counselor-食之无味
(1092
)
溶出度
试验的开发和验证【中英文对照版】
INTRODUCTION
.
、八
、
-
刖言
Purpose
目的
The Dissoluti on Procedure: Developme
ntand Validati on
<1092>
provides a comprehe nsive approach
coveri ng items to con siderfor develop ing
and validati ng dissoluti on procedures
and the accompa nyingan alytical
procedures. It addresses the use of
automati on throughout the testa nd provides
guida nee and criteria for validatio n.
It also addresses thetreatme nt of the data
gen erated and the in terpretati on of
accepta nee criteriafor immediate- and
modified-release solid oral dosage
forms.
溶出实验
：
开发和验证
（
1092
）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 developme
nt an dvalidati on of
dissoluti on
procedures, with a focus on solid oral dosage ny
of the con cepts prese nted, however,
may be applicable to other dosageforms and
routes of adm ini strati on. Gen eral
recomme ndati ons are give n with the un
dersta nding that
modificati
ons of the apparatus and procedures as give n in
USP gen eral
chapters n eed to be justified.
<1092><
/p>
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 orga
ni zati on of <1092> follows the seque nee of acti
ons ofte n
performed in the developme
nt and validatio n of a dissoluti on test.
The secti ons appear in the follow ing
seque nee.
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
Choos ing a Medium and Volume
1.3
溶出介质和体积选择
1.4
Choos ing 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 Deaerati
on
2.1
脱气
2.2
Si nkers
2.2
沉降篮
2.3
Agitatio n
2.3
转速
2.4
Study Design
2.4
研究设计
2.4.1 TimePoi nts
2.4.1
取样时间点
2.4.2
Observatio ns
2.4.2
观察
2.4.3
Sampli ng
2.4.3
取样
2.4.4
Clea ning
2.4.4
清洗
2.5
Data Ha ndli ng
2.5
数据处理
2.6
Dissoluti on Procedure
Assessme nt
2.6
溶出方法评估
3.
ANALYTICAL
FINISH
3.
完成分析
3.1 Sample Process ing
3.1
样品处理
3.2
Filters
3.2
过滤
3.3
Ce ntrifugati on
3.3
离心
3.4
Analytical Procedure
3.4
分析方法
3.5
Spectrophotometric An
alysis
3.5
光谱分析
3.6
HPLC
3.6HPLC
法
4.
AUTOMATION
4.
自动化
4.1 Medium
Preparati on
4.1
介质的配制
4.2
Sample In troduct ion
and Timi ng
4.2
定时进样
4.3
Sampling and Filtration
4.3
取样和过滤
4.4
Clea ning 4.4
清洗
4.5
Operati ng Software and
Computatio n of Results
4.5
操作软件和计算的结果
5.
VALIDATION
5.
验证
5.1
Specificity/Placebo Interferenee
5.1
专属性
/
安慰剂（辅料）干扰
5.2
Lin earity and
Range
5.2
线性和范围
5.3
Accuracy/Recovery
5.3
准确度
/
回收率
5.4
Precisi on
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
Robust
ness
5.5
耐用性
5.6
Stability of Sta ndard and Sample
Soluti ons 5.6
样品溶液和标准溶液的稳定性
5.7
Con siderati ons for
Automati on
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
Exte nded-Release Dosage
Forms
6.3
延长释放剂型
6.4
Multiple Dissolution
Tests
6.4
多个溶解度试验
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
1. PRELIMINARYASSESSMENT
(FOR EARLY STAGES OF PRODUCT
6.5.3
延长释放剂型
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
developme nt can beg in, it is importa nt to
characterize the molecule sothat the
filter, medium, volume of medium, and
apparatus can be chose n properly in
order to evaluate the performa nee 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、
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
Filtrati onis a key sample-preparati on
step in achiev ing accurate test
results. Thepurpose of filtration is to
remove undissolved drug and
excipie nts
from thewithdraw n soluti on. 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 positi oned on the
cannu la.
为获得准确试验结果，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试验结果出现偏差，
样管中没有过滤器，应立即对溶出度样品进行过滤。
Filtrati on also removes in
solubleexcipie nts that may otherwise in terfere
with the
an alytical fini sh. Select
ionof the proper filter material is importa nt and
should be
因此，如果取
accomplished,
andexperimentally justified, early in the
development of the dissoluti
on
procedure. Importa nt characteristics to con sider
whe n choosing a filtermaterial
are
type, filter size, and pore size. The filter that
is selectedbased on evaluati on
duri ng
the early stages of dissoluti on procedure
developme ntmay n eed to be rec
on
sidered at a later time point. Requalification has
to beconsidered after a change
in
compositi on of the drug product or cha nges in
thequality of the in gredie nts
(e.g.
particle size of microcrystalli ne 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，但在后期试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 n eeded. If the drug substa nee particle size
is
very small(e.g., microni zed or nan
oparticles), it can be challe nging to find a
filterpore size that excludes these
small particles.
用于溶出试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
?
70
ym,
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
< br>
如，微分化
颗粒或纳米颗粒
)
，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 in
teract withdissoluti on media to affect the
recovery of the in dividual
solutes and
must bec on sidered on a case-by-case basis.
Differe nt filter materials
exhibitdiffere nt drug-b inding
properties. Perce ntage of drug loss from the
filtratedue to
binding may be depe
ndent on the drug concen trati on. Therefore
theadsorptive in terfere
nee should be
evaluated on sample soluti ons at differe ntconcen
trati ons bracketi ng the
expected
concen trati on ran ge. Where the drugadsorptio n
is saturable, discardi ng an in
itial
volume of filtrate may allow thecollection of a
subsequent solution that approaches
the
origi nal soluti onconcen trati on. Alter native
filter materials that mi ni mize adsorptive
in terfere nee can usually be found.
