pendulum-兰亭集序翻译
（
1092
）溶出度实验的开发和验证【中英文
对照版】
INTRODUCTION
前言
Purpose
目的
The
Dissolution Procedure: Developmentand Validation
<1092> provides a
comprehensive approach covering items
to considerfor developing and validating
dissolution procedures and the
accompanyinganalytical procedures. It addresses
the use
of automation throughout the
testand provides guidance and criteria for
validation. It
also addresses
thetreatment of the data generated and the
interpretation of acceptance
criteriafor immediate- and modified-
release solid oral dosage forms.
溶出实验
:
开发和验证（
1092
< br>）指导原则
提供了在溶出度方法开发和验证过程中
以及采
用相应分析方法时需要考虑的因素。
本指导原则贯穿溶出度实验的全部过
程，
并对方法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所生
成的数据和接受标准进行说明。
Scope
范围
Chapter <1092> addresses the
development andvalidation of dissolution
procedures, with a focus on solid oral
dosage of the concepts presented,
however, may be applicable to other
dosageforms and routes of administration. General
recommendations are given with
theunderstanding that modifications of the
apparatus
and procedures as given in
USP
general chapters need to
be justified.
<1092>
章节讨论了溶出度
实验的开发和验证，重点是口服固体制剂。所提出
的许多概念也可能适用于其他剂型和给
药途径。关于设备和方法的修改部分在
USP
通则中给出了合理
的说明。
The organization of
<1092> follows the sequence of actions often
performed inthe
development and
validation of a dissolution test. The sections
appear inthe following
sequence.
在进行溶解度实验的开发和验证时，
常遵循指导原则
<1092>
，
具体内容如下：
1. PRELIMINARY ASSESSMENT (FOR EARLY
STAGES OF
PRODUCTDEVELOPMENT/DISSOLUTION METHOD
DEVELOPMENT)
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
Performing Filter Compatibility
1.1
滤膜相容性研究
1.2 Determining Solubility and
Stability of DrugSubstance in Various Media
1.2
原料药在不同溶出介质中溶解度测定和稳定性研究
1.3 Choosing a Medium and Volume
1.3
溶出介质和体积选择
1.4 Choosing an Apparatus
1.
4
溶出设备选择（桨法和篮法以及其他方法）
2. METHOD DEVELOPMENT
2.
方法开发
2.1 Deaeration
2.1
脱气
2.2 Sinkers
2.2
沉降篮
2.3 Agitation
2.3
转速
2.4 Study Design
2.4
研究设计
2.4.1 TimePoints
2.4.1
取样时间点
2.4.2 Observations
2.4.2
观察
2.4.3 Sampling
2.4.3
取样
2.4.4 Cleaning
2.4.4
清洗
2.5 Data Handling
2.5
数据处理
2.6 Dissolution Procedure Assessment
2.6
溶出方法评估
3. ANALYTICAL FINISH
3.
完成分析
3.1 Sample Processing
3.1
样品处理
3.2 Filters
3.2
过滤
3.3 Centrifugation
3.3
离心
3.4 Analytical
Procedure
3.4
分析方法
3.5
Spectrophotometric Analysis
3.5
光谱分析
3.6 HPLC
3.6HPLC
法
4. AUTOMATION
4.
自动化
4.1 Medium Preparation
4.1
介质的配制
4.2 Sample Introduction and Timing
4.2
定时进样
4.3 Sampling and Filtration
4.3
取样和过滤
4.4 Cleaning
4.4
清洗
4.5 Operating
Software and Computation of Results
4.5
操作软件和计算的结果
5. VALIDATION
5.
验证
5.1 Specificity/Placebo Interference
5.1
专属性
/
安
慰剂（辅料）干扰
5.2 Linearity and
Range
5.2
线性和范围
5.3 Accuracy/Recovery
5.3
准确度
/
回收率
5.4 Precision
5.4
精密度
5.4.1 REPEATABILITY OF ANALYSIS
5.4.1
重复性
5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS
5.4.2
中间精密度
/
耐用性
5.4.3
REPRODUCIBILITY
5.4.3
重现性
5.5 Robustness
5.5
耐用性
5.6 Stability of Standard and Sample
Solutions
5.6
样品溶液和标准溶液的稳定性
5.7 Considerations for Automation
5.7
自动操作注意事项
6. ACCEPTANCE CRITERIA
6.
可接受标准
6.1 Immediate-Release Dosage Forms
6.1
速释剂型
6.2 Delayed-Release Dosage Forms
6.2
延迟释放剂型
6.3 Extended-Release Dosage Forms
6.3
延长释放剂型
6.4 Multiple Dissolution Tests
6.4
多个溶解度实验
6.5 Interpretation of Dissolution
Results
6.5
溶出结果说明
6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS
6.5.1
即时释放剂型
6.5.2 DELAYED-RELEASE DOSAGE FORMS
6.5.2
延迟释放剂型
6.5.3 EXTENDED-RELEASE DOSAGE FORMS
6.5.3
延长释放剂型
1. PRELIMINARYASSESSMENT
(FOR EARLY STAGES OF PRODUCT
DEVELOPMENT/DISSOLUTION
METHODDEVELOPMENT)
1.
前期评估（产品开发
/
溶出度方法开发的初期阶段）
Beforemethod development
can begin, it is important to characterize the
molecule
sothat the filter, medium,
volume of medium, and apparatus can be chosen
properlyin
order to evaluate the
performance of the dosage form.
在开始溶出方法
开发之前，
我们对用以评价制剂溶出行为的滤膜、
溶出介质、<
/p>
溶出介质体积和溶出设备进行适当的筛选是非常重要的。
1.1 Performing Filter
Compatibility
1.1
滤膜相容性研究
Filtrationis a key sample-preparation
step in achieving accurate test results.
Thepurpose
of filtration is to remove
undissolved drug and excipients from thewithdrawn
solution.
If not removed from the
sample solution, particles of thedrug will
continue to dissolve
and can bias the
results. Therefore, filteringthe dissolution
samples is usually necessary
and should
be done immediately ifthe filter is not positioned
on the cannula.
为获得准确实验结果，
过滤
是样品制备的一个关键步骤。
过滤的目的是为了
除去溶出液中<
/p>
未溶解的药物和辅料
。
如果不把未溶解的
药物和辅料从样品溶液中
除去，
那么未溶解的药物颗粒将会继续
溶解使实验结果出现偏差，
因此，
如果取
样管中没有过滤器，应立即对溶出度样品进行过滤。
Filtration also removes
insolubleexcipients that may otherwise interfere
with the
analytical finish. Selectionof
the proper filter material is important and should
be
accomplished, andexperimentally
justified, early in the development of the
dissolutionprocedure. Important
characteristics to consider when choosing a
filtermaterial are type, filter size,
and pore size. The filter that is selectedbased on
evaluation during the early stages of
dissolution procedure developmentmay need to be
reconsidered at a later time point.
Requalification has to beconsidered after a change
in
composition of the drug product or
changes in thequality of the ingredients (e.g.
particle
size of microcrystalline
cellulose).
过滤也可除去可能会干扰分析测定的不溶性辅料。
选择适当的过滤材料是非
常重要，
应该在早期溶出
方法开发的过程中通过实验确定和完成。
在选择滤膜时
有必要重
点考虑滤膜的材料、
型号和孔径大小。
通常对早期阶段溶出方法
开发过
程的评价选择过滤器，
但在后期实验中如果制剂成分改变
或组成成分质量变化可
能需要重新考虑过滤器，（例如：微晶纤维素粒径的改变）。
Examples of filters used in
dissolutiontesting can be cannula filters, filter
disks or frits,
filter tips, or
syringefilters. The filter material has to be
compatible with the media and
the pore
sizes range from 0.20 to 70 mm, however, filters
of other
poresizes can be used as
needed. If the drug substance particle size is
very small(e.g.,
micronized or
nanoparticles), it can be challenging to find a
filterpore size that excludes
these
small particles.
用于溶出实验的过滤器有管路过滤器、
过滤盘或玻璃过滤器、
滤头或针头式
过滤器。过滤
材料必须与介质和药物相适合。常见孔径大小范围：
0.20
～
70μm
，
如果需要也可使用其他孔径
大小的过滤器。
如果原料药的粒度很小
（例如，
微分
化颗粒或纳
M
颗粒）
，
找到一个合适的过滤器过滤这些小颗粒至今仍具有挑战性。
Adsorption of the drug(s) by
the filtermay occur and needs to be evaluated.
Filter
materials will interact
withdissolution media to affect the recovery of
the individual
solutes and must
beconsidered on a case-by-case basis. Different
filter materials
exhibitdifferent drug-
binding properties. Percentage of drug loss from
the filtratedue to
binding may be
dependent on the drug concentration. Therefore
theadsorptive
interference should be
evaluated on sample solutions at
differentconcentrations
bracketing the
expected concentration range. Where the
drugadsorption is saturable,
discarding
an initial volume of filtrate may allow
thecollection of a subsequent solution
that approaches the original
solutionconcentration. Alternative filter
materials that
minimize
adsorptiveinterference can usually be found.
Prewetting of the filter with the
medium maybe necessary. In addition, it
is important that leachables from the filter
donot interfere with the analytical
procedure. This can be evaluated by analyzingthe
filtered dissolution medium and
comparing it with the unfiltered medium.
