TW201609709A - 呈晶形之索非布弗（Ｓｏｆｏｓｂｕｖｉｒ）及其製備方法 - Google Patents

呈晶形之索非布弗（Ｓｏｆｏｓｂｕｖｉｒ）及其製備方法 Download PDF

Info

Publication number
TW201609709A
TW201609709A TW104123244A TW104123244A TW201609709A TW 201609709 A TW201609709 A TW 201609709A TW 104123244 A TW104123244 A TW 104123244A TW 104123244 A TW104123244 A TW 104123244A TW 201609709 A TW201609709 A TW 201609709A
Authority
TW
Taiwan
Prior art keywords
ketone
sofosbuvir
crystalline form
product
dissolving
Prior art date
Application number
TW104123244A
Other languages
English (en)
Inventor
默洛 賈伯帝
馬塔 卡斯塔帝
葛拉齊安諾 卡斯塔帝
莎拉 赫爾邁
Original Assignee
Ｈｃ製藥公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51628377&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TW201609709(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Ｈｃ製藥公司 filed Critical Ｈｃ製藥公司
Publication of TW201609709A publication Critical patent/TW201609709A/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01L—MEASURING FORCE, STRESS, TORQUE, WORK, MECHANICAL POWER, MECHANICAL EFFICIENCY, OR FLUID PRESSURE
    • G01L15/00—Devices or apparatus for measuring two or more fluid pressure values simultaneously
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01L—MEASURING FORCE, STRESS, TORQUE, WORK, MECHANICAL POWER, MECHANICAL EFFICIENCY, OR FLUID PRESSURE
    • G01L27/00—Testing or calibrating of apparatus for measuring fluid pressure
    • G01L27/002—Calibrating, i.e. establishing true relation between transducer output value and value to be measured, zeroing, linearising or span error determination
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01L—MEASURING FORCE, STRESS, TORQUE, WORK, MECHANICAL POWER, MECHANICAL EFFICIENCY, OR FLUID PRESSURE
    • G01L27/00—Testing or calibrating of apparatus for measuring fluid pressure
    • G01L27/007—Malfunction diagnosis, i.e. diagnosing a sensor defect
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Abstract

