CN1337888A - 声波冲击喷射结晶设备和工艺 - Google Patents
声波冲击喷射结晶设备和工艺 Download PDFInfo
- Publication number
- CN1337888A CN1337888A CN00803070A CN00803070A CN1337888A CN 1337888 A CN1337888 A CN 1337888A CN 00803070 A CN00803070 A CN 00803070A CN 00803070 A CN00803070 A CN 00803070A CN 1337888 A CN1337888 A CN 1337888A
- Authority
- CN
- China
- Prior art keywords
- liquid
- liquid stream
- spout
- probe
- sonicated
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
- C30B7/10—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by application of pressure, e.g. hydrothermal processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0036—Crystallisation on to a bed of product crystals; Seeding
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/20—Jet mixers, i.e. mixers using high-speed fluid streams
- B01F25/23—Mixing by intersecting jets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/20—Jet mixers, i.e. mixers using high-speed fluid streams
- B01F25/25—Mixing by jets impinging against collision plates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
- B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
- B01F31/83—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations comprising a supplementary stirring element
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
- B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
- B01F31/85—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations with a vibrating element inside the receptacle
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/80—Mixing plants; Combinations of mixers
- B01F33/82—Combinations of dissimilar mixers
- B01F33/822—Combinations of dissimilar mixers with moving and non-moving stirring devices in the same receptacle
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
- B01J19/10—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing sonic or ultrasonic vibrations
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/18—Stationary reactors having moving elements inside
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J4/00—Feed or outlet devices; Feed or outlet control devices
- B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
- C30B29/54—Organic compounds
- C30B29/58—Macromolecular compounds
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00051—Controlling the temperature
- B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
- B01J2219/00087—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor
- B01J2219/00094—Jackets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00164—Controlling or regulating processes controlling the flow