过滤时可能会发生药物的吸附，
需要进行评估。
过滤材料将
与溶出介质相互
作用，
影响每个溶质的回收率应该根据具体问题
进行考虑。
不同的过滤材料表现
出与药物结合的不同特性。由于
药物与滤膜结合引起药物从滤液中损失的比例，
可能依赖于药物浓度。
< br>因此，
应采用预期浓度范围内不同浓度的样品溶液来评估
滤膜吸附干扰。
由于药物吸附是可饱和的，
弃去一定体积的初滤
液，
收集续滤液，
以达到接近原来的溶液浓度的样品也是可取的
。
通常选择适合的过滤材料，
最大
限度
地减少滤膜吸附干扰，
润湿滤膜对减少吸附也是必要的。
此外，
过滤后的溶
出物不干扰分析检测也是非常重要的，
这可以通过过滤后的溶出介质过滤与未过
滤的溶出介质进行比较，评估滤膜是
否干扰分析测定。
The filter size
should be based on thevolume to be withdrawn and
the amount of
particles to be
separated. Use of thecorrect filter dimensions
will improve throughput
and recovery,
and also reduceclogging. Use of a large filter for
small-volume filtration
can lead to
loss ofsample through hold-up volume, whereas
filtration through small
filter
sizesneeds higher pressures and longer times, and
the filters can clog quickly.
根据要过滤样品溶液
的体积以及样品溶液中颗粒的量选择滤膜孔径。
使用正
确的滤膜
孔径将提高溶液的通过率和回收率，
并减少滤膜堵塞。
使用大孔
径滤膜
过滤小体积溶液，
能够导致样品溶液损失量过大而收集不
到所用样品量；
使用小
孔径滤膜过滤，需要更高的压力和较长的
时间，并且溶液迅速堵塞滤膜。
Filters used
for USP Apparatus 4 needspecial attention because
they are integrated in
the flow-through
olved particles may deposit on the filters,
creating
resistance to theflow.
USP
仪器
4
中使用的过滤器
需要特别注意，
因为它们在流动过程中使用。
不
溶颗粒会沉积在过滤器，产生流动阻力。
In
the case of automated systems,selection of the
filter with regard to material and pore
size can be done in asimilar manner to
manual filtration. Flow rate through the filter
and
cloggingmay be critical for filters
used in automated systems. Experimental
verification that a filter
isappropriate may be accomplished by comparing the
responses
for filtered andunfiltered
standard and sample solutions. This is done by
first preparing
asuitable standard
solution and a sample solution. For example,
prepare atypical
dissolution sample in
a beaker and stir vigorously with a
magneticstirrer to dissolve the
drug
load standard solutions, comparethe results for
filtered solutions
(after discarding
the appropriate volume) tothose for the unfiltered
solutions. For
sample solutions,
compare the resultsfor filtered solutions (after
discarding the
appropriate volume) to
those forcentrifuged, unfiltered solutions.
在自动化系统的情况下，
关于过滤器滤膜材料和孔径大小可以用类似的方式<
/p>
通过手动过滤进行选择。
在自动化系统中通过过滤器的流量和过滤
器的堵塞可能
是至关重要的。通过实验比较过滤和未过滤的标准溶液和样品溶液的含量差
别，
验证该过滤器是合适的。
首先制备一个合适的标准溶液和样
品溶液。
例如，
在烧
杯中制备一个标准
溶解样品，
用磁力搅拌器搅拌使药物完全溶解。
对于标准溶液，
比较过滤溶液
（弃去的适当体积后）
和
未过滤溶液的含量测定结果；
对于样品溶
液，比较过滤（弃去适
当体积后）、离心、未过滤样品溶液的含量测定结果。
1.2
Determining Solubility and Stability of
DrugSubstance in Various Media
< br>1.2
原料药在不同溶出介质中的溶解度测定和稳定性研究
Physical and chemical characteristics
of the drug substance need to be determinedas
part of the process of selecting the
proper dissolution medium. Whendeciding the
composition of the medium for
dissolution testing, it is importantto evaluate
the
influence of buffers, pH, and if
needed, different surfactantson the solubility and
stability of the drug substance.
Solubility of the drugsubstance is usually
evaluated by
determining the saturation
concentration ofthe drug in different media at
37°
using the
shake-flask
solubility method(equilibrium solubility). To
level out potential ion effects
between
the drugand the buffers used in the media,
mixtures of hydrochloric acid and
sodiumhydroxide are used to perform
solubility investigations
。
this is in addition tothe
typical buffer solutions. In certain
cases, it may be necessary to evaluatethe
solubility of
the drug at temperatures
other than 37°
(i.e., 25°
).
The pHof the clear supernatant
should
be checked to determine whether the pH
changesduring the solubility test.
Alternative approaches for solubility
determinationmay also be used.
在选择合适溶出介
质的过程中，
需要确定原料药的物理化学特性。
当需要确
定溶出度实验中溶出介质的组成时，有必要评估缓冲液、
pH
值、以及不同的表
面活性剂（如果需要）对药物的溶解度和稳定性的影响
。在
37
℃温度条件下，
采用摇瓶溶解
法
（平衡溶解度）
测定原料药在不同介质中的饱和浓度，
来评估药
物的溶解性。
为了消除溶出介质中药
物和缓冲液之间离子的潜在影响，
使用盐酸
和氢氧化钠的混合物
对溶解度进行研究，
这是一种典型的缓冲溶液。
在某些情况
下，评估药物在
37
℃以外条件下（即，<
/p>
25
℃）的溶解度可能也是必要的。在溶
解度实验过程中应检查上清溶液的
pH
值，
以确定在溶解过程中
pH
值是否改变。
也可使用其他可供选择的方法进行溶解度测定。
Typical media for dissolution
mayinclude the following (not listed in order of
preference): diluted hydrochloricacid,
buffers (phosphate or acetate) in the physiologic
pH range of
1.2
–
7.5, simulatedgastric or
intestinal fluid (with or without enzymes),and
water. For somedrugs, incompatibility
of the drug with certain buffers or salts may
influencethe choice of buffer. The
molarity of the buffers and acids used can
influencethe solubilizing effect, and
this factor may be evaluated.
溶出的典型介质包括
（未按照优先顺序列出）：稀盐酸、在生理
pH
值范围
为
1.2-7.5
缓冲溶液（磷酸盐或者醋酸盐
）、模拟胃液或肠液（含有或不含有酶）
和水。
对于一些药物，
与药物不相容的特定缓冲液或盐可能会影响缓冲剂的选择。
所使
用的缓冲液和酸的体积摩尔浓度能够改变药物的增溶作用，
这个因素也需要
评估。
Aqueous solutions
(acidic or buffersolutions) may contain a
percentage of a surfactant
[e.g.,
sodium dodecylsulfate (SDS),polysorbate, or
lauryldimethylamine oxide] to
enhance
thesolubility of the drug. The surfactants
selected for the
solubilityinvestigations should cover
all common surfactant types, i.e.,
anionic,nonionic, and cationic. When a
suitable surfactant has been identified,different
concentrations of that surfactant
should be investigated to identifythe lowest
concentration needed
to
achieve sink conditions. Typically,the surfactant
concentration is above its critical
micellar concentration(CMC).
Table 1
shows a list of some
of the surfactants used
indissolution
media. Approximate CMC values are provided with
referenceswhenavailable. The list is
not comprehensive and is not intended to exclude
surfactantsthat are not listed. Other
substances, such ashydroxypropyl b
-cyclodextrin,have been used as
dissolution media additives to enhance dissolution
of
poorlysoluble U.S. Food and Drug
Administration (FDA) maintains
adatabase of dissolution methods,
including information on dissolution mediathat
have
been used
(1)
. Typically, the amount
of surfactant added issufficient to achieve sink
conditions in the desired volume of
dissolutionmedium.
有时候水溶性介质中
（酸性水溶液或缓冲溶液）
可能添加一定比例的表面活
性剂（如
十二烷基硫酸钠（
SDS
），聚山梨醇酯，或十二烷基二甲基氧
化胺）以
提高药物的溶解度。
选择用于溶解度研究的表面活性剂
时应涵盖所有常用种类的
表面活性剂，
比如阴离子、
非离子型和阳离子，
当已经确定一个合适的表面活性
剂时，
应对表面活性剂的不同浓度进行研究，
以确定达到漏槽
条件所需的最低浓
度。一般情况下，表面活性剂的浓度高于它的临界胶束浓度（
CMC
）。
表
1
列
出了溶出介质中常用的表面活性剂，表中提供了
CMC
的近似临界值，以便我们
参考，此外，表中所列表面
活性剂并不全面，不能排除未列出的表面活性剂。其
他表面活性剂，
如羟丙基
β
-
环糊精，
已被用来作为溶出介质添加剂提高难溶性化
合物的溶解度，美国食品药品管
理局（
FDA
）溶出度数据库中，已经收载含有羟
丙基
β
-
环糊精的溶出介质
（
1
）。通常情况下，表面活性剂的加入量以满足达到
漏槽条件所需的溶出介质体积。
It is
important to control thegrade and purity of
surfactants because use of different
grades could affectthe solubility of
the drug. For example, SDS is available in both a
technicalgrade and a high-purity grade.
Obtaining polysorbate 80 from different
sourcescan affect its suitability when
performing high-performance
liquidchromatography (HPLC) analysis. <
/p>
由于使用不同级别的表面活性剂会影响药物的溶解度，
因此要控制
表面活性
剂的级别和纯度。
例如，
SD
S
只有在工业级和高纯度级才可以使用。
在使用
HPLC
方法进行分析时，不同来源的聚山梨酯（吐温）
80
会影响它的适用性。
There may be effects of counter-ions
orpH on the solubility or solution stability of
the
surfactant solutions. Forexample, a
precipitate forms when the potassium salt for the
phosphate bufferis used at a
concentration of 0.5 M in combination with SDS.
This can
beavoided by using the sodium
phosphate salt when preparing media with SDS.
反离子或
pH
值可能会影响表面活性剂溶液的溶
解性或稳定性。例如，当含
有
SDS
的
磷酸盐缓冲液中钾盐浓度为
0.5mol/L
时，就形成了沉淀
析出，但是使
用磷酸钠制备含有
SDS
的介质时，可以避免这种现象发生。
Table 1.
