Summary of Some Experiences in Pellet Coating Research
First, the coating material factors
1. Selection of coating material - influence of cloud point Due to the irreversible proton pump inhibitors omeprazole, esomeprazole, lansoprazole and the like due to the structural characteristics of the compound itself, it is necessary to prepare an enteric preparation. The commonly used enteric materials have acidic functional groups, so a layer of barrier (isolation) is usually applied between the API and the enteric material during the development and imitation of the azole drug preparation, and of course other packages are required. The drug that was cloaked.
In order to extend the patent protection time for omeprazole drugs, AstraZeneca mentioned in the subsequent patents that the HPC used in the coated garments has a cloud point of not less than 38 ° C, which not only satisfies the release requirements of the dosage form, but also enables The patent period of the dosage form is extended and protected. The requirements for the cloud point of the polymer are also mentioned in the patent of the esomeprazole magnesium enteric coated tablet.
According to the processing experience encountered in the development process, the temperature of the polymer solution is gradually increased. When the temperature is lower than the cloud point of the polymer, the solution becomes transparent; when the temperature of the polymer solution reaches the cloud point; in the solution The polymer aggregates and the solution changes from a transparent state to a turbid state. The increase in temperature weakens the hydration of the hydrophilic group of HPC, which is beneficial to the formation of aggregates and is responsible for the decrease in the critical micelle concentration with increasing temperature.
It has been reported in the literature that when the Kelvin temperature is 310.15 K (ie, the dissolution medium is 37.0 ° C), the critical micelle concentration of HPC is less than 0.007 mmol·L -1 . When the concentration is greater than CMC, the molecules are present in an aggregate state in an aqueous solution. For reference, if the cloud point of the polymer is lower than the temperature of the dissolution profile, the polymer will affect the dissolution rate of the API and affect the drug release. The polymer such as HPMC and HPC with different cloud points can be selected according to the speed of dissolution of the self-made preparation and the reference preparation, and the polymer with different cloud points can be used to prepare a solution with a certain ratio.
Cloud point determination: The polymer is formulated into a mass fraction of about 3% solution, heated in a water bath, and gradually warmed up. The solution temperature when the solution appears turbid is the cloud point, in °C.
2, the selection of coating materials - molecular weight impact due to the difference between the technology and raw material sources, the same type of HPMC, domestic HPMC molecular weight range is wider than the foreign production of HPMC molecular weight range. The HPMC solution with the same mass fraction was prepared by using domestic and imported HPMC. The viscosity of the domestic HPMC solution was slightly larger.
For drugs whose release rate is sensitive to polymer viscosity, the effect of polymer molecular weight on the release rate of drug-loaded pill and coated gown is investigated. If the viscosity of the polymer has little or no effect on the release of the drug, the domestic brand will be the first to be selected. In order to exclude the suspicion of advertising and the protection of domestic manufacturers, the HPMC brand is not mentioned in this article.
Second, the raw material factors
1. The influence of the crystal form of the raw material drug The general preparation uses the raw material medicine to stabilize the crystal form. The fluidized bed preparation of the pellets is dominated by the bottom spray method, and the medicine suspension and the drug solution are used for medicine.
The drug suspension is a poor solvent of the drug or a solvent in which the drug is sparingly soluble to prepare a drug-containing suspension, and the drug is insoluble or slightly soluble in the solvent. When preparing the pellets in a fluidized bed, the solvent volatilizes, and a space network structure is formed between the binders, and the drug is coated on the pellet core. The raw material medicine is not suitable for crystal transformation or micro-transformation, and the influence of crystal form on drug dissolution occurs. Very small. While the drug solution is supplied to prepare the pellets, the drug may be coated on the pellet core in the form of crystal transformation, partial crystal transformation or amorphous crystal.
The mode of administration of the generic drug preparation pellet can be determined according to the API crystal form in the reference preparation.
2. The particle size of the drug substance is prepared by using a drug suspension to prepare a drug-loaded pellet. The particle size of the API has an effect on the yield, and the small particle size has a relatively high yield relative to the large particle size. If the particle size of the easily soluble or slightly soluble drug has little effect on the dissolution rate of the drug, the API particle size can be appropriately reduced.
The smaller the particle size of the poorly soluble drug, the larger the surface area, the larger the area of ​​the surrounding medium, and the higher the dissolution rate, especially for poorly soluble drugs. The dissolution process is often the rate-limiting process of the absorption process, and the particle size and drug absorption may be There is a certain relationship.
General R&D will examine the effect of particle size of poorly soluble drugs on dissolution. If the particle size and the yield are contradictory when the poorly soluble drug is prepared into pellets or drug-loaded pellets with a smaller particle size (particle size ≤ 0.5 mm), it may be considered whether the drug solution is used for the drug supply (see also the reference formulation crystal). Type decision). Preparation of drug-loaded pellets using a drug solution does not require an API particle size, but it is necessary to consider whether the crystal form of the API in the formulation uses the drug supply mode.
Third, the inlet humidity
1. When the inlet air humidity is too large and the fluidized bed is used to prepare the drug-loaded pellets, the inlet air humidity needs to be strictly controlled. If the inlet air humidity is relatively large, the fluidized bed drying efficiency is too low at this time, which affects the structural compactness of the pellets, such as the drug-loading pill, the barrier layer or the functional coating layer, which may cause the dissolution to be too fast.
