溶出度检查法美国药典USP-711
美国药典-溶出方法
711 DISSOLUTIONThis general chapter is harmonized with the corresponding texts of the European Pharmacopoeia and/or the Japanese Pharmacopoeia. These pharmacopeias have undertaken not to make any unilateral change to this harmonized chapter.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.This test is 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 apparatus described herein, use the one specified in the individual monograph. Where the label states that an article is enteric-coated, and where a dissolution or disintegration test that does not specifically state that it is to be applied to delayed-release articles is included in the individual monograph, the procedure and interpretation given for Delayed-Release Dosage Forms is applied unless otherwise specified in the individual monograph. For hard or soft gelatin capsules and gelatin-coated tablets that do not conform to the Dissolution specification, repeat the test as follows. Where water or a medium with a pH of less than 6.8 is specified as the Medium in the individual monograph, the same Medium specified may be used with the addition of purified pepsin that results in an activity of 750,000 Units or less per 1000 mL. For media with a pH of 6.8 or greater, pancreatin can be added to produce not more than 1750 USP Units of protease activity per 1000 mL.USP R EFERENCE S TANDARDS11—USP Chlorpheniramine Maleate Extended-Release Tablets RS. USP Prednisone Tablets RS.APPARATUSApparatus 1 (Basket Apparatus)The assembly consists of the following: a vessel, which may be covered, made of glass or other inert, transparent material1; 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. The water bath or heating device permits holding the temperature inside the vessel at 37 ± 0.5 during the test and keeping 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, or vibration beyond that due tothe smoothly rotating stirring element. An apparatus that permits observation of the specimen and stirring element during the test is preferable. The vessel is cylindrical, with ahemispherical bottom and with one of the following dimensions and capacities: for a nominal capacity of 1 L, the height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm; for a nominal capacity of 2 L, the height is 280 mm to 300 mm and its inside diameter is 98 mm to 106 mm; and for a nominal capacity of 4 L, the height is 280 mm to 300 mm and its inside diameter is 145 mm to 155 mm. Its sides are flanged at the top. Afitted cover may be used to retard evaporation.2 The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble that could affect the results. A speed-regulating device is used thatallows the shaft rotation speed to be selected and maintained at the specified rate given in the individual monograph, within ±4%.Shaft and basket components of the stirring element are fabricated of stainless steel, type 316, or other inert material, to the specifications shown in Figure 1. 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 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.Figure 1. Basket Stirring ElementApparatus 2 (Paddle Apparatus)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 not more than 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 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 Figure 2. The distance of 25 ± 2 mm 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 comprise a single entity. A suitable two-part detachable design may be used provided the assembly remains firmly engaged during the test. The paddle blade and shaft may be coated with a suitable coating so as to make 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 not more than a few turns of wire helix, may be attached to dosage units that would otherwise float. An alternative sinker device is shown in Figure 2a. Other validated sinker devices may be used.Figure 2. Paddle Stirring ElementFigure 2a. Alternative sinker. All dimensions are expressed in mm.Apparatus 3 (Reciprocating