呈α結晶型之索非布弗(Sofosbuvir)、其製備方法及其用於醫藥組成物之用途。

Description

呈晶形之索非布弗(Sofosbuvir)及其製備方法
本發明係有關於索非布弗(Sofosbuvir)的穩定多晶型及其製備方法。
索非布弗是用於治療C型肝炎的前驅藥。
C型肝炎是由C型肝炎病毒(HCV)引發的傳染病，其主要感染肝臟。感染經常沒有症狀，但C型肝炎的慢性感染可能導致肝臟形成瘢痕，及最終導致肝硬化，通常係在數年之後變顯著。有些病例中肝硬化可能發展成肝衰竭、肝癌、食道靜脈曲張、及胃靜脈曲張。HCV主要係經由直接接觸被感染的血液傳播，主要係經由靜脈注射藥物、設備消毒不全、及輸血所引起。
C型肝炎病毒在50%至80%感染病毒的病人引發慢性感染，而其中有約40%至80%接受治療。一般而言，患有因病毒造成的肝臟變化的病人建議接受藥物治療；參考治療法是接受PEG化干擾素α及利巴威靈(ribavirin)的組合歷時24週或48週時間，取決於HCV病毒基因型。觀察到此種療法導致獲得50%至60%病例的改善。於較為難治的基因型，此二藥物組合博賽潑維(boceprevir)及特拉潑維(telaprevir)使用，獲得40%至70%的治癒率。該種療法的副作用頻繁：半數病人有流感樣症狀，三分之一的病人有情緒問題，再 者，前六個月內接受治療比起一旦C型肝炎已經變成慢性病之後更有效。
索非布弗是用於治療C型肝炎的藥物，年初經EMA核准，其以口服使用及以停止病毒複製對病毒生命週期的直接作用機轉，作為HCV之RNA聚合酶NS5B RNA依賴型泛基因型前驅藥抑制劑，其可結合入HCV RNA NS5B聚合酶內及作為鏈終結劑。
再者，比較接受其它治療的病人，索非布弗業已顯示肝病併發症病例數目減少及副作用數目減少。
索非布弗為式(I)化合物
化學名稱(2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-二側氧基嘧啶-1-基)-4-氟-3-羥基-4-甲基-四氫呋喃-2-基]甲氧基-苯氧基-磷醯基]-胺基丙酸異丙基酯，商品名Sovaldi®及描述於US 8,563,530。
參考文獻中已知索非布弗的若干多晶型。
US 8,618,076描述索非布弗的結晶型、水合形式及溶劑合形式，定名為1型(結晶)、2型(結晶)、3型(氯仿溶劑合物)、4型(水合物)、5型(結晶)、及6型(結晶)，也描述兩種非晶型。
多晶型現象乃分子於固體狀態時具有多於一種結晶型或多於一種非晶型的性質。已知有些物質只存在有一種結晶型或一種非晶型；其它物質確實可具有兩種或更多種結晶型。多晶型為具有相同分子式但具有不同的物理性質的不同固體，該等物理性質 比起同一個家族裡的其它多晶型的物理性質可能更為優異或更為不利。
有機化學活性成分的形態對其藥物化學的發展相當 要緊。一種結晶型比較其它結晶型可能具有多項優點。用於一種結晶型的適當製程可能給活性成分的製造商帶來數種優點，諸如，使用的步驟或溶劑更為價廉或較低的環境衝擊，期望產物的產率更高及純度更高。
一種有機化合物的多晶型現象、結晶型數目、結晶型 安定性、及結晶型於活有機體內的表現是無法預測的。一種化合物的不同多晶型具有不同的晶格能量，因而顯示不同的固態之物體性質(諸如形狀、密度、熔點、顏色、安定性、溶解速率、研磨容易度、造粒等)。於多晶型現象中，此等形態上的差異對下列各方面有重大影響：研磨固體的流動性(流動性係有關該材料藉此於加工成醫藥製品過程中接受處理的容易程度)；不同投藥劑型的運輸及儲藏安定性；製造不同投藥劑型的能力；於極性或非極性溶劑內之溶解度、於質子性或質子惰性溶劑內之溶解度；於水性溶液中之溶解度；於胃液中之溶解度；於血液中之溶解度；及最後於生物利用率。
活性成分於病人胃液中之溶解速率對療效上有影 響，原因在於其決定了藉口服投藥時活性成分在血液中所能達到的最高濃度。多晶型的其它重要性質影響活性成分在藥物劑型中轉換形式的容易程度，影響散劑劑型或粒劑劑型的流動性，及影響表面性質，該表面性質決定了一旦被壓縮成錠劑時該晶型的晶體是否將彼此沾黏。
