溶出度检查法美国药典USP-711

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。

<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<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。

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。

溶出度（Dissolution rate）概念及测定方法发布时间： 2007-12-7 浏览次数： 4025 次化学药品溶出度方法实验研究初探溶出度（Dissolution rate）也称溶出速率，是指在规定的溶剂和条件下，药物从片剂、胶囊剂、颗粒剂等固体制剂中溶出的速度和程度。

测定固体制剂溶出度的过程称为溶出度试验（Dissolution test），它是一种模拟口服固体制剂在胃肠道中的崩解和溶出的体外试验方法。

药物溶出度检查是评价制剂品质和工艺水平的一种有效手段，可以在一定程度上反映主药的晶型、粒度、处方组成、辅料品种和性质、生产工艺等的差异，也是评价制剂活性成分生物利用度和制剂均匀度的一种有效标准，能有效区分同一种药物生物利用度的差异，因此是药品质量控制必检项目之一。

一般认为，难溶性（一般指在水中微溶或不溶）药物，因制剂处方与生产工艺造成临床疗效不稳定的药物以及治疗量与中毒量相接近的药物（包括易溶性药物），其口服固体制剂质量标准中必须设定溶出度检查项。

另外固体制剂的处方筛选及生产工艺流程制订过程中，也需对所开发剂型的溶出度做全面考察。

一个可行的溶出度试验法应是在不同时间、地点对同一制剂的溶出度测定或不同的操作者之间的测定都必须达到试验结果具有良好的重现性。

为了达到以上目的，必须对溶出度测定试验进行全面充分的研究。

溶出度研究试验主要包括以下内容：（1）溶出介质的选择，（2）溶出介质体积的选择，（3）溶出方法（转篮法与桨法）的选择，（4）转速的选择，（5）溶出度测定方法的验证，（6）溶出度均一性试验（批内），（7）重现性试验（批间）等。

近来在新药审评中发现，部分研究单位在进行溶出度研究时存在一些问题，主要表现在溶出度研究资料过于简单或溶出度研究内容不够全面。

现予以具体分析，希望能对溶出度研究有一定的帮助。

1、溶出介质的选择：通常情况下，溶出介质首选水，其次是0.1mol/L盐酸、缓冲液（pH值3～8）、人工胃液或人工肠液；若介质中加适量有机溶剂如异丙醇、乙醇或加分散助溶剂如十二烷基硫酸钠（0.5%以下）等，应有文献依据，并尽量选用低浓度，必要时应做生物利用度考察。

中、美、英三国新版药典溶出度、释放度检查方法比较许鸣镝胡琴摘要：目的通过对中国药典、美国药典和英国药典中溶出度、释放度测定方法的比较，使广大药物分析工作者了解其异同，为新药开发及进出口检验服务。

方法就其历史沿革，最新版所采用的仪器装置和结果判定等方面进行比较和讨论。

结果三国药典收载的仪器装置各有异同，结果判定差异较大，应引起注意。

结论如何能准确有效地监控药物释放过程，仍是有待深入研究和完善的课题。

关键词溶出度；释放度；中国药典；美国药典；英国药典中图分类号：R921 文献标识码：E文章编号：1001-2494(2000)07-0491-04溶出度和释放度是指药物从片剂、胶囊剂和其它缓释、控释制剂中，在规定介质内，在一定条件下的溶出速度和溶出程度，是评价药物制剂质量的内在指标，是制剂质量控制的重要手段。

在药检工作中，经常要查阅中国药典、美国药典和英国药典。

中国药典是我国药品的最高法典，而美国药典和英国药典由于历史悠久，技术先进又具有代表性，在世界各国有较大影响。

有些国家没有药典，而以美国药典和英国药典为标准，在世界药品贸易中也常以其标准来要求。

综观新版三国药典所收载的溶出度、释放度检查方法在很多方面趋向一致，但又在某些方面存在差别。

下面仅就其历史沿革，最新版所采用的仪器装置和结果判定要求等方面进行比较和讨论。

1 历史沿革1.1 中国药典中国药典在1985年版引入溶出度检查法时，设定篮法、桨法及类似于流室法的装置等3种装置，1990年版仅保留了前2种装置，1995年版中增订了小杯法装置，并引入了释放度检查法，至2000年版又增加了测定透皮贴剂释放度所需的桨碟装置，方法发展很快。

1.2 美国药典美国药典自1970年版（第18版）率先引入溶出度检查法，最初只设转篮法装置，且无图例。

1975年版（第19版）增加了转篮法的图例，但与现在试验的篮法装置也不相同。

1980年版（第20版）增设了桨法装置和改造后的崩解仪两种装置，未给出图例，也无统一的仪器配件尺寸规格。

溶出度检测方法建立及验证标准操作规程不能缺少。

1.检测目的
研究流行病学试剂的溶出度(释放度)，为评价该试剂的质量提供参考依据。

2.检测原理
根据溶出度系数的定义，即测试样品中所含有活性成分在溶剂中的溶出量除以该活性成分在样品中的总量的百分比，在给定条件下，测试流行病学分析样品的溶出度(释放度)。