Cylinder)NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIAThe assembly consists of a set of cylindrical, flat-bottomed glass vessels; a set of glassreciprocating 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 reciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels and, 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 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 thereciprocation 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 specimens and reciprocating cylinders is preferable. The vessels are provided with an evaporation cap that remains in place for the duration of the test. The components conform to the dimensionsshown in Figure 3 unless otherwise specified in the individual monograph.Figure 3. Apparatus 3 (reciprocating cylinder)Apparatus 4 (Flow-Through Cell)The assembly consists of a reservoir and a pump for the Dissolution Medium; a flow-through cell; and a water bath that maintains the Dissolution Medium at 37 ± 0.5. Use the specified cell size as given in the individual monograph.The pump forces the Dissolution Medium upwards through the flow-through cell. The pump has a delivery range between 240 and 960 mL per hour, with standard flow rates of 4, 8, and 16 mL per minute. It must deliver a constant flow (±5% of the nominal flow rate); the flow profile is sinusoidal with a pulsation of 120 ± 10 pulses per minute. 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.The flow-through cell (see Figures 4 and 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 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 (see Figures 4 and 5) is available for positioning of special dosage forms, for example, inlay tablets. The cell is immersed in a water bath, and the temperature is maintained at 37 ± 0.5.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 otherwise.)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.)The apparatus uses a clamp mechanism and two O-rings to assemble the cell. The pump is separated from the dissolution unit in order 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 1.6-mm inner diameter and chemically inert flanged-end connections.APPARATUS SUITABILITYThe determination of suitability of a test 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 (Apparatus 1 and Apparatus 2), dip rate (Apparatus 3), and flow rate of medium (Apparatus 4).Determine the acceptable performance of the dissolution test assembly periodically.The suitability for the individual apparatus is demonstrated by the Performance Verification Test. Performance Verification Test, Apparatus 1 and 2— Test USP Prednisone Tablets RS according to the operating conditions specified. The apparatus 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.Performance Verification Test, Apparatus 3— Test USP Chlorpheniramine Maleate Extended-Release Tablets RS according to the operating conditions specified. The apparatus is suitable if the results obtained are within the acceptable range stated in the technical data sheet specific to the lot used.Performance Verification Test, Apparatus 4— [To come.]PROCEDUREApparatus 1 and Apparatus 2IMMEDIATE-RELEASE DOSAGE FORMSPlace the stated volume of the Dissolution Medium (±1%) in the vessel of the specified apparatus given in the individual 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, andimmediately operate the apparatus at the 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, not less than 1 cm from the 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 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 assaymethod.3 Repeat the test with additional dosage form units.If automated equipment is used for sampling or the apparatus is otherwise modified, verification that the modified apparatus will produce results equivalent to those obtained with the standard apparatus described in this general chapter is necessary.Dissolution Medium— A suitable dissolution medium is used. Use the solvent specified in the individual monograph. The volume specified refers to measurements made between 20and 