Prewetti ng of the filter with the medium maybe n
ecessary .In addition, it is important
that leachables from the filter donot in terfere
with the
an alytical procedure. This
can be evaluated by analyzingthe filtered
dissolution medium
and comparing it
with the un filtered 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。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
dime nsions
will improve throughput and recovery, and also
reducecloggi ng. Use of a large filter
for small-volume filtratio n can
lead
to loss ofsample through hold-up volume, whereas
filtrati on
through small filter sizes
needs higher pressures and Ion ger 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 n eedspecial atte nti on because
they
are in tegrated in the flow-
through process.U ndissolved 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,selectio n 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.
Experime ntal
verification that a
filter isappropriate may be accomplished by
compari ng the resp on ses
for filtered
andun filtered sta ndard and sample solutions.
This is done by first preparing
asuitable standard soluti on and a
sample soluti on. For example, prepare atypical
dissoluti on sample in a beaker and
stir vigorously with a mag neticstirrer to
dissolve the
drug load sta ndard solutions,
comparethe results for filtered solutions
(after discarding the appropriate
volume) tothose for the un filtered soluti ons.
For sample
solutions, compare the
resultsfor filtered solutions (after discarding
the appropriate
volume) to those
forcentrifuged, un filtered soluti ons.
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
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
过试验比较
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
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 substa nce n eed to be determ inedas
part of the process of selecting the
proper dissoluti on medium. When decidi ng the
compositi on of the medium for
dissoluti on testi ng, it is importa ntto evaluate
the in flue
nce of
buffers,
pH,
and if
needed,
different
surfactantson
the
solubility
and stability
of
the
drug
substa nee. Solubility of the
drugsubsta nee is usually evaluated by determ
ining the saturati
on concen trati on
ofthe drug in differe nt media at 37
°
using the shake-flask solubility
method
（
equilibrium
solubility
）
. To level out
potential ion effects betwee n the druga nd
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 soluti ons. In
certa in cases,
it may be n ecessary to evaluatethe solubility of
the drug at temperatures
other than 37 pHof the clear super nata
nt should be checked to determ ine whether the
pH cha ngesduri ng the solubility test.
Alter native approaches for solubility determ in
ati
onmay 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
试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
37
C
温度条件下，
面活性剂（如果需要）对药物的溶解度和稳定性的影响。在
<
/p>
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
C
以外条件下（即，
25
C
）
的溶解度可能也是必要的。在
溶解度试验
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 dissoluti on mayin
clude the followi ng
（
not
listed in order of prefere
nee
）
:
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,
in compatibility of the drug
with certa in buffers or salts may
in
flue ncethe choice of buffer. The molarity of the
buffers and acids
used can in flue
ncethe solubiliz ing 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
为
1.2-7.5
pH
值范围
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，
也需要评估。
Aqueous
soluti ons (acidic or buffersolutio ns) may
contain a
perce ntage of a surfacta nt
[e.g., sodium dodecylsulfate
(SDS),polysorbate, or lauryldimethylami
ne oxide] to enhance
thesolubility of
the drug. The surfacta nts selected for the
solubility inv estigati ons should
cover all com mon surfacta nt types, i.e.,
anionic,nonionic,
and cati onic. Whe n
a suitable surfacta nt has bee n iden
tified,differe nt concen tratio ns
of
that surfacta nt should be in vestigated to ide
ntifythe lowest concen trati on n eeded to
achieve sink conditions. Typically,the
surfactant concentration is above its critical
micellar
concen trati on( CMC).
Table 1 shows a list of
这个因素
some of the
surfacta nts used in dissoluti on media.
Approximate CMC values are
provided
with refere nceswhe navailable. The list is not
comprehe nsive and is not inten ded to
exclude surfacta ntsthat are
not
listed. Other substa nces, such ashydroxypropyl b
-cyclodextri
n,have bee n used as dissoluti on media additives
to
enhance dissoluti on of
poorlysoluble compo un U.S. Food and
Drug Admi nistrati on
（
FDA
）
mai ntains adatabase of dissoluti on
methods, in clud ing in formati on on
dissoluti on mediathat have bee n
used
（
1
）
.
Typically, the amount of surfactant added
issufficient to
achieve sink con diti
ons in the desired volume of dissoluti onm edium.
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
CMC
）。表
1
列
度。一般情况下，表面活性剂的浓度高于它的临界胶束浓度（
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
俟环糊精，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
俟环糊精的溶出介
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 importa nt to con trol thegrade
and purity of surfacta nts because
use
of differe nt grades could affectthe solubility of
the drug. For
example, SDS is available
in both a tech ni calgrade and a high-purity
grade. Obtai ning polysorbate 80 from
differe nt sourcesca n affect its
suitability whe n perform ing high-
performa nee liquidchromatography (HPLC) an
alysis.
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，
SDS
只有在工业级和高纯度级才可以使用。在使用
< br>
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 whe n the potassium salt for the phosphate
bufferis
used at a concen trati on of
0.5 M in comb in ati on with SDS. This can
beavoided by using the sodium phosphate
salt whe n prepari ng 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。<
/p>
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. Com mon ly
Used Surfacta nts with Critical Micelle
Concen trati ons
表
1
常见表面活性剂的临界胶束浓度
基就験胡
^
P
CMC
:
坯重量七电〕
v
^-O.23^
吸加
01
冉”
61
珈
2-4+J
却
，强霰號心
1
［壽”
十
六走塞三戸塞填化婪
（
CEAB5
中
节義黒釜〔季蛙生
1622
）
心
< br>糞
.
