Let’s start with a brief introduction
- The original product is tablet, which is made in Japan. The excipients are microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose and magnesium stearate.
- The raw material is dissolved rapidly under acid condition, and it is dissolved in about 10 minutes, and the dissolution rate is more than 85%; About 75% of water and ph6.8 were dissolved in 30 minutes, and 85% in 45 minutes.
- Self made capsule, acid medium is basically the same as the original research, water and pH 6.8 dissolution 30 minutes 40%, 60 minutes 60%.
- The dissolution method is paddle method, capsule and dissolution sinker. The dissolution phenomenon is that the capsule shell dissolves in about 2 minutes, and the contents rapidly disintegrate, but some contents can not disintegrate (speeding up the speed is not enough).
Analysis of the reasons:
- At first, it was speculated that incomplete disintegration would lead to slow dissolution, but the dissolution still could not reach 85% after solution.
- After the raw material is crushed, the agglomeration in the dissolution sinker is insoluble again. To solve the problem of agglomeration, the raw material will settle at the bottom of the cup and will not stir up. The dissolution rate can’t be more than 85% after speeding up the rotating speed.
- What method (except adding surfactant) can increase dissolution?
- If the capsule has a dissolution sinker, the reference tablet should also be placed. If the capsule shell dissolves quickly, you can consider not adding basket.
- We have a similar situation in one project. The capsule floats on the page without dissolution sinker, and the dissolution phenomenon is inconsistent with the tablet reference.
- What is the proportion of API in self-developed capsules? Is the prescription type consistent with the reference tablet? If there is no disintegrating agent in the original prescription, can we consider adding disintegrating agent? Carboxymethyl cellulose and hydroxypropyl methylcellulose in the prescription should be adhesives, which may lead to the phenomenon that the building owner said the agglomeration can not be dispersed.
- Looking at the reference dissolution data, it seems that the solubility of API in various media is OK, so it should be considered as a drug with high solubility. This kind of medicine is very sensitive to magnesium stearate (including dosage and lubrication time). Have you ever investigated it?
The dissolution sinker does have an impact. I think it is caused by the high viscosity of raw materials.
Let’s make clear the function of excipients first. What you mean by CMC is CMC sodium. In this prescription, CMC sodium is obviously a disintegrant, not a binder. HPMC is the adhesive. Many adhesives, also disintegrate agents, including pvpk30 have disintegrating effect in a certain amount and usage.
Disintegrants and adhesives are generally high polymer materials, and their common point is that when they meet with water, they will swell first and disintegrate in the process of swelling.
The viscosity of disintegrating agent is small (this is why the disintegration of the preparation is not fast but slow when someone increases the disintegration dose). When the amount of adhesive is small, it will also show obvious disintegration effect.
I have experienced the most classic prescription (which was made by the master at that time) is to change the ordinary tablets into disintegrating tablets. After using the so-called super disintegrating agents for many times, it is not ideal. Finally, starch and methylcellulose are used as disintegrating agents, and the effect and taste are surprisingly good (the disintegrating particles are very delicate). This should be the reason.
The usage and dosage of sodium carboxymethyl cellulose should be more comprehensive.
In addition, if the API has viscosity, the particles should be made harder, and the amount of magnesium stearate can be larger (anti viscosity), but it should not be over lubricated.
– Is there no aggregation of API in the original tablets? Is aggregation only in alkaline environment? Is the crystal form and hygroscopicity of the raw material consistent with that of the reference preparation? How about changing the preparation process?
– You take out the magnesium stearate, fill in the capsule of granule, throw it into the basket of water, and see if there will be reunion
– If the dissolution curves of capsules and tablets are completely fitted, there will be risks. Due to the difference The main problem caused by the modification is the principle of comparison of dissolution curves in vitro. In the dissolution cup, the difference of early point release caused by the characteristics of dosage form can not reflect the situation in vivo to a large extent. If the main acid medium and pH4.5 do almost, you can try to do animal or pre be. We also have a tablet to capsule, the dissolution curve can not be (early point), mainly on the late dissolution, now we are ready to do a pre test.
-In order to try to grind the original tablets slightly, and then pack them into capsules to see if there is agglomeration, so as to determine whether it is the influence of capsule shell.
In addition, it is suggested that the formulation and process should be explored according to the dosage form of the photo agent, and then the capsule should be changed after it is consistent with the original research.