25. If the Dissolution Medium is a buffered solution, adjust the solution so that its pH is within 0.05 unit of the specified pH given in the individual monograph. [NOTE—Dissolvedgases can cause bubbles to form, which may change the results of the test. If dissolved gases influence the dissolution results, dissolved gases should be removed prior to testing.4 ] Time— Where a single time specification is given, the test may be concluded in a shorter period if the requirement for minimum amount dissolved is met. Specimens are to be withdrawn only at the stated times within a tolerance of ±2%.Procedure for a Pooled Sample for Immediate-Release Dosage Forms—Use this procedure where Procedure for a Pooled Sample is specified in the individual monograph. Proceed as directed in Procedure for Apparatus 1 and Apparatus 2 in Immediate-Release Dosage Forms. Combine equal volumes of the filtered solutions of the six or twelve individual specimens withdrawn, and use the pooled sample as the test specimen. Determine the average amount of the active ingredient dissolved in the pooled sample.EXTENDED-RELEASE DOSAGE FORMSProceed as directed for Immediate-Release Dosage Forms.Dissolution Medium— Proceed as directed for Immediate-Release Dosage Forms.Time— The test-time points, generally three, are expressed in hours.DELAYED-RELEASE DOSAGE FORMS NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIAUse Method A or Method B and the apparatus specified in the individual monograph. All test times stated are to be observed within a tolerance of ±2%, unless otherwise specified. Method A—Procedure (unless otherwise directed in the individual monograph)—ACID STAGE— Place 750 mL of 0.1 N hydrochloric acid in the vessel, and assemble the apparatus. Allow the medium to equilibrate to a temperature of 37 ± 0.5. Place 1 dosage unitin the apparatus, cover the vessel, and operate the apparatus at the specified rate given in the monograph.After 2 hours of operation in 0.1 N hydrochloric acid, withdraw an aliquot of the fluid, and proceed immediately as directed under Buffer Stage.Perform an analysis of the aliquot using a suitable assay method. The procedure is specified in the individual monograph.BUFFER STAGE— [NOTE—Complete the operations of adding the buffer and adjusting the pH within 5 minutes. ]With the apparatus operating at the rate specified in the monograph, add to the fluid in the vessel 250 mL of 0.20 M tribasic sodium phosphate that has been equilibrated to 37 ± 0.5. Adjust, if necessary, with 2 N hydrochloric acid or 2 N sodium hydroxide to a pH of 6.8 ±0.05. Continue to operate the apparatus for 45 minutes, or for the specified time given in the individual monograph. At the end of the time period, withdraw an aliquot of the fluid, and perform the analysis using a suitable assay method. The procedure is specified in the individual monograph. The test may be concluded in a shorter time period than that specified for the Buffer Stage if the requirement for the minimum amount dissolved is met at an earlier time.Method B—Procedure (unless otherwise directed in the individual monograph)—ACID STAGE— Place 1000 mL of 0.1 N hydrochloric acid in the vessel, and assemble theapparatus. Allow the medium to equilibrate to a temperature of 37 ± 0.5. Place 1 dosage unit in the apparatus, cover the vessel, and operate the apparatus at the rate specified in the monograph. After 2 hours of operation in 0.1 N hydrochloric acid, withdraw an aliquot of thefluid, and proceed immediately as directed under Buffer Stage.Perform an analysis of the aliquot using a suitable assay method. The procedure is specified in the individual monograph.BUFFER STAGE— [NOTE—For this stage of the procedure, use buffer that previously has been equilibrated to a temperature of 37 ± 0.5. ] Drain the acid from the vessel, and add to the vessel 1000 mL of pH 6.8 phosphate buffer, prepared by mixing 0.1 N hydrochloric acid with 0.20 M tribasic sodium phosphate (3:1) and adjusting, if necessary, with 2 N hydrochloric acid or 