The causes and solutions of the direct pressing of powder in the process of powder pressing tablet
Tablets due to the advantages of accurate measurement, good stability, easy preparation and administration, is still by far the most commonly used clinical dosage form. In the trend of great development, powder direct compression (PDC) is becoming an important method of preparation of tablet. PDC is a process that directly compacts the raw material powder and the appropriate excipient after screening and mixing evenly, without pressing the granules (wet granulation or dry granulation). At present, PDC technology has become the focus and trend of large scale pharmaceutical companies in recent years. However, most tablets, especially domestic tablets, have not yet adopted PDC technology, because the technology has many restrictive factors. In addition to the influence of production cost, GMP specification and the operation inertia of the pharmaceutical industry, the biggest obstacle to the wide application of PDC technology is the defect of the technology itself, mainly including the problem of sticking and blanking, and the control of the raw material itself by powder metallurgy. Sticky impact is due to fine powder adherence on punch die ring. When tablet is pressed, tablets are glued to a layer or a small part, causing the surface of tablets not smooth, rough or uneven. It is very common in the process of tablet pressing, but it is difficult to solve the problem in the production practice for many years. In the process of PDC, many drugs, especially those with large viscosity and poor fluidity, are very vulnerable to the problem of stickiness. Usually this kind of medicine is converted into capsules, granules and other forms, even in tablets, there is less content, medication frequency high, leading to poor patient compliance, also make the manufacturers spend more manpower and material resources in the process of research, increase the equipment investment. According to the statistics, only 20% of the active medicinal ingredients can be prepared by PDC method. Many Chinese medicinal materials have a great demand for effective extraction, but they are unable to make tablets because of their viscosity. They are encountered in the export of EU, North America and other countries. Therefore, it is very important to solve the problem of adhesive punching to improve the production process of the tablet. On the basis of summarizing the literature and practical experience, the author makes a discussion on the causes and solutions of the problem of sticky flushing in the process of PDC.
A. The reason of sticking
1.1With low melting point component of prescription
For PDC powder contained in the amount of water, can increase the plasticity of particles decreased elasticity, and is extruded to the tabletting process water film formed on the powder for powder outside, close to each other, to produce cohesive, thus forming. If the moisture content in the powder is high, dry and wet is not uniform, and the moisture content is easy to be induced, the sticky phenomenon will occur frequently during the pressing process. If the powder is not dry enough, it should be dried properly before the press. If the raw material powder contains easily wet ingredients, when the powder is too much, too small, fine powder with large surface area and wet air interface, sticking problem will be more serious. When the powder contains the elements which are easily cohesive, such as borneol, the particles gather quickly after the powder is crushed. Because the borneol is solid at room temperature, highly volatile accumulation occurred after the total surface area of the powder cohesion, and smooth area were reduced. If PDC is used for powder or sieve sieve but this is too large, so that the people of borneol is not timely dispersed and with other components are evenly mixed, it may lead to sticking. The low melting point component is melted or softened by the effect of compression heat during the press, and it adhered to the surface of the punch after the decompression. Psoralen tablets, tablets and prescription of Xiaohuoluo Yaotuitong Dan tablets contain low melting component frankincense and myrrh (frankincense and myrrh melting point were 78 degrees and 87 degrees), they and other groups easily uneven mixing occurs when sticking, especially continuous work in the high temperature season or long time compression, resulting in punch overheating, sticking problem is more serious.
1.2 viscous raw material shortage or improper selection of adhesives
Or different varieties of the same species from different origin of raw materials may have some differences in the composition and surface structure, so even in the same formula, may also occur sticking. In addition, the choice of adhesives is also important. If the adhesion strength of the adhesive is insufficient, the air in the powder can not be eliminated in time when the adhesive is compressed, which will cause the weak bonding force between the powder and the loose pieces or lobes. If the adhesive force of adhesives is too large, the hardness of tablets will increase and disintegration will be delayed. It may not meet the requirements of disintegration time and dissolution of People's Republic of China Pharmacopoeia. If the adhesive is not selected properly, even if the adhesive has enough adhesion force between the particles, the fine powder will distribute evenly, but the adhesion between the particles is less than the adhesion between the tablet and the punch. When the pressure of the tablet press is large enough, with the increase of the pressing time, the temperature of the punch increases, so that the fine powder adheres to the punch. If the powder contains moisture content, the sticking phenomenon will become more obvious.
1.3 lubricant dosage is insufficient or uneven distribution
In order to make the tablet pressed from the die hole smoothly and reduce the adhesion between the tablet and punch die, tablets should be added into the right amount of lubricant. Lubricants have a particularly important role when the fluidity of the active medicinal ingredients is very poor and accounts for a large proportion of the whole mass. If the amount of lubricants is insufficient, with the lengthening of the pressing time and the increase in the heat of the punch, the adhesion between the punch and the tablet will increase, which leads to the sticky impact. If the lubricant distribution is uneven, the adhesive force between the local and the punch of the tablet is greater than the adhesion force between the particles. The particles on the surface of the tablet will adhere to the punch to make the pressed tablet form defective.