3.检测设备
（1）精密天平：可以精确测量多种样品的重量；
（2）放大器：可放大样品重量变化的比例，并让测得的数值更加易读；
（3）滴定装置：可以精确测量样品溶出的量；（4）烧杯：放置样品进行溶出度测试；
（5）试剂：用于溶出度测试；
（6）微量秤：可精确测量微量物质的质量。

4.检测材料
（1）流行病学分析样品；
（2）室温恒温水浴；
（3）溶剂；
（4）标准溶液；
（5）蒸馏水；
（6）其他用于试验的相关试剂。

5.检测步骤
（1）准备样品：将流行病学分析样品称取合适重量（根据实验要求），放入烧杯中；
（2）加入溶剂：向烧杯中加入溶剂，均匀混合使其混匀；
（3）置入恒温水浴：将烧杯放入室温恒温水浴中。

Official February 1, 2012〈711〉 Dissolution 1material 1; a motor; a metallic drive shaft; and a cylindrical 〈711〉 DISSOLUTIONbasket. 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 atThis general chapter is harmonized with the correspond-37±0.5° during the test and keeping the bath fluid in con-ing texts of the European Pharmacopoeia and/or the Japa-stant, smooth motion. No part of the assembly, including nese Pharmacopoeia . These pharmacopeias have undertaken the environment in which the assembly is placed, contrib-not to make any unilateral change to this harmonized utes significant motion, agitation, or vibration beyond that chapter.due to the smoothly rotating stirring element. An apparatus Portions of the present general chapter text that are na-that permits observation of the specimen and stirring ele-tional USP text, and therefore not part of the harmonized ment during the test is preferable. The vessel is cylindrical,text, are marked with symbols (33) to specify this fact.with a hemispherical bottom and 3with one of the follow-This test is provided to determine compliance with the ing dimensions and capacities: for a nominal 3 capacity of 1dissolution requirements 3where stated in the individual L, the height is 160 to 210 mm and its inside diameter is monograph 3 for dosage forms administered orally. In this 98 to 106 mm; 3for a nominal capacity of 2 L, the height is general chapter, a dosage unit is defined as 1 tablet or 1280 to 300 mm and its inside diameter is 98 to 106 mm;capsule or the amount specified. 3Of the types of apparatus and for a nominal capacity of 4 L, the height is 280 to 300described herein, use the one specified in the individual mm and its inside diameter is 145 to 155 mm 3. Its sides monograph. Where the label states that an article is en-are flanged at the top. A fitted cover may be used to retard teric-coated, and where a dissolution or disintegration test evaporation.2 The shaft is positioned so that its axis is not that does not specifically state that it is to be applied to more than 2 mm at any point from the vertical axis of the delayed-release articles is included in the individual mono-vessel and rotates smoothly and without significant wobble graph, the procedure and interpretation given for Delayed-that could affect the results. A speed-regulating device is Release Dosage Forms is applied unless otherwise specified used that allows the shaft rotation speed to be selected and in the individual monograph. For hard or soft gelatin cap-maintained at the specified rate 3given in the individual sules and gelatin-coated tablets that do not conform to the monograph 3 within ±4%.Dissolution specification, repeat the test as follows. Where Shaft and basket components of the stirring element are water or a medium with a pH of less than 6.8 is specified fabricated of stainless steel, type 316, or other inert mate-as the Medium in the individual monograph, the same Me-rial, to the specifications shown in Figure 1. A basket having dium specified may be used with the addition of purified a gold coating of about 0.0001 inch (2.5 µm) thick may be pepsin that results in an activity of 750,000 Units or less used. A dosage unit is placed in a dry basket at the begin-per 1000 mL. For media with a pH of 6.8 or greater, pan-ning of each test. The distance between the inside bottom creatin can be added to produce not more than 1750 USP of the vessel and the bottom of the basket is maintained at Units of protease activity per 1000 mL.25±2 mm during the test.1The materials should not sorb, react, or interfere with the specimen being Change to read:tested.2If a cover is used, it provides sufficient openings to allow ready insertion of the thermometer and withdrawal of specimens.USP Reference Standards 〈11〉—••(RB 1-Feb-2012) USP Pred-nisone Tablets RS.3Change to read:APPARATUSApparatus 1 (Basket Apparatus)The assembly consists of the following: a vessel, which may be covered, made of glass or other inert, transparentFigure 1. Basket stirring element.the inside bottom of the vessel is maintained during thetest. The metallic or suitably inert, rigid blade and shaft Apparatus 2 (Paddle Apparatus)comprise a single entity. A suitable two-part detachable de-sign may be used provided the assembly remains firmly Use the assembly from Apparatus 1, except that a paddle engaged during the test. The paddle blade and shaft may formed from a blade and a shaft is used as the stirring be coated with a suitable coating so as to make them inert. element. The shaft is positioned so that its axis is not more The dosage unit is allowed to sink to the bottom of the than 2 mm from the vertical axis of the vessel at any point vessel before rotation of the blade is started. A small, loose and rotates smoothly without significant wobble that could piece of nonreactive material, such as not more than a