2 N sodium hydroxide to a pH of 6.8 ± 0.05. [NOTE—This may also be accomplished by removing from the apparatus the vessel containing the acid and replacing it with another vessel containing the buffer and transferring the dosage unit to the vessel containing the buffer. ]Continue to operate the apparatus for 45 minutes, or for the specified time given in the individual monograph. At the end of the time period, withdraw an aliquot of the fluid, and perform the analysis using a suitable assay method. The procedure is specified in the individual monograph. The test may be concluded in a shorter time period than that specified for the Buffer Stage if the requirement for minimum amount dissolved is met at an earlier time.Apparatus 3 (Reciprocating Cylinder)NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA IMMEDIATE-RELEASE DOSAGE FORMS Place the stated volume of the Dissolution Medium in each vessel of the apparatus, assemble the apparatus, equilibrate the Dissolution Medium to 37 ± 0.5, and remove the thermometer. Place 1 dosage-form unit in each of the six reciprocating cylinders, taking care to exclude air bubbles from the surface of each dosage unit, and immediately operate the apparatus asspecified in the individual monograph. During the upward and downward stroke, thereciprocating cylinder moves through a total distance of 9.9 to 10.1 cm. Within the time interval specified, or at each of the times stated, raise the reciprocating cylinders and withdraw a portion of the solution under test from a zone midway between the surface of theDissolution Medium and the bottom of each vessel. Perform the analysis as directed in the individual monograph. If necessary, repeat the test with additional dosage-form units.Dissolution Medium—Proceed as directed for Immediate-Release Dosage Forms under Apparatus 1 and Apparatus 2.Time—Proceed as directed for Immediate-Release Dosage Forms under Apparatus 1 and Apparatus 2.EXTENDED-RELEASE DOSAGE FORMSProceed as directed for Immediate-Release Dosage Forms under Apparatus 3.Dissolution Medium—Proceed as directed for Extended-Release Dosage Forms under Apparatus 1 and Apparatus 2.Time—Proceed as directed for Extended-Release Dosage Forms under Apparatus 1 and Apparatus 2.DELAYED-RELEASE DOSAGE FORMSProceed as described for Delayed-Release Dosage Forms, Method B under Apparatus 1 and Apparatus 2 using one row of vessels for the acid stage media and the following row of vessels for the buffer stage media and using the volume of medium specified (usually 300 mL).Time—Proceed as directed for Immediate-Release Dosage Forms under Apparatus 1 and Apparatus 2.Apparatus 4 (Flow-Through Cell)IMMEDIATE-RELEASE DOSAGE FORMSPlace the glass beads into the cell specified in the monograph. Place 1 dosage unit on top of the beads or, if specified in the monograph, on a wire carrier. Assemble the filter head,and fix the parts together by means of a suitable clamping device. Introduce by the pump the Dissolution Medium warmed to 37 ± 0.5 through the bottom of the cell to obtain the flow rate specified in the individual monograph and measured with an accuracy of 5%. Collect theeluate by fractions at each of the times stated. Perform the analysis as directed in the individual monograph. Repeat the test with additional dosage-form units.Dissolution Medium—Proceed as directed for Immediate-Release Dosage Forms under Apparatus 1 and Apparatus 2.Time—Proceed as directed for Immediate-Release Dosage Forms under Apparatus 1 and Apparatus 2.EXTENDED -RELEASE DOSAGE FORMSProceed as directed for Immediate-Release Dosage Forms under Apparatus 4.Dissolution Medium —Proceed as directed for Immediate-Release Dosage Forms under Apparatus 4.Time —Proceed as directed for Immediate-Release Dosage Forms under Apparatus 4.DELAYED -RELEASE DOSAGE FORMSProceed as directed for Delayed-Release Dosage Forms under Apparatus 1 and Apparatus 2, using the specified media.Time —Proceed as directed for Delayed-Release Dosage Forms under Apparatus 1 and Apparatus 