Commonly Used Surfactants with Critical Micelle
Concentrations
表
1
常见表面活性剂的临界胶束浓度
Routinely, the dissolution medium is
buffered
。
however, the useof purified water as
the dissolution medium is suitable for
products with adissolution behavior independent
of the pH of the medium. There are
severalreasons why purified water may not be
preferred. The water quality can
varydepending on its source, and the pH of the
water is
not as strictly controlledas
the pH of buffer solutions. Additionally, the pH
can vary
from day to dayand can also
change during the run, depending on the drug
substance
andexcipients. Use of an
aqueous
–
organic solvent
mixture as a dissolution mediumis
discouraged
。
however,with proper justification this
type of medium may beacceptable.
通常，溶出介
质为缓冲盐溶液，但是，对于非
pH
值依赖性的制剂可以使用<
/p>
纯化水作为溶出介质。
不推荐使用纯化水作为溶出介质的原因：<
/p>
水的质量变化取
决于它的来源，而水的
p
H
值不像缓冲溶液能够严格控制；此外，若药物和辅料
的溶出对
pH
值敏感时需要考虑使用缓冲液。
另
外使用水
-
有机溶剂混合物作为溶
出介
质也是不推荐的，但是，特殊情况下（有充分适当的理由），也是可以接受
的。
Investigations of the stability
of thedrug substance should be carried out, when
needed,
in the selected
dissolutionmedium with excipients present, at
37°
. This elevated
temperature has thepotential to
decrease solution stability (degradation).
Stability
should allowfor sufficient
time to complete or repeat the analytical
procedure.
Physicalstability may be of
concern when precipitation occurs because of
lowersolubility at room or refrigerated
temperature.
必要时，
应该对原料药的稳定性进
行考察，
在所选择的溶出介质中加入辅料，
在
< br>37
℃条件下进行考察。这种升高的温度会潜在的降低溶液的稳定性（降解）。<
/p>
稳定性实验应考虑到有足够的时间来完成或重复分析过程。
当因室
温或冷藏贮存
时降低药物的溶解度而发生沉淀时，物理稳定性也需要关注。
1.3 Choosing aMedium and
Volume
1.3
溶出介质和体积的选择
When developing a dissolution
procedure, one goal is to have sinkconditions,
which are
defined as having a volume of
medium at least three timesthe volume required to
form a
saturated solution of drug
substance. When sinkconditions are present, it is
more likely
that dissolution results
will reflectthe properties of the dosage form. A
medium that
fails to provide
sinkconditions may be acceptable if it is
appropriately justified. The
compositionand volume of dissolution
medium are guided by the solubility
example, the choice and concentration of a
surfactant need to be
justifiedfrom the
solubility data and the dissolution profiles.
当开发一个溶出实验方法时，
首先要满足漏槽条件，
漏槽条件定义为溶出介
质体积至少为药物达到饱和溶液所需体积的三倍。
当满足漏槽条件后，
溶出度结
果能够更好的反映药
物制剂的质量。
在适当条件下，
介质不满足漏槽条件也是可
以接受的。
溶解介质的组成和体积应根据溶解度的实验结果进行调整
。
例如，
表
面活性剂种类和浓度选择，
需要根据药物溶解度数据和溶出曲线进行调整。
The
use of enzymes in the dissolutionmedium is
permitted, in accordance with
Dissolution
<711>, when
dissolution failures occur as a result of cross-
linkingwith
gelatin capsules or
gelatin-coated products. A discussion of
thephenomenon of
crosslinking and
method development using enzymes can be found
in
Capsules
–
Dissolution Testing and Related Quality
Attributes
<1094>. Validation
should be performed with the method
using enzymesaccording to section
5.
Validation
.
当交联明胶胶囊或明胶包衣的制剂溶
出失败时，在溶出介质中允许加入酶，
这同
溶出度
<711>
指导原则
一致。在
“
Capsules
–
Dissol
ution Testing and
RelatedQuality Attrib
utes<1094>”
中可以找到发生交联现象的讨论和采用酶进行
< br>方法开发的研究。
根据
第
5
节验证
，
使用酶方法按照溶出度方法学验证
的要求进
行验证。
Another
option is to use media thatfollow more closely the
composition of fluids in the
stomach
and intestinaltract. These media may contain
physiological surface-active
ingredients, suchas taurocholates. The
media also may contain emulsifiers (lecithin)
andcomponents such as saline solution
that increase osmolality. Also, the ionicstrength
or molarity of the buffer solutions may
be manipulated. The media aredesigned to
represent the fed and fasted state in
the stomach and media may be
very
useful in modeling in vivo dissolutionbehavior of
immediate-release (IR) dosage
forms, in
particular those containinglipophilic drug
substances, and may help in
understanding the dissolutionkinetics
of the product related to the physiological
make-up of the digestivefluids. Results
of successful modeling of dissolution kinetics
have beenpublished,mainly for IR
products. In the case of extended-release dosage
formswith reduced effect of the drug
substance on dissolution behavior, the use ofsuch
media needs to be evaluated
differently. In vitro performance testing doesnot
necessarily require media modeling the
fasted and postprandial states
(12,13)
.
另一种选择是使用
更贴近于胃和肠道流体组分的介质。
这些溶出介质可以含
有生理
表面活性成分，如牛黄胆酸。这些溶出介质也可能含有乳化剂（卵磷脂）
和增加渗透压的
组分，
比如生理盐水溶液。
同时，
缓冲
液的离子强度或体积摩尔
浓度是可以控制的。设计的溶出介质模拟了进食和空腹状态下的
胃和肠内状态。
这些溶出介质对速释制剂
（
IR
）
建立体内溶解行为模型方面是非常有用的，
特别
是这些速释制剂中含有脂溶性的原料药，
可
能有助于理解和消化液的生理组成相
关的制剂溶出动力学。
溶解
动力学的模型已成功建立，
主要用于速释制剂。
对缓
释剂型减少药物溶解行为的影响，使用的这些溶出介质需要有区别地进行评估。
体外性能测试并不一定需要在空腹和餐后状态建立溶出介质模型。
An acid stage is part of the testing
ofdelayed-release products by Method A or Method
B in <711>. For drugs with acid
solubility less than 10% of the labelclaim or
drugs that
degrade in acid the
usefulness of the acid stage indetecting a coating
failure is
compromised. This would be
handled on acase-by-case basis. Possible
resolutions
include the addition of
surfactant tothe acid stage, or adjustment of the
specifications.
对于肠溶制剂，
酸中释放度
是溶出度的一部分
（
<711>
方法<
/p>
A
或者方法
B
）
。
针对于药物标签中说明在酸中释放度不得过标示量的
10%
或者防止酸液中降解
而进行抗酸包衣的药
物。
根据具体情况进行解决，
可能的解决方案包括：
酸性介
质中添加表面活性剂或者调整质量标准）
During selection of the
dissolutionmedium, care should be taken to ensure
that the drug
substance is
suitablystable throughout the analysis. In some
cases, antioxidants such as
ascorbicacid may be used in the
dissolution medium to stabilize the drug. There
areoccasions where such actions are not
sufficient. For compounds that rapidlydegrade
to form a stable degradant, monitoring
the degradant alone or incombination with a
drug substance may be more suitable
than analyzing only thedrug substance. In situ
spectroscopic techniques tend to be
less affected bydegradation when compared with
HPLC analysis (including UHPLC and
other liquidchromatographic approaches).
在选择溶解介质时，应注意采取措施确保原料药在整个分析过程中的稳定
性。在某些
情况下抗氧化剂，如抗坏血酸的，可用于在溶出介质中，以保证药物
的稳定性。
有些时候加入这些抗氧剂是不够的。
化合物快速降解形成稳定的降解
物，
单独监测降解物或与原料药联合监控可能比只分析原料药更适合
。
与高效液
相色谱分析比较
（包括超高
效液相色谱等液相色谱法）
，
原位光谱分析受降解的
影响较小。
For compendial
Apparatus 1 (basket) andApparatus 2 (paddle), the
volume of the
dissolution medium can
vary from 500 to1000 mL. Usually, the volume
needed for the
dissolution test can be
determinedin order to maintain sink conditions. In
some
cases, the volume can be increased
tobetween 2 and 4 L, using larger vessels and
depending on the concentration andsink
conditions of the drug
。
justification for this
approach is expected. Inpractice, the
volume of the dissolution medium is usually
maintained within the compendial
rangegiven above. Alternatively, it may be
preferable to switch to other
compendialapparatus, such as a reciprocating
cylinder
(Apparatus 3), reciprocating
holder(Apparatus 7), or flow-through cell
(Apparatus 4).
Certain applications may
require lowvolumes of dissolution media (e.g.,
100
–
200 mL)
when
the use of a paddle orbasket is preferred. In
these cases, an alternative,
noncompendial apparatus(e.g., small-
volume apparatus) may be used.
对于药典仪器
1
（篮法）和仪器
2
（桨法），溶出介质的体积可以从
500
到
< br>1000
毫升不同。通常情况下，溶出介质的体积应当满足漏槽条件。在某些情况
下，根据药物的浓度和漏槽条件，可使用较大的溶出杯，体积可以增加至
2
～
4
升（这种方法必须有充
分的理由）。实际上，溶出介质的体积通常在药典规定范
围内。可供选择时，选用药典规
定的其他仪器也是可取的，如往复式气缸（仪器
3
），往复架（
仪器
7
），或流通池（仪器
4
）。当某些仪器需要较少体积的溶出
介质（例如，
100-200
毫升）时，首选桨法或篮法。在这些情况下，非药典仪器
仪器（例如，体积小的仪器）也可以选择使用。
1.4 Choosingan Apparatus
1.4
溶出设备选择（桨法和篮法以及其他方法）
The choice ofapparatus is based on
knowledge of the formulation design and the
practicalaspects of dosage form
performance in the in vitro test system. In
general,
acompendial apparatus should
be selected.
