药物稳定性实验

1150药物稳定性

The term ―stability,‖ with respect to a drug dosage form, refers to the chemical and physical integrity of the dosage unit and, when appropriate, the ability of the dosage unit to maintain protection against microbiological contamination. The shelf life of the dosage form is the time lapse from initial preparation to the specified expiration date. The monograph specifications of identity, strength, quality, and purity apply throughout the shelf life of the product.

The stability parameters of a drug dosage form can be influenced by environmental conditions of storage (temperature, light, air, and humidity), as well as the package components. Pharmacopeial articles should include required storage conditions on their labeling. These are the conditions under which the expiration date shall apply. The storage requirements specified in the labeling for the article must be observed throughout the distribution of the article (i.e., beyond the time it leaves the manufacturer up to and including its handling by the dispenser or seller of the article to the consumer). Although labeling for the consumer should indicate proper storage conditions, it is recognized that control beyond the dispenser or seller is difficult. The beyond-use date shall be placed on the container label.

就药物制剂而言，术语“稳定性”是指单位剂量药物理化性质的完整程度以及在适当情况下对微生物污染的抵抗能力。制剂的有效期指从生产至失效期的期限。在有效期内，产品须符合各论中有关鉴别、效价、质量和纯度的规定。

药物制剂的稳定性参数可能受到它所贮存的环境（温度、光照、空气和湿度）的影响，还受到包装材料的影响。药典收载的药物制剂的标签应标明贮存条件。在有效期内，药品应在规定的各条件下贮存。药品在分销过程中（即从药品离开生产商后直到由配药员处理或销售者卖给消费者）必须遵守标签上规定的贮存要求。尽管对于消费者来说药品标签应标明合适的贮存条件，但是药品在由配药员或销售者到达消费者手中时，对贮存环境的控制是很困难的。药品的失效期应在容器标签上注明。

Stability Protocols

Stability of manufactured dosage forms must be demonstrated by the manufacturer, using methods adequate for the purpose. Monograph assays may be used for stability testing if t hey are stability-indicating (i.e., if they accurately differentiate between the intact drug mol ecules and their degradation products). Stability considerations should include not only the specific compendial requirements, but also changes in physical appearance of the product that would warn users that the product's continued integrity is questionable.

Stability studies on active substances and packaged dosage forms are conducted by means of ―real-time,‖ long-term tests at specific temperatures and relative humidities representing storage conditions experienced in the distribution chain of the climatic zone(s) of the coun try or region of the world concerned. Labeling of the packaged active substance or dosage form should reflect the effects of temperature, relative humidity, air, and light on its stab ility. Label temperature storage warnings will both reflect the results of the real-time stora ge tests and allow for expected seasonal excursions of temperature.

稳定性试验

生产商必须通过合适的方法证明药物剂型的稳定性。如果各论中的含量测定法可以指示稳定性，那么它们就可以用于稳定性试验（即含量测定法能准确区分出完整的药物分子和它

们的降解产物）。在考察药物的稳定性时，不仅应包括药典对其的要求，还应包括药物物理性状的改变，这些可以提示使用者药物的完整性是否有问题。

按照规定时间点考察活性成分和药物制剂的稳定性。长期试验是在特定的温度、相对湿度条件下进行的，此条件代表销售此药品的相关国家或地区所在的气候带。已包装的活性成分或药物制剂的标签（Labeling）中应标明温度、相对湿度、空气和光照对它们的稳定性的影响。标签（Label）标识的贮存温度的要求不仅要考虑稳定性试验的结果，还要考虑到预期的季节性的温度偏差。