2.INTERPRETATIONImmediate-Release Dosage FormsUnless otherwise specified in the individual monograph , the requirements are met if the quantities of active ingredient dissolved from the dosage units tested conform to Acceptance Table 1. Continue testing through the three stages unless the results conform at either S 1 or S 2. The quantity, Q, is the amount of dissolved active ingredient specified in the individual monograph , expressed as a percentage of the labeled content of the dosage unit; the 5%, 15%, and 25% values in Acceptance Table 1 are percentages of the labeled content so that these values and Q are in the same terms. Acceptance Table 1Immediate-Release Dosage Forms Pooled Sample — Unless otherwise specified in the individual monograph, the requirements are met if the quantities of active ingredient dissolved from the pooled sample conform to the accompanying Acceptance Table for a Pooled Sample.Stage NumberTested Acceptance CriteriaS 16Each unit is not less than Q + 5%.S 26Average of 12 units (S 1 + S 2) is equal to or greater than Q, and no unit isless thanQ 15%.S 312Average of 24 units (S 1 + S 2 +S 3) is equal to or greater than Q , not morethan 2 units are less than Q 15%, and no unit is less than Q 25%.Continue testing through the three stages unless the results conform at either S 1 or S 2. The quantity, Q is the amount of dissolved active ingredient specified in the individual monograph, expressed as a percentage of the labeled content.Acceptance Table for a Pooled SampleExtended-Release Dosage FormsUnless otherwise specified in the individual monograph , the requirements are met if the quantities of active ingredient dissolved from the dosage units tested conform to Acceptance Table 2. Continue testing through the three levels unless the results conform at either L 1 or L 2. Limits on the amounts of active ingredient dissolved are expressed in terms of the percentage of labeled content. The limits embrace each value of Q i , the amount dissolved at each specified fractional dosing interval. Where more than one range is specified in the individual monograph , the acceptance criteria apply individually to each range. Acceptance Table 2Stage Number Tested Acceptance Criteria S 16Average amount dissolved is not less thanQ + 10%.S 26Average amount dissolved (S 1 + S 2) is equal to or greater than Q + 5%.S 312Average amount dissolved (S 1 + S 2 + S 3) is equal to or greater than Q.Level NumberTested CriteriaL 16No individual value lies outside each of the stated ranges and no individualvalue is less than the stated amount at the final test time.L 26The average value of the 12 units (L 1 + L 2) lies within each of the statedranges and is not less than the stated amount at the final test time; none ismore than 10% of labeled content outside each of the stated ranges; andnone is more than 10% of labeled content below the stated amount at thefinal test time.L 312The average value of the 24 units (L 1 + L 2 + L 3) lies within each of the statedranges, and is not less than the stated amount at the final test time; not morethan 2 of the 24 units are more than 10% of labeled content outside each ofthe stated ranges; not more than 2 of the 24 units are more than 10% oflabeled content below the stated amount at the final test time; and none ofthe units is more than 20% of labeled content outside each of the statedranges or more than 20% of labeled content below the stated amount at thefinal test time.Delayed-Release Dosage FormsNOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA .Acid Stage — Unless otherwise specified in the individual monograph , the requirements of this portion of the test are met if the quantities, based on the percentage of the labeledcontent, of active ingredient dissolved from the units tested conform to Acceptance Table 3. Continue testing through all levels unless the results of both acid and buffer stages conform at an earlier level. Acceptance Table 3Buffer Stage — Unless otherwise specified in the individual monograph , the requirements