溶出度检查法美国药典USP711.doc

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1、word DISSOLUTION溶出度(USP39-NF34 Page540)General chapterDissolutionis being harmonized with the corresponding texts of theEuropean Pharmacopoeiaand/or theJapanese Pharmacopoeia. These pharmacopeias have undertaken to not make any unilateral change to this harmonized chapter.通如此溶出度与欧盟药典和日本药典中的相应局部相统一。这

2、三部药典承诺不做单方面的修改。Portions of the present general chapter text that are nationalUSPtext, and therefore not part of the harmonized text, are marked with symbols to specify this fact.本章中的局部文字为本国USP内容，并没有与其他药典统一。此局部以标注。This test is provided to determine pliance with the dissolution requirementswhere state

3、d in the individual monographfor dosage forms administered orally. In this general chapter, a dosage unit is defined as 1 tablet or 1 capsule or the amount specified.Of the types of apparatus designs described herein, use the one specified in the individual monograph. Where the label states that an

4、article is enteric coated and a dissolution or disintegration test does not specifically state that it is to be applied todelayed-releasearticles and is included in the individual monograph, the procedure and interpretation given forDelayed-Release Dosage Formsare applied, unless otherwise specified

5、 in the individual monograph.本测试用于检测药品口服制剂的溶出度是否符合各论中的规定。本章中，除另有规定外，单位制剂定义为1片或1粒胶囊。对于本章中所述多种仪器，使用各论中规定的种类。除各论中另有规定外，如果检品是肠溶衣片且各论中的溶出度或崩解时限检查项下没有特别指出适用迟释剂的，使用本章中适用于迟释剂的流程和解释。FOR DOSAGE FORMS CONTAINING OR COATED WITH GELATIN涂有或包含明胶的剂型If the dosage form containing gelatin does not meet the criteria in

6、 the appropriateAcceptance Table(seeInterpretation,Immediate-Release Dosage Forms,Extended-Release Dosage Forms, orDelayed-Release Dosage Forms) because of evidence of the presence of cross-linking, the dissolution procedure should be repeated with the addition of enzymes to the medium, as described

7、 below, and the dissolution results should be evaluated starting at the first stage of the appropriateAcceptance Table. It is not necessary to continue testing through the last stage (up to 24 units) when criteria are not met during the first stage testing, and evidence of cross-linking is observed.

8、如果剂型中含有明胶，其不符合验收表中的标准见判断，速释制剂，延释制剂，缓释制剂，因为存在明胶交联结合作用，它的溶解过程与外加的媒介酶是重复的，见下面的描述，并且溶解结果可以通过适当的验收表的开始的第一阶段标准进展评估。如果溶出结果不满足第一阶段的测试标准，那么就没有必要继续测试到最后阶段，并且也证明了明胶交联结合作用的存在。Gelatin, in the presence of certain pounds and/or in certain storage conditions, including but not restricted to high humidity and temper

9、ature, may present cross-linking. A pellicle may form on the external and/or internal surface of the gelatin capsule shell or on the dosage form that prevents the drug from being released during dissolution testing (see more information inCapsulesDissolution Testing and Related Quality Attributes).明

10、胶，存在于某一处方和/或某一储存条件下，如：高温高湿，可能存在明胶交联结合作用。在胶囊壳或其他剂型的外外表和/或内外表形成一层膜阻止溶出试验过程中药物的释放见胶囊-溶出度检测和相关质量属性。NoteAll references to a chapter aboveare for information purposes only, for use as a helpful resource. These chapters are not mandatory unless explicitly called out for this application.注-超过章节的所有引用应用的目的仅为提

11、供参考信息。这些章节是非强制的，除非另有规定。的溶出介质Enzyme:Pepsin, activity determined by the procedure inpurified pepsin, in theReagent Specificationssection酶：胃蛋白酶，活性视试剂规格局部中的胃蛋白酶提纯过程而定。Amount:A quantity of pepsin that results in an activity of NMT 750,000 Units/L of dissolution medium数量：一些胃蛋白酶对溶出介质提供NMT 750,000 单位/L的生物活性

12、Dissolution Medium with pH 4.0 and 4.0 和的溶出介质Enzyme:Papain, activity determined by theAssaytest in the monograph forPapain; or bromelain, activity determined by the procedure inbromelain, in theReagent Specificationssection酶：木瓜蛋白酶，活性视木瓜蛋白酶专论中的分析测试而定；或菠萝蛋白酶，活性视试剂规格局部中的菠萝蛋白酶生产过程而定。Amount:A quantity o

