Abstract: Objective: To establish the optimal particle sizing dispersion method for Domperidone API by laser diffraction. ?

Method: Using Bettersizer 2600, an automatic laser diffraction particle size analyzer with both dry and wet dispersion system, to systematically study the particle size distribution of Domperidone API. The research investigated the impact of dispersing intensity on the particle size analysis, including different air pressures of dry dispersion, different stirring speeds and ultrasonic dispersing time of wet dispersion. Conclusion: By comparing the measurement results of both wet and dry dispersion methods, the wet dispersion method is recommended since it can provide more accurate results and more reasonable data correlation.

Domperidone that acts primarily on the chemoreceptor triggering region outside the blood-brain barrier, as the representative of the second generation of gastroprokinetic agent, is a synthetic benzimidazole derivative. It is a dopamine receptor blocker with anti- vomiting effect by blocking peripheral dopamine receptors, thereby enhancing the stomach motility and increasing the lower esophageal sphincter pressure. Domperidone is widely used in the treatment of flatulence, esophageal reflux, and vomit caused by chemotherapy. Since the solubility of the Domperidone particles has great ?influence on the absorption in the body, it is necessary to examine the influence of the particle size on the product quality. The difference of particle size distribution among batches could lead to inconsistency in dissolution and body absorption; furthermore, affect the efficacy and safety of drugs directly. Therefore, the effect of particle size distribution on product quality must be researched. The USP has clear regulations on API particle sizing by laser diffraction method, such as the structure and principle of the instrument, the specific method of dry and wet dispersions, the factors in the measurement process, etc. ?

However, for specific drugs, there is no related instruction on how to evaluate and choose wet or dry dispersion method. This paper carried out a systematic research on how to choose dispersion method when measuring particle size distribution of Domperidone API in accordance with the USP and the ISO 13320.

1.Experiment

1.1 Instruments

Bettersizer 2600 laser particle size analyzer from Bettersize Instrument Ltd; MS303S electronic scale from Mettler Toledo; SC ultrasonic cleaner from Shanghai Shengyan Ultrasonic Instrument Co.,Ltd.

1.2 Sample and reagent

Two sets of Domperidone API sample:

No.1: non-micronized sample (batch No.0068116-17);

No.2: micronized sample;

Tween 80 for analytical reagent; Purified water.

2.Particle size distribution measurement and method evaluation

2.1 Dry dispersion method

2.1.1 Study on the methodology of dry dispersion method

Dry dispersion is to transport powder particles by compressed air, disperse powder particles by collision of particles and particles, collision of particles and pipe, and airflow shear.API powder was composed by small organic molecules particles, which could break under the shear stress and collision. In order to ensure the dispersal of large agglomerate without breaking the original particles, the USP requires investigating the effect of different dispersive intensity on test results (USP 429):

In dry dispersion experiments, we investigated the effect of dispersed pressure on the particle sizing results. The dispersed pressure ranged from 0.05 MPa to 0.4 MPa, and a set of data was tested every 0.05 MPa.Abscissa: dispersion pressure; Ordinate: particle size; Blue curve: D10; Orange curve: D50; Grey curve: D90.

編輯切換為居中

The ideal pressure titration curve, as the dispersed pressure increases, the particle size gradually decreases, and the curve gradually reaches a stable period. If pressure increases further, the curve will go further downward, which corresponds to the gradual dispersal of large agglomerate to single particles. If the pressure is further increased, the drug particles could break. However, the difficulty of drug particle sizing is that there is no strict boundary between aggregate dispersion and single particle breakage, so further experiments are needed. Figure 2 showed that there was an obvious "stable platform" of the micronized sample, which represented the results between 0.2 MPa and 0.35 MPa. However, when increasing the pressure of the non-micronized sample, there was no "stable platform" and particle size of the sample decreased continuously, which was generally the signal of the particle ?breakage. For further diagnosis, we captured the image of non micronized sample (Figure 3), which shown that the sample was semitransparent irregular crystal particles. Judging from the state, the sample was easy to break. When increasing the dry dispersion pressure, the risk of particle breakage ?would increase consequently.