few affect the results. The vertical center line of the blade turns of wire helix, may be attached to dosage units that passes through the axis of the shaft so that the bottom of would otherwise float. An alternative sinker device is shown the blade is flush with the bottom of the shaft. The paddle in Figure 2a. Other validated sinker devices may be used. conforms to the specifications shown in Figure 2. The dis-tance of 25±2 mm between the bottom of the blade andOfficial February 1, 2012〈711〉 Dissolution3ing the environment in which the assembly is placed, con-tributes significant motion, agitation, or vibration beyondthat due to the smooth, vertically reciprocating cylinder. Adevice is used that allows the reciprocation rate to be se-lected and maintained at the specified dip rate 3given inthe individual monograph3 within ±5%. An apparatus thatpermits observation of the specimens and reciprocating cyl-inders is preferable. The vessels are provided with an evap-oration cap that remains in place for the duration of thetest. The components conform to the dimensions shown inFigure 3 unless otherwise specified 3in the individualmonograph3.Figure 2. Paddle stirring element.Figure 2a. Alternative sinker. All dimensions are expressedin mm.Apparatus 3 (Reciprocating Cylinder)NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIAFigure 3. Apparatus 3 (reciprocating cylinder).The assembly consists of a set of cylindrical, flat-bot-tomed glass vessels; a set of glass reciprocating cylinders;inert fittings (stainless steel type 316 or other suitable ma-Apparatus 4 (Flow-Through Cell) terial), and screens that are made of suitable nonsorbingand nonreactive material and that are designed to fit theThe assembly consists of a reservoir and a pump for the tops and bottoms of the reciprocating cylinders; and a mo-Dissolution Medium; a flow-through cell; and a water bath tor and drive assembly to reciprocate the cylinders verticallythat maintains the Dissolution Medium at 37±0.5°. Use the inside the vessels and, if desired, index the reciprocatingspecified cell size 3as given in the individual monograph3. cylinders horizontally to a different row of vessels. The ves-The pump forces the Dissolution Medium upwardssels are partially immersed in a suitable water bath of anythrough the flow-through cell. The pump has a delivery convenient size that permits holding the temperature atrange between 240 and 960 mL per hour, with standard 37±0.5° during the test. No part of the assembly, includ-flow rates of 4, 8, and 16 mL per minute. It must deliver aconstant flow (±5% of the nominal flow rate); the flow pro-file is sinusoidal with a pulsation of 120±10 pulses perminute. A pump without pulsation may also be used. Dis-solution test procedures using a flow-through cell must becharacterized with respect to rate and any pulsation.The flow-through cell (see Figures 4 and 5), of transpar-ent and inert material, is mounted vertically with a filtersystem (specified in the individual monograph) that pre-vents escape of undissolved particles from the top of thecell; standard cell diameters are 12 and 22.6 mm; the bot-tom cone is usually filled with small glass beads of about 1-mm diameter with one bead of about 5 mm positioned atthe apex to protect the fluid entry tube; and a tabletholder (see Figures 4 and 5) is available for positioning ofspecial dosage forms, for example, inlay tablets. The cell isimmersed in a water bath, and the temperature is main-tained at 37±0.5°.Figure 5. Apparatus 4, small cell for tablets and capsules(top), tablet holder for the small cell (bottom). (All meas-urements are expressed in mm unless noted otherwise.)The apparatus uses a clamp mechanism and two O-ringsto assemble the cell. The pump is separated from the disso-lution unit in order to shield the latter against any vibra-tions originating from the pump. The position of the pumpshould not be on a level higher than the reservoir flasks.Tube connections are as short as possible. Use suitably inerttubing, such as polytef, with about 1.6-mm inner diameterand chemically inert flanged-end connections.APPARATUS SUITABILITYThe determination of suitability of a test assembly to per-Figure 4. Apparatus 4, large cell for tablets and capsules form dissolution testing must include conformance to the (top), tablet holder for the large cell (bottom). (All meas-dimensions and tolerances of the apparatus as given above. urements are expressed in mm unless noted otherwise.)In addition, critical test parameters that have to be moni-tored periodically during use include volume and tempera-ture of the Dissolution Medium, rotation speed (Apparatus 1and Apparatus 2), dip rate (Apparatus 3), and flow rate ofmedium (Apparatus 4).Determine the acceptable performance of the dissolutiontest assembly periodically.3The suitability for the individualOfficial February 1, 2012〈711〉 Dissolution 5apparatus is demonstrated by the Performance Verification ment for minimum amount dissolved is met. Specimens are Test .to be withdrawn only at the stated times within a tolerance of ±2%.Performance Verification Test, Apparatus 1 and 2—Test USP Prednisone Tablets RS according to the operating 3Procedure for a Pooled Sample for Immediate-conditions specified. The apparatus is suitable if the results Release Dosage Forms —Use this procedure where Proce-obtained are within the acceptable range stated in the dure for a Pooled Sample is specified in the individual mono-technical data sheet specific to the lot used and the appa-graph. Proceed as directed for Immediate-Release Dosage ratus tested.Forms under Apparatus 1 and Apparatus 2 in the Procedure section. Combine equal volumes of the filtered solutions of Performance Verification Test, Apparatus 3—•[To the six or twelve individual specimens withdrawn, and use come.]