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Saccharide Compounds (AREA)
- Compounds Of Alkaline-Earth Elements, Aluminum Or Rare-Earth Metals (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Analysing Materials By The Use Of Radiation (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Continuous Casting (AREA)
Abstract
提供药物化合物结晶的方法,该方法是在装有机械搅拌器(18)的结晶器内,在足以获得液流微混合的速度下,使液体喷流(12)与另一液体喷流(14)猛烈撞击,液流(12)含有药物化合物,如Z-3-[1-(4-氯苯基)-1-(4-甲基磺酰基苯基)亚甲基]-二氢呋喃-2-酮或[R-(R*,R*]-4-[2,4-二氟苯基-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基-4-噻唑基]苄腈以及溶剂,如二甲亚砜,另一液流(14)含反溶剂,如水。液体的微混合遇到超声能(24),以促进小晶体生成,所得晶体的95%其直径小于1微米。
Description
相关申请
本申请要求1999年1月29日递交的美国案名35§119(e)暂定申请号60/117878申请的优先权,该申请题目为“声波冲击喷射结晶设备和工艺”。此申请的全部内容在这里被收作参考。
发明领域
本发明针对生产亚微米级颗粒所用的结晶设备和工艺。
发明背景
对药物来说,生成均匀的很小颗粒是普遍的工艺难题。通常,较小的颗粒可提供两种非常理想的药物质量,即较高的生物利用率和较快的溶解速度。在美国专利5314506中,描述了一种利用双冲击喷射法获得均匀颗粒的方法。然而,利用美国专利5314506中的方法所形成的颗粒仅最多小至3微米,所形成结晶大部分为3~20微米。
这些现有技术生成小颗粒的一般方法,包括以位于良好搅拌烧瓶中的两个冲击液体喷射器,获得高强度的微混合。在这两个喷射流彼此撞击的点,存在极高过饱和作用。作为这种高度过饱和的结果,该两种液体冲击点上,混合的很小容积中发生极快的结晶。因为在冲击点,新晶体恒定地成核,因此生成极大量的晶体。当形成大量晶体时,虽然并非所有的晶体都很小,但其平均粒度很小。
本发明的新颖设备和工艺,采用冲击喷射法在结晶过程获得高强度的微混合。高强度微混合的技术背景在美国专利5314506中作了详细讨论,此专利在此收作参考。
本发明概述
本发明是关于结晶出亚微米级颗粒的新颖设备和方法,这些颗粒的平均粒径小于1微米,本发明产生其稳定性和纯度大大改善的高表面积最终晶体产品。当使用相同质量和种类的进料化合物时,与用现有技术公知的标准慢结晶法加上研磨法所制得的颗粒相比,用本发明方法产生的纯的高表面积颗粒显示优越的晶体结构。在晶体结构方面的这些改进,导致分解速度降低,并因而使结晶产物或药物组合物的货架寿命延长。此外,用本发明设备所形成的药物结晶较小,提供具有较高生物利用率和较高溶解速度的晶体。
更具体地说,本发明的新颖设备的工艺涉及沿冲击喷射器附加一个声波处理探针,以使液体高强度微混合,以便在连续结晶过程中,在成核之前,形成均匀的组合物。
本发明的新颖设备和工艺提供了高纯度和高稳定性的高表面积亚微米级颗粒的直接结晶法。
附图简要描述
图1表示本发明的晶体生产体系的示意图,它描绘了位于烧瓶16内的两个冲击喷射器12、14,搅拌器18及声波探针22。
图2是图1中A处限定部份的局部放大图,说明该两冲击喷口尖端大体上对置,而冲击喷口尖端与近距离声波探针尖端处于同一平面。
本发明详述
本发明的新颖工艺包括烧瓶中的声处理探针(或近距离声波探针)的安置,烧瓶中还装有液体喷射器以形成冲击液体喷射流,从而在结晶过程中于成核之前产生高强度微混合。虽然优选使用两个喷口使液体微混合,但是可以使用两个或多个喷口以混合两种或多种液体。一种液体喷射流通常是用产品饱和了的溶剂,而另一种液体喷射流通常含有反溶剂。当两个冲击喷口彼此大体上相对排布、即彼此处于或接近于180°的角度,而且彼此所处距离为0.4″时,能产生最大微混合作用。
如图1所示,此冲击喷射设备包括第一喷射器12和第二喷射器14,它们在高架搅拌器18搅动的烧瓶16(优选1000ml烧瓶)中大体上彼此相对排列。烧瓶16装有大部分物料或液体13,宜与来自第二喷射器14的物质(反溶剂)是同一物质。第一喷射器12和第二喷射器14分别具有喷射小孔12a和14a,这些小孔彼此大体上成180°排布,彼此相距0.4″。如图1所示,而且如图2更清楚显示,第一和第二喷射小孔12a和14a之间所限定的距离20限定了一个冲击点,在此点,来自第一喷射器12的液体和来自喷射器14的液体彼此冲击,并在烧瓶16中微混合。
被泵送通过第一、第二喷射器12、14的液体可以是不同的溶剂组合物。一种液体可以是被结晶的药物化合物的溶液,或者是溶剂的混合物(通常称作“料液”),而另一种液体可以是溶剂或溶剂混合物,这些溶剂可以从溶液中引发化合物的沉淀(通常称作“反溶剂”),因其对该化合物有相对较低溶剂化性能而选取。这类溶剂和反溶剂可以包括(但不限于)水、甲醇、乙醇、DMSO(二甲基亚砜)、IPA(异丙醇)、DMF(二甲基甲酰胺)或丙酮。
另一方面,用于本发明的这两种液体可以同是被结晶的药物化合物在相同适宜溶剂或溶剂混合物中的溶液,但它们处于不同温度下,而且,随着瞬间温度的降低能引起成核/沉淀作用。可以在用于本方法的液体中加入少量合适的表面活性剂,以减轻微混合结晶过程中可能会发生的凝结作用,可以使用的适用表面活性剂包括(但不限于)Tween 80,Cremophor A25,Cremophor EL,Pluronic F68,PluronicF127,Brij 78,Klucel,Plasdone K90,Methocel E5,及PEG(mw20,000)等等。