are met if the quantities of active ingredient dissolved from the units tested conform to Acceptance Table 4. Continue testing through the three levels unless the results of both stages conform at an earlier level. The value of Q in Acceptance Table 4 is 75% dissolved unless otherwise specified in the individual monograph . The quantity, Q specified in the individual monograph is the total amount of active ingredient dissolved in both the Acid and Buffer Stages , expressed as a percentage of the labeled content. The 5%, 15%, and 25% values in Acceptance Table 4 are percentages of the labeled content so that these values and Q are in the same terms. Acceptance Table 4Level NumberTested CriteriaA 16No individual value exceeds 10% dissolved.A 26Average of the 12 units (A 1 +A 2) is not more than 10% dissolved, and no individual unit is greater than 25% dissolved.A 312Average of the 24 units (A 1 + A 2 +A 3) is not more than 10% dissolved, andno individual unit is greater than 25% dissolved.Level NumberTested CriteriaB 16Each unit is not less than Q + 5%.B 26Average of 12 units (B 1 + B 2) is equal to or greater than Q, and no unit isless thanQ – 15%.B 312Average of 24 units (B 1 + B 2 + B 3) is equal to or greater than Q, not morethan 2 units are less than Q – 15%, and no unit is less than Q – 25%.1The materials should not sorb, react, or interfere with the specimen being tested.2If a cover is used, it provides sufficient openings to allow ready insertion of the thermometer and withdrawal of specimens.3Test specimens are filtered immediately upon sampling unless filtration is demonstrated to be unnecessary. Use an inert filter that does not cause adsorption of the active ingredient or contain extractable substances that would interfere with the analysis.4One method of deaeration is as follows: Heat the medium, while stirring gently, to about 41, immediately filter under vacuum using a filter having a porosity of 0.45 µm or less, with vigorous stirring, and continue stirring under vacuum for about 5 minutes. Other validated deaeration techniques for removal of dissolved gases may be used.Auxiliary Information—Please check for your question in the FAQs before contacting USP. Array USP34–NF29 Page 278Pharmacopeial Forum: Volume No. 35(3) Page 719。
溶出度检查法美国药典USP-711
<711> DISSOLUTION溶出度(USP39-NF34 Page 540) General chapter Dissolution <711> 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 chapter.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 is 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 apparatus 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 individual 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。
美国药典25版收载的溶出度品种概况
美国药典25版收载的溶出度品种概况美国药典25版收载的溶出度品种概况溶出度系指药物从片剂或胶囊剂等固体制剂在规定溶剂中溶出的速度和程度，溶出限度以标示量的百分数表示，是一种模拟口服固体制剂在胃肠道中崩解和溶出体外试验，是控制药物制剂质量的检测方法，是研究固体及半固体制剂所含主药的晶型、粒度、处方组成、辅料品种和性质、生产工艺等对制剂质量统一性的新方法。
因此溶出度已迅速发展成为广泛应用于质量标准中的检验方法。
美、英、日、中国药典已把溶出度列为保证药物制剂安全有效的重要检测项目。
现将美国药典25版收载溶出度品种内容概述如下：1、美国药典25版共收载的片剂和胶囊有698个品种，其中进行溶出度品种有535个，约占77%。
缓释制剂一般测定释放度，如碳酸锂延迟释放片、盐酸多西环素延迟释放胶囊、吲哚美辛持续释放片、阿斯匹林持续释放片。
阴道片和溶液片一般采用崩解时限，如克霉唑阴道片、盐酸可卡因溶液片。
无机盐类制剂如硅镁铝片、氧化镁片、碳酸钙镁鍶复方片，溶出量测定方法繁琐，需用效价测定或溶出量难以测定的品种，如维生素D2片剂或胶囊、酯化雌激素片、已烯雌酚片、颠茄提取片、洋地黄片、依托红霉素胶囊及片、三乙酰竹桃霉素胶囊、胡箩卜素片等均采用崩解时限。
2、采用仪器装置有1法（转篮法）211个品种，2法（桨法）约332个品种，采用释放度装置3法（往复瓶法）3个品种，如卡马西平片、盐酸羟嗪片、碘甲腺氨酸钠片。
有的品种设2～4种测定法按标签中规定选择测定。
3、转速 I法转速100rpm 185个品种II法转速50rpm 228个品种（也有采用转速35rpm、75rpm、120rpm、150rpm）。
4、溶出介质以水（245个品种），0.01mol/L～0.1mol/L盐酸溶液（约146个品种）为主，其他介质有：醋酸盐缓冲液（pH4.5），磷酸盐缓冲液（pH4.0～ 8.6），三羟基甲基氨基甲烷溶液(pH7.2～9.0)，不含酶的人工胃液或人工肠液等。
溶出度检查法
溶出度的基本概念•溶出度：系指活性药物从片剂胶囊剂或颗粒剂等制剂在规定条件下溶出的速率和程度•溶出曲线：系把不同时间点测得的溶出量按次序依次连接起来，成为一条连续的曲线。
•溶出曲线可以看成是由具有其本身溶出特征的不同时间溶出量组成的集合。
•溶出曲线表示制剂的整个溶出过程，相同处方同一生产工艺的产品，其溶出曲线应该是相近的。
•规定条件中的时间如果是一点，测得的溶出量就是单点溶出度；时间如果是连续多个点，测得的溶出量按次序连起来就是溶出曲线。
•溶出曲线是溶出度的表达形式之一，它可以更直观的反映溶出过程的规律。