根据对处方设计的认知和体外实验剂型的实际特点选择仪器
。
一般来说，
首
选药典仪器。
For solid oral dosage forms,
Apparatus1 and Apparatus 2 are used most
frequently.
When Apparatus 1 or
Apparatus 2 isnot appropriate, another official
apparatus may be
used. Apparatus
3(reciprocating cylinder) has been found
especially useful for
chewable
tablets,soft gelatin capsules, delayed-release
dosage forms, and
nondisintegrating-
typeproducts, such as coated beads. Apparatus 4
(flow-through cell)
may offeradvantages
for modified-release dosage forms and immediate-
release dosage
formsthat contain active
ingredients with limited solubility. In addition,
Apparatus4
may have utility for
multiple dosage form types such as soft
gelatincapsules, beaded
products,
suppositories, or depot dosage forms, as well
assuspension-type
extended-release
dosage forms. Apparatus 5 (paddle over disk)and
Apparatus 6
(rotating cylinder) are
useful for evaluating and testingtransdermal
dosage forms.
Apparatus 7
(reciprocating holder) has application tonon-
disintegrating, oral
modified-release
dosage forms, stents, and implants,as well as
transdermal dosage
forms. For semisolid
dosage forms, the generallyused apparatus include
the vertical
diffusion cell, immersion
cell, andflow-through cell apparatus with the
insert for topical
dosage forms
(seeSemisolid Drug
Products
—
Performance Tests
<1724>).
对于口服固体制剂，
仪器
< br>1
和仪器
2
使用最多。
当仪器
1
或仪器
2
不适用时，
可以使用其他官方仪器。已发现仪器
3
（往复气缸）适用于咀嚼片、软胶囊、缓
释制剂和不崩解
型产品（如包衣小球）。仪器
4
（流通池）对活性成分的溶解度
有限的缓释剂型和速释剂型提供了很多优势。
此外，
仪器
4
可用于多种剂型类型，
如软胶囊，微球制剂，栓剂，或贮库型产品，以及悬浮型缓释剂型。仪器
5
（桨
盘）和仪器
6
（旋
转缸）适用于评价和测试的经皮给药制剂。仪器
7
（往复架）<
/p>
适用非崩解制剂，
口服缓释剂型，
支架，
和植入物，
以及透皮制剂。
半固态剂型
，
常用的仪器包括立式扩散池，浸入细胞，流通单元仪器适用局部制剂（
see
Semisolid
DrugProducts
—
Performance
Tests
<1724>
）。
Some changes can be made to
thecompendial apparatus
。
for example, a basket mesh
size other than the typical40-mesh
basket (e.g., 10-, 20-, or 80-mesh) may be used
when
the need isclearly documented by
supporting data. Care must be taken that baskets
areuniform and meet the dimensional
requirements specified in <711>.
对药典仪器配
件也可以进行一些调整；例如，除了药典仪器
40
目以外的其<
/p>
他规格的溶出篮（例如：
10
，
20
或者
80
目），通
过充足的数据进行详细的阐明
后也可以使用。必须注意的是篮网孔径必须是均匀的并且满
足
<711>
规定的尺寸
要求。
A noncompendial apparatus may
have someutility with proper justification,
qualification, and documentation
ofsuperiority over the standard equipment. For
example, a small-volume apparatuswith
mini paddles and baskets may be considered
for low-dosage strengthproducts. A
rotating bottle or dialysis tubes may have utility
for
microspheresand implants, peak
vessels, and modified flow-through cells for
special
dosageforms including powders
and stents.
非药典溶出仪器具有优于药典标准仪器的合适设备、
资质和文件。
例如，
一
个小体积的溶出仪器配有小桨或者小篮可以用于低剂量制剂。
旋转瓶或透析管可
能适用于微球、植入制剂，改进的流通池适用于特殊剂型包括粉末和支架。
2. METHODDEVELOPMENT
2.
方法的开发
A properly designed test should
yielddata that are not highly variable, and should
be
free of significant variability in
the results can make it difficult
to
identifytrends or effects of formulation changes.
Sample size can affect the
observedvariability. One guidance
defines dissolution results as highly variable if
therelative standard deviation (RSD) is
more than 20% at time points of 10 min orless
and more than 10% at later time points
for a sample size of 12
(14)
.However,during
method development, smaller sample
sizes may be used, and theanalyst will need to
make a judgment dissolution
results,however, exhibit less variability.
In the development of a
dissolutionprocedure the source of the variability
should be
investigated, and
attemptsshould be made to reduce variability
whenever possible. The
two most
likelycauses are the formulation itself (e.g.,
drug substance, excipients,
ormanufacturing process) or artifacts
associated with the test procedure (e.g.,coning,
tablets sticking to the vessel wall or
basket screen). Visualobservations are often
helpful for understanding the source of
the variabilityand whether the dissolution test
itself is contributing to the
variability. Anytime the dosagecontents do not
disperse
freely throughout the vessel
in auniform fashion, aberrant results can occur.
Depending
on the problem, theusual
remedies include changing any of the following
factors: the
apparatustype, speed of
agitation, level of deaeration,sinker type, or
composition ofthe
medium.
合理
设计一个实验保证数据稳定性
（即较低的变异性）
，
并且能够明显反映
出样品稳定性问题。
结果的高变
异难以确定处方变化的趋势和处方变化对溶出度
结果的影响。样本大小影响所观察到的变
异性。如果在
10
分钟
12
个样本的相
对标准偏差（
RSD
）不得过
20%
或者后续取样点的
RSD
值大于
10%
。，指导原则
对
溶出度实验结果定义为高变异性。
然而，
在方法开发过程中，
可以使用较小的样
本量，需要对分析作
出相应的判断。大多数溶出结果，表现出较少的变异性。在
溶出度实验开发过程中应对产
生变异的原因进行研究，
只要有可能，
应尝试减少
变异性。引起变异性的两个最可能的原因是制剂本身（例如，原料药，辅料，或
制剂工艺）和与检测过程相关的处理过程（例如，溶出漩涡，片粘在溶出杯壁或
篮网上
）
。
实验过程的观察往往有助于查找产生变异的原因或者溶出度
测定方法
本身是否会产生变异性。
任何时间内剂量含量不能均匀
地分散在整个容器中，
异
常结果就可能发生。
< br>根据不同的问题，
通常的调节方法包括下列任何一个因素的
改变：仪器，转速，脱气程度，沉降篮类型，或者溶出介质的组成。
Many causesof variability can be found
in the formulation and manufacturing process.
Forexample, poor content
uniformity,process inconsistencies,
excipientinteractions or
interference,
film coating, capsule shell aging, and hardeningor
softeningof the dosage
form on
stability may be sources of variability
andinterferences.
在处方开发和制剂工艺中，
可以找到产生变异的许多原因。
例如，
含量均匀
度的差异，工艺的不一致，辅料的相互作用或干扰，包衣，胶囊壳老化，制剂稳
定性考查中出现的硬化或软化是产生和干扰变异的原因。
2.1 Deaeration
2.1
脱气
Thesignificance of deaeration of the
dissolution medium should be determinedbecause
air bubbles can act as a barrier to the
dissolution process if presenton the dosage unit
or
basket mesh and can adversely affect
the reliability ofthe test results. Furthermore,
bubbles can cause particles to cling to
theapparatus and vessel walls. Bubbles on the
dosage unit may
increasebuoyancy,leading to an increase in the
dissolution rate, or may
decrease the
availablesurface area, leading to a decrease in
the dissolution rate. Poorly
solubledrugs are most sensitive to
interference from air
bubbles
。
therefore,deaeration
may be
needed when testing these types of products. A
deaerationmethod is described
as a
footnote in the
Procedure
section of <711>.Typicalsteps include
heating the
medium, filtering, and
drawing a vacuum for a shortperiod of time. Other
methods of
deaeration are available and
are in routineuse throughout the industry. Once a
suitable
deaeration process is
identified,it should be documented as part of the
dissolution
procedure. The extent
ofdeaeration can be evaluated by measuring the
total dissolved
gas pressure or
bymeasuring the concentration of dissolved oxygen
in water. For
example, anoxygen
concentration below 6 mg/L has been found
effective as a marker
foradequate
deaeration of water for the Performance
Verification Test with
USPPrednisone
Tablets RS.
应明确溶出介质脱气的目的，
因为在
溶解过程中如果在剂量单位或篮网出现
气泡，会起到一个屏障作用，影响实验结果的可靠
性。此外，气泡会使颗粒粘在
设备和容器壁上。
剂量单位上的气
泡可能会增加浮力，
导致溶解速率增加，
或者
< br>也有可能会减少可接触的表面积导致溶出率下降。
气泡对难溶性药物的干扰最敏<
/p>
感；
因此检验这些类型的产品时需要脱气。
在
<711>
部分附录
中描述了脱气
方法。
典型的脱气方法：
加热、
过滤和
在短时间内抽真空。
其他脱气方法和常规使用的
脱气方法也是可
用的。
一旦确定一个合适的脱气方法，
应该作为溶出方法的一部
分记录下来。
通过测量总溶解气体压力或通过测量水中溶解的气
体浓度来评估脱
气的程度。
例如，
使用
USP
的性能验证测试泼尼松龙片校正片发现水中氧浓度低
于
6
毫克
/
升时，表明水已充分脱气。
Media
containing surfactants usuallyare not deaerated
because the process results in
excessive foaming, and usuallythe
effect of dissolved air on the dissolution process
is
mitigated by thereduced surface
tension of the medium. Sometimes, deaerating the
medium beforeadding surfactants can be
effective.
