溶出度检查法美国药典

1、精选优质文档-倾情为你奉上<711> DISSOLUTION溶出度(USP39-NF34 Page 540)General chapter is being harmonized with the corresponding texts of the European Pharmacopoeia and/or the Japanese Pharmacopoeia. These pharmacopeias have undertaken to not make any unilateral change to this harmonized c

2、hapter.通则<711>溶出度与欧盟药典和日本药典中的相应部分相统一。这三部药典承诺不做单方面的修改。Portions of the present general chapter text that are national USP text, and therefore not part of the harmonized text, are marked with symbols to specify this fact.本章中的部分文字为本国USP内容，并没有与其他药典统一。此部分以（   ）标注。This test i

3、s provided to determine compliance with the dissolution requirements  where stated in the individual monograph  for 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 app

4、aratus designs described herein, use the one specified in the individual monograph. Where the label states that an article is enteric coated and a dissolution or disintegration test does not specifically state that it is to be applied to delayed-release articles and is included in the indi

5、vidual monograph, the procedure and interpretation given for Delayed-Release Dosage Forms are applied, unless otherwise specified 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

6、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 the appropriate Acceptance Table (see Interpretation, Immediate-Release Dosage Forms, Extended-Release Dosage Forms, or Dela

7、yed-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 below, and the dissolution results should be evaluated starting at the first stage of the appropriate Acceptance

8、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.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行评估。如果

9、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 compounds and/or in certain storage conditions, including but not restricted to high humidity and temperature, may present cross-linking. A pellicle may form on the external and/or internal surface of the gelatin

10、 capsule shell or on the dosage form that prevents the drug from being released during dissolution testing (see more information in ).明胶，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表面和/或内表面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<1094> ）。Note  All references to a chapter a

11、bove <1000> are 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<1000>章节的所有引用应用的目的仅为提供参考信息。这些章节是非强制的，除非另有规定。Dissolution Medium with pH 4.0 pH 4.0的溶出介质Enzyme: Peps

12、in, activity determined by the procedure in , in the Reagent Specifications section 酶：胃蛋白酶，活性视试剂规格部分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。Dissolution Medium with

13、 pH >4.0 and <6.8 pH >4.0 和 <6.8的溶出介质Enzyme: Papain, activity determined by the Assay test in the monograph for  or bromelain, activity determined by the procedure in, in the Reagent Specifications section 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，活性视试剂规格部分中的菠萝

14、蛋白酶生产过程而定。Amount: A quantity of 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

15、位/L的生物活性。Dissolution Medium with pH 6.8 pH 6.8的溶出介质Enzyme: Pancreatin, protease activity determined by the procedure in Assay for protease activity (Casein digestive power) in the monograph for  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

16、 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 550,000 单位/L的蛋白酶活性。Dissolution Medium Containing Surfactant or Other Ingredients Known to Denature the Enzyme含有表面活性剂或其他已知成分变性酶的溶出介质If the dissolution medium contains surfactant or other ingred

17、ients that are known to denature the enzyme used, a pretreatment step in the dissolution testing of the dosage form 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

18、 according to the medium pH. The amount of enzyme added is appropriate to the volume of dissolution medium used 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

19、 such that the final volume is obtained when the ingredient is added at the end of the pretreatment step. All of 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.

20、 The required pretreatment time should be evaluated on a case-by-case basis and should be scientifically justified. 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

21、for 30 min after the addition of the ingredient.  如果溶出介质中添加了表面活性剂或其他已知成分的变性酶，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来确定加入酶的量，此处的溶出介质不含有表面活性剂和原料。酶加入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加入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

22、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，那么加入原料后实验还要继续进行30min。USP Reference Standards 11  USP Prednisone Tablets RS. USP参考标准<11>-USP强的松片 RS。APPARATUS仪器Apparatus 1 (Basket Apparatus) 第1法（篮法）The assembly consists of the fo

23、llowing: a vessel, which may be covered, and made of glass or other inert, transparent material; a motor; a metallic drive shaft; and a cylindrical basket. The vessel is partially immersed in a suitable water bath of any convenient size or heated by a suitable device, such as a heating jacket.

