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%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
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 essential.Documenting 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试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.Uneven 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.
2.Air bubbles on the inside of the vessel or on the apparatus or dosage unit.Sheen on the apparatus is also a sign of air bubbles. This observation wouldtypically be made when assessing the need to deaerate the medium.
3.Dancing or spinning of the dosage unit, or the dosage unit being hit by thepaddle. 4.Adhesion 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.
5.Pellicles or analogous formations, such as transparent sacs or rubbery, swollenmasses surrounding the capsule contents.
6.Presence of large floating particles or chunks of the dosage unit, especiallyat the surface of the media.
7.Observation of the disintegration rate (e.g., percentage reduction in size ofthe dosage unit within a certain time frame).
8.Complex 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.
9.Whether the dosage form lands in the vessel center or off-center, and ifoff-center, whether it sticks there.
10.Time 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.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。
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。实例包括在试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 useful.Dissolution 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 f2 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.
f2相似因子不适用于15分钟溶出量大于85%的制剂。如果使用f2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%（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%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