其一端有探针尖端24的声波处理探针或近距离声波探针22(优选20千赫声波处理探针)位于烧瓶16之内。另一方面,声波探针22的探针尖端24在整个结晶过程中被浸没在结晶淤浆中。为获得最大有效性,声波探针22的探针尖端24宜位于尽可能靠近冲击点20的地方,如图2所示。探针尖端24在结晶淤浆中可以提供高达500瓦的功率,这除上述条件外,还取决于几个工艺参数,如温度、液体粘度及固体百分含量。在紧邻冲击喷口12、14处加入超声能量,可生成小于1微米的平均粒径。
根据本发明,液体被以12米/秒的最低线速度泵过第一、第二喷口12、14。此液体由一种或多种溶剂组成,此液体可以包括药物化合物与溶剂和反溶剂的混合物,或者单纯地是溶剂与反溶剂的混合物。当这两种液体出现并在小孔尖端12a、14a之间的中点相遇时,产生高强度微混合,并形成结晶淤浆圆片。每一种喷射流宜独立地保持在0°至100℃范围内某一个温度之下,这取决于所用的溶剂和药物化合物。为保证在大部分物料13中良好混合,在整个结晶过程中用混合器或搅拌器18,如Rushton涡轮机或其他高剪切叶轮使搅拌速度维持在>300RPM,当然本发明并不限于这类混合器或搅拌器。如图1所示,搅拌器18位于带有第一、第二喷射器12、14以及声波探针22的烧瓶16之中。搅拌器18宜位于接近第一、第二喷射器12、14的地方,但不应干扰冲击点20处的微混合。
在冲击点22内,重要的是应将声波探针尖端24适当放置。对探针尖端24两种放置法加以比较表明,探针尖端24若低于喷射小孔12a、14a以及因此位于冲击点20之外,比起探针尖端24位于与喷口小孔12a、14a同一水平,而因此处于冲击点20之内,会生成稍大的晶体。例如,在下面实施例中引用的实验44032-006-12和44032-006-18中,探针尖端24位于喷口小孔12a、14a平面之下约1英寸处。所得整批晶体的平均粒度为0.5164和0.5178微米,小于0.500微米的晶体分别占97.499%和97.092%。与此相反,在探针尖端24位于喷口小孔12a、14a同一平面、并且位于冲击点20之内的实验44032-006-27之中,则形成平均粒径为0.5129微米、小于0.5000微米的结晶体占99.987%。
不管所用喷射器的数目,喷口小孔均应如此安置,使得喷射出的液流能以高强度进行冲击。液体的冲击是必要的,这样能立即产生强湍流。关键的是,当使用两个喷口时,它们必须如此安置,使得它们的小孔大体引彼此相对,有助于合适的液体冲击.
下面的实施例用于解说本发明这一目的,而不应理解为对本发明范围或精神实质的限制。应该明白,尚存在落入所附权利要求限定的本发明精神及范围内的其他实施方案。
实施例1(Z-3-[1-(4-氯苯基)-1-(4-甲基磺酰苯基)亚甲基]-二氢呋喃-2-酮的结晶,实验号42216-195
(1)在65-75℃下将152.5克上述药物化合物溶于300ml DMSO(二甲基亚砜)中。在2℃下把1200ml水(R0级质量,已过滤)冷却。将浓溶液和水都装入一个搅拌着的有夹套溶器中。通过加热或冷却夹套而维持内容物所希望的温度。将加工液体循环通过加料管线以获得稳态温度和流动速度。
(2)将300ml水(RO级质量,已过滤)加到冲击容器中。在整个结晶过程中夹套温度维持在2℃。
(3)以机械搅拌器和最大声波处理功率,将溶液和水喷射物以1∶4质量流速进行冲击。浓溶液通过0.020″喷嘴的流速为0.18公斤/分,而水通过0.040″喷嘴的流速为0.72公斤/分。
(4)结晶结束时,将产物过滤,然后用约100ml水(RO质量,已过滤)进行洗涤。把滤饼在真空下70℃干燥至干。产率89.4%,不包括由溶液容器及循环管线回收的24.19克。
(5)用80目筛子过筛而将干产品分开。API空气筛(aerosizer)分析,得知平均粒度为0.54微米,95%的颗粒小于0.94微米。
有关BMS-225969试验的总结实验号 平均粒径 %<0.5000μm 第95百分位的粒径42216-157-20 0.5090微米 99.011 0.5086微米42216-158 0.5124 98.097 0.508742216-159 0.5376 92.224 0.937344032-006-12 0.5164 97.499 0.508744032-006-18 0.5178 97.092 0.508844032-006-27 0.5129 97.987 0.5087
实施例2[R-(R*,R*)]-4-[2-[2,4-二氟苯基)-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基-4-噻唑基]苄腈的结晶,实验号42216-027
(1)将50克上述药物化合物在70℃下溶于150ml DMSO(二甲基亚砜)中,并将此溶液精加工过滤。把1000ml水(RO级质量,已过滤)加温至20℃。将浓溶液及水都装入一个搅拌着的夹套容器中。通过加热或冷冻夹套使内容物维持在所希望的温度。将加工液体循环通过供料管线以获得稳态温度和流速。
(2)将300ml水(RO级质量,已过滤)装到冲击容器中。整个结晶过程中将夹套温度维持在20℃。
(3)以机械搅拌器和最大声波处理功率,将溶液和水喷射物以1∶4质量流速进行冲击。浓溶液通过0.020″喷嘴的流速为0.18公斤/分,而水通过0.040″喷嘴的流速为0.72公斤/分。
(4)结晶结束时,将产物过滤并用2升水(RO级质量,已过滤)洗涤。把滤饼在真空下70℃干燥至干。
(5)用80目筛子过筛而将干产品分开。API空气筛(aerosizer)分析,得知平均粒度为0.5324微米,95%颗粒小于0.8321微米。实验号 平均粒度 %<0.5000μm 第95百分位的粒径42216-028-10 0.5324微米 91.563 0.8321微米
Claims (17)
1.一种用于药物化合物结晶的方法,包括在安置的两个或多个液体喷射器口所限定的间隔内,放置声波处理探针尖,使得从该液体喷口喷出的液体流在该间隔内产生冲击,于该液流撞击点形成高湍流点,各液流均有足够线速度,在成核前实现高强度溶液微混合作用,所述声波处理探针在紧靠冲击液流处提供超声能,以对成核作用施加影响并促成细晶体形成,所述晶体有至少95%其直径小于1微米。