•(RB 1-Feb-2012)the pooled sample as the test specimen. Determine the av-Performance Verification Test, Apparatus 4—[To erage amount of the active ingredient dissolved in the come.]3pooled sample.3PROCEDUREEXTENDED -RELEASE DOSAGE FORMSProceed as directed for Immediate-Release Dosage Forms .Apparatus 1 and Apparatus 2Dissolution Medium—Proceed as directed for Immedi-ate-Release Dosage Forms .Time—The test-time points, generally three, are ex-pressed in hours.IMMEDIATE -RELEASE DOSAGE FORMSPlace the stated volume of the Dissolution Medium (±1%)DELAYED -RELEASE DOSAGE FORMS NOT ACCEPTED BY THEin the vessel of the specified apparatus 3given in the indi-JAPANESE PHARMACOPOEIA vidual monograph 3, assemble the apparatus, equilibrate the Dissolution Medium to 37±0.5°, and remove the thermom-Use Method A or Method B and the apparatus specified eter. Place 1 dosage unit in the apparatus, taking care to 3in the individual monograph 3. All test times stated are to exclude air bubbles from the surface of the dosage unit,be observed within a tolerance of ±2%, unless otherwise and immediately operate the apparatus at the specified rate specified.3given in the individual monograph 3. Within the time inter-Method A—val specified, or at each of the times stated, withdraw a Procedure 3(unless otherwise directed in the individual specimen from a zone midway between the surface of the monograph)3—Dissolution Medium and the top of the rotating basket or blade, not less than 1 cm from the vessel wall. [NOTE —ACID STAGE —Place 750 mL of 0.1 N hydrochloric acid in Where multiple sampling times are specified, replace the the vessel, and assemble the apparatus. Allow the medium aliquots withdrawn for analysis with equal volumes of fresh to equilibrate to a temperature of 37±0.5°. Place 1 dosage Dissolution Medium at 37° or, where it can be shown that unit in the apparatus, cover the vessel, and operate the replacement of the medium is not necessary, correct for apparatus at the specified rate 3given in the monograph 3.the volume change in the calculation. Keep the vessel cov-After 2 hours of operation in 0.1 N hydrochloric acid,ered for the duration of the test, and verify the tempera-withdraw an aliquot of the fluid, and proceed immediately ture of the mixture under test at suitable times.] Perform as directed under Buffer Stage .the analysis 3as directed in the individual monograph 3 us-Perform an analysis of the aliquot using a suitable assay ing a suitable assay method.3 Repeat the test with addi-method. 3The procedure is specified in the individual tional dosage form units.monograph.3If automated equipment is used for sampling or the ap-BUFFER STAGE —[NOTE —Complete the operations of adding paratus is otherwise modified, verification that the modified the buffer and adjusting the pH within 5 minutes.]apparatus will produce results equivalent to those obtained With the apparatus operating at the rate specified 3in the with the standard apparatus described in this general chap-monograph 3, add to the fluid in the vessel 250 mL of 0.20ter is necessary.M tribasic sodium phosphate that has been equilibrated to Dissolution Medium—A suitable dissolution medium is 37±0.5°. Adjust, if necessary, with 2N hydrochloric acid used. Use the solvent specified 3in the individualor 2N sodium hydroxide to a pH of 6.8 ± 0.05. Continue monograph 3. The volume specified refers to measurements to operate the apparatus for 45 minutes, or for the speci-made between 20° and 25°. If the Dissolution Medium is a fied time 3given in the individual monograph 3. At the end buffered solution, adjust the solution so that its pH isof the time period, withdraw an aliquot of the fluid, and within 0.05 unit of the specified pH 3given in the individual perform the analysis using a suitable assay method. 