Controlled Room Temperature

Controlled room temperature (see Storage Temperature and Humidity in Preservation, Packa ging, Storage, and Labeling under General Notices and Requirements) delineates the allowa ble tolerance in storage circumstances at any location in the chain of distribution (e.g., ph armacies, hospitals, and warehouses). This terminology also allows patients or consumers t o be counseled as to appropriate storage for the product. Products may be labeled either t o store at ―Controlled room temperature‖ or to store at temperatures ―up to 25°‖ where l abeling is supported by long-term stability studies at the designated storage condition of 25°. Controlled room temperature limits the permissible excursions to those consistent wit h the maintenance of a mean kinetic temperature calculated to be not more than 25°. Se e Mean Kinetic Temperature. The common international guideline for long-term stability st udies specifies 25 ±2°at 60 ±5% relative humidity. Accelerated studies are specified a t 40 ±2°and at 75 ±5% relative humidity. Accelerated studies also allow the interpret ation of data and information on short-term spikes in storage conditions in addition to the excursions allowed by controlled room temperature.

The term ―room temperature‖ is used in different ways in different countries, and for prod ucts to be shipped outside the continental U.S. it is usually preferable for product labeling to refer to a maximum storage temperature or temperature range in degrees Celsius.

受控的室温

受控的室温（见通则和要求中保存，包装、贮存和标签项下的贮存温度和湿度）描述了药品销售地的贮存环境（如药房、医院和仓库）的允许偏差。这个术语建议病人或消费者在合适的条件贮存药物。药品的标签会标示贮存于“受控的室温”或者“不超过25度”，此贮存条件是由贮存于25度的长期稳定性研究得到的。受控的室温的允许偏差与平均运动温度一致，不超过25度。一般国际指导原则规定长期稳定性研究的条件为25±2℃，相对湿度60±5%。加速稳定性研究的条件为40±2℃，相对湿度75±5%。除了受控室温允许的偏离外，加速试验也可提供关于贮存条件下短期偏移信息与数据的解释。

药品要运输到北美大陆外的其他国家，在这些不同国家，术语“室温”有不同的表达方式。所以对于药品的标签来说，最好使用以摄氏度标明的最高贮存温度或温度范围。

Mean Kinetic Temperature

Mean Kinetic Temperature (MKT) is defined as the single calculated temperature at which the total amount of degradation over a particular period is equal to the sum of the indivi dual degradations that would occur at various temperatures. Thus, MKT may be considere d as an isothermal storage temperature that simulates the nonisothermal effects of storage t emperature variation. It is not a simple arithmetic mean. MKT is calculated from temperat

ures in a storage facility. The temperatures for calculating MKT can be conveniently colle cted using electronic devices that measure temperatures at frequent intervals (e.g., every 15 minutes). MKT can be calculated directly or the data can be downloaded to a computer for processing. For dispensing sites, such as pharmacies and hospitals, where the use of s uch instruments may not be feasible, devices such as high-low thermometers capable of in dicating weekly high and low temperatures over a 52-week period may be employed. The arithmetic mean of the weekly high and low temperatures is then used in the calculation of MKT. MKT is calculated by the following equation (derived from the Arrhenius equat ion):

平均运动温度

平均运动温度（MKT ）定义为一个计算温度，一段时间内在这个温度药品的降解总量等于在贮存时不同温度药品降解的总和。因此，MKT 可以被认为是等温的贮存温度，用它来模拟不等温的贮存温度变化。它并不是简单的算术平均。MKT 是由一个贮存装置中测得的温度计算出来的。用来计算MKT 的温度可以很容易通过电子设备测定出，此装置测定温度的间隔很短（例如：每15分钟）。可以使用电子设备直接计算MKT,也可以将数据下载到电脑中再计算。在配药的地方，例如药剂室或者医院，使用以上装置可能不太可行，但可以使用如高低温度测量设备这样的装置，它能测量出52周内的周最高和周最低温度。周最高和周最低温度的算术平均用于计算MKT 。下列公式用于计算MKT （由阿仑尼乌斯方程推导出）：

in which T k is the mean kinetic temperature; D H is the heat of activation, 83.144 kJ·m ole 1 (unless more accurate information is available from experimental studies); R is the u niversal gas constant, 8.3144 × 10 3 kJ·mole 1 ·degree 1; T 1 is the value for the temper ature recorded during the first time period, e.g., the first week; T 2 is the value for the t emperature recorded during the second time period, e.g., second week; and T n is the val ue for the temperature recorded during the nth time period, e.g., nth week, n being the to tal number of storage temperatures recorded (minimum of 52 weekly entries) during the a nnual observation period. [ note — All temperatures, T, are absolute temperatures in degree s Kelvin (K). ]