一種多晶型可具有與非晶型或任何其它多晶型不同 的熱表現狀態。熱表現狀態可經由諸如毛細管熔點及差分掃描量熱術(DSC)等技術於實驗室中測量，且可用以區別各種多晶型。一種多晶型可具有不同的光譜性質，其可經由X光粉末繞射(XRPD)檢測。
發現一種醫藥化合物之新穎多晶型給予了改良該產 品之特性的另一項可能。製藥技術專家使用標靶釋放概況或使用其它特性，諸如流體性及於水性液中之溶解速率，擴充他/她的針對發展藥物劑型有用的結晶形式知識。
本發明之目的係獲得新穎安定的非吸濕性結晶形式，該結晶型可使用容易的可重複再現的方法製備且具有優異的產率及容易的工業應用性。
發明人今日發現一種安定的且非吸濕性的索非布弗之結晶形式，適合用於製備安定的醫藥配方，其係以使用一種粒徑分布而允許良好壓縮能力及良好流動性所能獲得者。
因此本發明之目的為一種索非布弗的結晶形式，後文中又稱為α型，根據圖1，其特徵在於XRPD包含於約7.96；10.28；12.32；16.64；17.00；18.56；19.28；19.88；20.72；21.88；23.08；24.24；25.16；27.00；27.96±0.2度2θ之峰。
圖1為索非布弗α型之XRPD。
新穎多晶型之特徵亦在於粒徑分布(PSD)，其中90% 粒子之大小為10微米至50微米，及具有下列參數：
本發明之又一目的為一種呈α結晶型之索非布弗之製備方法，該方法包含將索非布弗溶解於酮類之步驟，及該溶解所獲得的溶液之結晶化步驟。
用於本發明之方法目的的酮類係選自於由丙酮、甲基乙基甲酮、異丁基甲基甲酮、及二乙基甲酮所組成的組群；酮類較佳地係選自於由甲基乙基甲酮及異丁基甲基甲酮所組成的組群。
較佳地，結晶步驟係藉冷卻溶液或藉徐緩蒸發去除溶劑獲得。
依據一較佳具體例，本發明之方法包含下列步驟：i.於50℃至60℃之範圍內之溫度，將索非布弗溶解於異丁基甲基甲酮；ii.將得自步驟i之該溶液於攪拌下冷卻至20℃之溫度直到產物沈澱；iii.藉過濾分離得自步驟ii之該產物；iv.於真空下乾燥得自步驟iii之該產物。
依據本發明之索非布弗α型的製備方法特別簡單且具有容易的工業應用性。
因此，本發明之進一步目的為索非布弗α型作為藥物及醫藥組成物之用途，其中含有索非布弗α型作為活性成分混合合 宜載劑。
除非另行載明否則本案中使用的全部術語須瞭解為 業界已知之共通性意義。「約」一詞包含任何度量上的尋常實驗誤差。
雖然已經以特徵化特性描述本發明，但熟諳技藝人士 顯然易知的其相當例及修改例皆係含括於本發明。
現在將藉由數個實施例例示本發明，但非限制性。
[實施例]
繞射光譜XRPD係使用CuKa管(40 Kv，30 Ma)作為X光源，於周圍溫度，透過繞射計APD 2000 Ital結構進行。資料係以於2q的3度至40度之範圍內0.02度/秒之掃描速度，經由2q連續掃描收集。
[實施例1]
於攪拌下，5克索非布弗懸浮於反應燒瓶內的15毫升異丁基甲基甲酮中，溫度維持於約50/60℃，反應混合物維持於此等條件下直到完全溶解。溫度調整至約20℃，混合物於攪拌下維持約1小時時間。所得固體經過濾出且以異丁基甲基甲酮(2x5毫升)於20℃溫度洗滌，及於真空下於45-50℃之烤爐內乾燥，獲得4.5克索非布弗α型。
PSD=d(0.1)：1.831μm；d(0.5)：5.263μm；d(0.9)：20.369μm.
[實施例2]
於攪拌下，5克索非布弗懸浮於反應燒瓶內的15毫升 甲基乙基甲酮中，溫度調整至約50-60℃，反應混合物維持於此等條件下直到完全溶解，所得溶液移轉入結晶器內。於室溫蒸發去除溶劑，獲得5克索非布弗α型。
[實施例3]
於攪拌下，5克索非布弗懸浮於反應燒瓶內的15毫升丙酮中，溫度調整至約50-60℃，反應混合物維持於此等條件下直到完全溶解，所得溶液移轉入結晶器內。於室溫蒸發去除溶劑，獲得5克索非布弗α型。