3The monograph 3. [NOTE —Dissolved gases can cause bubbles to procedure is specified in the individual monograph. The form, which may change the results of the test. If dissolved test may be concluded in a shorter time period than that gases influence the dissolution results, dissolved gases specified for the Buffer Stage if the requirement for the min-should be removed prior to testing.4]imum amount dissolved is met at an earlier time.3Time—Where a single time specification is given, the Method B—test may be concluded in a shorter period if the require-Procedure 3(unless otherwise directed in the individual monograph)3—3Test specimens are filtered immediately upon sampling unless filtration is demonstrated to be unnecessary. Use an inert filter that does not cause ACID STAGE —Place 1000 mL of 0.1 N hydrochloric acid in adsorption of the active ingredient or contain extractable substances that the vessel, and assemble the apparatus. Allow the medium would interfere with the analysis.4One method of deaeration is as follows: Heat the medium, while stirring to equilibrate to a temperature of 37±0.5°. Place 1 dosage gently, to about 41°, immediately filter under vacuum using a filter having a unit in the apparatus, cover the vessel, and operate the porosity of 0.45 µm or less, with vigorous stirring, and continue stirring apparatus at the rate specified 3in the monograph 3. After 2under vacuum for about 5 minutes. Other validated deaeration techniques hours of operation in 0.1 N hydrochloric acid, withdraw anfor removal of dissolved gases may be used.aliquot of the fluid, and proceed immediately as directed DELAYED -RELEASE DOSAGE FORMSunder Buffer Stage .Perform an analysis of the aliquot using a suitable assay Proceed as directed for Delayed-Release Dosage Forms,method. 3The procedure is specified in the individual Method B under Apparatus 1 and Apparatus 2 using one monograph.3row of vessels for the acid stage media and the following BUFFER STAGE —[NOTE —For this stage of the procedure, use row of vessels for the buffer stage media and using the buffer that previously has been equilibrated to a tempera-volume of medium specified (usually 300 mL).ture of 37±0.5°.] Drain the acid from the vessel, and add Time —Proceed as directed for Immediate-Release Dosage to the vessel 1000 mL of pH 6.8 phosphate buffer, pre-Forms under Apparatus 1 and Apparatus 2.pared by mixing 0.1 N hydrochloric acid with 0.20 M tri-basic sodium phosphate (3:1) and adjusting, if necessary,with 2N hydrochloric acid or 2N sodium hydroxide to a Apparatus 4 (Flow-Through Cell)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 IMMEDIATE -RELEASE DOSAGE FORMSand transferring the dosage unit to the vessel containing the buffer.]Place the glass beads into the cell specified 3in theContinue to operate the apparatus for 45 minutes, or for monograph 3. Place 1 dosage unit on top of the beads or, if the specified time 3given in the individual monograph 3. At specified 3in the monograph 3, on a wire carrier. Assemble the end of the time period, withdraw an aliquot of the the filter head, and fix the parts together by means of a fluid, and perform the analysis using a suitable assaysuitable clamping device. Introduce by the pump the Disso-method. 3The procedure is specified in the individual mon-lution Medium warmed to 37±0.5° through the bottom of ograph. The test may be concluded in a shorter time pe-the cell to obtain the flow rate specified 3in the individual riod than that specified for the Buffer Stage if the require-monograph 3 and measured with an accuracy of 5%. Col-ment for minimum amount dissolved is met at an earlier lect the eluate by fractions at each of the times stated.time.3Perform the analysis as directed 3in the individualmonograph 3. Repeat the test with additional dosage-form Apparatus 3 (Reciprocating Cylinder)units.Dissolution Medium —Proceed as directed for Immedi-ate-Release Dosage Forms under Apparatus 1 and Apparatus 2.NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIATime —Proceed as directed for Immediate-Release Dosage IMMEDIATE -RELEASE DOSAGE FORMS Forms under Apparatus 1 and Apparatus 2.Place the stated volume of the Dissolution Medium ineach vessel of the apparatus, assemble the apparatus, equi-EXTENDED -RELEASE DOSAGE FORMSlibrate the Dissolution Medium to 37±0.5°, and remove the thermometer. Place 1 dosage-form unit in each of the six Proceed as directed for Immediate-Release Dosage Forms reciprocating cylinders, taking care to exclude air bubbles under Apparatus 4.from the surface of each dosage unit, and immediately op-Dissolution Medium —Proceed as directed for Immedi-erate the apparatus as specified 3in the individualate-Release Dosage Forms under Apparatus 4.monograph 3. During the upward and downward stroke,Time —Proceed as directed for Immediate-Release Dosage the reciprocating cylinder moves through a total distance Forms under Apparatus 4.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 DELAYED -RELEASE DOSAGE FORMSzone midway between the surface of the Dissolution Me-dium and the bottom of each vessel. Perform the analysis as Proceed as directed for Delayed-Release Dosage Forms directed 3in the individual monograph 3. If necessary, repeat under Apparatus 1 and Apparatus 2, using the specified the test with additional dosage-form units.media.Dissolution Medium —Proceed as directed for Immedi-Time —Proceed as directed for Delayed-Release Dosage ate-Release Dosage Forms under Apparatus 1 and Apparatus Forms under Apparatus 1 and Apparatus 2.2.Time —Proceed as directed for Immediate-Release Dosage Forms under Apparatus 1 and Apparatus 2.INTERPRETATIONEXTENDED -RELEASE DOSAGE FORMSImmediate-Release Dosage FormsProceed as directed for Immediate-Release Dosage Forms under Apparatus 3.Unless otherwise specified 3in the individualmonograph 3, the requirements are met if the quantities of Dissolution Medium —Proceed as directed