含有表面活性剂的溶出介质由于脱气过程会产生过多气泡通常不
容易脱气，
通常采用减少溶出介质中的表面张力，来减轻溶解的空气对溶解过程产生的影
响，有时，在加入表面活性剂之前对溶出介质进行脱气是有效的。
To determine whetherdeaeration of the
medium is necessary, compare results from
dissolution samplesrun in non-
deaeratedmedium and medium deaerated using a
compendial technique,as described
above. If no effect of deaeration is detected,
this experiment could serve
asjustification that deaeration is not required in
the future.
If there is aneffect,
however, then it isnecessary to carefully control
this parameter,
andit is prudent to
characterize the robustness of the deaeration
process.
Thedissolvedgas content of
deaerated media under atmospheric pressure is
unstable
and willtend toward
saturation. Manipulationsof the deaerated medium
such as
stirringor pouring can increase
the rate at which atmospheric gases are
redissolved.
确定溶出介质是否需要脱气是必要的，
如上面所描述的，
使用药典技术中的脱气
方法，
比较样品在脱气和未脱气的溶出介质中的溶出实验结果。
如果检测结果表<
/p>
明脱气对溶出结果没有影响，该实验就可以作为不需要进行脱气的理由进行说
明。
如果脱气对实验结果有影响，
那么有必要准确控
制这个参数，
详细描述脱气
过程中耐受性特点。
在大气压强下，
脱气介质中溶解的气体量是不稳定的，
会趋
向饱和。比如搅拌或倾倒已脱气的介质可以增加气体的再溶解速率。
2.2 Sinkers
2.2
沉降篮
Sinkersare often used to adjust the
buoyancy of dosage forms that would otherwisefloat
during testing with Apparatus 2. When
sinkers are used, a detaileddescription of the
sinker must be provided in the written
procedure. It may beuseful to evaluate different
sinker types, recognizing that sinkers
cansignificantly influence the dissolution profile
of a dosage unit. Whentransferring the
procedure, the same sinkers should be used, or if
a differentdesign is used, it should be
shown to produce equivalent results. There
areseveral types of commercially
available sinkers. In <711>, a harmonizedsinker is
described in
Figure
2a
.
在使用仪器
2
进行测试时，沉降篮通常用于调节易于漂浮的剂型。当使用沉
降蓝时，
必须对沉降篮仪器进行详细描述。
评估沉降篮的不同类型，
同时要认识
到沉降篮能够显著影响溶出曲线。
当转移
这个方法时，
应使用相同的沉降篮，
或
者如果使用不同设计的沉降篮，
应当证明两种不同的沉降篮产生的结果相同。
有
几种可用的商业类型的沉降篮。
在
<711>
中图
2a
中统一
对沉降篮进行了详细的描
述。
A
standard sinker can be made by using
theappropriate length of wire and coiling it
around a cylinder. For materials,use316
stainless steel wire, typically 0.032 inch/20
gauge, or other inertmaterial and wind
the wire around cylinders of appropriatediameter
(e.g., corkborers) for an appropriate
number of turns to fit the capsule shell type.
Sizesare shown in
Table
2
. Theends of the coil can be curved to
retain thecapsule within
the sinker
when they are immersed. Because the ends of
thewiremay be rough, they
may need to
be filed. If the sinker is handmade, thesinker
material and construction
procedure
instructionsshould be documented(e.g., dimension,
design, number of
coils)
。
if a commercial sinker is used,
thevendor part numbershould be reported if
available.
一个标准的沉降篮可以通过使用合适长
度的金属丝围绕圆柱体卷绕制成。使用
316
不锈钢丝为材料，
通常
0.032
英寸
/20
号，或其它惰性材料和缠绕适当直径
的圆柱体（如，木塞穿孔器）和缸丝匝
数量以适合胶囊壳的类型。表
2
中列出了
尺寸。
线圈的端部可以是弯曲的，
以保持胶囊在沉降篮内浸润
。
因为金属丝的端
部是粗糙的，
他们可
能需要修整。
如果沉降篮是手工制作，
应记录沉降篮的材料
和结构（例如，尺寸，设计，线圈数）。如果用的是商业沉降篮，应当提供供应
商零件号。
Table 2.
WireSinkers Used With Common Capsule Shell
Sizes
表
2
普通胶囊壳规格使用的沉降篮金属线尺寸
Although sinkers are typically used to
keep thedosage form at the bottom of the vessel,
they can also be used to keep
dosageforms from sticking to the vessel (e.g.,
film-coated
tablets). The sinkershould
be appropriate to the dosage
form
。
therefore,the same sinker
size maynot be suitable for all dosage-
form sizes. The sinker should not be too
tightaround the dosage form because
this may restrict interaction with the
sely, if wrapped too loosely, the
dosage form may escape soon after the
testbegins. The sinker should be small
enough that the capsule does not change
itsorientation within the should be
taken when testing capsules thathave
some cross-linking present, to keep the
sticky shell from attaching to thevessel bottom.
In this case, the harmonized sinker
design provided in
Figure2a
of <711>will be
advantageous.
虽然通常使用的沉降篮是为了保
持剂型在容器底部，它们也能够使剂型不粘
附在容器壁中（例如：薄膜包衣片）。沉降篮
应适合于剂型。因此，相同大小的
沉降篮可能不适合所有的剂型型号。
< br>沉降篮不应围绕剂型太紧或太松，
太紧可能
会限制剂型与
介质的相互作用，
太松剂型可能会逃脱。
在测试开始后不久。<
/p>
沉降
篮应该足够小使得胶囊在沉降篮内不能改变方向。
胶囊存在交联时，
实验时应小
心，
以保持胶囊壳不粘附在容器底部。
在这种情况下，
在<
/p>
<711>
图
2a
中统一提供
的沉降篮设计将是有利的。
2.3 Agitation
2.3
转速
Forimmediate-release capsule or tablet
formulations, Apparatus 1 (baskets) at
50
–
100
rpm or
Apparatus 2 (paddles) at 50or 75rpm are used
commonly. Other agitation speeds
are
acceptable with appropriatejustification. Rates
outside 25
–
150 rpmfor both
the
paddle and the basket are usually
not appropriatebecause of mixing inconsistencies
that
can be generated bystirring too
slow ortoo fast. Agitation rates between 25 and 50
rpm
are generally acceptable
forsuspensions.
对于速释胶囊或片剂，一般采用仪器
1
（篮法）
50
～
100 rpm
，或者仪器
2
（桨法）
50
或
75rpm
。
如果有合适的理由选择其他转速也是可以接受的。
< br>考虑到
转速太慢或太快产生混合不一致，
无论是篮法或者
桨法，
低于
25
rpm
或高于
150
rpm
的转速，均是不能接受的。对于混悬剂一般推荐转速
25rpm
～
50rpm
。
For dosage forms that exhibit
coning(mounding) under the paddle at 50 rpm, the
coning
can be reduced by increasingthe
paddle speed to 75 rpm, thus reducing the artifact
and
improving the justified, 100 rpm
may be used with Apparatus 2, especially
forextended-release products.
Decreasing or increasing the apparatus
rotationspeed
may be justified if to
achieve an in-vitro
–
in-vivo
correlation (IVIVC)the resulting
profiles better reflect in vivo
performance, or if the methodresults in better
discrimination without adversely
affecting method variability.
桨转速
50rpm
时，剂型在浆下存在圆锥（丘）状，将转速增加至
75 rpm
可
以减少圆锥状，从而提高溶出数据。尤
其是对于缓释制剂制剂，如果经过证明，
也可以采用桨法
100
rpm
转速。如果能够实现体内外相关性（
IVIVC
），使体外溶
出曲线更好的反应体内溶出特性，
或者在不影响方法差异性的情况下溶出结果具
有更好的区分力，增加或减小仪器转速均是
合理的。
Apparatus 3
(reciprocating cylinder)can be used at dip rates
ranging from 5 to 30
dips/min. The
hydrodynamics areinfluenced by the cylinder's
reciprocating motion and
the resulting
movement ofthe sample in the medium. The
reciprocating motion of the
cylinder
and screenmay cause foaming if the medium contains
surfactants. Addition of
ananti-foaming
agent such as simethicone or
n
-octanol may be useful
foravoiding
foaming from surfactants. <
/p>
仪器
3
（往复缸）可用于浸率范围
5
～
30
dips
/
分钟。气缸的往复运动影响流
体力学和样品在介质中溶出结果
。
如果溶出介质中含有表面活性剂，
在气缸和监
视器的往复运动会引起起泡。
加入消泡剂，
如硅油或正
辛醇，
可避免表面活性剂
产生的泡沫。
Apparatus 4(flow-through cell) is
described in <711> with standard flow rates of 4,
8,and 16 mL/min. Other flow rates for
Apparatus 4 can be used if justified and ifwithin
the capacity of the pump to conform
with the requirements in
á
711?
. Agitationin
Apparatus 4 is not only related to the
pump speed but can also be affectedby cell
diameter. At a set flow rate, as
measured by volume, the 12-mm cellwill develop a
greater linear fluid velocity than is
achieved in the 22.6-mmcell. Apparatus 4 can be
configured with the addition of glass
beads in theentry cone of the flow-through cell
(packed column) or without glass
beads(open column).
仪器
4
(
流通池
)
在
<711>
中描述了标准流速
4
、
8
、
16ml/min
。如果经过验证
并且在该泵的承受的能力范围内符合
<711>
的要求，
仪器
4<
/p>
也可以使用其他流速。
在仪器
4
中搅动不仅影响泵的速度也影响孔直径。
通过测定体积设定流速，
12mm
孔径比
22.6mm
孔径产生的线性流速要大。仪器
4
在流体单元的入口通
过加入玻
璃珠（填充柱）或者去掉玻璃珠（开放柱）进行配置。
2.4 Study Design
2.4
研究设计
Selectionof the agitation rate and
other study design elements for the dosage
form,whether immediate release or
modified release, should conform to
therequirements and specifications
(i.e., apparatus, procedures, andinterpretation)
given in <711>.
