobile phase mixing condition was operated as follows: For 19 min, mobile phase A was changed from 100% to 0%, and mobile phase B was changed from 0% to 100%. After elution with mobile phase B 100% till 36 min, the elution was changed from mobile phase A 0% to 100% till 46 min.
Mobile phase A: buffer/acetonitrile (70:30, v/v)
Mobile phase B: buffer/acetonitrile (50:50, v/v)
Buffer: 9.2g of K2HPO4 and 47.2g of KH2PO4 were dissolved in 2 L of purified water
Diluent: 3.4g of KH2PO4 was dissolved in 1 L of purified water and adjusted to pH 3.0
Detector wave length: 260nm
Flow rate: 1.2mL/min
Table 2
Figure PCTKR2010001867-appb-T000002
Table 3
Figure PCTKR2010001867-appb-T000003
As shown in Tables 2 and 3, under both 5℃ and accelerated condition, novel Forms A and B maintained the content of 98.85% ~ 100.48% and the total amount of decomposition product of 0.25% ~ 0.66%, thereby exhibiting highly excellent stability.
Experiment 5: Dissolution Test
Using the novel Form B prepared in Example 11 of the present invention and the Form I prepared in Example 1 of WO99/04774 as raw materials, each formulation was manufactured by the technique disclosed in Example 1 of WO00/35460. Dissolution rates were compared in 0.01N HCl solution, pH 1.2 buffer solution (NaCl 20g + 37% HCl 68~70mL + distilled water 9L), pH 4.0 buffer solution (sodium acetate 7.38g + acetic acid 25mL + distilled water 9L), pH 6.0 buffer solution (KH2PO4 68g + NaOH + distilled water 10L) and pH 7 distilled water. Experiments were repeated 3 times for each case, and the average values are represented in Table 4.
Table 4
Figure PCTKR2010001867-appb-T000004
The results in Table 4 show that the formulation utilizing the novel Form B of the present invention exhibits a dissolution rate superior to that of the formulation utilizing the existing Form I.

Claims (26)