for Extended-active ingredient dissolved from the dosage units tested Release Dosage Forms under Apparatus 1 and Apparatus 2.conform to Acceptance Table 1. Continue testing through Time —Proceed as directed for Extended-Release Dosage the three stages unless the results conform at either S 1 or Forms under Apparatus 1 and Apparatus 2.S 2. The quantity, Q , is the amount of dissolved active ingre-dient 3specified in the individual monograph 3, expressed as a percentage of the labeled content of the dosage unit; the 5%, 15%, and 25% values in Acceptance Table 1 are per-Official February 1, 2012〈711〉 Dissolution 7centages of the labeled content so that these values and Q Acceptance Table 2are in the same terms.Number Level TestedCriteriaAcceptance Table 1No individual value lies outside each of the stated ranges and no individual value is Number L 16less than the stated amount at the final Stage Tested Acceptance Criteriatest time.S 16Each unit is not less than Q + 5%.The average value of the 12 units (L 1 + L 2)Average of 12 units (S 1 + S 2) is equal to or lies within each of the stated ranges and S 26greater than Q, and no unit is less than Q is not less than the stated amount at the − 15%.final test time; none is more than 10% of Average of 24 units (S 1 + S 2 +S 3) is equal L 26labeled content outside each of the stat-to or greater than Q , not more than 2S 312ed ranges; and none is more than 10%units are less than Q − 15%, and no unit of labeled content below the stated is less than Q − 25%.amount at the final test time.The average value of the 24 units (L 1 + L 23Immediate-Release Dosage Forms Pooled Sample—+ L 3) lies within each of the stated Unless otherwise specified in the individual monograph, the ranges, and is not less than the stated requirements are met if the quantities of active ingredient amount at the final test time; not more dissolved from the pooled sample conform to the accom-than 2 of the 24 units are more than panying Acceptance Table for a Pooled Sample. Continue 10% of labeled content outside each of testing through the three stages unless the results conform the stated ranges; not more than 2 of the at either S 1 or S 2. The quantity, Q , is the amount of dis-L 31224 units are more than 10% of labeled solved active ingredient specified in the individual mono-content below the stated amount at the graph, expressed as a percentage of the labeled content.final test time; and none of the units is more than 20% of labeled contentAcceptance Table for a Pooled Sampleoutside each of the stated ranges or more than 20% of labeled content below the Number stated amount at the final test time.Stage TestedAcceptance CriteriaAverage amount dissolved is not less than S 16Q + 10%.Average amount dissolved (S 1 + S 2) is Delayed-Release Dosage FormsS 26equal to or greater than Q + 5%.Average amount dissolved (S 1 + S 2 + S 3) is S 312equal to or greater than Q .NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA 3Acid Stage—Unless otherwise specified 3in the individ-ual monograph 3, the requirements of this portion of the Extended-Release Dosage Formstest are met if the quantities, based on the percentage of the labeled content, of active ingredient dissolved from the Unless otherwise specified 3in the individualunits tested conform to Acceptance Table 3. Continue test-monograph 3, the requirements are met if the quantities of ing through all levels unless the results of both acid and active ingredient dissolved from the dosage units tested buffer stages conform at an earlier level.conform to Acceptance Table 2. Continue testing through the three levels unless the results conform at either L 1 or L 2.Acceptance Table 3Limits on the amounts of active ingredient dissolved are expressed in terms of the percentage of labeled content.Number The limits embrace each value of Q i , the amount dissolved Level TestedCriteriaat each specified fractional dosing interval. Where more No individual value exceeds 10% dis-A 16than one range is specified 3in the individual monograph 3,solved.the acceptance criteria apply individually to each range.Average of the 12 units (A 1 + A 2) is not A 26more than 10% dissolved, and no indi-vidual unit is greater than 25% dissolved.Average of the 24 units (A 1 + A 2 + A 3) is not more than 10% dissolved, and no in-A 312dividual unit is greater than 25% dis-solved.Buffer Stage—Unless otherwise specified 3in the individ-ual monograph 3, 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 3in the individual monograph 3.The quantity, Q , 3specified in the individual monograph 3 is the total amount of active ingredient dissolved in both the Acid and Buffer Stages , expressed as a percentage of thelabeled content. The 5%, 15%, and 25% values in Accep-tance Table 4 are percentages of the labeled content so that these values and Q are in the same terms.Acceptance Table 4NumberLevel Tested CriteriaB16Each unit is not less than Q + 5%.Average of 12 units (B1 + B2) is equal to or B26greater than Q, and no unit is less than Q– 15%.Average of 24 units (B1 + B2 + B3) is equalto or greater than Q, not more than 2 B312units are less than Q – 15%, and no unitis less than Q – 25%.。