2.根据权利要求1的方法,其中使用两个液体喷射器,第一液体喷射器用于携带第一液流,而该第一液流含有DMSO与药物化合物的混合物,第二液体喷射器用于携带第二液流,该第二液流含有水。
3.根据权利要求2的方法,其中该第一和第二液体喷口大体上彼此相对,使得该第一和第二液流产生冲击,以达到高强度撞击。
4.根据权利要求1的方法,其中所述液流的至少一种含有表面活性剂。
5.根据权利要求1的方法,其中所述药物化合物选自(Z-3-[1-(4-氯苯基)-1-(4-甲基磺酰基苯基)亚甲基]-二氢呋喃-2-酮及[R-(R*,R*)]-4-[2-[2,4-二氟苯基)-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基-4-噻唑基]苄腈。
6.根据权利要求1的方法,其中各喷射流独立地处于约0℃至100℃范围内的某一温度。
7.根据权利要求1的方法,其中基本上所有晶体的直径都等于或小于1微米。
8.根据权利要求1的方法,其中液体喷口之间所限定的间隔是0.4英寸。
9.根据权利要求1的方法,其中所述声波处理探针的尖端位于液体喷口同一平面中的间隔内,于该点处,来自液体喷口的液流彼此冲击。
10.根据权利要求9的方法,其中所述声波处理探针提供30-150瓦范围内的功率。
11.生产亚微米级颗粒的结晶设备,包括:
结晶烧瓶;
两个或多个液体冲击喷射器;
搅拌器;以及
带有尖端的声波处理探针,其中该冲击喷射器、搅拌器及声波处理探针均位于该结晶烧瓶内,所述冲击喷射器喷口处于大体上彼此相对的位置,而该声波处理探针位于接近冲击喷口的位置,要使得该探针尖端处于与冲击喷口相同的平面上。
12.根据权利要求11的结晶设备,其中该设备包括两个液体冲击喷射器,第一液体喷射器用于携带第一液流,而第一液流含有DMSO与药物化合物的混合物,第二液体喷射器用于携带第二液流,该第二液流含有水。
13.根据权利要求12的结晶设备,其中该第一和第二液体喷射器大体上彼此相对,使得该第一和第二液流产生冲击,以达到高强度撞击。
14.根据权利要求11的结晶设备,其中所述搅拌器提供>300rpm的搅拌速度,此速度在整个结晶过程中始终保持着。
15.根据权利要求11的结晶设备,其中所述声波处理探针是20千赫探针。
16.根据权利要求15的结晶设备,其中所述声波处理探针对位于该烧瓶中的该第一及第二液流提供范围为30-50瓦的功率。
17.根据权利要求11的方法,其中所述药物化合物选自(Z-3-[1-(4-氯苯基)-1-(4-甲基磺酰基苯基)亚甲基]-二氢呋喃-2-酮及[R-(R*,R*)]-4-[2-[2,4-二氟苯基)-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基-4-噻唑基]苄腈。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11787899P | 1999-01-29 | 1999-01-29 | |
US60/117878 | 1999-01-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1337888A true CN1337888A (zh) | 2002-02-27 |
CN1182903C CN1182903C (zh) | 2005-01-05 |
Family
ID=22375317
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008030707A Expired - Fee Related CN1182903C (zh) | 1999-01-29 | 2000-01-20 | 声波冲击喷射结晶设备和工艺 |
Country Status (13)
Country | Link |
---|---|
US (1) | US6302958B1 (zh) |
EP (1) | EP1173265B1 (zh) |
JP (1) | JP3862957B2 (zh) |
CN (1) | CN1182903C (zh) |
AT (1) | ATE313366T1 (zh) |
AU (1) | AU755470B2 (zh) |
BR (1) | BR0007396A (zh) |
CA (1) | CA2361078A1 (zh) |
DE (1) | DE60024982T2 (zh) |
DK (1) | DK1173265T3 (zh) |
ES (1) | ES2251965T3 (zh) |
TR (1) | TR200101891T2 (zh) |
WO (1) | WO2000044468A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103551100A (zh) * | 2013-10-31 | 2014-02-05 | 华南理工大学 | 一种连续快速反应结晶提高晶体稳定性的装置及方法 |
CN110087461A (zh) * | 2016-09-29 | 2019-08-02 | 杰阿克斯生物技术股份有限公司 | 用于调整植物生长和减少植物水消耗的方法和组合物 |
US11634368B2 (en) | 2018-03-28 | 2023-04-25 | Jrx Biotechnology, Inc. | Agricultural compositions |
Families Citing this family (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9828721D0 (en) | 1998-12-24 | 1999-02-17 | Glaxo Group Ltd | Novel apparatus and process |
GB9914398D0 (en) * | 1999-06-22 | 1999-08-18 | Bp Exploration Operating | Reduction in solids deposition |