In order to further determine the appropriate dry dispersion pressure, the particle size distributions of non- micronized samples were tested under different pressures (Figure 4).The results indicated that with the increase of dispersion pressure, the maximum particle size decreased from 150- 100 μm to 30-20 μm. The image proved the existence of few coarse particles with size around 100 μm.

Furthermore, these coarse particles could be identified as single particle instead of agglomerated ones (Figure 5-6).

It was not factual that the maximum particle size is 30-20 μm. Therefore, we could reach the conclusion that the particles were broken when dispersion pressure reached to above 0.3 MPa. Considered the pressure titration curve (Figure 2) and the fragility of the sample itself, 0.2 MPa was selected to test particle size distribution of Domperidone API.

2.1.2 Research on the precision of dry dispersion method

Based on the above experiments, Domperidone API was measured under dispersion pressure 0.2 MPa. Figure 7 & 8 shown the particle size distribution curves and repeatability data of non-micronized and micronized samples. The repeatability results for both samples far exceeded the requirements of the USP: repeatability of D50 was smaller than 2.1% while those of D10 and D90 were smaller than 3.5%, which proved that the dry dispersion method was reliable to measure particle size distribution of Domperidone API.

2.2 Wet dispersion method

2.2.1 Study on the methodology of wet dispersion ?method

Domperidone API is insoluble in water. After wetted by surfactant, sample was dispersed in water by stir and ultrasonic dispersion. Due to its fragility, the dispersion intensity should be low. At the same time, in order to investigate the influence of dispersed intensity on sample particles, two dispersion methods: stir and ultrasonic dispersion were applied respectively (Figure 9 & 10).

From Figure 9 & 10, we could find out that the results were not stable when sample was only stirred. Besides,considered the characteristics of wet dispersion, the drug particles could still be adherent. But the stability was greatly improved after the low intensity ultrasonic dispersion. Meanwhile, ultrasonic had little influence on the particle size distribution. Its main effect was on large particle trailing.

The repeatability of measurement results under low intensity ultrasonic dispersion was greatly improved, so the subsequent wet dispersion adopted the low-intensity ultrasonic method.

2.2.2 Research on the precision of wet dispersion method

Keep the above conditions unchanged, we investigated the precision of particle size distribution data when sample was dispersed by low-intensity ultrasonic. Figure 11 and 12 indicated the particle size distribution and repeatability data by wet dispersion of the non- micronized and micronized samples. Compared with the dry dispersion, the repeatability was greatly improved: the relative deviations of D50 and D90 were below 0.7%, and that of D10 was below 2.6%. It proved that the wet dispersion was more ?reliable than dry dispersion when measuring particle size distribution of Domperidone API.

2.3 Compare and evaluate dry and wet dispersion methods

First of all, in terms of test precision, wet dispersion was obviously better than dry dispersion. It was mainly because particles passed the test area only once for dry dispersion, while passed repeatedly for wet dispersion, which provided a higher sampling frequency of wet dispersion.Secondly, from the perspective of relative rationality of data, Figure 13 & 14 were the particle size distribution data of non-micronized and micronized sample by dry and wet dispersion methods. For wet dispersion method, the ?particle size distribution peak moved to small particles after micronization. D10, D50, and D90 all decreased with different extents. However, for dry dispersion method, large particles changed greatly before and after micronization, while fine particles rarely changed.

3.Conclusion Reference

Overall, for particle size distribution measurement of Domperidone API, both wet and dry dispersion methods could provide high precision results. However, since Domperidone API is fragile, adequate data support is required for sample dispersion, especially for dry dispersion method. Compared with dry dispersion, wet dispersion was observed to provide data with better repeatability, correlation, and ?rationality. Therefore, wet dispersion method is relatively reasonable to analyze particle size distribution of Domperidone API.

[1] Aifen Liu. Research on gastrointestinal motility pharmaceutical [J]. China Practical Medicine, 2008, 34(3): 200-201.

[2] CHP second version appendix in 2010 [S]. Beijing: China medicine scientific press 2010:405-406.

[3] Zhukang Chen, Guiliang Chen, Huiyi Li. Research on pharmaceutical and its preparation particle size distribution analysis. [J]. CHP standard, 2012, 13(6): 405.