适用范围•★水中难溶药物的制剂•★水中虽易溶，但处方与工艺造成阻溶的制剂•★治疗剂量与中毒剂量接近的制剂•★缓释制剂、控释制剂、肠溶制剂、透皮贴剂等•★易溶的药物，也应考察溶出度•※如果全部样品（n>6）均在15分钟内溶出85％以上，则可以不将溶出度列入标准•※国家药品标准中已列出溶出项：不要轻易删除溶出度项用途•新制剂的研发：研究筛选处方•仿制药体外溶出曲线一致性考察•处方、工艺、原辅料、设备、设施变更后的质量一致性考察•控制产品质量•评价产品批内均一性•评价产品质量•评价不同企业产品的一致性•溶出度的实质：是最大程度最大限度的模拟药物的体内过程，通过建立体内外相关性来达到用体外释放数据来预测体内的目的二、溶出度测定法在中国药典的沿革•1、方法沿革• 1985年版篮法、桨法• 1995年版篮法、桨法、小杯法•2、品种沿革• 1985年版 7个• 1990年版 44个• 1995年版 128个• 2000年版 205个• 2005年版 275个• 2010年版 418个•3、仪器发展：第一代：常规溶出度试验仪：•第二代自动取样溶出度试验仪：第三代：光钎原位实时在线•溶出度试验仪三、测药品溶出度的目的•溶出度是药物发挥疗效的重要一环，它的大小直接影响药物能否进入血液并且在一定时间内达到安全有效的血药浓度的重要因素，•1、比较药物成分在不同固体剂型中的溶出度。
溶出度检查法美国药典USP-711
溶出度检查法美国药典USP-711<711> DISSOLUTION溶出度(USP39-NF34 Page 540) General chapter Dissolution <711> 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 chapter.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 is 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 apparatus 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 individual 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。
美国药典溶出度试验方法的建立与验证指导原则的解读
小结
➢注重实操，关注细节。 ➢认真验证，数据为优。 ➢逻辑缜密，有理有节。 ➢宽容有度，得心应手。
重点关注
1、溶出的目的 2、造成溶出差异的因素
➢ 样品（是我们想知道，想找出的） ➢ 试验（是不想要的，应降到最低）
3、目测检视 4、方法学验证
谢谢！
溶出度与释放度的方法学验证
准确度
溶液稳 定性
专属性
验证 项目
耐用性
线性范 围
精密度
测定方法与验证-方法学验证
专属性
胶囊
辅料与其他 活性成分
沉降篮
干扰来自何方？如何除去干扰？
测定方法与验证-方法学验证
专属性应注意的问题
• 空白包括：其他活性成分（复方制剂中）、 辅料、包衣、油墨、沉降篮、胶囊壳、装 置（桨、杆、篮）等。
自动取 样
对比验证 内容
试验设计
取样应注意的问题
➢ 手动取样与自动取样要进行比较验证 ➢ 自动取样应注意日常性能检查和维护 ➢ 自动取样的装置要注意对溶出杯中流体力学的
干扰。 ➢ 自动取样的验证还包括：
残留药物的扣减 药物的吸附 洗涤或循环洗涤
试验设计
滤膜吸附及验证
滤过与离心
滤膜吸附的考察
滤膜吸附的验证
美国药典溶出度试验 方法的建立与验证指
导原则的解读
2017.6.30
涵盖内容
▪ 总体评价 ▪ 溶出介质 ▪ 溶出仪器 ▪ 实验设计 ▪ 测定方法与验证
总体评价
限度 范围
区分 力
总体 评价
稳定 性
变异 范围
总体评价-限度
▪ 限度范围应考虑的问题
1、多批次的考量 2、具有代表性 3、具有针对性（针对重点药品） 4、考虑样品的稳定性
药品溶出度的限度
药品溶出度的限度
药品溶出度的限度可以根据欧洲药典（EP）、美国药典（USP）等药典标准来确定。
根据这些标准，一般要求药品在一定时间范围内，溶出的量达到一定的百分比。
具体的限度取决于药品的性质、用途和剂型等因素。
例如，对于口服固体制剂，药典要求通常规定在30分钟至120分钟内，药品的释放量应达到某个百分比，如EP要求在45分钟内释出至少75%的活性成分。
对于注射剂或其他需要快速溶出药效的制剂，药典通常要求90%的药品在特定时间内（如30分钟）溶解。
此外，一些国家和地区可能有自己的药典标准，药品溶出度的限度可能会有所不同。
因此，具体的药品溶出度的限度应根据适用的药典标准进行评估和确定。
溶出度测定法
溶出度测定法标准操作规程目的：建立溶出度测定法标准操作规程范围：适用于溶出度测定法操作职责：QC检验人员对本操作规程实施负责依据：《中国药典》2020年版四部规程：1 简述溶出度是指活性药物从片剂、胶囊剂或颗粒剂等制剂在规定条件下溶出的速率和程度。
凡检查溶出度的制剂，不再进行崩解时限的检查。
2 测定方法测定前，应对仪器装置进行调试，使转篮底部距溶出杯底部25mm±2mm。
除另有规定外，分别量取经脱气处理的溶出介质900ml，置各溶出杯内，加温，待溶出介质温度恒定在37℃±0.5℃后，取供试品6片（粒、袋），分别投入6个干燥的转篮内，按照各品种项下的规定调节电动机转速，待其平稳后，将转篮降入溶出杯中，自供试品接触溶出介质起，立即计时；至规定的取样时间，吸取溶出液适量（取样位置应在转篮顶端至液面的中点，距溶出杯内壁10mm处；在多次取样时，所量取溶出介质的体积之和应在溶出介质的±1%之内，如超过总体积的1%时，应及时补充溶出介质，或在计算时加以较正），立即用适当的微孔滤膜（滤孔应不大于0.8μm，并使用惰性材料制成的滤器，以免吸附活性成分或干扰分析测定）过滤，自取样至滤过应在30秒钟内完成。
取澄清滤液，照该品种项下规定的方法测定，计算每片（粒、袋）的溶出量。
3 结果判定（符合下述条件之一者地，方可判为符合规定）3.1 6片（粒、袋）中，每片（粒、袋）的溶出量按标示量计算，均不低于规定限度（Q）。
3.2 6片（粒、袋）中，如有1～2片（粒、袋）低于Q，但不低于Q－10%，且其平均溶出量不低于Q。
3.3 6片（粒、袋）中，有1～2片（粒、袋）低于Q，其中仅有1片低于Q－10%，但不低Q－20%，且其平均溶出量不低于Q时，应另取6片(粒、袋)复试；初、复试的12片(粒、袋)中有1～3片(粒、袋)低于Q，其中仅有1片(粒、袋) 低于Q－10%，但不低Q－20%，且其平均溶出量不低于Q。
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<711> DISSOLUTION溶出度(USP39-NF34 Page 540) General chapter Dissolution <711> 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 chapter.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 is 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 apparatus 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 individual 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 AcceptanceTable(see Interpretation, Immediate-Release Dosage Forms, Extended-Release Dosage Forms, or Delayed-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 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 capsule shell or on the dosage form that prevents the drug from being released during dissolution testing (see more information in Capsules—Dissolution Testing and Related Quality Attributes <1094>).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> ）。
N OTE—All references to a chapter above <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:Pepsin, activity determined by the procedure in purified pepsin, 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 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 Papain; or bromelain, activity determined by the procedure in bromelain, 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 procedurein Assay for protease activity(Casein digestive power) in the monograph for Pancreatin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 550,000 单位/L的蛋白酶活性。