GB0016002D0 (en) * | 2000-06-29 | 2000-08-23 | Glaxo Group Ltd | Novel process for preparing crystalline particles |
GB0016040D0 (en) * | 2000-06-29 | 2000-08-23 | Glaxo Group Ltd | Novel process for preparing crystalline particles |
GB0015981D0 (en) * | 2000-06-29 | 2000-08-23 | Glaxo Group Ltd | Novel process for preparing crystalline particles |
US6610223B2 (en) * | 2001-03-30 | 2003-08-26 | Picoliter Inc. | Focused acoustic energy in the generation of solid particles |
US6596206B2 (en) | 2001-03-30 | 2003-07-22 | Picoliter Inc. | Generation of pharmaceutical agent particles using focused acoustic energy |
US6869551B2 (en) | 2001-03-30 | 2005-03-22 | Picoliter Inc. | Precipitation of solid particles from droplets formed using focused acoustic energy |
NZ529258A (en) * | 2001-05-05 | 2004-07-30 | Accentus Plc | Formation of small crystals |
KR20050037477A (ko) * | 2001-10-17 | 2005-04-22 | 이 아이 듀폰 디 네모아 앤드 캄파니 | 로터-스테이터 장치와 입자 생성을 위한 방법 |
GB0201400D0 (en) | 2002-01-22 | 2002-03-13 | Glaxo Group Ltd | Novel apparatus and process |
GB0216700D0 (en) | 2002-07-18 | 2002-08-28 | Astrazeneca Ab | Process |
AU2003291757A1 (en) * | 2002-11-08 | 2004-06-03 | Bristol-Myers Squibb Company | Formulations of low solubility bioactive agents and processes for making the same |
US20040098839A1 (en) * | 2002-11-27 | 2004-05-27 | Pfizer Inc. | Crystallization method and apparatus using an impinging plate assembly |
GB0302673D0 (en) | 2003-02-06 | 2003-03-12 | Astrazeneca Ab | Pharmaceutical formulations |
US7041144B2 (en) * | 2003-03-04 | 2006-05-09 | Five Star Technologies, Inc. | Hydrodynamic cavitation crystallization process |
TWI371274B (en) * | 2003-10-23 | 2012-09-01 | Bristol Myers Squibb Co | Process for making sterile aripiprazole of desired mean particle size |
WO2005051511A1 (ja) * | 2003-11-28 | 2005-06-09 | Mitsubishi Chemical Corporation | 有機化合物微粒子の製造方法 |
US7507823B2 (en) * | 2004-05-06 | 2009-03-24 | Bristol-Myers Squibb Company | Process of making aripiprazole particles |
US7314516B2 (en) * | 2004-12-29 | 2008-01-01 | Five Star Technologies, Inc. | Hydrodynamic cavitation crystallization device and process |
DE102005053862A1 (de) * | 2005-11-04 | 2007-05-10 | Pharmasol Gmbh | Verfahren und Vorrichtung zur Herstellung hochfeiner Partikel sowie zur Beschichtung solcher Partikel |
US20070149640A1 (en) * | 2005-12-28 | 2007-06-28 | Sasa Andjelic | Bioabsorbable polymer compositions exhibiting enhanced crystallization and hydrolysis rates |
US8236904B2 (en) | 2005-12-28 | 2012-08-07 | Ethicon, Inc. | Bioabsorbable polymer compositions exhibiting enhanced crystallization and hydrolysis rates |
