Suspension injection, is a kind of preparation prepared by dispersing solid drugs in liquid for intramuscular or intravenous injection. Suspension injections generally increase the single dose and prolong the drug release time by reducing the drug solubility.
At present, most FDA approved suspension injections have sustained drug release characteristics (from hours to days or weeks). At the same time, FDA believes that the high shear characteristics of traditional dissolution methods may lead to significant differences between the results of drug dissolution in vitro and pharmacokinetic behavior in vivo.
In the FDA dissolution method database, the flow-through cell method with lower fluid shear force is included for the in vitro release test of a variety of suspension injections, such as betamethasone acetate / betamethasone sodium phosphate injection suspension, medroxyprogesterone acetate injection suspension, prednisolone acetate injection suspension, etc.
This article will share a case study on the in vitro release of a suspension injection, and eva1uate the influence of different test conditions of paddle method and flow-through cell method on the in vitro release of suspension injection in the process of method development.
Dissolution System
Paddle Method（USP Apparatus 2): Raytor RT612-AT Automatic Sampling Dissolution System
Flow-Through Cell Method（USP Apparatus 4): Raytor RT7 Flow-Through Cell Dissolution System
Method Screening
In the early screening process, we compared the in vitro release behavior of suspension injection under different test conditions of paddle method and flow-through cell method. The in vitro release results of each test condition are shown in the figure below (due to the technical confidentiality agreement, the specific parameters of the test conditions and dissolution medium will be omitted):
The expected in vivo release time of this suspension injection is 12 hours. The high shear property of the paddle test results in the rapid release of the sample in vitro, which is different from the expected in vivo release time.
In contrast, the flow-through cell method can provide a fluid environment closer to the drug release site. By adjusting the test parameters of the flow-through cell, we can obtain the dissolution curves of different release rates, such as Method A ~ Method C in the above figure. Then, according to the expected release time of the sample in vivo, we choose Method B as the basis for the next step of method optimization.
Experimental Result
After further optimizing the parameters of the method, the repeatability and discrimination of the test results of the flow-through cell method can meet the expectations of customers.
Among them, take three batches of suspension injection samples (Lot A, Lot B, Lot C) with different production process as an example. Under the optimized test conditions, three batches of samples with different formation processes showed different in vitro release behavior. Through these differentiated in vitro release test results, we can effectively eva1uate the effects of different formation processes on the release of suspension injections.
Result Discussion
In the FDA dissolution method database, the in vitro release tests of suspension injections that can be queried basically use the flow-through cell method. It can be seen that the flow-through cell method has obvious technical advantages in the in vitro release test of suspension injection, which is difficult to be replaced by other dissolution methods.
The low shear characteristic of the flow-through cell method makes the release time of the sample easier to coincide with the expectation in vivo, which can better reflect the release behavior of the suspension injection in a gentle fluid environment. Considering that there is no strong fluid shear force in the in vivo release environment of suspension injection, it can be predicted that the flow-through cell method can better eva1uate the in vivo release behavior of suspension injection.
In addition, for suspension injection, the fluid shear force of dissolution method is lower, which also means that this method can have better discrimination, and it is easier to find the influence of different process parameters or different prescr1ption design on sample release, so as to provide good data support for preparation research and development and process prescr1ption optimization.