Secrets of particle size analysis for Pharmaceutical Preparation and Raw material

Particle size significantly impacts drug dissolution, a key factor in drug quality. This note addresses common confusion in particle size analysis, clarifying how to interpret varying results from different test conditions or manufacturers to find the "true" granular outcome.

Jump to a section: 

• • 1. Why are the results different from different manufacturers?
  • 2. How do you deal with this situation as a manufacturer of pharmaceutical preparations or raw materials?
  • 3. How to do methodology and verification?
  • 4. How to choose dry method or wet method?

The improvement of drug quality is the basic principle for developing overall strategies. For the current evaluation system, dissolution is a top priority, and the particle size of the pharmaceutical preparation has an important influence on the dissolution curve. However, everyone still faces a lot of confusion about particle size analysis. For example, the results are different in different test conditions, but which one is more reliable? Why do some samples have different results from different manufacturers? Whose granular results are closer to "truth"?

1. Why are the results different from different manufacturers?

In general, two reasons lead to the differences in results, one caused by optical path structures and algorithms. The laser diffraction particle size analyzer obtains the particle size distribution by inverse calculation of Mie theory using an optical model. However, when developing an instrument, how do you know whether the model you selected is correct? How do you determine whether the detector position and the optical path are reasonable and accurate? The answer is to use spherical standard particles with known particle sizes for research! Therefore, establishing the detection system step by step, each manufacturer determines its own model and algorithm based on spherical standard particles. Generally, the spherical particle diffraction spot is a concentric circle, but the slit diffraction is a set of stripes.

Various particle shapes are different under this background, rod-shaped microcrystalline cellulose, agglomerated lactose, irregular API, spherical granulation, etc., which means that the diffraction spot is also extremely complicated. Therefore, various differences are generated in particle size results. This is the reason why the results of the spherical standard sample are similar for different manufacturers, but the results of the actual raw material and pharmaceutical preparation are quite different.

Generally, the significant difference may come from the dispersion method. There are two methods to disperse the drug particles, dry and wet. Each instrument will be equipped with a dispersing attachment that disperses the drug particles into individual "particles" to pass through the measurement area. However, due to design, patent, etc., energy delivery of each manufacturer is difference. The circulation pipe, speed and ultrasonic output may be completely different. Although the output power is same, the structure is different, resulting in a difference in the actual energy to the particles. If the wet method can reduce this difference and risk by introducing external ultrasound, the dry method has no way to avoid this risk, because the dry dispersion is integrated with the instrument. For example, Bettersize instruments disperses the sample with different venturi pipe. The early one is connected by the straightthrough pipeline. While another supplier inhales and then disperses the particles by means of “tornado” with negative pressure. These treatments vary in characteristics, which leads to the increase of risk of measurement results.

Someone may be confused immediately. No matter what kind of pipeline, as long as the samples are scattered into "small particles", shouldn't the results be close? Indeed, it should be the same in theory, but it is actually not the case. For example, a raw auxiliary powder, if its adhesion is low, the flowability is perfect, and the distribution is narrow, the result should be close and be similar to the wet method. However, if your sample is "comparative sticky", "poor mobility" and "wide distribution", do you still think that your particle results are the same? For example, can a glass bead sample be the same as drug? That is the reason why you must be aware that this sample may be tubedependent, pressure-dependent, and the differences from different instruments may be large when you choose a dry method.

The above is the result of the dry measurement of a salt-caving raw material drug. The upper, middle and lower parts of the figure are the results of the A supplier's model 1, model 2 and model 3 dry dispersion accessory, which shows D50 is around 20 microns for model 1 and D50 is around 80 microns for model 2, and the difference of D90 may be even larger. Can you make a conclusion which pipe or instrument is better? You have no way to prove it. Three results have been pressure titrated and have good precision. Someone will think that the results can be confirmed by images. However, it is difficult to determine the particle size through the image method whose size is between less than 1 micron and up to several hundred micrometers, because the range is similar, but the ratio is very different. How do you determine it? Is the “peak” in front of the particle size distribution reasonable? Unsure, this is the current situation for dry method.

2. How do you deal with this situation as a manufacturer of pharmaceutical preparations or raw materials? 

3. How to do methodology and verification?

The methodology is to study all the influencing factors, identify critical quality attributes (CQA) that may affect measurement results, and then evaluate and confirm these factors. After confirming the conditions, a series of verifications should be performed, including precision verification and cross-verification.

For the factor of ultrasound, we can study the effects of different ultrasound times (1min, 2min, 3min, 5min...) and different ultrasonic power (30w, 50w, 100w...) on the results. For the obscuration factor, we can study the effect of different obscuration (3%, 7%, 10%, 15%, 20%...) on the results. Sometime according to the characteristics of the sample, the factor of sampling method, circulation, pressure, PH, surfactant and dispersant also be considered. At the same time, through image technology, photoresist counter technology, etc., to check the rationality of the results.

4. How to choose dry method or wet method?

Powder can be tested either by suspension dispersion or by air pressure dispersion testing, so customers are confused about how to choose dry or wet method. In fact, these two methods can be adopted in the Pharmacopoeia, but how to choose these two methods and reduce the risk? Some people think that powder should be measured by dry method, wet measurement, stress that wet method may change the crystal form of the particles, surfactant is easy to produce bubbles, if the use of solvents will produce waste, the influencing factors are difficult to control. The dry sample wet test theory emphasizes that the dry test is easy to “break” the particles, the fine powder is “not blown”, and the control factors are less.

Some people think that the powder should be measured by dry method, because the medium may change the crystal form of the particles and bubbles are easily generated from the surfactant. If the solvent is used as the medium, the waste will be generated after the measurement and the factors that affect measurement results will increase. The people who think that the powder should be measured by wet method emphasizes the dry method is easy to “break” the particles, the fine powder is not easy “dispersed”, and the ways of controlling risk are less. However, I don't think the above points are objective. For example, a drug tablet needs to be released and absorbed in the stomach, that is in a wet environment. When we still adopt the dry method to obtain the result, can we say it is more reasonable? On the other hand, it is difficult to find a good solution or solvent to suspend the particles for the wet method. What if the surfactant produces solubilization or bubbles? What if different raw materials have different solvents? What if the raw materials dissolve or dissolves slightly in the solvent?

In fact, suppliers will promote instruments based on the advantages of their products. How can we avoid the misleading from suppliers? Although the final result is not absolute, we should determine the measurement method according to the property of the sample, the condition of application and the advantages and disadvantages of the dry and wet methods. Each decision should be made based on data. Of course, we should refer to the relevant companies and previous practices, which can save our time.

In the face of increasingly strict supervision and changes in the situation, I hope that our pharmaceutical companies can effectively improve the quality of the drugs. Only the quality of drugs is getting better, can our company develop more stable.

About the Author

Bettersizer 2600 The Bettersizer 2600 utilizes proven Laser Diffraction Technology to measure particle sizes ranging from 0.02 to 2,600 μm.  ● Wide particle size range: 0.02 to 2,600 μm (wet dispersion); 0.1 to 2,600 μm (dry dispersion); 2.0 to 3,500 μm (dynamic imaging) ● Dual optical system: Laser Diffraction and Dynamic Imaging ● Advanced laser diffraction system: combination of Fourier and inverse Fourier design Learn more