13、f papain that results in an activity of NMT 550,000 Units/L of dissolution medium, or a quantity of bromelain that results in an activity of NMT 30 gelatin-digesting units (GDU)/L of dissolution medium数量：一些木瓜蛋白酶对溶出介质提供NMT 550,000 单位/L的生物活性；一些菠萝蛋白酶对溶出介质提供NMT 30明胶消化单位/L的生物活性。的溶出介质Enzyme:Pancreatin, pr

14、otease activity determined by the procedure inAssay for protease activity(Casein digestive power) in the monograph forPancreatin酶：胰液素，蛋白酶活性视胰液素专论中的蛋白酶活性酪蛋白消化能力分析中的生产过程而定。Amount:A quantity of pancreatin that results in a protease activity of NMT 2000 Units/L of dissolution medium数量：一些胰液素对溶出介质提供NMT 55

15、0,000 单位/L的蛋白酶活性。Dissolution Medium Containing Surfactant or Other Ingredients Known to Denature the Enzyme含有外表活性剂或其他成分变性酶的溶出介质If the dissolution medium contains surfactant or other ingredients that are known to denature the enzyme used, a pretreatment step in the dissolution testing of the dosage f

16、orm may be applied. This pretreatment step is done using the specified dissolution medium without the surfactant or the ingredient and with the addition of the appropriate amount of enzyme according to the medium pH. The amount of enzyme added is appropriate to the volume of dissolution medium used

17、in the pretreatment. To achieve the specified medium volume for the final dissolution testing, the pretreatment step may be conducted with a smaller volume of medium without the ingredient such that the final volume is obtained when the ingredient is added at the end of the pretreatment step. All of

18、 the other conditions of the test (apparatus, rotation, or flow rate) should remain as described in the method or monograph. Typically, the duration of the pretreatment step is NMT 15 min. The required pretreatment time should be evaluated on a case-by-case basis and should be scientifically justifi

19、ed. This time should be included in the total time of the test. As an example, if the total time of the test is 45 min and 15 min are used in the pretreatment step, the test will continue for 30 min after the addition of the ingredient.如果溶出介质中添加了外表活性剂或其他成分的变性酶，那么此溶出实验就要把预处理步骤考虑进去。预处理过程就是是根据溶出介质的pH来确

20、定参加酶的量，此处的溶出介质不含有外表活性剂和原料。酶参加的量要适合预处理所用的溶出介质的体积。为了达到最终溶出试验所需要的特定的溶出介质的体积，预处理阶段所用的溶出介质不含原料的体积要稍微小点，如此在预处理最后阶段参加原料的时候方可获得最终的溶出介质体积。其他所有的测试条件如：设备、转速、流速应该与方法或专论中描述的一致。通常预处理阶段的持续时间为NMT 15 min。所需的预处理时间应该根据具体案例具体分析，且应该科学、合理。预处理时间应该包含在实验的总时间里。例如，如果实验的总时间为45min，预处理时间为15min，那么参加原料后实验还要继续进展30min。USP Reference

21、Standards11USP Prednisone Tablets RS.USP参考标准-USP强的松片 RS。APPARATUS仪器Apparatus 1 (Basket Apparatus) 第1法篮法The assembly consists of the following: a vessel, which may be covered, and made of glass or other inert, transparent material;1a motor; a metallic drive shaft; and a cylindrical basket. The vessel

22、 is partially immersed in a suitable water bath of any convenient size or heated by a suitable device, such as a heating jacket. The water bath or heating device permits holding the temperature inside the vessel at 37 0.5 during the test and keeps the bath fluid in constant, smooth motion. No part o

23、f the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating, stirring element. An apparatus that permits observation of the specimen and of the stirring element during the test is preferab

24、le. The vessel is cylindrical, with a hemispherical bottom andwith one of the following dimensions and capacities: for a nominalcapacity of 1 L, the height is 160210 mm, and its inside diameter is 98106 mm;for a nominal capacity of 2 L, the height is 280300 mm, and its inside diameter is 98106 mm; a

25、nd for a nominal capacity of 4 L, the height is 280300 mm, and its inside diameter is 145155 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation.2The shaft is positioned so that its axis is NMT 2 mm at any point from the vertical axis of the vessel and rotates smoo

