European PharmacopoeiaEP10.0Specification for Solution Clarity Inspection

<2.2.1Clarity and opalescence of liquids>

The effect produced by the absorption or scattering of light by submicron particles, or uneven light density, is called opalescence. When there are no particles or inhomogeneity in the solution, a clear solution will be obtained.

When inspecting under the following conditions, if the transparency of the tested liquid is similar to that of water or the solvent used, or its opalescence is not higher than that of the reference suspensionI(See table)2.2.1.-1）If the milky light is more obvious, it is considered that the tested liquid is transparent.

By comparing with the prescribed reference suspensionICompare (see table)2.2.1.-1）Visually inspect whether it meets the requirements of the monograph. However, once the applicability of the instrument is established as described below, the instrument method can also be used to determine compliance with the monograph requirements and reference suspensions can be usedI-IVCalibrate with water or the solvent used.

visual method

Use the same colorless transparent neutral glass test tube with a flat base and an inner diameter of15-25 mmCompare the liquid to be tested with the newly prepared reference suspension as follows. Ensure that the depth of each layer in the two test tubes is the same (approximately)40 mm）.

Preparation of reference suspension5After minutes, compare the liquid under diffuse sunlight and observe vertically against a black background.

System SuitabilityThe diffusion of light must ensure the reference suspensionIIt can be easily separated from the water zone and referenced to the suspensionIICan be easily compared with the reference suspensionIDistinguish (see table)2.2.1.-1）.

Instrument method

Instrumental evaluation provides a more discriminative testing method for transparency and opalescence, which does not rely on the visual acuity of the analyst. Numerical results are more useful for process control and quality monitoring, especially in stability studies. For example, it is possible to extrapolate from previous numerical data on stability to determine whether a given batch of formulations will exceed the shelf life limit before the expiration date.

Turbidity method and turbidity method

When observing the suspension at a right angle to the incident light direction, the system appears milky white due to the scattering of light by the suspension particles (Tyndall effect). Part of the light beam entering the turbid liquid is transmitted, another part is absorbed, and the remaining part is scattered by suspended particles. The light scattering effect of suspended particles can be indirectly measured by observing transmitted light (turbidity method), or directly measured by measuring scattered light (turbidity method). Turbidity method and turbidity method are more reliable in the low turbidity range, and there is a linear relationship between turbidity value and detector signal. As the turbidity increases, not all particles are exposed to incident light, and the scattered or transmitted radiation of other particles will be hindered in reaching the detector.

The construction of calibration curves is crucial for quantitative measurement. Linearity must be based on at least4A concentration level. The reference suspension must exhibit sufficiently stable turbidity and must be produced under clear conditions.

Measurement in ratio mode

Due to the negative interference caused by color, which attenuates incident and scattered light and reduces turbidity values, instruments with ratio modes are used to measure the opalescence of colored liquids. The impact is so significant that even samples of medium color cannot be measured using traditional turbidity meters.

In turbidity or turbidity methods, the ratio mode is used to determine the transmission measurement and90The ratio of scattered light measurement. This program compensates for the reduced light caused by the color of the sample. The spectral sensitivity of instruments with ratio mode is approximately550 nmUsing tungsten lamps as light sources2700 KWorking under the color temperature of the filament. Other suitable light sources can also be used. Silicon photodiodes and photomultiplier tubes are commonly used as detectors to record changes in scattered or transmitted light from samples. Measured by the main detector90±2.5Scattered light at °, other detectors measure the front and rear scattered (reflected light) as well as transmitted light. Measured through calculation90The ratio of scattered light to the sum of forward scattered light and transmitted light components can be used to obtain the result.

The instrument used is calibrated according to known turbidity standards and can automatically measure turbidity. The test results are obtained directly from the instrument and compared with the specifications in each monograph.

Alternatively, it can also be achieved by using the maximum emission wavelength of860 nmThe spectral bandwidth is60 nmInfrared light-emitting diode（IR LED）As an instrument light source to eliminate the influence of sample color.

Instrument requirements

Instruments that meet the following characteristics and are validated using the following reference suspension can be used instead of visual inspection to determine compliance with the requirements of the monograph.

