In nanocrystalline tablets, the API is generally nanocrystallized to a particle size of less than 1 μm particles. Through the nanocrystallization of API, the purposes of increasing solubility and dissolution, increasing adhesion to biofilm and reducing food interference can be achieved.
For example, sirolimus is a new and efficient third-generation immunosuppressant. It is an immunosuppressant with low toxicity and great application potential.
However, sirolimus has poor water solubility and low dissolution, which makes it difficult to be absorbed by human body and poor bioavailability. After nano treatment, it can effectively improve the problems of low solubility and low drug bioavailability.
On the contrary, because the API will be nanosized to the particle size less than 1 μm, some nanocrystalline tablets will show a rapid release rate under the traditional dissolution method. Limited by the traditional dissolution method, the in vitro release test data may not be ideal.
This paper will share the case of in vitro release test of a nanocrystalline tablet product using paddle method and flow-through cell method, and compare the difference between the traditional dissolution method (paddle method) and the more modern dissolution method (flow-through cell method) in the determination of nanocrystalline tablets.
Experimental Method
In order to control the variables in the test process, the experimental parameters of the two methods will be consistent as much as possible. For example, the paddle method and the flow-through cell method use the same sampling time point and dissolution medium. Due to the technical confidentiality agreement, the key parameters of the experimental method will be omitted in this paper.
Paddle Method（USP Apparatus 2)
Dissolution System: Raytor RT612-AT Automatic Sampling Dissolution System
Apparatus: Paddle
Rotational Speed: 50 RPM
Dissolution Medium Volume: 900 mL
Temperature: 37.0 ± 0.5 ℃
Sampling Time Point: 5，10，15，20，25，30，40 min
Flow-Through Cell Method（USP Apparatus 4)
Dissolution System: Raytor RT7 Flow-Through Cell Dissolution System
Flow-through cell: 22.6mm inner diameter large cell
Temperature: 37.0 ± 0.5 ℃
Sampling Time Point: 5，10，15，20，25，30，40 min
Experimental Result
Paddle Method（USP Apparatus 2)
The dissolution results of six samples tested in parallel by paddle method are as follows, and the relative standard deviation (RSD) of the final dissolution results is 0.86%:
Flow-Through Cell Method（USP Apparatus 4)
The dissolution results of six samples tested in parallel by flow-through cell method are as follows, and the relative standard deviation (RSD) of the final dissolution results is 1.07%:
Result Discussion
As shown in the figure below, the dissolution rate of the nanocrystalline tablets under the test condition of paddle method is faster than that of flow-through cell method. For some nanocrystalline products with fast release rate, under the test conditions of paddle method, the method may have insufficient differentiation force or insufficient data to calculate the similarity factor due.
In addition, from the analysis of fluid environment and filtration system, the flow-through cell method is also more advantageous than the paddle method.
Fluid Environment
The flow-through cell has a more gentle fluid environment than the paddle method, and the release rate of the sample will slow down significantly. Many literatures point out that the fluid environment of the flow-through cell will be closer to the fluid environment in the human gastrointestinal tract than the traditional dissolution method.
For the paddle method, in order to prevent the particles generated in the sample release process from forming cone accumulation at the bottom of the dissolution vessel and affecting its release, it is generally necessary to ensure a rotational speed of at least 50rpm. If the rotational speed is further reduced, the risk of uneven mixing may also be introduced.
According to the test results and relevant research literature, the fluid shear force of paddle method at 50 rpm is higher than that of flow-through cell method. Higher fluid shear force will accelerate the dissolution of the sample, and may also lose part of the discrimination.
Filtration System
The difference of filtration system between the two methods is also worth discussing. The front end of the sampling needle of traditional dissolution methods such as paddle method needs to be equipped with a cylindrical filter element to avoid pumping incompletely dissolved API particles into the pipeline system during sampling, resulting in abnormal results.
At present, the minimum pore diameter of cylindrical filter element can only be 1 μm. However, the particle size of API in nanocrystalline tablets is less than 1 μm. Therefore, the traditional dissolution method is very likely to pump small API particles into the pipeline system in the sampling process of nanocrystalline tablets dissolution test.
Although the needle filter with smaller aperture (disc filter) can be installed in the middle of the pipeline system or at the front end of the injection needle to block the API particles less than 1 μm , but this may also lead to the enrichment of API particles in the needle filter and re dissolution during sampling at subsequent time points, resulting in abnormal dissolution results.
The filter chamber at the top of the flow-through cell can be equipped with filter membrane systems with various apertures, so as to ensure that the sample solution entering the sampling system from the flow-through cell has been effectively filtered. Tiny and undissolved API particles will be trapped in the flow-through cell until they dissolve into free API.
In conclusion, the flow-through cell method has obvious advantages over the traditional dissolution method in terms of fluid environment and filtration system when testing the in vitro release of nanocrystalline tablets. We further recommend using the flow-through cell method to study the in vitro release of nanocrystalline tablets.