一矣厠
20
C
匕巨
20
）
P
黄
2
棗哺盹龙去迫
&CD
p
左礙矣酸赏乙二諄寸箔醯
CLlbrason
P
醍更乙境篦疔法茫
CCremophorELD
门
燮呈乙餐臭哇零聲
CBnj353
P
左去概脊
(Triton
X-1001
。
.
< br>三却基「芒睪壬
斗
-
兰
W
刊〔
LDA6
匸
0.055*^-0.036%
C0.92-L.0mMj
卫
01
却诚
4
曲?）
匸
QL07%4).O9%J
茁
0.025^0.08%^
O.O1%43
0.02%^
0.013%^
-
0.62
略
3,
加
3.7
P
4+J
非哥子
八
3
M J
3
r ■.
Rout in ely,
the dissoluti on medium is buffered; however, the
useof purified water as the
dissolution
medium is suitable for products with adissoluti on
behavior in depe ndent of
the pH of the
medium. There are severalreas ons 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.
Additi on
ally, the pH can vary from day to daya nd can also
cha nge
duri ng the run, depe nding on
the drug substa nee an dexcipie nts. Use
of an aqueous -orga nic solve nt
mixture as a dissoluti on mediumis discouraged;
however,with proper justificati on 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：
水的质量变化取
决于它
的来源，而水的
pH
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<
/p>
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 substanee should be carried
out, whe n n eeded, in the selected
dissoluti onm edium with exeipie nts
prese nt, at 37
°
. This elevated temperature has thepote
ntial to
decrease solution stability
（
degradation
）
. Stability should allowfor suffieie nt time
to
complete or repeat the an alytical
procedure.
Physicalstability may be of
concern whe n precipitati on 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
37
C
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）
稳定性试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 Choos ing aMedium and Volume
1.3
溶出介质和体积的选择
Whe n develop
ing a dissoluti on 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 substanee. When sinkconditions
are
present, it is more likely that
dissoluti on 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 inv estigatio example, the choice and
concen trati on of a surfacta nt n
eed
to be justifiedfrom the solubility data and the
dissolution profiles.
当开发一个溶出试验方法时，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试验结果进行调整。
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 en zymes in the dissolutio nm edium is
permitted, in
accorda nee with
Dissoluti on <711>, whe n dissoluti on failures
occur
as a result of cross-l inkin
gwith gelat in capsules or gelat in-coated
products. A discussi
on of thephe
nomenon of crossli nking and method development
using enzymes can be
found in
Test ing and Related Quality Attributes
Capsules -Dissolution
<1094>. Validatio n should be
5.
performed with the method
using en zymesaccord ing to sect ion
Validati on
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
Cap
sules -Dissolution Testi ng and RelatedQuality
Attributes<1094>
中可以找到发生交联现象的讨论和采用
酶进行方法开发的研究。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。
Ano ther opti on is to use media
thatfollow more closely the
composition
of fluids in the stomach and intestinaltract.
These media
may con tai n physiological
surface-active in gredie nts, suchas
taurocholates. The media
also may
contain emulsifiers (lecith in) an dcomp onents
such as sali ne solutio n that in
crease osmolality. Also, the
ionicstrength or molarity of the buffer solutions
may be man
ipulated. The media aredesig
ned to represe nt the fed and fasted state in the
stomach
and smalli ntesti media may be
very useful in modeli ng in vivo dissolutio
nbehavior of immediate-release (IR)
dosage forms, in particular those containin
glipophilic
drug substa nces, and may
help in un dersta nding the dissoluti onkin etics
of the product
related to the
physiological make-up of the digestivefluids.
Results of successful modeling
of
dissolution kinetics have bee npublished,ma inly
for IR products. In the case of exte
nded-release dosage formswith reduced
effect of the drug substance on dissolution
behavior, the use ofsuch media needs to
be evaluated differe ntly .In vitro performa nce
testi ng does not n ecessarily require
media modeli ng the fasted and postpra ndial
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<
/p>
)
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 test ing 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
usef uln ess of the acid stage
in detect ing a coati ng failure is
compromised. This would be han dled on
acase-by-case basis. Possible resolutio ns in
clude the additi on of surfacta nt
tothe acid stage, or adjustme nt of the
specificati ons.
对于肠溶制剂，酸中释放度是溶出度的一部分（<
/p>
＜
711
＞
方法
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
< br>
质中添加
表面活性剂或者调整质量标准）
During selecti on of the
dissoluti onm edium, care should be take n to en
sure that the
drug substa nee is
suitablystable throughout the an alysis. In some
cases, an tioxida nts
such as
ascorbicacid may be used in the dissolution medium
to stabilize the drug. There
areoccasions where such acti ons are
not sufficie nt. For compo unds that
rapidlydegrade
to form a stable degrada
nt, mon itori ng the degrada nt alone or in comb
in ati on with a
drug substa nee may be
more suitable than analyzing only thedrug
substanee. In situ
spectroscopic tech
niq ues tend to be less affected bydegradati on
whe n compared with
HPLC an alysis
（
in clud ing 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 compe
ndial Apparatus 1 (basket) an dApparatus 2
(paddle), the volume of the
dissolution
medium can vary from 500 to1000 mL.