一致性评价重磅参考资料：（USP1092）溶出度试验的开发和验证2015-12-25刘建华医药信息新药开发译者：刘建华国药集团工业有限公司前言目的：溶出度试验的开发和验证（1092）目的是为溶出度的测定提供了全面的开发和验证的方法以及相应的分析技术。

本指导原则贯穿溶出度测定的全部过程，并对方法验证提供了指导和验证标准。

同时它还涉及对普通制剂和缓释制剂产生的数据和接受标准进行说明。

范围：本指导原则讨论了溶出度试验的开发和验证，重点是固体口服剂型。

所提出的概念也可能适用于其他剂型和给药途径。

对于一些不同于USP章节中的设备和程序均已给出合适的解释。

本指导原则的基本框架如下：1.前期评估（对产品开发以及溶出度方法开发的前期研究评估）1.1滤膜相容性研究（PerformingFilterCompatibility）1.2原料药在不同溶媒中溶解度和稳定性的测定1.3选择溶出介质和体积1.4选择溶出设备（桨法和篮法以及其他方法）2.方法开发2.1脱气2.2沉降2.3搅拌2.4研究设计2.4.1取样时间点2.4.2观察2.4.3取样2.4.4清洗2.5数据处理2.6溶出度试验的评估3.分析整理3.1样品的处理3.2过滤3.3离心3.4分析过程3.5光谱分析3.6HPLC分析4.程序化4.1溶出介质的准备4.2样品的选择和取样时间的设计4.3取样和过滤4.4清洗4.5使用软件和计算机处理结果4.6找出需要验证的存在偏差的过程5.验证5.1专属性/安慰剂的干扰5.2线性和范围5.3准确度/回收率5.4精密度试验5.4.1重复性试验5.4.2中间精密度试验5.4.3重现性试验5.5耐用性试验5.6对照品和供试品的稳定性试验5.7程序化验证6.接受标准6.1普通速释制剂6.2缓释制剂6.3控释制剂6.4多重溶出度试验6.5溶出度结果的解释6.5.1普通速释制剂6.5.2缓释制剂6.5.3控释制剂7.参考文献1.前期评估（对产品发展以及溶出度方法开发的前期研究评估）在方法开发之前，对用以评价剂型的溶出行为的滤膜、溶出介质、介质体积和溶出设备进行筛选是非常重要的。

一致性评价重磅参考资料溶出度试验的开发和验证溶出度试验是一种重要的药物品质控制方法，用于评估药物的释放速度和特性。

为了确保一致性评价的准确性和一致性，美国药典(USP)发布了有关溶出度试验的通用章节USP1092、这个章节详细说明了溶出度试验的开发和验证，对于药物制剂的一致性评价提供了重要的参考资料。