不管是速释制剂或者是缓控
释制剂，
对转速选择和剂型的其他研究设计，
均
应符合
<711>
规范要求（即仪器，方法和说明）。
2.4.1 TIME
POINTS
2.4.1
取样时间点
For
immediate-release dosage forms, theduration of the
dissolution procedure is
typically
30
–
60
min
。
in most
cases, asingle time point specification is
adequate for
pharmacopeial purposes.
Formethod development, however, a sufficient
number of
time points should beselected
to adequately characterize the ascending and
plateau
phases of thedissolution curve.
Industrial and regulatory concepts of product
comparabilityand performance may
require additional time points, which may also be
requiredfor product registration or
approval. According to the
BiopharmaceuticsClassification System
referred to in severalFDA Guidances, highly
soluble,highly permeable drugs
formulated into very rapidly dissolving products
neednot be subjected to a profile
comparison if they can be shown to release 85%
ormore of the drug substance within 15
min. For these types of products, aone-point test
or disintegration will suffice.
However, most products do notfall into this
category.
Dissolution profiles of
immediate-release productstypically show a gradual
increase
reaching
85%
–
100% at about
30
–
45 min. Thus,sufficient
dissolution time points are
chosen to
characterize the performancefor most immediate-
release products. For some
products,including suspensions,useful
information may be obtained from earlier points,
e.g., 5
–
10 min.
Forslower-dissolving products, time points later
than 60 min may be
ution test times for
compendial tests are usually established on
thebasis of
an evaluation of the
dissolution profile data.
对于速释制剂，溶出度测定时
间通常为
30
～
60 min
；在大多数情况下，单
点取样设计足够满足药典的控制要求。
但是，
对于方法的开发阶段，
应选择足够
多的时间点来充分表征溶出量增加和达到溶出平台的趋势。
工业和法规概
念对产
品的相似性和产品性能进行研究需要增加取样时间点，
产
品的注册或批准同样需
要。
根据
FDA
指导原则中生物药剂学分类系统，
高溶解性高渗透性药物
（快速溶
出药物），如果在
15
分钟内溶出度达到
85%
以上，可不再进行曲线考察
，单点
实验就足够了。
然而，
大多数产
品不属于这一分类。
速释制剂的溶出度通常呈逐
渐增加趋势，一
般在
30
～
45
分钟溶出达到
85%
～
100%
。因此，大多数速释制剂
会选择充足的时间点来表征产品的溶出特性
。
对于一些产品，
包括悬浮液，
早期<
/p>
取样时间点获得的信息比较有用，
例如，
5
，
10
分钟。
对于溶出速度较慢的产品，
60
分钟后的时间点可能是有用的
。药典中规定溶解度实验时间的确定通常是建
立在对溶出曲线数据评估的基础之上。
The f
2
similarityfactor may not be useful when more than
85% is dissolved at 15 min. If
the
f2similarity factor is to be used,multiple time
points for the dissolution testare
required, with at least two time points
with mean percent dissolved(typically for n = 12)
below 85% dissolved and only one point
above 85% forboth products (16). Therefore,
the addition of early time points may
be useful.
f
2
相似因子
不适用于
15
分钟溶出量大于
85%<
/p>
的制剂。如果使用
f
2
< br>相似因子
进行比较，
需要进行多个时间点溶出度测定，<
/p>
至少两个取样时间点平均溶出值低
于
85
%
（一般是
n=12
）
并且两组产品的溶出度值只有一个时间点大于
85%
。
因此，
在早期增加时间点检查是有必要的。
For testing anextended-release
dosage form, at least three time points are
chosen, to
guardagainst dose dumping,
to define the in vitro release profile, and to
show
thatessentially complete release
(>80%) of the drug is achieved. Additionalsampling
times may be useful. Certain IVIVC
criteria, such as level Bcorrelation (according to
In
Vitro and In Vivo
Evaluation of DosageForms
<1088>),
require the experimental
determination
of the timeto dissolve 100% of the label claim.
Selection of the final time
points
isreflective of the data from the drug release
profile that are generated
duringdevelopment. For products
containing more than a single active
ingredient,determine the drug release
for each active ingredient.
对于缓释剂型溶出实验，
至少选择三个时间点确定体外释放曲线，
以防止剂
量释放不完全，并要求药物释放完全（
>80%
）。
增加取样时间点可能是有用的。
根据体内外相关标准，如
B
级相关（根据“
In
Vitro
and
In
Vivo
Evaluation
of
Dosage Forms
<1088>”）需要根据实验确
定药物释放
100%
的时间点。在开发过
程中，
最后时间点的选择是为了反映药物释放曲线。
对于含有
多个活性成分的产
品，需要确定每种活性成分的药物释放。
Delayed-release dosage formsusually
require specifications for at least two time
points
。
therefore, it isimportant during
development to evaluate the entire dissolution
profile. In thecase of enteric-coated
dosage forms, the functionality of the coating
isusually proven by challenge in an
acid medium, followed by a demonstration
ofdissolution in a higher-pH medium.
Chapter <711> gives a standard buffer medium
for that stage of testing but other
mediamay be used if justified. The timing of the
acid
stage is typically 2 h, andrelease
in the buffer is similar to the timing
forimmediate-release forms. Fordelayed-
release dosage forms that are not enteric
coated, setting of specificationsis
different. Unlike delayed release, the onset of
release
is not determined by
theexperimental design, which is the pH
change
。
multivariatespecifications,therefore,
may be needed to definetime ranges and
corresponding percentageranges
< br>延迟释放剂型通常需要至少设计
2
个时间点，
因此，
在开发过程中对整个溶
出曲线进行评估是非
常重要的。
至于肠溶包衣制剂，
通常用在酸介质中的抗酸能
力来证明包衣作用，
然后证明在一个较高的
pH
值介质中的溶出度，
在
<711>
章节
给出了标准的缓冲介质中的溶解行为
（如果经过验证其他溶出介质也是可以使用
的）。酸中释放时间通常是
2
小时，与速释制剂在缓冲液中释放时间类似。对于
没
有进行肠溶包衣的缓释剂型，
规格设定是不同的。
不像延迟释放
，
不能通过实
验设计、
pH
值变化来确定初始释放
,
因此，多种规格的制剂可
能需要确定时间范
围和相应的百分比范围。
So-called infinity points canbe useful
during development studies. To obtain an infinity
point, the paddleor basket speed is
increased at the end of the run (after the last
time
point)for a sustained period
(typically, 15
–
60 min),
after which time an
additionalsample is
taken. Although there is no requirement for 100%
dissolution in
theprofile, the infinity
point can be compared to content uniformity data
and
mayprovide useful information about
formulation characteristics during
initialdevelopment or about method
bias.
所谓的无穷点在开发研究中是有用的。
为了获得一
个无穷大点，
在运行结束
后（一般是最后一个取样时间点）增加
桨或篮的转速，并维持一段时间（通常是
15
～
60
分钟），在这段时间后，取样测定。虽然在溶出曲线中不要求
100%
的溶
出，
但是无限
点可以比较药物的均一性，
并可以提供有用的信息，
用于评估初
始
开发过程中的制剂特性或方法偏差。
2.4.2 OBSERVATIONS
2.4.2
观察
Visual observations and recordings
ofproduct dissolution and disintegration behavior
are useful because dissolutionand
disintegrationpatterns can be indicative of
variables
in the formulation
ormanufacturing process. For visual observation,
proper
lighting (with
appropriateconsideration of photo-degradation) of
the vessel contents
and clear
visibilityin the bath are nting observations by
drawing
sketches andtaking photographs
or videos can be instructive and helpful for
thosewho
arenot able to observe the
real-time dissolution test. Observations are
especiallyuseful
during method
development andformulation optimization. It is
importantto record
observations of all
six vessels to determine if the observation isseen
in all six
vessels, or just a few. If
the test isperformed to assist with formulation
development,
provide any
uniqueobservations to theformulator. Examples of
typical observations
include, butare
not limited to, the following:
观察并记录产品的
崩解和溶出行为是有用的，
因为崩解和溶出方式可以为处
方和工
艺提供详细的信息。
观察过程中，
为清晰观察溶出杯中内容物，
提供适当
程度的光（适当考虑光降解）是必不可少的。绘制草图
、拍摄照片或录像记录观
测结果，
对那些不能够实时观察溶出度
实验的人来说是有用的。
观察溶出过程变
化对方法开发和配方优
化特别有用。重要的是要记录所有六个溶出杯的观察结
果，
以确
定是否在六个容器中观察到该结果，
或者仅仅是几个溶出杯观察到该结
< br>果。
如果测试的目的是为了协助处方开发，
为处方设计提
供任何观察到的独特现
象。通常观察到的现象包括，但不限于以下内容：
distribution of particles
throughout the vessel. This can occur when
particlescling to the sides of the
vessel, when there is coning or mounding
directlyunder
the apparatus (e.g.,
below the basket or paddle), when particles float
atthe surface of the
medium, when film-
coated tablets stick to the vessel, and/orwhen
off-center mounds
are formed.
bubbles on the inside of the vessel or
on the apparatus or dosage on the
apparatus is also a sign of air
bubbles. This observation wouldtypically be made
when
assessing the need to deaerate the
medium.
g or spinning of the dosage
unit, or the dosage unit being hit by thepaddle.
on of particles to the paddle or the
inside of the basket, which may beobserved
upon removal of the stirring deviceat
the end of the run.
les or analogous
formations, such as transparent sacs or rubbery,
swollenmasses
surrounding the capsule
contents.
ce of large floating
particles or chunks of the dosage unit,
especiallyat the
surface of the media.
ation of the disintegration rate (e.g.,
percentage reduction in size ofthe dosage
unit within a certain time frame).
x disintegration of the coating of
modified or enteric-coated products,[e.g.,
the partial opening and splittingapart
(similar to a clamshell) orincomplete opening of
the shell], accompanied by the release
of air bubbles andexcipients.
r the
dosage form lands in the vessel center or off-
center, and ifoff-center,
whether it
sticks there.
required for the
complete dissolution of the capsule shell or for
tabletdisintegration.