24、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 of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation

25、, 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 preferable. The vessel is cylindrical, with a hemispherical bottom and  with one of the following dimensions and c

26、apacities: for a nominal  capacity 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; and for a nominal capacity of 4 L, the height is 280300 mm, and its inside diamet

27、er is 145155 mm  . Its sides are flanged at the top. A fitted cover may be used to retard evaporation. The shaft is positioned so that its axis is NMT 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble that could affect the resul

28、ts. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the specified rate  given in the individual monograph  within ±4%.设备由下列部分组成：有盖或无盖的溶出杯，由玻璃或其他惰性的透明材料1制成；马达；转轴；转篮。溶出杯部分浸没在合适大小的水浴中，或者由合适的装置加热，例如电热套。水浴或加热装置需能在测试过程中将杯内温度保

29、持在37±0.5，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。可以使用合适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

30、规定值的±4%范围内。Shaft and basket components of the stirring element are fabricated of stainless steel, type 316, or other inert material, to the specifications shown in . A basket having a gold coating of about 0.0001 inch (2.5 µm) thick may be used. A dosage unit is placed in a dry basket

31、 at the beginning of each test. The distance between the inside 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，将一剂药品至于干燥的篮筐中。在测试过程中，溶出杯底部到篮筐底部的距离应保持在25±2mm。Figure 1. Basket stirri

32、ng element.图1. 转篮组成Apparatus 2 (Paddle Apparatus) 第2法（桨法）Use the assembly from Apparatus 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 sm

33、oothly without significant wobble that could affect the results. The vertical center 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 in . The distance of 25 ± 2 mm

34、between the bottom of the blade and the inside bottom of the vessel is maintained during the test. The metallic or suitably inert, rigid blade and shaft compose a single entity. A suitable two-part, detachable design may be used, provided that the assembly remains firmly engaged during the test. The

35、 paddle blade and shaft may be coated with a suitable coating so as to make both of them inert. 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

36、 to dosage units that would otherwise float. An alternative sinker device is shown in . 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25±2mm。金属或硬质的叶片

37、和转轴应是一个整体。两部分组合的设计也可以使用，只要组件在检测过程中牢固固定在一起。可以在桨叶和转轴上涂布合适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mm）Apparatus 3 (Reci

38、procating Cylinder) 第3法（往复圆筒法）not accepted by the japanese pharmacopoeia日本药典未收录The assembly consists 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 suitab

39、le nonsorbing and nonreactive material and that are designed to fit the tops and bottoms of the reciprocating 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

40、. The vessels are partially immersed in a suitable water bath of any convenient size that permits 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 vibratio

41、n beyond that due to the smooth, vertically reciprocating cylinder. A device is used that allows the reciprocation rate to be selected and maintained at the specified dip rate  given in the individual monograph  within ±5%. An apparatus that permits observation of the specim

42、ens and reciprocating cylinders is preferable. The vessels are provided with evaporation caps that remain in place for the duration of the test. The components conform to the dimensions shown in , unless otherwise specified  in the individual monograph  .所用设备包含一套圆柱形平底玻璃杯；一套玻

43、璃往复圆筒；惰性配件（316号不锈钢或其他合适的材质）；由合适的非吸附，不反应材料制成的筛网，挡在往复圆筒的上下两端；一套马达和传动装置，将圆筒在玻璃杯中垂直往复运动，如果需要，也可以将往复圆筒平行移至另一行玻璃杯中。玻璃杯部分浸没在合适尺寸的水浴中，水浴温度保持在37±0.5。仪器的任何部件，以及仪器所处的环境，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%范围内。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，各部分的尺寸如图3所示。Figure 3.