Claims (10)

  1. 一種呈α結晶型之索非布弗(Sofosbuvir)，其特徵在於X光粉末繞射譜(XRPD)包含下列之峰：7.96；10.28；12.32；16.64；18.56；19.28；19.88；20.72；21.88；23.08；24.24；25.16；27.00；27.96±0.2度2θ。
  2. 一種製備請求項1之索非布弗之方法，其特徵在於其包含將索非布弗溶解於酮類之步驟，及由該溶解所獲得溶液之結晶化步驟。
  3. 如請求項2之方法，其中，該等酮類係選自於丙酮、甲基乙基甲酮、異丁基甲基甲酮、及二乙基甲酮。
  4. 如請求項2或3之方法，其中，該等酮類係選自於甲基乙基甲酮及異丁基甲基甲酮。
  5. 如請求項2至4中任一項之方法，其中，該結晶化係藉冷卻獲得或藉溶劑蒸發獲得。
  6. 如請求項2至5中任一項之方法，其中，包含下列步驟：i.於50℃至60℃之範圍內之溫度，將索非布弗溶解於異丁基甲基甲酮；ii.將得自步驟i之該溶液冷卻至20℃之溫度直到產物沈澱；iii.過濾得自步驟ii之該產物；iv.於真空下乾燥得自步驟iii之該產物。
  7. 一種醫藥組成物，其包含請求項1之索非布弗。
  8. 如請求項1之索非布弗，其係用作為藥物及用於醫藥組成物。
  9. 如請求項2之方法，其中，使用該方法獲得的索非布弗具有粒徑分布(PSD)其中90%粒子之大小係在10微米至50微米之範圍。
  10. 如請求項2之方法，其中，使用該方法獲得的索非布弗具有下 列粒徑分布(PSD)：d(0.1)：1.831μm；d(0.5)：5.263μm；d(0.9)：20.369μm。
TW104123244A 2014-08-01 2015-07-17 呈晶形之索非布弗（Ｓｏｆｏｓｂｕｖｉｒ）及其製備方法 TW201609709A (zh)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
ITMI20141411 2014-08-01

Publications (1)

Publication Number Publication Date
TW201609709A true TW201609709A (zh) 2016-03-16

Family

ID=51628377

Family Applications (1)

Application Number Title Priority Date Filing Date
TW104123244A TW201609709A (zh) 2014-08-01 2015-07-17 呈晶形之索非布弗（Ｓｏｆｏｓｂｕｖｉｒ）及其製備方法

Country Status (11)

Country Link
US (2) US9845335B2 (zh)
EP (1) EP3174889B1 (zh)
CN (1) CN106687470A (zh)
AR (1) AR101368A1 (zh)
BR (1) BR112017002153A2 (zh)
CA (1) CA2956869A1 (zh)
ES (1) ES2773674T3 (zh)
MX (1) MX2017001487A (zh)
TW (1) TW201609709A (zh)
UY (1) UY36250A (zh)
WO (1) WO2016016327A1 (zh)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3845221B1 (en) 2014-06-13 2023-12-13 Ratiopharm GmbH Solid state forms of sofosbuvir
WO2016156512A1 (en) * 2015-04-01 2016-10-06 Sandoz Ag A process for preparing a crystalline form of sofosbuvir
US10738071B2 (en) * 2016-03-17 2020-08-11 Mylan Laboratories Limited Polymorphic forms of sofosbuvir
CN106496295A (zh) * 2016-10-19 2017-03-15 上海博志研新药物技术有限公司 索非布韦晶型6的制备方法
EP3661944A1 (en) 2017-08-03 2020-06-10 Sandoz AG Sofosbuvir hydrate
CN109467577A (zh) * 2018-12-06 2019-03-15 南通常佑药业科技有限公司 一种索非布韦晶型及无定型产品的制备方法
CN109517018B (zh) * 2018-12-29 2021-05-04 石药集团中奇制药技术（石家庄）有限公司 一种索磷布韦新晶型及其制备方法
WO2021203409A1 (zh) * 2020-04-10 2021-10-14 南京正大天晴制药有限公司 一种用于治疗丙肝的无引湿性低变异性新晶型