Usually, the volume n eeded for the
dissoluti on test can be
determ inedin
order to maintain sink con diti ons. In some
cases, the volume can be in creased
tobetwee n 2 and 4 L, using larger vessels and
depe
nding on the concen trati on
andsink con diti ons of the drug; justificati on
for this
approach is expected. In
practice, the volume of the dissolution medium is
usually
maintained within the
compendial rangegiven above. Alternatively,
it may be preferable to switch to other
compe ndialapparatus, such
as a
reciprocati ng cyli nder (Apparatus 3),
reciprocati ng holder(Apparatus 7), or
flow-
through cell (Apparatus 4).
Certai n applicatio ns may require
lowvolumes of dissoluti on media
(e.g.,
100
-200 mL) whe n the use of a paddle
orbasket is preferred.
In these cases,
an alter native, non compe ndial apparatus(e.g.,
small-volume apparatus)
may be used.
对于药典仪器
1
(
< br>篮法
)
和仪器
2
(
桨法
)
，溶出介质的体积
可以从
500
到
1000
毫升不
< br>同。通常情况下，溶出介质的体积应当满足漏槽条件。在某些
< br>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
Choos ingan 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 kno wledge of the
formulatio n desig n and the
practicalaspects of dosage form
performa nee in the in vitro test system .In gen
eral,
acompe ndial apparatus should be
selected.
根据对处方设计的认知和体外试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, Apparatusl and Apparatus 2 are
used
most freque ntly. Whe n Apparatus
1 or Apparatus 2 isnot appropriate, ano ther
official
apparatus may be used.
Apparatus 3
（
reciprocati ng
cyli nder
）
has bee n found
especially useful for chewable
tablets,soft gelati n capsules, delayed-release
dosage
forms, and non dis in tegrati
ng-typeproducts, such as coated beads.
Apparatus 4
（
flow-through
cell
）
may offeradva ntages
for modified-release dosage
forms and
immediate-release dosage formsthat con tai n
active in gredie nts with limited
solubility. In additi on, Apparatus4
may have utility for multiple dosage form types
such as
soft gelat in capsules, beaded
products, suppositories, or depot dosage forms, as
well
assuspe nsion-type exte nded-
release
dosage forms. Apparatus 5
(paddle over disk)a nd Apparatus 6 (rotat ing cyli
nder) are
useful for evaluati ng and
testi ngtra nsdermal dosage forms. Apparatus 7
(reciprocat ing
holder) has applicatio
n tonon-dis in tegrati ng, oral modified-release
dosage forms, ste
nts, and impla nts,as
well as tran sdermal dosage forms. For semisolid
dosage forms, the
gen erallyused apparatus in clude the
vertical diffusi on cell, immersi on cell, an
dflow-
through cell apparatus with the
insert for topical dosage forms (seeSemisolid Drug
Products
—
Performa nee Tests
<1724>
）
.
对于口服固体制剂
，仪器
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）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
—
Performanee
Tests
<1724>
）。
Some cha nges can be made to thecompe
ndial apparatus; for example,
a basket
mesh size other tha n the typical40-mesh basket
（
e.g., 10-,
20-,
or 80-mesh
）
may be used whe
n the n eed isclearly docume nted by support ing
data. Care must be take n 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
他规格的溶出篮
(
例如：
10
，
20
或者
80
目
< br>)
，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
的尺寸要求。
A non
compe ndial apparatus may have someutility with
proper justification, qualification,
and documentation ofsuperiority over
the sta ndard equipme nt. For example, a
small-
volume apparatuswith mini paddles
and baskets may be con sidered for low-dosage stre
<711>
规定
ngthproducts. A
rotati ng bottle or dialysis tubes may have
utility for microspheresa nd
impla nts,
peak vessels, and modified flow-through cells for
special dosageforms in clud
ing powders
and ste nts.
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 desig ned 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 formulatio
n cha nges. 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 thea nalyst will n
eed to make a judgme nt accord
in
dissolutio n results,however, exhibit less
variability .In the developme nt of a
dissoluti on procedure the source of
the variability should be investigated, and
attemptsshould be made to reduce
variability whe never possible. The two most
likelycauses are the formulation itself
(e.g., drug substanee, excipients, orma nu facturi
ng
process) or artifacts associated
with the test procedure (e.g.,c oning, tablets
stick ing to
the vessel wall or basket
scree n). Visualobservati ons are ofte n helpful
for un dersta
nding the source of the
variabilityand whether the dissolution test itself
is con tribut ing to
the variability.
Any time the dosageccontents do not disperse
freely throughout the vessel
in
auniform fashi on, aberra nt results can occur.
Depending on the problem, theusual
remedies in clude cha nging any of the
follow ing factors: the apparatustype, speed of
agitati on, level of deaerati on,sin
ker type, or compositi on ofthe medium.
合理设计一个试验保证数据稳定性
(
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
验结果定义为高变异性。
10
分钟
12
个样本的相
然而，在方法开发过程中，可以使用较小的样
对标准偏差
(
RSD
不得过<
/p>
20%
或者后续取样点的
RSD
值大于
10%
，指导原则对
溶出度试
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
溶出度试
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）。试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
< br>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，
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
manu facturi ng
process. Forexample, poor content uni
formity,process incon siste ncies,
excipie nti nteractio ns or in terfere
nee, film coati ng, capsule shell agi ng, and
harde nin
gor softe nin gof the dosage
form on stability may be sources of variability
andin terfere
nces.