Measurement unit:NTU(Turbidity measurement unit).NTUIt is based on the turbidity of the first grade standard of fumarate. Can also be usedFTU(Fumalazine turbidity unit) orFNU(Fumalazine turbidity unit), equivalent toNTUIn the low turbidity area (highest)40 NTU）. These units are applicable to all3Various instrument methods (turbidity method, turbidity method, and ratio mode).

- Measurement range:0.01-1100 NTU

- Resolution:0-9.99 NTUWithin the scope, it is0.01 NTU；10.0-99.9 NTUWithin the scope, it is0.1 NTUFor values greater than100 NTUThe scope is1 NTU

Accuracy: Range within0-20 NTUThe accuracy deviation of the readings is ± (the deviation of the readings)10%+0.01 NTU）； The scope is20-1100 NTUWhen the reading is accurate, the deviation is ±7.5%.

Repeatability: in0-20 NTUThe repeatability within the range is ±0.05 NTUIn20-1100 NTUThe repeatability of readings within the range is ±2%.

Instruments with measurement range or resolution, accuracy, and repeatability capabilities different from those mentioned above have been effectively validated and can also be applied for their intended purposes.

Control of instrument performance

- Calibration: Use at least4Calibrate with a reference suspension of formalin to cover the measurement range of interest. The reference suspension described in this chapter or an appropriate reference standard calibrated based on the primary reference suspension can be used.

–Scattered light: in0-10 NTUwithin the scope of<0.15 NTUIn10-1100 NTUwithin the scope of<0.5 NTUScattered light refers to the light that reaches the turbidity detector, not the result of sample scattering. Stray light is always a positive interference and an important source of error in low range turbidity measurements. The sources of stray light include defects and scratches in the sample cell, internal reflections in the optical system, contamination of optical components or sample cells by dust, and electronic noise. Instrument design can also affect stray light. In ratio mode measurement, the influence of stray light can be ignored.

It is also necessary to verify the specific substance to be analyzed/The testing method of the product is used to demonstrate its analytical ability. The instrument and method should be consistent with the properties of the substance to be tested.

The measurement of standards and samples should be carried out under the same temperature conditions, preferably at20 °Cand25 °Cbetween.

Reference suspension

Fumalazine has several ideal properties that make it an excellent turbidity liquid standard. It can be repeatedly prepared from analyzed raw materials; Its physical properties make it an ideal light scattering calibration standard; Formazine polymer is composed of chains of different lengths that fold into random configurations, resulting in particles of various shapes and sizes that can be analyzed for different particle sizes and shapes found in real samples; The stable fumarate suspension that can be used to prepare stable diluted turbidity standards is commercially available and can be used after comparison with the prepared standards.

All steps for preparing the following reference suspension are included25±3°CGo ahead.

硫酸肼溶液. Translate into English1.0 gDissolve hydrazine sulfate in water and dilute with the same solvent until100.0 mL. standing4-6Hour.

Primary milky white suspension (formalin suspension)In100 mLIn a frosted glass stoppered flask, place2.5 gHexamethylenetetramine dissolved in25.0 mLin the water. add25.0 mLHydrazine sulfate solution. Mix and let stand24Hour. If the suspension is stored in a glass container without surface defects, it can be stabilized2A month. Suspension must not adhere to glass and must be mixed before use.

Milk white standard turbidity solutionUsing water will15.0 mLDilute the primary milky white suspension to1000.0 mLThe suspension is newly prepared and can be stored24Hour.

Reference suspensionAccording to the table2.2.1-1Prepare reference suspension. Mix and shake well before use.

In ratio mode, reference suspensionI-IVThe measurement results show that the concentration is related to the measuredNTUThere is a linear relationship between the values (see table)2.2.1.-2）.

Solution:

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1Special umbrella shed light for clarity inspection

HN-100AType andHN-200AThe specialized umbrella shed lamp for clarity inspection meets the instrument requirements for visual method detection of solution clarity in various pharmacopoeias. It has a light source of light forest belt type, which can effectively reduce the stimulation of light on the eyes during visual inspection. Its illuminance can reach up to5000 LuxAmong themHN-200AType specific umbrella shed light has been addedRGBTri color light source can be used for clarity detection of colored samples.

2TheYH-CLS-1201Clarity inspection analyzer

This instrument adopts a full-color LCD touch screen for operation and control, which can directly detect the clarity of injection raw materials and injections, and has four levels of permission management and audit tracking functions*GMPThe data integrity requirement is an effective instrument for conducting liquid consistency evaluation.