WO2008035028A1 (en) * | 2006-09-19 | 2008-03-27 | Fujifilm Manufacturing Europe B.V. | Preparation of fine particles |
GB0705159D0 (en) * | 2007-03-19 | 2007-04-25 | Prosonix Ltd | Process for making crystals |
GB0714223D0 (en) * | 2007-07-20 | 2007-08-29 | Fujifilm Mfg Europe Bv | Preparation of fine particles |
JP2010232895A (ja) * | 2009-03-26 | 2010-10-14 | Fuji Xerox Co Ltd | 通信制御装置及び情報処理装置 |
CN102497858B (zh) * | 2009-06-19 | 2015-03-04 | 纳米模型匈牙利有限公司 | 纳米颗粒替米沙坦组合物及其制备方法 |
KR101317736B1 (ko) * | 2009-06-22 | 2013-10-15 | 파나소닉 전공 주식회사 | 탄성 표면파를 사용하는 미스트 또는 미세 기포의 발생 방법 및 미스트 또는 미세 기포 발생 장치 |
CA3023725C (en) | 2009-10-22 | 2021-09-14 | Vizuri Health Sciences Llc | Methods of producing hydrated flavonoids and use thereof in the preparation of topical compositions |
KR101823706B1 (ko) * | 2010-03-22 | 2018-01-30 | 인스틸로 게엠베하 | 마이크로입자 또는 나노입자의 제조 방법 및 제조 장치 |
FR2960164B1 (fr) * | 2010-05-21 | 2014-03-28 | Centre Nat Rech Scient | Procede de production d'un materiau nanometrique et reacteur pour sa mise en oeuvre |
WO2013041944A1 (en) | 2011-09-19 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of micronized candesartan cilexetil |
WO2014137982A1 (en) | 2013-03-08 | 2014-09-12 | The Board Of Trustees Of The University Of Illinois | Ultrasonic method and apparatus for producing particles having a controlled size distribution |
US9732068B1 (en) | 2013-03-15 | 2017-08-15 | GenSyn Technologies, Inc. | System for crystalizing chemical compounds and methodologies for utilizing the same |
US20170050337A1 (en) * | 2013-05-02 | 2017-02-23 | Melior Innovations, Inc. | Formation apparatus, systems and methods for manufacturing polymer derived ceramic structures |
JP6233919B2 (ja) * | 2013-08-30 | 2017-11-22 | 国立研究開発法人科学技術振興機構 | タンパク質吸着気泡噴出部材、タンパク質結晶装置及びタンパク質結晶化方法、並びにタンパク質結晶切削装置及びタンパク質結晶切削方法 |
WO2017048807A1 (en) * | 2015-09-17 | 2017-03-23 | Jrx Biotechnology, Inc. | Approaches for improving skin hydration or moisturization |
JP6852316B2 (ja) * | 2016-09-06 | 2021-03-31 | 住友金属鉱山株式会社 | 化学反応装置、および、化学反応装置を用いた粒子の製造方法 |
CN108057413A (zh) * | 2018-02-07 | 2018-05-22 | 英丽化学(上海)股份有限公司 | 一种甲基八溴醚类阻燃剂制备进入的溶剂混合装置 |
MX2019002091A (es) * | 2019-02-21 | 2020-08-24 | Bioactivos Y Nutraceuticos De Mexico S A De C V | Máquina para mezclar por medio de ultrasonido. |
WO2020205539A1 (en) | 2019-03-29 | 2020-10-08 | Vizuri Health Sciences Consumer Healthcare, Inc. | Compositions and methods for the prevention and treatment of radiation dermatitis, eczema, burns, wounds and certain cancers |