26、thly and without significant wobble that could affect the results. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the specified rategiven in the individual monographwithin 4%.设备由如下局部组成：有盖或无盖的溶出杯，由玻璃或其他惰性的透明材料1，并且容许杯内液体持续、平缓的流动。整个仪器包括周围的环境，除了平稳

27、转动的搅拌部件，不得有明显的运动，搅动或振动。仪器最好能允许在检测过程中能够观察到检品和搅拌部件。溶出杯为圆柱形，底部为半球形，尺寸和容积如下：名义容积1L的，高160-210mm，内径98-106mm；名义容积2L的，高280-300mm，内径98-106mm；名义容积4L的，高280-300mm，内径145-155mm。内壁顶部有缘。可以使用适宜的盖子减缓溶剂蒸发2。转轴与溶出杯的纵轴在任意部位不得相差差过2mm，转动平滑，无明显摇晃以至于影响检测结果。速度调节装置控制转轴的转速，并可维持在各论中规定值的4%X围内。Shaft and basket ponents of the stirr

28、ing element are fabricated of stainless steel, type 316, or other inert material, to the specifications shown inFigure 1. A basket having a gold coating of about 0.0001 inch (2.5 m) thick may be used. A dosage unit is placed in a dry basket at the beginning of each test. The distance between the ins

29、ide bottom of the vessel and the bottom of the basket is maintained at 25 2 mm during the test.转轴和篮筐组件由316号不锈钢或者其他惰性材料制成，尺寸如图1所示。可使用镀金厚度0.0001英寸2.5m的篮筐。开始检测时，将一剂药品至于枯燥的篮筐中。在测试过程中，溶出杯底部到篮筐底部的距离应保持在252mm。Figure 1. Basket stirring element.图1. 转篮组成Apparatus 2 (Paddle Apparatus) 第2法桨法Use the assembly fro

30、mApparatus 1, except that a paddle formed from a blade and a shaft is used as the stirring element. The shaft is positioned so that its axis is NMT 2 mm from the vertical axis of the vessel at any point and rotates smoothly without significant wobble that could affect the results. The vertical cente

31、r line of the blade passes through the axis of the shaft so that the bottom of the blade is flush with the bottom of the shaft. The paddle conforms to the specifications shown inFigure 2. The distance of 25 2 mm between the bottom of the blade and the inside bottom of the vessel is maintained during

32、 the test. The metallic or suitably inert, rigid blade and shaft pose a single entity. A suitable two-part, detachable design may be used, provided that the assembly remains firmly engaged during the test. The paddle blade and shaft may be coated with a suitable coating so as to make both of them in

33、ert. The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material, such as NMT a few turns of wire helix, may be attached to dosage units that would otherwise float. An alternative sinker device is shown inFigure

34、 2a. Other validated sinker devices may be used.使用第1法中的设备，除了使用一个由叶片和转轴组成的桨作为搅拌单元。转轴与溶出杯的纵轴在任意部位不得相差差过2mm，转动平滑，无明显摇晃以至于影响检测结果。叶片的垂直中性线穿过转轴的轴线，叶片的下缘与转轴底部平齐。桨的尺寸应符合图2中的规定。在测试过程中，叶片底部与溶出杯底部的距离应保持在252mm。金属或硬质的叶片和转轴应是一个整体。两局部组合的设计也可以使用，只要组件在检测过程中结实固定在一起。可以在桨叶和转轴上涂布适宜的涂层以使其为惰性。在桨叶开始旋转前，将一剂药品沉至溶出杯底。如果药剂浮在页面

35、上，可以在其上附着一个惰性，松弛的小部件，例如几圈线圈，使其沉没。图2是一种可替代使用的沉子。其他经验证的沉子也可以使用。Figure 2. Paddle stirring element.图2. 搅拌桨组成Figure 2a. Alternative sinker. All dimensions are expressed in mm.图2a. 可选的沉降篮单位均为mmApparatus 3 (Reciprocating Cylinder) 第3法往复圆筒法not accepted by the japanese pharmacopoeia日本药典未收录The assembly consis

36、ts of a set of cylindrical, flat-bottomed glass vessels; a set of glass reciprocating cylinders; inert fittings (stainless steel type 316 or other suitable material), and screens that are made of suitable nonsorbing and nonreactive material and that are designed to fit the tops and bottoms of the re