  1. Form A of crystalline adefovir dipivoxil wherein the powder XRD pattern represents the characteristic peaks at 2θ = 12.9, 25.9 and 28.1.
  2. Form A of crystalline adefovir dipivoxil according to Claim 1 wherein the powder XRD pattern represents the characteristic peaks at 2θ = 4.4, 8.7, 12.9, 17.2, 19.8, 21.6, 25.9, 28.1 and 30.38 ± 0.3o.
  3. Process for preparing Form A of crystalline adefovir dipivoxil according to Claim 1 characterized in that
    (a) adefovir dipivoxil is dissolved in 2 to 7 times by weight of the good solvent acetone with respect to the weight of adefovir dipivoxil, water is added to this solution as a crystallization solvent in the amount of 20 to 40 times by weight with respect to the weight of adefovir dipivoxil, and the crystal thus obtained is collected, or
    (b) adefovir dipivoxil is dissolved in 2 to 5 times by weight of the good solvent 1-methylpyrrolidinone or in 5 to 15 times by weight of the good solvent ethanol with respect to the weight of adefovir dipivoxil, water is added to this solution as a crystallization solvent in the amount of 10 to 30 times by weight with respect to the weight of adefovir dipivoxil, and the crystal thus obtained is collected.
  4. The process of Claim 3 wherein the temperature at the step of adding crystallization solvent is maintained at 0 to 30℃ in (a) and at 0 to 10℃ in (b).
  5. The process of Claim 3 wherein the collected crystal is dried at the temperature of 35℃ or lower in (a) and 30℃ or lower in (b).
  6. Form B of crystalline adefovir dipivoxil wherein the powder XRD pattern represents the characteristic peaks at 2θ = 7.3, 16.3, 17.2 and 22.2.
  7. Form B of crystalline adefovir dipivoxil according to Claim 6 wherein the powder XRD pattern represents the characteristic peaks at 2θ = 6.4, 7.3, 8.6, 9.7, 12.6, 13.5, 16.3, 17.2, 19.5, 20.8, 22.2 and 26.0 ± 0.3o.
  8. Process for preparing Form B of crystalline adefovir dipivoxil according to Claim 6 characterized in that Form A of crystalline adefovir dipivoxil collected according to the process of Claim 3 is dried at the temperature of 35 to 45℃.
  9. Form C of crystalline adefovir dipivoxil wherein the powder XRD pattern represents the characteristic peaks at 2θ = 8.1, 8.8, 9.5, 24.5, 25.3 and 32.9.
  10. Form C of crystalline adefovir dipivoxil according to Claim 9 wherein the powder XRD pattern represents the characteristic peaks at 2θ = 8.1, 8.8, 9.5, 15.4, 17.2, 17.6, 19.7, 21.8, 24.5, 25.3, 26.8, 28.9 and 32.9 ± 0.3o.
  11. Process for preparing Form C of crystalline adefovir dipivoxil according to Claim 9 characterized in that adefovir dipivoxil is dissolved in 2 to 7 times by weight of the good solvent acetone with respect to the weight of adefovir dipivoxil, water is added to this solution as a crystallization solvent in the amount of 7 to 13 times by weight with respect to the weight of adefovir dipivoxil, and the crystal thus obtained is collected.
  12. The process of Claim 11 wherein the mixture is not stirred after the addition of water, and the growth of crystal is induced by maintaining the constant cooling temperature at 0 to 10℃ for 5 to 30 h.
  13. Form D of crystalline adefovir dipivoxil wherein the powder XRD pattern represents the characteristic peaks at 2θ = 3.8 and 13.0.
  14. Form D of crystalline adefovir dipivoxil according to Claim 13 wherein the powder XRD pattern represents the characteristic peaks at 2θ = 3.8, 7.2, 10.4, 12.4, 13.0, 15.9, 17.5, 21.0 and 23.3 ± 0.3o.
  15. Process for preparing Form D of crystalline adefovir dipivoxil according to Claim 13 characterized in that
    (a) adefovir dipivoxil is dissolved in 1 to 5 times by weight of the good solvent chloroform with respect to the weight of adefovir dipivoxil, n-heptane is added to this solution as a crystallization solvent in the amount of 1 to 5 times by weight with respect to the weight of adefovir dipivoxil, and the crystal thus obtained is collected, or
    (b) adefovir dipivoxil is dissolved in 0.5 to 2 times by weight of the good solvent ethyl acetate with respect to the weight of adefovir dipivoxil, this solution is added to the crystallization solvent n-heptane of the amount of 10 to 100 times by weight with respect to the weight of adefovir dipivoxil, and the crystal thus obtained is collected.
  16. The process of Claim 15 wherein (a) further comprises the step of stirring the mixture at the temperature of -10 to 30℃ for 4 to 20 h after the addition of crystallization solvent.
  17. The process of Claim 15 wherein (b) further comprises the step of stirring the mixture at the temperature of -20 to 20℃ for 4 to 20 h after the addition of crystallization solvent.
  18. Form E of crystalline adefovir dipivoxil wherein the powder XRD pattern represents the characteristic peak at 2θ = 3.4.
  19. Form E of crystalline adefovir dipivoxil according to Claim 18 wherein the powder XRD pattern represents the characteristic peaks at 2θ = 3.4, 6.9, 11.8, 12.7, 15.7, 17.2, 20.7, 21.5, 22.5 and 23.3 ± 0.3o.
  20. Process for preparing Form E of crystalline adefovir dipivoxil according to Claim 18 characterized in that adefovir dipivoxil is dissolved at 10 to 40℃ in 3 to 40 times by weight of the good solvent methyl acetate or acetonitrile with respect to the weight of adefovir dipivoxil, and the good solvent is evaporated under reduced pressure at the same temperature.
  21. Form F of crystalline adefovir dipivoxil wherein the powder XRD pattern represents the characteristic peak at 2θ = 5.6.
  22. Form F of crystalline adefovir dipivoxil according to Claim 21 wherein the powder XRD pattern represents the characteristic peaks at 2θ = 5.6, 6.9, 11.8, 12.7, 15.7, 17.2, 20.7, 21.5, 22.5 and 23.3 ± 0.2o.
  23. Process for preparing Form F of crystalline adefovir dipivoxil according to Claim 21 characterized in that adefovir dipivoxil is dissolved in 5 to 20 times by weight of the good solvent isopropyl alcohol with respect to the weight of adefovir dipivoxil, cyclohexane is added to this solution as a crystallization solvent in the amount of 10 to 40 times by weight with respect to the weight of adefovir dipivoxil, and the crystal thus obtained is collected.
  24. The process of Claim 23 which further comprises the step of stirring the mixture at the temperature of -20 to 20℃ for 10 to 40 h after the addition of crystallization solvent.
  25. Form G of crystalline adefovir dipivoxil wherein the powder XRD pattern represents the characteristic peaks at 2θ = 6.9, 12.7, 15.7, 17.2, 20.7, 21.5, 22.5 and 23.3 ± 0.2o.
  26. Process for preparing Form G of crystalline adefovir dipivoxil according to Claim 25 characterized in that adefovir dipivoxil is dissolved in 1 to 5 times by weight of the good solvent chloroform with respect to the weight of adefovir dipivoxil, n-hexane is added to this solution as a crystallization solvent in the amount of 5 to 30 times by weight with respect to the weight of adefovir dipivoxil, and the crystal thus obtained is collected.
PCT/KR2010/001867 2009-03-26 2010-03-26 Novel crystal forms of adefovir dipivoxil and processes for preparing the same WO2010110622A2 (en)

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EP10756377.7A EP2411392B1 (en) 2009-03-26 2010-03-26 Novel crystal forms of adefovir dipivoxil and processes for preparing the same
US13/256,197 US9169257B2 (en) 2009-03-26 2010-03-26 Crystal forms of adefovir dipivoxil and processes for preparing the same
RU2011143166/04A RU2485121C1 (en) 2009-03-26 2010-03-26 Novel crystalline forms of adefovir dipivoxil and methods for production thereof
CN201080013954.6A CN102365283B (en) 2009-03-26 2010-03-26 Novel crystal forms of adefovir dipivoxil and processes for preparing same
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ITMI20071594A1 (en) * 2007-08-02 2009-02-03 Solmag Spa MONOHYDRATE CRYSTALLINE FORM OF ADEFOVIR DIPIVOXIL
CN102716136A (en) * 2012-06-25 2012-10-10 上海益生源药业有限公司 High-dose clinorhomboidal adefovir dipivoxil preparation, and preparation method and application thereof
CN103665044B (en) * 2013-12-20 2015-07-15 悦康药业集团有限公司 Adefovir dipivoxil compound
CN107663217B (en) * 2016-07-28 2021-03-02 苏州朗科生物技术股份有限公司 Tenofovir alafenamide crystal compound and preparation method thereof

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US20120101273A1 (en) 2012-04-26
JP5642766B2 (en) 2014-12-17
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CN102365283A (en) 2012-02-29
RU2011143166A (en) 2013-05-10
KR20100108297A (en) 2010-10-06
US9169257B2 (en) 2015-10-27
RU2485121C1 (en) 2013-06-20
EP2411392A4 (en) 2012-10-10

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