44、 Apparatus 3 (reciprocating cylinder).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 the Dissolution medium; a flow-through cell; and a water bath that maintains theDissolution medium at 37 ± 0.5°. Use the specified

45、 cell size  as given in the individual monograph  .所用设备包含一个溶出介质的容器和相应的泵，一个流通池和水浴。水浴将溶出介质保持在37±0.5。使用各论中规定的尺寸。The pump forces the Dissolution medium upward through the flow-through cell. The pump has a delivery range between 240 and 960 mL/h, with standard flow rate

46、s 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 pulses/min. A pump without pulsation may also be used. Dissolution test procedures using a flow-through cell must be characterized with resp

47、ect 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脉冲。The flow-through cell (see  and ), of transparent and inert material, is mounted vertically with a fil

48、ter 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 is usually filled with small glass beads of about 1-mm diameter with one bead of about 5 mm, positioned at the apex t

49、o protect the fluid entry tube; and a tablet holder (see  and ) is available for positioning of special dosage forms, e.g., inlay tablets. The cell is immersed in a water bath, and the temperature is maintained at 37 ± 0.5°.由透明且惰性材料制成的流通池（见图4和图5）垂直安放，配有过滤系统（在各论中规定）以防止未溶解的颗粒从

50、流通池顶部逸出。标准的流通池直径为12和22.6mm。底部的锥形通常填有直径约1mm的小玻璃珠，其中一颗约5mm大的玻璃珠置于顶点处，以保护液体输入管。流通池配有药片架（见图4和图5）一满足特殊制剂的需要，如泡腾片。流通池浸没在37±0.5的水浴中。专心-专注-专业Figure 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 ot

51、herwise.)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 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 use

52、s a clamp mechanism and two O-rings to assemble the cell. The pump is separated from the 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 possib

53、le. 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。使用合适的惰性管线，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 of a test

54、 assembly to perform dissolution testing must include conformance to the dimensions and tolerances of the apparatus as given above. In addition, critical test parameters that have to be monitored periodically during use include volume and temperature of the Dissolution medium, rotation speed (A

55、pparatus 1 and Apparatus 2), dip rate (Apparatus 3), and flow rate of medium (Apparatus 4).溶出度测试仪器的适用性必须包括与上述各仪器在尺寸和限度上的一致性。另外，必须在使用过程中定期观测的关键测试参数包括：溶出介质的温度和体积，转速（第1法和第2法），浸没频率（第3法）和溶出介质流速（第4法）。Determine the acceptable performance of the dissolution test assembly periodically.  T

56、he suitability for the individual apparatus is demonstrated by the Performance verification test.定期检测溶出度测试设备的性能。单个设备的适用性由性能验证测试给出。Performance verification test, Apparatus 1 and Apparatus 2: Test USP Prednisone Tablets RS according to the operating conditions specified. The appara

57、tus is suitable if the results obtained are within the acceptable range stated in the technical data sheet specific to the lot used and the apparatus tested.性能验证测试，第1法和第2法：根据规定的操作条件测试USP强的松片RS。如果结果在技术数据表上该批次和所用仪器的的可接受范围内，则设备是适用的。Performance verification test, Apparatus 3: To come.性能验证测试，第3法待续Pe

58、rformance verification test, Apparatus 4: To come. 性能验证测试，第4法待续 PROCEDURE测试方法Apparatus 1 and Apparatus 2第1法和第2法immediate-release dosage forms速释制剂Place the stated volume of the Dissolution medium (±1%) in the vessel of the specified apparatus  given in the individua

59、l monograph  , assemble the apparatus, equilibrate the Dissolution medium to 37 ± 0.5°, and remove the thermometer. Place 1 dosage unit in the apparatus, taking care to exclude air bubbles from the surface of the dosage unit, and immediately operate the apparatus at the

60、 specified rate  given in the individual monograph  . Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the Dissolution medium and the top of the rotating basket or blade, NLT 1 cm from the

61、vessel wall. Note  Where multiple sampling times are specified, replace the aliquots withdrawn for analysis with equal volumes of fresh Dissolution medium at 37° or, where it can be shown that replacement of the medium is not necessary, correct for the volume change in

62、the calculation. Keep the vessel covered for the duration of the test, and verify the temperature of the mixture under test at suitable times.  Perform the analysis  as directed in the individual monograph  using a suitable assay method. Repeat the test with additional dosage form units.将各论中给出的溶出介质量（±1%）加入到规定的容器中，组装好设备，平衡溶出介质温度在37±0.5，移出温度计。将1单位剂量的药品小心加入设备中，注意避免表面产生气泡。立即按照各