1.
颗粒在整个容器内分布不均。
这可以发生在颗粒附着到容器的两侧，
篮下或者
桨下有锥型堆积物，当物品浮在介质表面，当薄膜衣片粘在
杯壁，和
/
或当偏离
中心的堆状物形成
。
2.
气泡在容器内或仪器上或单片
制剂上。
仪器上的光泽也是气泡的标志。
在评估
是否需要进行溶出介质脱气时会进行这些观察。
3.
单位制剂摇晃或者旋转，或溶出桨击中单位制剂。
4.
实验结束后，颗粒粘附于桨或篮内。
5.
薄膜或类似的结构，如透明囊或橡皮囊，围绕胶囊内容物的膨胀部
分。
6.
尤其在溶出介质表面，存在
大量的漂浮颗粒或块状物。
7.
观察
的崩解速度
（例如，
在一定的时间范围内，
在剂量单位大小的百分比减少）
。
8.
包衣修饰或肠溶性产品的复杂崩解
[
例如，部分开放和分裂（类似于翻盖）或
不完整的外壳开口
]
，伴随气泡和辅料的释放。
9.<
/p>
剂型是否位于中心还是偏离中心，如果偏离中心，是否粘附。
<
/p>
10.
胶囊壳完全溶解或片剂崩解所需的时间。
< br>
Observationsalso help to document
that the proper procedure has been followed, or
more importantly,that a deviation has
occurred. Examples include the confirmation that
a dosageform is actually in the vessel
during the test or that more than one dosageform
are inadvertently in the same vessel,
or that a filter from theautosampler has dropped
into the vessel.
发生偏差时，
观察也有助于证明所进行操作方法的正确性或哪些操作方法是
重要的。
实例包括在实验期间确认在容器中实际存在的是一种剂型，
或同一容
器
无意中存在多种剂型，或自动进样器的过滤器掉进容器中。
2.4 Study Design
2.4
研究设计
Selectionof the agitation rate and
other study design elements for the dosage
form,whether immediate release or
modified release, should conform to
therequirements and specifications
(i.e., apparatus, procedures, andinterpretation)
given in <711>.
不管是速释制剂或者是缓控
释制剂，
对转速选择和剂型的其他研究设计，
均
应符合
<711>
规范要求（即仪器，方法和说明）。
2.4.1 TIME
POINTS
2.4.1
取样时间点
For
immediate-release dosage forms, theduration of the
dissolution procedure is
typically
30
–
60
min
。
in most
cases, asingle time point specification is
adequate for
pharmacopeial purposes.
Formethod development, however, a sufficient
number of
time points should beselected
to adequately characterize the ascending and
plateau
phases of thedissolution curve.
Industrial and regulatory concepts of product
comparabilityand performance may
require additional time points, which may also be
requiredfor product registration or
approval. According to the
BiopharmaceuticsClassification System
referred to in severalFDA Guidances, highly
soluble,highly permeable drugs
formulated into very rapidly dissolving products
neednot be subjected to a profile
comparison if they can be shown to release 85%
ormore of the drug substance within 15
min. For these types of products, aone-point test
or disintegration will suffice.
However, most products do notfall into this
category.
Dissolution profiles of
immediate-release productstypically show a gradual
increase
reaching
85%
–
100% at about
30
–
45 min. Thus,sufficient
dissolution time points are
chosen to
characterize the performancefor most immediate-
release products. For some
products,including suspensions,useful
information may be obtained from earlier points,
e.g., 5
–
10 min.
Forslower-dissolving products, time points later
than 60 min may be
ution test times for
compendial tests are usually established on
thebasis of
an evaluation of the
dissolution profile data.
对于速释制剂，溶出度测定时
间通常为
30
～
60 min
；在大多数情况下，单
点取样设计足够满足药典的控制要求。
但是，
对于方法的开发阶段，
应选择足够
多的时间点来充分表征溶出量增加和达到溶出平台的趋势。
工业和法规概
念对产
品的相似性和产品性能进行研究需要增加取样时间点，
产
品的注册或批准同样需
要。
根据
FDA
指导原则中生物药剂学分类系统，
高溶解性高渗透性药物
（快速溶
出药物），如果在
15
分钟内溶出度达到
85%
以上，可不再进行曲线考察
，单点
实验就足够了。
然而，
大多数产
品不属于这一分类。
速释制剂的溶出度通常呈逐
渐增加趋势，一
般在
30
～
45
分钟溶出达到
85%
～
100%
。因此，大多数速释制剂
会选择充足的时间点来表征产品的溶出特性
。
对于一些产品，
包括悬浮液，
早期<
/p>
取样时间点获得的信息比较有用，
例如，
5
，
10
分钟。
对于溶出速度较慢的产品，
60
分钟后的时间点可能是有用的
。药典中规定溶解度实验时间的确定通常是建
立在对溶出曲线数据评估的基础之上。
The f
2
similarityfactor may not be useful when more than
85% is dissolved at 15 min. If
the
f2similarity factor is to be used,multiple time
points for the dissolution testare
required, with at least two time points
with mean percent dissolved(typically for n = 12)
below 85% dissolved and only one point
above 85% forboth products (16). Therefore,
the addition of early time points may
be useful.
f
2
相似因子
不适用于
15
分钟溶出量大于
85%<
/p>
的制剂。如果使用
f
2
< br>相似因子
进行比较，
需要进行多个时间点溶出度测定，<
/p>
至少两个取样时间点平均溶出值低
于
85
%
（一般是
n=12
）
并且两组产品的溶出度值只有一个时间点大于
85%
。
因此，
在早期增加时间点检查是有必要的。
For testing anextended-release
dosage form, at least three time points are
chosen, to
guardagainst dose dumping,
to define the in vitro release profile, and to
show
thatessentially complete release
(>80%) of the drug is achieved. Additionalsampling
times may be useful. Certain IVIVC
criteria, such as level Bcorrelation (according to
In
Vitro and In Vivo
Evaluation of DosageForms
<1088>),
require the experimental
determination
of the timeto dissolve 100% of the label claim.
Selection of the final time
points
isreflective of the data from the drug release
profile that are generated
duringdevelopment. For products
containing more than a single active
ingredient,determine the drug release
for each active ingredient.
对于缓释剂型溶出实验，
至少选择三个时间点确定体外释放曲线，
以防止剂
量释放不完全，并要求药物释放完全（
>80%
）。
增加取样时间点可能是有用的。
根据体内外相关标准，如
B
级相关（根据“
In
Vitro
and
In
Vivo
Evaluation
of
Dosage Forms
<1088>”）需要根据实验确
定药物释放
100%
的时间点。在开发过
程中，
最后时间点的选择是为了反映药物释放曲线。
对于含有
多个活性成分的产
品，需要确定每种活性成分的药物释放。
Delayed-release dosage formsusually
require specifications for at least two time
points
。
therefore, it isimportant during
development to evaluate the entire dissolution
profile. In thecase of enteric-coated
dosage forms, the functionality of the coating
isusually proven by challenge in an
acid medium, followed by a demonstration
ofdissolution in a higher-pH medium.
Chapter <711> gives a standard buffer medium
for that stage of testing but other
mediamay be used if justified. The timing of the
acid
stage is typically 2 h, andrelease
in the buffer is similar to the timing
forimmediate-release forms. Fordelayed-
release dosage forms that are not enteric
coated, setting of specificationsis
different. Unlike delayed release, the onset of
release
is not determined by
theexperimental design, which is the pH
change
。
multivariatespecifications,therefore,
may be needed to definetime ranges and
corresponding percentageranges
< br>延迟释放剂型通常需要至少设计
2
个时间点，
因此，
在开发过程中对整个溶
出曲线进行评估是非
常重要的。
至于肠溶包衣制剂，
通常用在酸介质中的抗酸能
力来证明包衣作用，
然后证明在一个较高的
pH
值介质中的溶出度，
在
<711>
章节
给出了标准的缓冲介质中的溶解行为
（如果经过验证其他溶出介质也是可以使用
的）。酸中释放时间通常是
2
小时，与速释制剂在缓冲液中释放时间类似。对于
没
有进行肠溶包衣的缓释剂型，
规格设定是不同的。
不像延迟释放
，
不能通过实
验设计、
pH
值变化来确定初始释放
,
因此，多种规格的制剂可
能需要确定时间范
围和相应的百分比范围。
So-called infinity points canbe useful
during development studies. To obtain an infinity
point, the paddleor basket speed is
increased at the end of the run (after the last
time
point)for a sustained period
(typically, 15
–
60 min),
after which time an
additionalsample is
taken. Although there is no requirement for 100%
dissolution in
theprofile, the infinity
point can be compared to content uniformity data
and
mayprovide useful information about
formulation characteristics during
initialdevelopment or about method
bias.