The following is an example of a typical storage and distribution temperature range in Ke lvin degrees and the conversion factors used to convert this range into degrees Fahrenheit and Celsius.

Kelvin (K) Fahrenheit (F) Celsius (C)

288.1–303.1 59–86 15–30

Conversion Factors:

Fahrenheit to Kelvin = {[(F 32) × 5/9] + 273.1}

Celsius to Kelvin = 273.1 + C

Fahrenheit to Celsius = [(F 32) × 5/9]

e －⊿H/RT 1＋e －⊿H/RT 2＋…＋e －⊿H/RT n

n ( )

-ln ⊿H/R

T k ＝

公式中T k代表平均动力温度；⊿H代表激活的热能，83.144KJ．mole-1（除非从试验研究中能得到更精确的信息）；R代表气体常数，8.3144×10-3KJ．mole-1．degree-1；T1为第一时间段记录的温度数值，例如，第一周；T2为第二时间段记录的温度数值，例如，第二周；T n为第n时间段记录的温度数值，例如，第n周，n为记录的贮存温度的总数（每周一次记录，在每年的监测周期内最小为52次）【注释：所有温度T，为绝对温度，单位为开尔文（K）。】下面是典型的贮存和流通温度范围的例子（单位为开尔文），通过转换因子将此范围转换为华氏温度和摄氏度范围。

Kelvin（K）Fahrenheit（℉）Celsius（℃）

288.1-303.1 59-86 15-30

转换公式：

华氏温度转换为开尔文={[(℉－32)×5/9]＋273.1}

摄氏温度转换为开尔文=273.1＋℃

华氏温度转换为摄氏温度=[(℉－32)×5/9]

Climatic Zones

For convenience in planning for packaging and storage, and for stability studies, internatio nal practice identifies four climatic zones, which are described in Table 1. The United Sta tes, Europe, and Japan are characterized by zones I and II. The values in Table 1 are bas ed on observed temperatures and relative humidities, both outside and in rooms, from whi ch mean kinetic temperatures and average humidity values are calculated.1 Derived values are based on inspection of data from individual cities and on allowances for a margin of safety in assignment of these specified conditions.

＊Data recorded as ＜19°calculated as 19°.

＊＊Calculated mean kinetic temperature.

＊＊＊Partial pressure of water vapor.

气候带

为了包装和贮存的方便，以及稳定性试验，国际上规定了四个气候带，见表1。美国、欧洲和日本在第一和第二气候带。表1的数据中，平均运动温度和平均湿度是由室外和室内测定的温度和湿度计算得到的。推导出的数据是由个别国家的监测数据得到的，符合规定条件的允许偏差。

表1.国际气候带

＊＊计算的平均运动温度

＊＊＊水蒸气的分压力

A discussion of aspects of drug product stability that are of primary concern to the pharmacist in the dispensing of medications may be found under Stability Considerations in Dispensing Practice<1191>.

Inasmuch as this chapter is for purpose of general information only, no statement herein is intended to modify or supplant any of the specific requirements pertinent to pharmaceutical preparations, which are given elsewhere in this Pharmacopeia.

对于药剂师最关注的药物制剂稳定性中的配药的稳定性见配药工作中的药品稳定性保持<1191>。

由于本章只是阐述一般信息，没有修改或取代相关的药物制剂的特殊要求，这些在药典其他地方有说明。