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 Deaerati on
2.1
脱气
Thesig nifica nee of deaerati on of the
dissoluti on medium should be determ in
edbecause air bubbles can act as a
barrier to the dissoluti on 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
in creasebuoya ncy,lead ing to an in crease in the
dissoluti on rate, or may decrease the
availablesurface area, leadi ng to a decrease in
the
dissoluti on rate. Poorly
solubledrugs are most sen sitive to in terfere nee
from air
bubbles; therefore,deaerati on
may be n eeded whe n testi ng these types of
products. A
deaerati onm ethod is
described as a foot note in the Procedure sect ion
of
<711>.Typicalsteps in elude heati ng
the medium, filtering, and drawing a vacuum for a
shortperiod of time. Other methods of
deaerati on are available and are in routi neuse
异
常结果
就可能发生。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
throughout
the in dustry. Once a suitable deaeratio n process
is identified,it should be
documented
as part of the dissolution procedure. The exte nt
ofdeaerati on can be
evaluated by
measuri ng the total dissolved gas pressure or
bymeasuri ng the concen trati
on of
dissolved oxyge n in water. For example, ano xyge
n concen tratio n below 6 mg/L
has bee
n found effective as a marker foradequate deaerati
on of water for the Performa
nee
Verificati on Test with USPPred nis one 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，影响试验结
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
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
< br>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<
/p>
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
surfacta nts usuallyare not deaerated because the
process results in
excessive foam ing,
and usuallythe effect of dissolved air on the
dissoluti on process is
mitigated by
thereduced surface tension of the medium.
Sometimes, deaerat ing the
medium
beforeaddi ng surfacta nts 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
determ ine whetherdeaerati on of the medium is n
ecessary,
compare results from
dissoluti on samplesr un in
non-
deaeratedmedium and medium deaerated using a compe
ndial tech niq ue,as
described above.
If no effect of deaeratio n is detected, this
experime nt could serve
asjustificati
on that deaerati on is not required in the future.
If there is an effect, however,
the n it isn ecessary to
carefully con trol this parameter, an dit is prude
nt to characterize
the robust ness of
the deaerati on process.
Thedissolvedgas content of deaerated
media un der atmospheric pressure is un stable
and willte nd toward saturatio n. Mani
pulatio nsof the deaerated medium such as stirri
ngor pouri ng can in crease 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试验结果。如果检测结果表
<
/p>
明脱气对
溶出结果没有影响，该试验就可以作为不需要进行脱气的
理由进行说
明。如果脱气对试验
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，
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
Si nkers
2.2
沉降篮
Sin kersare ofte n used to adjust the
buoya ncy of dosage forms that would
otherwisefloat
duri ng test ing with
Apparatus 2. When sin kers are used, a
detaileddescripti on of the sin
ker
must be provided in the
会趋
writte n procedure. It may beuseful to
evaluate differe nt sin ker types, recog nizing
that
sin kers can sig nifica ntly in
flue nee the dissoluti on pro a dosage un it. Whe
ntran sferri
ng the procedure, the same
si nkers should be used, or if a differentdesign
is used, it
should be shown to produce
equivale nt results. There areseveral types of
commercially
available sin kers. In
<711>, a harm oni zeds in ker is described in
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
Figure
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 sta ndard
sin ker can be made by using theappropriate len
gth of wire and coili ng it
around a
cyli nder. For materials,use316 sta in less steel
wire, typically 0.032 in ch/20
gauge,
or other in ertmaterial and wi nd the wire around
cyli nders of appropriatediameter
(e.g., corkborers) for an appropriate
nu mber of tur ns to fit the capsule shell type.
Sizesare show n in Table 2 . Thee nds
of the coil can be curved to retain thecapsule
within the sin ker whe n they are
immersed. Because the ends of thewiremay be rough,
they may n eed to be filed. If the sin
ker is han dmade, thes in ker material and con
struct
ion procedure in structi on
sshould be docume nted(e.g.,
dimension,
design, number of coils
）
; if
a commercial sinker is used,
theve ndor
part nu mbershould 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. WireSi nkers Used With Com mon
Capsule Shell Sizes
表
2
普通胶囊壳规格使用的沉降篮金属线尺寸
腋壽壹型号
ttOr
延壬释放
#lfU#2
金属线长度
12
10
8
言轻
Ccm')
O.S
0.7
0.55
软木辜孔数睪
4
3
Although sin kers 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 sin ker
size maynot be suitable for all dosage-form sizes.
The sinker
should not be too tightaro und the
dosage form because this may restrict in teract
ion with
the medium.C on versely, if
wrapped too loosely, the dosage form may escape
soon after
the testbeg ins. The sin ker
should be small eno ugh that the capsule does not
cha nge
itsorie ntatio n within the
should be taken when testing capsules thathave
some cross-linking present, to keep the
sticky shell from attach ing to thevessel bottom
.In
this case, the harm oni zed sin ker
desig n provided in Figure2a of <711>will be adva
ntageous.
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
< br>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。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。沉降
篮应该足够小使得胶囊在
沉降篮内不
能改变方向。
的沉降篮设计将是有利的。
2.3
Agitatio n
2.3
转速
Forimmediate-release capsule or tablet
formulatio ns. Apparatus 1
(baskets) at
50
-
100 rpm or Apparatus 2
(paddles) at 50or 75rpm
胶囊存在交联时，试验时应小
心，以保持胶囊壳不粘附在容器底部。
在这种情况下，在
<711>
图
2a
中统一提供
are used
com monly. Other agitatio n speeds are acceptable
with
appropriatejustificati on. Rates
outside 25
—
150
rpmfor both the
paddle and the basket
are usually not appropriatebecause of mixing
incon siste ncies that can be gen
erated bystirri ng too slow ortoo fast.
Agitati on rates betwee n 25 and 50 rpm
are gen erally acceptable
forsuspe
nsions.
