【正文】 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 (., drug substance, excipients, ormanufacturing process) or artifacts associated with the test procedure (.,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 position ofthe medium.合理設(shè)計一個試驗保證數(shù)據(jù)穩(wěn)定性（即較低的變異性），并且能夠明顯反映出樣品穩(wěn)定性問題。結(jié)果的高變異難以確定處方變化的趨勢和處方變化對溶出度結(jié)果的影響。樣本大小影響所觀察到的變異性。如果在10分鐘 12個樣本的相對標(biāo)準(zhǔn)偏差（RSD）不得過20%或者后續(xù)取樣點的RSD值大于10%。，指導(dǎo)原則對溶出度試驗結(jié)果定義為高變異性。然而，在方法開發(fā)過程中，可以使用較小的樣本量，需要對分析作出相應(yīng)的判斷。大多數(shù)溶出結(jié)果，表現(xiàn)出較少的變異性。在溶出度試驗開發(fā)過程中應(yīng)對產(chǎn)生變異的原因進(jìn)行研究，只要有可能，應(yīng)嘗試減少變異性。引起變異性的兩個最可能的原因是制劑本身（例如，原料藥，輔料，或制劑工藝）和與檢測過程相關(guān)的處理過程（例如，溶出漩渦，片粘在溶出杯壁或籃網(wǎng)上）。試驗過程的觀察往往有助于查找產(chǎn)生變異的原因或者溶出度測定方法本身是否會產(chǎn)生變異性。任何時間內(nèi)劑量含量不能均勻地分散在整個容器中，異常結(jié)果就可能發(fā)生。根據(jù)不同的問題，通常的調(diào)節(jié)方法包括下列任何一個因素的改變：儀器，轉(zhuǎn)速，脫氣程度，沉降籃類型，或者溶出介質(zhì)的組成。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.在處方開發(fā)和制劑工藝中，可以找到產(chǎn)生變異的許多原因。例如，含量均勻度的差異，工藝的不一致，輔料的相互作用或干擾，包衣，膠囊殼老化，制劑穩(wěn)定性考查中出現(xiàn)的硬化或軟化是產(chǎn)生和干擾變異的原因。 DeaerationThesignificance 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.應(yīng)明確溶出介質(zhì)脫氣的目的，因為在溶解過程中如果在劑量單位或籃網(wǎng)出現(xiàn)氣泡，會起到一個屏障作用，影響試驗結(jié)果的可靠性。此外，氣泡會使顆粒粘在設(shè)備和容器壁上。劑量單位上的氣泡可能會增加浮力，導(dǎo)致溶解速率增加，或者也有可能會減少可接觸的表面積導(dǎo)致溶出率下降。氣泡對難溶性藥物的干擾最敏感；因此檢驗這些類型的產(chǎn)品時需要脫氣。在711部分附錄中描述了脫氣方法。典型的脫氣方法：加熱、過濾和在短時間內(nèi)抽真空。其他脫氣方法和常規(guī)使用的脫氣方法也是可用的。一旦確定一個合適的脫氣方法，應(yīng)該作為溶出方法的一部分記錄下來。通過測量總?cè)芙鈿怏w壓力或通過測量水中溶解的氣體濃度來評估脫氣的程度。例如，使用USP的性能驗證測試潑尼松龍片校正片發(fā)現(xiàn)水中氧濃度低于6毫克/升時，表明水已充分脫氣。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.含有表面活性劑的溶出介質(zhì)由于脫氣過程會產(chǎn)生過多氣泡通常不容易脫氣，通常采用減少溶出介質(zhì)中的表面張力，來減輕溶解的空氣對溶解過程產(chǎn)生的影響，有時，在加入表面活性劑之前對溶出介質(zhì)進(jìn)行脫氣是有效的。To determine whetherdeaeration of the medium is necessary, pare results from dissolution samplesrun in nondeaeratedmedium and medium deaerated using a pendial 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.確定溶出介質(zhì)是否需要脫氣是必要的，如上面所描述的，使用藥典技術(shù)中的脫氣方法，比較樣品在脫氣和未脫氣的溶出介質(zhì)中的溶出試驗結(jié)果。如果檢測結(jié)果表明脫氣對溶出結(jié)果沒有影響，該試驗就可以作為不需要進(jìn)行脫氣的理由進(jìn)行說明。如果脫氣對試驗結(jié)果有影響，那么有必要準(zhǔn)確控制這個參數(shù)，詳細(xì)描述脫氣過程中耐受性特點。在大氣壓強下，脫氣介質(zhì)中溶解的氣體量是不穩(wěn)定的，會趨向飽和。比如攪拌或傾倒已脫氣的介質(zhì)可以增加氣體的再溶解速率。 SinkersSinkersare 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 mercially available sinkers. In 711, a harmonizedsinker is described in Figure 2a.在使用儀器2進(jìn)行測試時，沉降籃通常用于調(diào)節(jié)易于漂浮的劑型。當(dāng)使用沉降藍(lán)時，必須對沉降籃儀器進(jìn)行詳細(xì)描述。評估沉降籃的不同類型，同時要認(rèn)識到沉降籃能夠顯著影響溶出曲線。當(dāng)轉(zhuǎn)移這個方法時，應(yīng)使用相同的沉降籃，或者如果使用不同設(shè)計的沉降籃，應(yīng)當(dāng)證明兩種不同的沉降籃產(chǎn)生的結(jié)果相同。有幾種可用的商業(yè)類型的沉降籃。在711中圖2a中統(tǒng)一對沉降籃進(jìn)行了詳細(xì)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 inch/20 gauge, or other inertmaterial and wind the wire around cylinders of appropriatediameter (., corkborers) for an appropriate number of turns to fit the capsule shell type. S