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
EP2752422B1 (en) * 2010-03-31 2017-08-16 Gilead Pharmasset LLC Stereoselective synthesis of phosphorus containing actives
CN103804446A (zh) * 2014-02-27 2014-05-21 苏州东南药业股份有限公司 一种3,5-二苯甲酰基-2-去氧-2-氟-2甲基-D-核糖-γ-内酯的制备方法
CZ307789B6 (cs) * 2014-04-15 2019-05-09 Zentiva, K.S. Způsob výroby biologicky účinných fosforamidátových léčiv
CN105153257B (zh) * 2014-06-12 2019-03-05 正大天晴药业集团股份有限公司 索非布韦的制备方法
CN105273022A (zh) * 2014-06-16 2016-01-27 深圳翰宇药业股份有限公司 一种索非布韦中间体以及由其制备索非布韦的方法
CZ2014502A3 (cs) * 2014-07-17 2016-01-27 Zentiva, K.S. Nová forma sofosbuviru a způsob její přípravy

Also Published As

Publication number Publication date
AR101368A1 (es) 2016-12-14
CA2956869A1 (en) 2016-02-04
MX2017001487A (es) 2017-12-15
US20170051004A1 (en) 2017-02-23
ES2773674T3 (es) 2020-07-14
CN106687470A (zh) 2017-05-17
EP3174889A1 (en) 2017-06-07
WO2016016327A1 (en) 2016-02-04
US9845335B2 (en) 2017-12-19
UY36250A (es) 2016-02-29
EP3174889B1 (en) 2019-11-20
US20180079771A1 (en) 2018-03-22
BR112017002153A2 (pt) 2018-07-03

Similar Documents

Publication Publication Date Title
TW201609709A (zh) 呈晶形之索非布弗（Ｓｏｆｏｓｂｕｖｉｒ）及其製備方法
JP7145931B2 (ja) 化合物の結晶多形、その製造方法及び用途
JP5566907B2 (ja) Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−３−メチル−ｌ−バリル−（４ｒ）−４−（（７−クロロ−４−メトキシ−１−イソキノリニル）オキシ）−ｎ−（（１ｒ，２ｓ）−１−（（シクロプロピルスルホニル）カルバモイル）−２−ビニルシクロプロピル）−ｌ−プロリンアミドの結晶フォーム
JP5520301B2 (ja) 強力なｈｃｖ阻害剤である２−チアゾリル−４−キノリニル−オキシ誘導体の結晶形態
WO2011095059A1 (zh) 达沙替尼多晶型物及其制备方法和药物组合物
CN108250122A (zh) 磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途
JP6501773B2 (ja) 結晶形態のダサチニブの塩
WO2008086729A1 (fr) Nouveaux composés de dihydropyrimidine et leurs utilisations dans la préparation de médicaments pharmaceutiques destinés au traitement et à la prévention des viroses
WO2016155578A1 (zh) 达格列净的新晶型及其制备方法
JP2014144916A (ja) ２−アシルアミノチアゾール化合物の結晶
WO2017158624A1 (en) Polymorphic forms of sofosbuvir
WO2022054096A1 (en) Solid forms of substituted polycyclic pyridone compounds and prodrugs therof and process of preparation thereof
WO2018135449A1 (ja) 抗重症熱性血小板減少症候群ウイルス薬
JP2016504364A (ja) コビシスタット塩
TW201917117A (zh) 一種炔基吡啶類脯胺醯羥化酶抑制劑的晶型及其製備方法
WO2022120209A1 (en) Solid forms of emetine
WO2017128837A1 (zh) 达卡他韦新晶型及其制备方法
WO2020151296A1 (zh) 双核苷酸前体药物及其制备方法
WO2014193881A1 (en) Crystalline form of n,n-dicyclopropyl-4-(1,5-dimethyl-1 h-pyrazol-3-ylamino)-6-ethyl-1 -methyl-1,6-dihyrdroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
KR101423630B1 (ko) 비칼루타미드와 니코틴아미드의 공결정
WO2015109925A1 (zh) 丙型肝炎药物的晶型及其制备方法、其药物组合物和用途
CN108218938B (zh) 联苯核苷氨基磷酸酯化合物的晶型及其制备方法与用途
CN107337702B (zh) 结晶型hcv抑制剂及其制备方法和应用
WO2015180253A1 (zh) 丙型肝炎药物的晶型及其制备方法、其药物组合物和用途
WO2021031997A1 (zh) 二氢嘧啶衍生物及其用途