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。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
conin g(m ounding) un der the paddle at
50 rpm, the coning can be reduced by in
creas in gthe paddle speed to
75 rpm,
thus reduci ng the artifact and impro ving the
data .If
justified, 100 rpm may be used
with Apparatus 2, especially
forexte nded-
release products. Decreas ing or in creas ing the
apparatus rotati on speed
may be
justified if to achieve an in-vitro
—
in-vivo
correlati on (IVIVC)the result ing
profiles better
reflect in
vivo performa nee, 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，
<
/p>
也可以采
用桨法
100rpm
转速。如果能够实现体内外相关性
(
IVIVC<
/p>
)
，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 (reciprocati
ng cyli nder)ca n be used at dip rates ranging
from 5 to 30
dips/mi n. The hydrod yn
amics arein flue need by the cyli nder's
reciprocat ing moti on
and the result
ing moveme nt ofthe sample in the medium. The
reciprocating motion of the
cyli nder
and scree nmay cause foami ng if the medium
contains surfacta nts. Additi on of
anan ti-foam ing age nt such as
simethic one or n-octanol may be useful
foravoiding
foaming from surfactants.
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
sta ndard flow
rates of 4, 8,a nd 16 mL/m in. Other flow rates
for
Apparatus 4 can be used if
justified and ifwithin the capacity of the pump to
conform with
the requireme nts in
a
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 con figured
with the
additi on of glass beads in thee ntry cone of the
flow-through cell
（
packed
colu
mn
）
or
without glass beads
（
ope n
colu mn
）
.
仪器
4
（
流
通池
）
在
＜
7
11
＞
中描述了标准流速
4
、
8
、
16ml/min
。如果经过验证
并
< br>且在该泵的承受的能力范围内符合
＜
711
＞
的要求，仪器
4
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。
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
Selecti onof the agitati on rate and
other study desig n eleme nts for the dosage
form,whether immediate release or
modified release, should conform to therequireme
nts
and specificati ons (i.e.,
apparatus, procedures, andin terpretati on) give n
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,
thedurati on of the dissolutio n procedure is
typically
30
-60 mi n; in
most cases, asi ngle time point
通过测定体积设定流速，
12mm
<
/p>
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
specificati on is
adequate for pharmacopeial purposes. Formethod
developme nt,
however, a sufficie nt nu
mber of time points should beselected to
adequately
characterize the asce nding
and plateau
phases of thedissoluti on
curve. In dustrial and regulatory con cepts of
product
comparabilitya nd performa nee
may require additi onal time poin ts, which may
also be
requiredfor product registrati
on or approval. Accordi ng to the
BiopharmaceuticsClassificati on System
referred to in severalFDA Guida nces, highly
soluble,highly
permeable drugs formulated into very rapidly
dissol ving products n eed not
be
subjected to a pro if they can be show n to
release 85% ormore of the drug substa nee
with in 15 min. For these types of
products, aon e-po int test or dis in tegrati on
will suffice.
However, most products do
notfall into this category. Dissolution profiles
of immediate-
release productstypically
show a gradual in crease reachi ng 85%
TOO% at about 30
-
45 min. Thus,sufficie nt
dissoluti on time poi nts are chose n
to characterize the performa ncefor most
immediate-
release products. For some
products,i ncludi ng suspe nsion s,useful in
formatio n may be
obta ined from
earlier poin ts, e.g., 5 TO min. Forslower-dissol
ving products, time points
later than
60 min may be ution test times for compe ndial
tests are usually
established on
thebasis of an evaluati on of the dissoluti on
pro.
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
旨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
试验就足够
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
< br>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
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
典中规定溶解度试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
< br>分钟溶出量大于
85%
勺制剂。如果使用
f
2
相似因子
进行比
较，需要进行多个时间点溶出度测定，至少两个取样时间点平均溶出值
低
于
85%(
—般是
n=12
)
并且两组产品的
溶出度值只有一个时间点大于
在早期增加时间点检查是有必要的。
For test ing an exte nded-release
dosage form, at least three time
points
are chose n, to guardaga inst dose dump ing, to
defi ne the in
vitro release profile,
and to show thatessentially complete release
(>80%) of the drug is achieved.
Additionalsampling times may be
useful.
Certa in IVIVC criteria, such as level Bcorrelati
on (accord ing to
In Vitro and In Vivo
Evaluati on of DosageForms
<1088>),
require the
85%
因此
,
experime ntal determ in ati on of the
timeto dissolve 100% of the label
claim. Selection of the final time
points isreflective of the data from
the drug release pro are gen erated
duri ngdevelopme nt. For products
containing more tha n a sin gle active
in gredie nt,determi ne the drug
release for each active in gredie nt. <
/p>
对于缓释剂型溶出试验，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
根据试验确定药物释放
品，需要确定每种活性成分的药物释放。
Delayed-release dosage formsusually
require specificati ons 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 fun cti on ality of
the coati ng isusually prove n by
100%
勺时间点。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
challe nge in an acid medium, followed
by a dem on strati on
ofdissoluti on in
a higher-pH medium. Chapter <711> gives a
sta ndard buffer medium for that stage
of test ing but other
mediamay be used
if justified. The timing of the acid stage is
typically
2 h, an drelease in the
buffer is similar to the timi ng
forimmediate-release forms. Fordelayed-
release dosage forms that
are not en
teric coated, setti ng of specificati on sis
differe nt. Un like
delayed release,
the on set of release is not determ ined by
theexperime ntal desig n, which is the
pH cha nge;
multivariatespecifications,therefore,
may be needed to definetime
ran ges and
corresp onding perce ntagera nges
延迟释放剂型通常需要至少设计
2<
/p>
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<
/p>
＞
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 duri ng
developme nt studies. To obta in an infinity
point, the paddleor basket speed is in
creased at the end of the run (after the last time
poin t)for a susta ined 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 in formatio
n about
formulatio n 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
?