2. If the inlet air humidity is too low, if the inlet air humidity is relatively small, the fluidized bed drying efficiency is high at this time, which is easy to cause spray drying and reduce the yield. Too low humidity to prepare pellets with smaller particle size is likely to cause static electricity in the draft tube and bed wall to affect the uniformity of the functional coating layer. Adding an appropriate amount of MS to the functional coating material reduces static electricity. The small test can be properly humidified with an air humidifier to prevent static electricity.
Fourth, the spray speed
The spray speed should not be too fast at the beginning, and the steady flow rate should be gradually increased by the small flow rate.
Fifth, the calculation of weight gain
In the preparation process, the pellets have the factors of coating, crushing, peeling, friction, collision, etc. In calculating the weight gain, the weight gain cannot be calculated by the increase of mass.
For example, when the drug-loaded pill is coated with a functional coating such as a barrier layer or an enteric layer, a small amount of drug peeling and abrasion may occur due to collision, friction and the like due to the coating of the functional coating layer. The quality of the drug pills is reduced. At this time, the weight gain is calculated according to the weighing, and the actual weight gain will be relatively large.
If the total weight of the loaded drug-loaded pill is 100 g and the mass is not lost, the total weight should be 130 g when the weight gain is 30%. However, in the actual pre-coating period, the drug-loaded pill will be partially lost, and the actual weight of the drug-loaded pill will be reduced. The functional coating of the coated drug will increase according to the weight gain to 130 g. Usually calculated according to the weighing method will be about 3% to 5% of the measured weight gain. The weighing method can be applied to roughly calculate the quality of the sprayed coating liquid.
Calculation method: the content of the drug-loaded pill is m1 (g/g), and the content after coating is functionally coated is m2 (g/g)
Weight gain = (m1- m2) / m2 * 100%
According to this method, the drug-loaded drug is stored in a poor amount, and the method can only obtain a relatively accurate weight gain.
In order to reduce the loss of the pre-loaded drug pills when coating the functional coating layer, a smaller liquid supply speed can be used, and the required atomization pressure is relatively small, and the fluidized state of the drug-loading pill is not severe, and the loss is less. After the drug-loading pills are evenly coated with the functional coating layer, the liquid supply speed and the atomization pressure are gradually increased. Appropriate amount of pigment can be added to the coating solution to determine how long it takes to apply a certain low liquid supply rate to evenly coat the drug-loaded pill with a thin layer of functional clothing (this method will waste some drug-loaded pills).
Sixth, the impact of the amount of feed
The depth of the static bed is related to the amount of feed. For the same type of fluidized bed, the more the feed amount, the higher the depth of the static bed. In the production process, with the preparation of the pellets, the more the pellets outside the guide tube, the greater the air resistance. When the air resistance reaches a certain level, the airflow is selected from the airflow distribution hole below the smaller diameter of the guide tube. When entering the guide tube, the air inlet frequency and the inlet air temperature are constant, the air volume entering the inside of the draft tube becomes larger, the heat entering the inside of the draft tube increases, and the spray drying effect generated inside the guide tube is enhanced. The rate is lowered, and at the same time, the air entering the outside of the draft tube cannot dry the pellets after spraying and stick and form the knot (the knot is easy to be knotted and agglomerated in the enteric layer).
In the process of pellet production, it is not advisable to feed too much, and if conditions permit, the distance between the draft tube and the air distribution plate can be appropriately increased as the amount of pellets increases, so that the number of pellets entering the inside of the draft tube per unit time Increase and reduce the thickness of the pellets outside the draft tube.
Seven, problems and solutions
Examples of problems encountered in the pilot study are as follows:
(1) The fluidized bed spray gun or the guide tube is installed tilted.
1 After the spray gun is installed, the atomizing airflow during coating is asymmetrical due to the symmetry of the air holes, and the atomization pressure is not good. The humidity of the pellet is too large and shifts in one direction and is diverted to the flow. The inside of the cylinder gradually accumulates and causes adhesion, which causes the twin or multiple pills to appear in the entire fluidized system. This phenomenon can be prevented by making the spray gun atomization hole symmetrical when the spray gun is installed.
2 The inclination of the guide tube installation will also appear inside the guide tube. At this time, due to the angle between the air flow and the guide tube, the upward air flow causes some coating liquid to spread into the inside of the guide tube, gradually accumulating, and partial over-wetting leads to the pellet. Adhesive, when installing the guide tube, you can determine whether the installation is tilted or not.
The fluidized bed equipment of Changzhou Zhiyang Machinery is easy to operate and PLC is controlled online.
(2) There is solid adhesion or blockage around the liquid outlet of the spray gun.
In the process of small test coating, since the gun body is relatively thin, the internal liquid is easily cured by heat during the coating, and gradually accumulates, causing partial blockage of the gun body, resulting in asymmetry of the spray and adhesion. After a period of coating, stop the machine and check the spray gun. If there is a muzzle blocked or stuck, the spray gun should be cleaned.
Because the air intake is small, the spray speed is larger than the drying rate, the pellets can not be dried in time, the surface of the pellets is too wet, and the surface viscosity is increased. The airflow cannot ensure that the bottom pellets are boiling, and the knot is gradually formed. At this time, it is possible to appropriately adjust the amount of intake air and increase the drying rate.
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