所谓的无穷点在开发研究中是有用的。
为了获得一
个无穷大点，
在运行结束
后（一般是最后一个取样时间点）增加
桨或篮的转速，并维持一段时间（通常是
15
～
60
分钟），在这段时间后，取样测定。虽然在溶出曲线中不要求
100%
的溶
出，
但是无限
点可以比较药物的均一性，
并可以提供有用的信息，
用于评估初
始
开发过程中的制剂特性或方法偏差。
2.4.2 OBSERVATIONS
2.4.2
观察
Visual observations and recordings
ofproduct dissolution and disintegration behavior
are useful because dissolutionand
disintegrationpatterns can be indicative of
variables
in the formulation
ormanufacturing process. For visual observation,
proper
lighting (with
appropriateconsideration of photo-degradation) of
the vessel contents
and clear
visibilityin the bath are nting observations by
drawing
sketches andtaking photographs
or videos can be instructive and helpful for
thosewho
arenot able to observe the
real-time dissolution test. Observations are
especiallyuseful
during method
development andformulation optimization. It is
importantto record
observations of all
six vessels to determine if the observation isseen
in all six
vessels, or just a few. If
the test isperformed to assist with formulation
development,
provide any
uniqueobservations to theformulator. Examples of
typical observations
include, butare
not limited to, the following:
观察并记录产品的
崩解和溶出行为是有用的，
因为崩解和溶出方式可以为处
方和工
艺提供详细的信息。
观察过程中，
为清晰观察溶出杯中内容物，
提供适当
程度的光（适当考虑光降解）是必不可少的。绘制草图
、拍摄照片或录像记录观
测结果，
对那些不能够实时观察溶出度
实验的人来说是有用的。
观察溶出过程变
化对方法开发和配方优
化特别有用。重要的是要记录所有六个溶出杯的观察结
果，
以确
定是否在六个容器中观察到该结果，
或者仅仅是几个溶出杯观察到该结
< br>果。
如果测试的目的是为了协助处方开发，
为处方设计提
供任何观察到的独特现
象。通常观察到的现象包括，但不限于以下内容：
distribution of particles
throughout the vessel. This can occur when
particlescling to the sides of the
vessel, when there is coning or mounding
directlyunder
the apparatus (e.g.,
below the basket or paddle), when particles float
atthe surface of the
medium, when film-
coated tablets stick to the vessel, and/orwhen
off-center mounds
are formed.
bubbles on the inside of the vessel or
on the apparatus or dosage on the
apparatus is also a sign of air
bubbles. This observation wouldtypically be made
when
assessing the need to deaerate the
medium.
g or spinning of the dosage
unit, or the dosage unit being hit by thepaddle.
on of particles to the paddle or the
inside of the basket, which may beobserved
upon removal of the stirring deviceat
the end of the run.
les or analogous
formations, such as transparent sacs or rubbery,
swollenmasses
surrounding the capsule
contents.
ce of large floating
particles or chunks of the dosage unit,
especiallyat the
surface of the media.
ation of the disintegration rate (e.g.,
percentage reduction in size ofthe dosage
unit within a certain time frame).
x disintegration of the coating of
modified or enteric-coated products,[e.g.,
the partial opening and splittingapart
(similar to a clamshell) orincomplete opening of
the shell], accompanied by the release
of air bubbles andexcipients.
r the
dosage form lands in the vessel center or off-
center, and ifoff-center,
whether it
sticks there.
required for the
complete dissolution of the capsule shell or for
tabletdisintegration.
1.
颗粒在整个容器内分布不均。
这可以发生在颗粒附着到容器的两侧，
篮下或者
桨下有锥型堆积物，当物品浮在介质表面，当薄膜衣片粘在
杯壁，和
/
或当偏离
中心的堆状物形成
。
2.
气泡在容器内或仪器上或单片
制剂上。
仪器上的光泽也是气泡的标志。
在评估
是否需要进行溶出介质脱气时会进行这些观察。
3.
单位制剂摇晃或者旋转，或溶出桨击中单位制剂。
4.
实验结束后，颗粒粘附于桨或篮内。
5.
薄膜或类似的结构，如透明囊或橡皮囊，围绕胶囊内容物的膨胀部
分。
6.
尤其在溶出介质表面，存在
大量的漂浮颗粒或块状物。
7.
观察
的崩解速度
（例如，
在一定的时间范围内，
在剂量单位大小的百分比减少）
。
8.
包衣修饰或肠溶性产品的复杂崩解
[
例如，部分开放和分裂（类似于翻盖）或
不完整的外壳开口
]
，伴随气泡和辅料的释放。
9.<
/p>
剂型是否位于中心还是偏离中心，如果偏离中心，是否粘附。
<
/p>
10.
胶囊壳完全溶解或片剂崩解所需的时间。
< br>
Observationsalso help to document
that the proper procedure has been followed, or
more importantly,that a deviation has
occurred. Examples include the confirmation that
a dosageform is actually in the vessel
during the test or that more than one dosageform
are inadvertently in the same vessel,
or that a filter from theautosampler has dropped
into the vessel.
发生偏差时，
观察也有助于证明所进行操作方法的正确性或哪些操作方法是
重要的。
实例包括在实验期间确认在容器中实际存在的是一种剂型，
或同一容
器
无意中存在多种剂型，或自动进样器的过滤器掉进容器中。
Figure 1. An example of a
plotof dissolution as a cumulative process.
Concentration,
C
,
is the amountof drug released per
volume of medium, and t represents time. This type
of
plotis readily observed in constant-
volume dissolution systems, such as Apparatus 1or
Apparatus 2, or Apparatus 4 in closed-
loop configuration.
图
1.
作为一个累积溶出率的例子。浓度（
C
）是每体积
溶出介质药物释放量
量；
t
代表时间。
这种类型的溶解曲线在体积恒定的溶解系统很容易观察到，如
仪器
1
或仪器
2
，或在仪器
4
闭环结构中。
Figure
2
An
example of a plot of theobserved concentration of
the sample taken for an
interval that
is negligiblysmall in relation to the time of the
overall dissolution process.
This
concentrationis propostional to the instantaneous
or fractional dissolution
rate(
< br>dc
/
dt
).This
type of plot is readily observed in continuous-
flow dissolution
systems,such as
Apparatus 4 in openloop configuration.
图
2.
在一个时间区间观察到样品浓度的释放曲线对于整个溶解
过程是非常小的，
这个浓度与瞬时或部分溶出速率呈正比
(
dc
/
dt
)
。这种类型的溶解曲线在体积恒定
的溶解系统很容易观察到，比如仪
器
4
开环结构中。
Cumulative dissolution profiles
represent the totalamount of drug dissolved from
the formulation over time.
Whencumulativedissolution is measured in
aconstant-volume system, no correction
forthe amount lost in sampling needs to be
made. Ifsample is removed from
thesystem, the amount consumed in analysis must be
accounted for in thecalculation.
Recirculatedsampling with Apparatus 1 or Apparatus
2,
or withApparatus 4 in the closed-
loop configuration (
Figure
3
), are allexamples
ofsystems that will produce cumulative
dissolution rates. WithApparatus 4 in the open
configuration (
Figure
4
), cumulativeratesaccounting for the
total amount of drug
dissolved across
the testinginterval are obtained by collecting and
analyzing the
entireoutflow from
eachindividual flow-through cell. With Apparatus 3
(
Figure 5
), the
medium ineach tube is sampled at theend
of the programmed interval, and the
analyzedconcentration represents the
cumulative dissolution rate during that interval.
累计溶出曲线代表药物随着时间从制剂中的溶出总量。当在一个恒定体积系
统中测定累计溶出度时，
取样损失量不需要进行校正。
如果样品从系统中移除分
析时消耗的量必须在计算时进行说明。
用仪器
1
或仪器
2
< br>或仪器
4
封闭系统结构
（图
3
）进行循环采样是所有平衡系统产生累积溶出速率的例子。用仪器
4
开放
结构（图
4
）通过收集和分析每个流通池的整个流出量的累积溶出速率在检测时
间间隔占药物溶出总量的比值。用仪器
3
（图
5
）在程序间隔的终点对每个管中
的溶出介质进
行采样，并且所分析的浓度表示在该时间间隔累积溶出速率。
Fractional dissolution ratesare
typically measured for a discrete interval. A
series of
such rates willproduce a step
function asthe dissolution profile. At any time,
the
cumulativedissolution rate from
this type of profile is the sum of the
type of profile is represented by Apparatus 3
using
multipletubes or Apparatus 4 in
the open-loop configurationwhere the total outflow
iscollected and analyzed for successive
intervals.A number of algebraic andnumerical
methods exist for transforming
cumulative and fractional dissolutionresults. The
differencein amount released for
successive time points can becalculated, and the
average release rate is determined by
the formula:
Result = (
M2
?
M1
)/(
t2
?
t1
)
M
= mass or percentage of label claim
t
= time
通常在离散区间测
定部分溶出速率，
一系列这样的溶出速率将产生溶出曲线
阶梯函
数。
在任何时间，
这种类型溶出曲线的累积溶出速率是先前时间
间隔的速
率总和。
这种类型的曲线代表仪器
3
用多个试管或仪器
4
开放系统结
构在连续间
隔收集总流出量进行分析。
在许多代数和数值方法中
存在累积转化和分级溶出实
验结果。计算连续时间点释放量的差值，平均释放率由下列公
式确定：
结果
=
（
M
2
-M
1
）
/
（
t
2
-t
1
）<
/p>
M=
标示量要求的质量和比例
t=
时间
As the difference of
t
2
from
t
1
is reduced, the average rate can be considered to
approachan instantaneous
rate. Samplingconsiderations and physical
constraints
onmeasurement of the mass
transfer at the medium interface of the dosage
formmakethe measurement of true
instantaneous dissolution impractical for
routinedetermination in the laboratory.
Fractional dissolution is measured forintervals
where the difference between
t
2
and
t
1
issmall,
relative to the total test time. The design
of
Apparatus 4 in the
openconfiguration permits a direct measurement of
the fractional
dissolution oversmall
time intervals. Forexample, if a 4-mL fraction of
outflow for
Apparatus 4running 16
mL/min is sampled, either by in situ detection or
offline, the