6
0
分
钟
)
，在
这段时间后，取样测定。虽然在溶出曲线中不要求
100%
勺溶
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。
242 OBSERVATIONS
242
观察
Visual observati ons and recordi ngs
ofproduct dissoluti on and dis in tegratio n
behavior
are useful because dissoluti
onand dis in tegratio npatterins can be in
dicative of variables
in the formulati
on orma nu facturi ng process. For visual
observati on, proper lighting
(with
appropriateconsideration of photo-degradation) of
the vessel contents and clear
visibility in the bath are esse nti ng
observati ons by draw ing sketches an
dtak ing photographs or videos can be
in structive and helpful for thosewho arenot able
to
observe the real-time dissoluti on
test. Observati ons are especiallyuseful duri ng
method
developme nt an dformulati on
optimizati on .It is importa ntto record observati
ons 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 formulatio n developme nt, provide any
uniq ueobservati ons to
theformulator.
Examples of typical observati ons in clude, butare
not limited to, the followi
ng:
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
够实时观察溶出度试验的人来说是有用的。
是否在六个容器中观察到该结果，
观察溶出过程变
或者仅仅是几个溶出杯观察到该结
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
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：
1. U neve n
distributi on of particles throughout the vessel.
This can occur whe n
particlescli ng to
the sides of the vessel, whe n there is coning or
mounding directl yun der
the apparatus
(e.g., below the basket or paddle), whe n
particles float atthe surface of the
medium, whe n film-coated tablets stick
to the vessel, an d/orwhe n off-ce nter mounds
are formed.
2.
Air bubbles on the in
side of the vessel or on the apparatus or dosage
un n on
the apparatus is also a sig n
of air bubbles. This observati on wouldtypically
be made whe
n assess ing the n eed to
deaerate the medium.
3.
Da
ncing or spinning of the dosage un it, or the
dosage un it being hit by thepaddle.
4.
Adhesi on of particles to the paddle or
the in side of the basket, which may beobserved
upon removal of the stirri ng deviceat
the end of the run.
5.
Pellicles or an alogous formati ons,
such as tran spare nt sacs or rubbery, swolle nm
asses surro unding the capsule conten
ts.
6.
Presence of large
floating particles or chunks of the dosage unit,
especiallyat the
surface of the media.
ati on of the dis in tegrati on rate
(e.g., perce ntage reducti on in size ofthe
dosage unit within a certain time
frame).
8.
Complex dis in
tegrati on of the coati ng of modified or
en teric-coated products,[e.g., the
partial ope ning and splitt in gapart (similar to
a
clamshell) orin complete ope ning of
the shell], accompa nied by the release of air
bubbles an dexcipie nts.
9.
Whether the dosage form lands in the
vessel cen ter or off-ce nter, and ifoff-ce nter,
whether it sticks there.
required for the complete
dissolution of the capsule shell or for tabletdisi
ntegrati
on.
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
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.
试验结束后，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.
剂型是否位于中心还是偏离中心，如果偏离中心，是否粘附。
10.
胶囊壳完全溶解或片剂崩解所需的时间。
Observati on salso help to docume nt
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 duri ng the test or that
more tha n 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。
实例包括在试验期间确认在容器中实际存在的是一种剂型，
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
Selecti onof
the agitati on rate and other study desig n eleme
nts for
the dosage form,whether
immediate release or modified
release,
或同一容器
/
或当偏离
should conform to
therequireme nts and specificati ons (i.e.,
apparatus, procedures, andin
terpretati
on) give n 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,
thedurati on of the dissolutio n procedure is
typically
30
-60 mi n; in
most cases, asi ngle time point
specificati on is adequate for
pharmacopeial purposes. Formethod developme nt,
however, a sufficie nt nu mber of time
points should beselected to adequately
characterize the asce nding and plateau
phases of thedissoluti on curve. In dustrial and
regulatory con cepts of product
comparabilitya nd performa nee may require additi
onal
time poin ts, which may also be
requiredfor product registrati on or approval.
Accordi ng to
the
BiopharmaceuticsClassificati on System referred to
in severalFDA Guida nces, highly
soluble,highly permeable drugs
formulated into very rapidly dissol ving products
n eed not
be subjected to a pro if they
can be show n to release 85% ormore of the drug
substa nee
with in 15 min. For these
types of products, aon e-po int test or dis in
tegrati on will suffice.
However, most
products do notfall into this category.
Dissolution profiles of
immediate-
release productstypically
show a gradual in crease reachi ng 85% TOO% at
about 30
dissoluti on time poi nts are
chose n to characterize the
performa
ncefor most immediate-release products. For some
products
」
ncludi
ng suspe nsion s,useful in formatio n may be obta
ined
—
45 min. Thus,sufficie
nt
from earlier
poin ts, e.g., 5
TO min. Forslower-
dissol ving products,
time points later
than 60 min may be ution test times
for
compe ndial tests are usually established on
thebasis of an
evaluati on of the
dissoluti on pro.