37、ciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels; if desired, index the reciprocating cylinders horizontally to a different row of vessels. The vessels are partially immersed in a suitable water bath of any convenient size that permits

38、holding the temperature at 37 0.5 during the test. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smooth, vertically reciprocating cylinder. A device is used that allows the reciprocat

39、ion rate to be selected and maintained at the specified dip rategiven in the individual monographwithin 5%. An apparatus that permits observation of the specimens and reciprocating cylinders is preferable. The vessels are provided with evaporation caps that remain in place for the duration of the te

40、st. The ponents conform to the dimensions shown inFigure 3, unless otherwise specifiedin the individual monograph.。仪器的任何部件，以与仪器所处的环境，都不应当引起明显的移动，搅动，振动，除了平滑的垂直往复运动的圆筒。使用设备维持往复速度在各论中所规定值的5%X围内。仪器最好可以在检测过程中观察到样品和往复圆筒。玻璃杯配有蒸发帽，在检测中一直盖在玻璃杯上。除另有规定外，各局部的尺寸如图3所示。Figure 3. Apparatus 3 (reciprocating cylinder

41、).图3. 图3 第3法往复圆筒法设备Apparatus 4 (Flow-Through Cell) 第4法流通池法The assembly consists of a reservoir and a pump for theDissolution medium; a flow-through cell; and a water bath that maintains theDissolution mediumat 37 0.5. Use the specified cell sizeas given in the individual monograph.。使用各论中规定的尺寸。The pu

42、mp forces theDissolution mediumupward through the flow-through cell. The pump has a delivery range between 240 and 960 mL/h, with standard flow rates of 4, 8, and 16 mL/min. It must deliver a constant flow (5% of the nominal flow rate); the flow profile is sinusoidal with a pulsation of 120 10 pulse

43、s/min. A pump without pulsation may also be used. Dissolution test procedures using a flow-through cell must be characterized with respect to rate and any pulsation.泵将溶出介质推动，向上通过流通池。泵的传输能力在240到960mL每小时之间，标准速率为4，8，16mL每分钟。泵的流速必须均匀名义流量的5%以内。泵的流量特性曲线应为正弦波，脉冲为每分钟120 10 冲。无脉冲泵也可以使用。使用流通池法的溶出度测试必须对应特定的流速和

44、脉冲。The flow-through cell (seeFigure 4andFigure 5), of transparent and inert material, is mounted vertically with a filter system (specified in the individual monograph) that prevents escape of undissolved particles from the top of the cell; standard cell diameters are 12 and 22.6 mm; the bottom cone

45、 is usually filled with small glass beads of about 1-mm diameter with one bead of about 5 mm, positioned at the apex to protect the fluid entry tube; and a tablet holder (seeFigure 4andFigure 5) is available for positioning of special dosage forms, e.g., inlay tablets. The cell is immersed in a wate

46、r bath, and the temperature is maintained at 37 0.5.的水浴中。26 / 26Figure 4. Apparatus 4: large cell for tablets and capsules (top); tablet holder for the large cell (bottom). (All measurements are expressed in mm unless noted otherwise.)图4. 第4法设备，盛装片剂和胶囊的大流通池上，大药片架下。除另有说明，所有尺寸单位为mm。Figure 5. Apparatus

47、 4: small cell for tablets and capsules (top); tablet holder for the small cell (bottom). (All measurements are expressed in mm unless noted otherwise.)图5 第4法设备，盛装片剂和胶囊的小流通池上，小药片架下。除另有说明，所有尺寸单位为mm。The apparatus uses a clamp mechanism and two O-rings to assemble the cell. The pump is separated from t

48、he dissolution unit to shield the latter against any vibrations originating from the pump. The position of the pump should not be on a level higher than the reservoir flasks. Tube connections are as short as possible. Use suitably inert tubing, such as polytef, with about a 1.6-mm inner diameter and chemically inert, flanged-end connections.流通池使用一个架子和2个O形圈固定。泵与溶出单元分开，以防止泵的振动干扰到后者。泵的水平位置不得高于溶出介质容器。管线连接尽可能短。使用适宜的惰性管线，如聚四氟乙烯，内径1.6mm。法兰连接也应为化学惰性。apparatus suitability设备适用性The determination of suitability