CN114682148A (zh) * | 2022-04-06 | 2022-07-01 | 南通和力磁材有限公司 | 一种防水磁性涂料生产备制装置及制作方法 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2751335A (en) | 1951-02-01 | 1956-06-19 | Exxon Research Engineering Co | Method and apparatus for mixing and contacting fluids |
US2876083A (en) * | 1953-06-29 | 1959-03-03 | Prietl Franz | Process of producing crystals from particles of crystallizable substance distributedin a liquid |
US4045454A (en) * | 1974-10-25 | 1977-08-30 | Sumitomo Chemical Company, Limited | Production of 1-nitroanthraquinone and 1-aminoanthraquinone |
US4567912A (en) | 1984-07-30 | 1986-02-04 | Acheson Industries, Inc. | Multiple spray nozzles |
US4663433A (en) | 1985-12-23 | 1987-05-05 | General Electric Company | Separation of cyclic oligomeric carbonate from high molecular weight polycarbonate |
SE8700213L (sv) * | 1987-01-21 | 1988-07-22 | Nobel Kemi Ab | Sett att framstella kristallina substanser |
CH671166A5 (en) * | 1987-07-01 | 1989-08-15 | Fershan Holding S A | Crystallisation nuclei formation - by turbulising soln. and applying mechanical energy to form nucleation sites |
CA2044706C (en) * | 1990-06-15 | 2003-02-25 | Michael Midler Jr. | Crystallization method to improve crystal structure and size |
US5074671A (en) | 1990-11-13 | 1991-12-24 | Dew Engineering And Development Limited | Mixing apparatus |
AU668246B2 (en) * | 1992-10-06 | 1996-04-26 | Merck & Co., Inc. | Dual jet crystallizer apparatus |
GB2276567B (en) * | 1993-04-03 | 1996-11-27 | Atomic Energy Authority Uk | Processing vessel |
TW339415B (en) * | 1994-04-28 | 1998-09-01 | Chisso Corp | Processing and manufacturing method of LCD elements |
DE19617085A1 (de) * | 1996-04-29 | 1997-10-30 | Bayer Ag | Verfahren zur Herstellung von feinstteiligen Kristallisationsprodukten |
US5767068A (en) * | 1997-02-13 | 1998-06-16 | Pathogenesis Corporation | Pure biologically active colistin, its components and a colistin formulation for treatment of pulmonary infections |
-
2000
- 2000-01-20 CN CNB008030707A patent/CN1182903C/zh not_active Expired - Fee Related
- 2000-01-20 TR TR2001/01891T patent/TR200101891T2/xx unknown
- 2000-01-20 EP EP00903377A patent/EP1173265B1/en not_active Expired - Lifetime
- 2000-01-20 ES ES00903377T patent/ES2251965T3/es not_active Expired - Lifetime
- 2000-01-20 JP JP2000595760A patent/JP3862957B2/ja not_active Expired - Fee Related
- 2000-01-20 DK DK00903377T patent/DK1173265T3/da active
- 2000-01-20 WO PCT/US2000/001461 patent/WO2000044468A1/en active IP Right Grant
- 2000-01-20 DE DE60024982T patent/DE60024982T2/de not_active Expired - Fee Related
- 2000-01-20 AU AU25133/00A patent/AU755470B2/en not_active Ceased