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
FD
对旨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
试验就足够了。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%
?<
/p>
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
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
典中规定溶解度试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%
勺制剂。如果使用
f
2
相似因子
进行比
较，需要进行多个时间点溶出度测定，至少两个取样时间点平均溶出值低
于
85%(
—般是
n=12
)
并且两组产品的溶
出度值只有一个时间点大于
在早期增加时间点检查是有必要的。
85%
因此
,
For test ing an exte nded-release
dosage form, at least three time points are chose
n, to
guardaga inst dose dump ing, to
defi ne the in vitro release profile, and to show
thatessentially complete release (>80%)
of the drug is achieved. Additionalsampling times
may be useful. Certa in IVIVC criteria,
such as level Bcorrelati on (accord ing to
In Vitro and In Vivo Evaluati on of
DosageForms
<1088>), require the
experime ntal determ in ati on of the
timeto dissolve 100% of the label claim. Selection
of
the final time points isreflective
of the data from the drug release pro are gen
erated duri
ngdevelopme nt. For
products containing more tha n a sin gle active in
gredie nt,determi
ne the drug release
for each active in gredie nt.
对于缓释剂型溶出试
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>'
)
需要根据试验确定药物释放
100%
勺时间点。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。
< br>
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 specificati ons 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 fun cti on ality
of the coati ng isusually prove
n by
challe nge in an acid medium, followed by a dem on
strati on ofdissoluti on in a
higher-pH
medium. Chapter <711> gives a
sta ndard
buffer medium for that stage of test ing but other
mediamay be used if justified. The
timing of the acid stage is typically
2 h, an drelease in the
buffer is similar to the timi ng
forimmediate-release forms. Fordelayed-
release dosage forms that
are not en
teric coated, setti ng of specificati on sis
differe nt. Un like
delayed release,
the on set of release is not determ ined by
theexperime ntal desig n, which is the
pH cha nge;
multivariatespecifications,therefore,
may be needed to definetime
ran ges and
corresp onding perce ntagera nges
延迟释放剂型通常需要至少设计
2<
/p>
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 duri ng
developme nt studies. To
obta in an
infinity point, the paddleor basket speed is in
creased at the
end of the run (after
the last time poin t)for a susta ined 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
in formatio n about formulatio n
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
开发过程中的制剂特性或方法偏差。
100%
勺溶
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
242 OBSERVATIONS
242
观察
Visual observati ons and recordi ngs
ofproduct dissoluti on and dis in tegratio n
behavior
are useful because dissoluti
onand dis in tegratio npatterins can be in
dicative of variables
in the formulati
on orma nu facturi ng process. For visual
observati on, proper lighting
（
with
appropriateconsideration of photo-
degradation
）
of the vessel
contents and clear
visibility in the
bath are esse nti ng observati ons by draw ing
sketches an
dtak ing photographs or
videos can be in structive and helpful for
thosewho arenot able to
observe the
real-time dissoluti on test. Observati ons are
especiallyuseful duri ng method
developme nt an dformulati on
optimizati on .It is importa ntto record observati
ons 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 formulatio n developme nt, provide any
uniq ueobservati ons to
theformulator.
Examples of typical observati ons in clude, butare
not limited to, the followi
ng:
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试验的人来说是有用的。
是否在六个容器中观察到该结果，
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
或者仅仅是几个溶出杯观察到该结
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：
1. U neve n distributi on of particles
throughout the vessel. This can
occur
whe n particlescli ng to the sides of the vessel,
whe n there is
coning or mounding
directl yun der the apparatus (e.g., below the
basket or
paddle), whe n particles float atthe surface of
the medium,
whe n film-coated tablets
stick to the vessel, an d/orwhe n off-ce nter
mounds are formed.
2.
Air bubbles on the in side of the
vessel or on the apparatus or
dosage un
n on the apparatus is also a sig n of air bubbles.
This
observati on wouldtypically be
made whe n assess ing the n eed to
deaerate the medium.
3.
Da ncing or spinning of the dosage un
it, or the dosage un it being hit
by
thepaddle.
4.
Adhesi on of
particles to the paddle or the in side of the
basket,
which may beobserved upon
removal of the stirri ng deviceat the end
of the run.
5.
Pellicles or an alogous formati ons,
such as tran spare nt sacs or
rubbery,
swolle nm asses surro unding the capsule conten
ts.
6. Presenee of large floating
particles or chunks of the dosage unit,
especiallyat the
surface of the media.
7.0bservati on of the dis in tegrati on
rate (e.g., perce ntage reducti on in size ofthe
dosage unit within a certain time
frame).
8.
Complex dis in
tegrati on of the coati ng of modified or
en teric-coated products,[e.g., the
partial ope ning and splitt in gapart (similar to
a
clamshell) orin complete ope ning of
the shell], accompa nied by the release of air
bubbles an dexcipie nts.
9.
Whether the dosage form lands in the
vessel center or off-center, and ifoff-ce nter,
whether it
sticks there.
10. Time required for the
complete dissolution of the capsule shell or for
tabletdis in
tegrati on.
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.
试验结束后，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.
剂型是否位于中心还是偏离中心，如果偏离中心，是否粘附。
10.
胶囊壳完全溶解或片剂崩解所需的时间。
Observati on salso help to docume nt
that the proper procedure has been followed, or
more importantly,that a deviation has
occurred.
Examples in elude the con
firmati on that a dosageform is actually in
the vessel duri ng the test or that
more tha n 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
包括在试验期间确认在容器中实际存在的是一种剂型，
无意中存在多种剂型，或自动进样器的过滤器掉进容器中。
或同一容器
Figure 1. An example of a
plotof dissolution as a cumulative process.
Concen trati on, C, is the
amoun tof drug released per volume of medium, and
t
represents time. This type of plotis
readily observed in con sta nt-volume dissoluti on
systems, such as Apparatus 1or
Apparatus 2, or Apparatus 4 in closed-
loop con figurati on.
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。