首先，USP1092章节说明了溶出度试验的目的和应用范围。

该章节强调了溶出度试验的重要性，以及它在药物品质控制中的应用。

溶出度试验可以用于评估药物的释放速度、药物的溶解特性以及药物的可溶性。

它可以帮助药物生产企业确保产品的一致性和质量，并帮助监管机构进行监管和评估。

然后，USP1092章节详细介绍了溶出度试验的开发和验证过程。

该章节首先说明了试验设备和试验条件的选择。

试验设备的选择应基于产品的特性和试验的要求，而试验条件的选择则应符合美国药典的要求。

章节中列出了一些可用于溶出度试验的设备和条件，以提供参考。

接着，USP1092章节讨论了试验方法的开发和验证。

在试验方法的开发过程中，需要选择适当的介质和操作条件，并设定合适的试验时间。

章节中提供了一些建议用于试验方法的开发。

在试验方法的验证过程中，需要验证试验方法的准确性、精确性、线性范围、灵敏度和选择性。

章节中给出了验证试验方法时应进行的测试和要求。

USP1092章节还强调了溶出度试验的数据分析和结果解释。

对于试验结果的分析和解释，需要参考适当的统计学原理和方法。

章节中提供了一些常用的统计学方法和指导，以帮助药物生产企业正确分析和解释试验结果。

最后，USP1092章节还包括了对溶出度试验的质量控制的要求。

该章节指出了试验过程中的质量控制点和限度。

它强调了每个质量控制点的重要性，以确保试验的准确性和一致性。

总之，USP1092章节是一本关于溶出度试验开发和验证的重要参考资料。

它详细阐述了试验的目的和应用范围，详细描述了试验方法的开发和验证过程，并给出了一些统计学原理和方法的指导。

溶出度指导原则解读1.溶出度测试方法：溶出度测试方法应符合标准，如美国药典（USP）或欧洲药典（EP）中的方法。

这些方法包括了合适的试剂、溶液条件和标准设备，以确保数据的可比性和准确性。

2.试剂选择：在溶出度测试中，使用的试剂应与实际使用条件相似，以确保测试结果能够准确地反映实际使用过程中的溶解性能。

试剂的选择应基于药物的特性，如溶解度、酸碱性等。

3.测试时间：溶解度测试中，测试时间的选择应基于药物的溶解特性。

一般来说，测试时间应足够长，以获取药物在一定时间内的溶解率数据。

测试时间的选择应根据药物的特性和制剂的设计要求，如缓释剂型可能需要较长的测试时间。

4.溶液条件：溶出度测试中，溶液条件的选择应考虑药物在实际使用过程中的生理环境。

溶液的pH值、温度和流动条件应符合实际使用条件，以保证测试结果的可靠性。

5.结果解释：根据溶出度测试的结果，可以评估药物制剂的溶解性能和生物等效性，以确保其在使用过程中的药效。

溶出度测试结果可以与相应的参考品相比较，以判断药物制剂的一致性和稳定性。

溶出度指导原则的目的是确保药物产品在使用过程中的有效性和可用性。

它有助于制药企业确定适当的工艺参数和质量控制标准，以确保药物制剂的一致性和可靠性。

同时，溶出度指导原则也有助于监测市场上的药物产品质量，从而保护患者的健康和安全。

总之，溶出度指导原则是一项重要的药物质量评估指标，它对于确保药物制剂的有效性和可用性至关重要。

在药物研发和生产过程中，遵循溶出度指导原则可以确保药物产品的一致性和质量，从而保护患者的健康和安全。

美国药典USP31 <71>无菌检查法无菌检查法此通则的各部分已经与欧洲药典和/或日本药典的对应部分做了协调。

不一致的部分用符号（）来标明。

下面这些步骤适用于测定是否某个用于无菌用途的药品是否符合其具体的各论中关于无菌检查的要求。

只要其性质许可，这些药品将使用供试产品无菌检查法项下的膜过滤法来检测。

如果膜过滤技术是不适合的，则使用在供试产品无菌检查法项下的培养基直接接种法。

除了具有标记为无菌通道的设备之外，所有的设备均须使用培养基直接接种法进行检测。

在结果的观测与理解项下包含了复验的规定。

由于无菌检查法是一个非常精确的程序，在此过程中程序的无菌状态必须得到确保以实现对结果的正确理解，因此人员经过适当的培训并取得资质是非常重要的。

无菌检查在无菌条件下进行。

为了实现这样的条件，试验环境必须调整到适合进行无菌检查的方式。

为避免污染而采取的特定预防措施应不会对任何试图在检查中发现的微生物产生影响。

通过在工作区域作适当取样并进行适当控制，来定期监测进行此试验的工作条件。

这些药典规定程序自身的设计不能确保一批产品无菌或已经灭菌。

这主要是通过灭菌工艺或者无菌操作程序的验证来完成。

当通过适当的药典方法获得了某物品中微生物污染的证据,这样获得的结果是该物品未能达到无菌检验要求的结论性证据，即便使用替代程序得到了不同的结果也无法否定此结果。

如要获得关于无菌检验的其他信息，见药品的灭菌和无菌保证<1211> 按照下面描述的方法配制实验用培养基；或者使用脱水培养基，只要根据其制造商或者分销商说明进行恢复之后，其能够符合好氧菌、厌氧菌、霉菌生长促进试验的要求即可。

使用经过验证的工艺对培养基进行灭菌操作。

下面的培养基已经被证实适合进行无菌检查。

巯基醋酸盐液体培养基主要用于厌氧菌的培养。

但其也用于检测好氧菌。

大豆酪蛋白消化物培养基适合于培养霉菌和好氧菌。

巯基醋酸盐液体培养基,L-胱氨酸, 氯化钠, 葡萄糖, 琼脂，呈颗粒状(水分含量不超过15%) 0.75 g 0.5 g 2.5 g 5.5/5.0 g L-胱氨酸,酵母提取物(水溶性) , 酪蛋白胰酶消化物,巯基乙酸钠,或者巯基乙酸,刃天青钠溶液(1 比1000)，新配制纯净水0.5 g 5.0 g 15.0 g 0.5 g 0.3 mL 1.0 mL 1000 mL将L-胱氨酸、氯化钠、葡萄糖、酵母提取物、酪蛋白胰酶消化物与纯净水混合，并加热至实现溶解。

阿齐沙坦片体外溶出方法
阿齐沙坦片是一种常用的抗高血压药物，其主要成分是阿齐沙坦。

阿齐沙坦片的体外
溶出方法是评价药物在体外释放速度和溶出特性的方法之一，对于评估药物的溶出性和释
放行为非常重要。

阿齐沙坦片的体外溶出方法通常采用美国药典（USP）提供的体外溶出试验仪进行实验。

具体步骤如下：
1. 准备样品：将一定数量的阿齐沙坦片称量，并记录质量。

2. 准备介质：根据USP的要求，使用适当的介质，例如模拟胃液或模拟肠液，将体外溶出试验仪的溶出槽中加入适量的介质。

3. 实验条件设置：根据USP的要求，设置适当的条件，例如温度、搅拌速度等。

4. 开始实验：将阿齐沙坦片放入溶出槽中，开始实验。

在一定时间间隔内，取出一
定量的样品。

5. 分析样品：将取出的样品进行分析，通常可以采用高效液相色谱法（HPLC）或紫外分光光度法等方法。

6. 计算溶出度：根据分析结果，计算出不同时间点上的溶出度，并绘制溶出度-时间
曲线。

对于阿齐沙坦片的体外溶出方法，有一些注意事项需要注意：
通过上述步骤，可以评估阿齐沙坦片在体外的溶出速度和溶出特性，为药物开发和质
量控制提供重要的参考。

美国药典附录《771》溶出度中收载的混合样品测定法可以借
鉴
周帼雄;何铭新;张玫
【期刊名称】《中国药品标准》
【年(卷),期】2003(004)001
【摘要】@@ 美国药典24版和25版附录〈771〉DISSOLUTION中增加了Procedure for a Pooled Sample for Capsules,Uncoated Tablets,and Plain Coated Tablets.有如下规定:
【总页数】1页(P63-63)
【作者】周帼雄;何铭新;张玫
【作者单位】江苏省药品检验所,南京,210008;广州市药品检验所,广州,510160;江苏省药品检验所,南京,210008
【正文语种】中文
【中图分类】R95
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