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。
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(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 precedingintervals.This 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试验结果。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=（M2-M1）/（t2-t1） M=标示量要求的质量和比例 t=时间
As the difference of t2fromt1is 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 t2and t1issmall, 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