- 2000-01-20 AT AT00903377T patent/ATE313366T1/de not_active IP Right Cessation
- 2000-01-20 CA CA002361078A patent/CA2361078A1/en not_active Abandoned
- 2000-01-20 BR BR0007396-2A patent/BR0007396A/pt not_active Application Discontinuation
- 2000-01-27 US US09/492,483 patent/US6302958B1/en not_active Expired - Fee Related
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103551100A (zh) * | 2013-10-31 | 2014-02-05 | 华南理工大学 | 一种连续快速反应结晶提高晶体稳定性的装置及方法 |
CN103551100B (zh) * | 2013-10-31 | 2015-10-28 | 华南理工大学 | 一种连续快速反应结晶提高晶体稳定性的装置及方法 |
CN110087461A (zh) * | 2016-09-29 | 2019-08-02 | 杰阿克斯生物技术股份有限公司 | 用于调整植物生长和减少植物水消耗的方法和组合物 |
US12082577B2 (en) | 2016-09-29 | 2024-09-10 | Jrx Biotechnology, Inc. | Methods and compositions for modifying plant growth and reducing water consumption by plants |
US11634368B2 (en) | 2018-03-28 | 2023-04-25 | Jrx Biotechnology, Inc. | Agricultural compositions |
Also Published As
Publication number | Publication date |
---|---|
DE60024982T2 (de) | 2006-07-06 |
ATE313366T1 (de) | 2006-01-15 |
US6302958B1 (en) | 2001-10-16 |
JP2002535379A (ja) | 2002-10-22 |
BR0007396A (pt) | 2001-10-30 |
EP1173265A4 (en) | 2002-11-13 |
JP3862957B2 (ja) | 2006-12-27 |
EP1173265A1 (en) | 2002-01-23 |
AU755470B2 (en) | 2002-12-12 |
DE60024982D1 (de) | 2006-01-26 |
AU2513300A (en) | 2000-08-18 |
CN1182903C (zh) | 2005-01-05 |
ES2251965T3 (es) | 2006-05-16 |
DK1173265T3 (da) | 2006-04-10 |
EP1173265B1 (en) | 2005-12-21 |
CA2361078A1 (en) | 2000-08-03 |
TR200101891T2 (tr) | 2001-12-21 |
WO2000044468A1 (en) | 2000-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1182903C (zh) | 声波冲击喷射结晶设备和工艺 | |
KR100408949B1 (ko) | 입자 크기를 개선하기 위한 반응성 결정화 방법 | |
JP3282731B2 (ja) | 結晶の構造および大きさを改良する結晶化方法 | |
JP3300349B2 (ja) | 重合触媒用均等サイズ活性担体粒子の製造方法 | |
CA2492709C (en) | Process for the preparation of crystalline nano-particle dispersions | |
JP4875984B2 (ja) | 所望の平均粒径を有する無菌のアリピプラゾールを製造する方法 | |
CN1295466A (zh) | 通过溶于压缩气体和表面活性剂制备(亚)微米级粒子的方法 | |
WO2004091571A2 (en) | Polymer coating/encapsulation of nanoparticles using a supercritical antisolvent process | |
EP1619198A1 (en) | Amorphous cefuroxime axetil and preparation process therefore | |
US20100184995A1 (en) | Process for the production of a crystalline glucagon receptor antagonist compound | |
US20040098839A1 (en) | Crystallization method and apparatus using an impinging plate assembly | |
MXPA01007522A (en) | Sonic impinging jet crystallization apparatus and process | |
MXPA01005310A (en) | Reactive crystallization method to improve particle size | |
JPH07292004A (ja) | 懸濁重合方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050105 Termination date: 20100220 |