1.4 instrument reason
Punch, the uneven length of central wear, local bulge, punch inward edge, lettering impression too deep, die surface roughness or defect, not clean, stained with anti rust oil or lubricating oil, a new angular punch without the formation of rounded shape, above all can make adhesion the punch and force of the tablet surface increases causing sticking. The main drug components in the powders attached to the punch surface of PDC were extracted by McDermott, and the content was determined by HPLC. It was found that the content of active pharmaceutical ingredients in the powder adhered to the punch surface increased with the increase of the number of pressed sheets, whether it was using a single punch press or a rotary tablet press, indicating that the powder adhered to the punch when pressed, so as to determine the viscous impact. The problem of sticking often occurs in rotary tablet press. Especially when the press time is too long or the continuous working time of the tablet press is too long, it will increase the heat of the punch and increase the temperature of the tablet, thus increasing the adhesion force of the punch surface and the tablet surface. When the press time is too long, the punch heat increases, will result in the tablet of fusible component melting. For example, the melting point of butyl p - hydroxybenzoate is only 68.4 C, and the adhesion between the punch and the tablet is increased after melting, which leads to the sticky impact.
1.5 preparation method of operation when
Tablet by using static pressure dry powder, such as van drying, infrared drying and microwave drying, less fine powder in the powder obtained by boiling, drying the more fine powder in the powder. In addition, during the drying process, the powder is rubbing against each other, without any binder or powder containing less adhesive. It is easy to be exposed. When the tablet is pressed, the adhesion between these powders is not enough, and they will stick to the punch. Therefore, the PDC process should reduce the dryness and friction of the dry powder as far as possible, and reduce the fine powder content, thus increasing its compressible property.
1.6 improper temperature and humidity
Indoor temperature is too high, the main ingredient of the lower melting point is not suitable for PDC. For example, alpha lipoic acid and the melting point of 63 DEG C, indoor temperature >40, particle polymerization reaction occurs to form crystals, which reduced liquidity. When the pressing time is longer and the punch temperature exceeds its melting point, the properties of a lipoic acid powder change, forming amorphous powder. The direct pressing is easy to occur sticky and punching, and the hardness of the tablets is not enough. Butyl p-hydroxybenzoate with low melting point (68.4 C), with the time prolonging tablet, the punch temperature may even exceed the melting point of butyl p-hydroxybenzoate, resulting in melting adhesion to the fusible component, the surface and the surface of the punch tablet has greatly increased, resulting in red clay. The moisture content of the powder can be increased by the high relative humidity in the room or the adhesion of the water on the surface of the punch.
2 Sticky solution at
2.1 Prescription Optimization materials, equipment and technology are the 3 key elements of production of pharmaceutical preparations.
Material as the basic material carrier preparation forming, its quality directly affects the quality of drugs. The PDC process has high requirements for the excipients, and the selection of filling agents and adhesives is strict. Liquidity, compressible, lubricity and drug holding capacity are necessary conditions for excipients. Besides, extensive adaptability and good reproducibility are also important. In general, it is difficult to meet the above requirements at the same time. The powder engineering is the operation technique to make the original excipients in physical modification or premixed treatment. Compared with the simple physical mixture of excipients, premixed powder flowability and compressibility, dilution capacity, load difference smaller. However, premix excipients can only improve the performance of excipients to a certain extent, and can not meet the requirements of PDC, but also need to select adhesives, fillers and disintegrating agents which are more suitable for PDC. The properties of the auxiliary materials used in PDC are better than those of the conventional auxiliary materials. They can not have particles and have better fluidity. It is found that the chitosan and hydrolysate gelatin after spray drying have good fluidity and compressible properties, which can be used in PDC. Microcrystalline cellulose (MCC) and powdered cellulose (PC) are the most commonly used adhesives for PDC, but their preparation methods and chemical properties are quite different, so their adhesive effects are also different. Recently, researchers have developed a new material to produce low crystallinity cellulose powder (LCPC), the crystallinity of 15 ~ 40, can be used for PDC. Compared with MCC and PC, LCPC has a better adhesion,. In the process of selecting auxiliary materials, PDC should consider the fluidity, compressibility, adhesion and disintegration, and optimize some auxiliary materials for the PDC process.
2.1.1 improve drug flow and pressure
Drug powder particle size, uniformity and crystal morphology can not meet the requirement of PDC, the drug can be improved by technical means of the appropriate flow and pressure. Maghsoodi and naproxen and disintegrating agent by crystallization technique (crystall - CO - agglomeration) made of premixed and premixed crystallization, crystallization is crushed into powder, greatly improve the fluidity of powder and compressibility. The disintegration of the prepared tablets by premixed crystalline powder is also significantly larger than the tablets of naproxen and the disintegrating agent. Ogienko was prepared by freeze-drying stable acetaminophen monoclinic crystal powder, the powder without adding auxiliary materials can meet the requirements of PDC, and good solubility. Kawashima et al. Based on the principle of emulsion solvent diffusion, spherical aggregates of ascorbic acid with good fluidity and filling properties were prepared by spherulite granulation process. The study of powder shows that spherical aggregates can greatly enhance the fluidity, filling and compressible properties of drugs, and increase the adhesion between powders, which can be applied to PDC. In addition, the adhesive is also a very important excipient in the PDC process. The low proportion of adhesives leads to sticky and poor adhesion, which can be adjusted by increasing the proportion of adhesives. If the powder is too much (>10), the adhesive force is not enough. If the adhesive force is not enough, we can use 6O ~ 100 sieve mesh to remove the fine powder, and then dry it, then mix the whole batch evenly and press it again. Therefore, it is important to change the size of the particle size, the crystalline form and the proportion of the adhesive to avoid the sticky impact.
2.1.2 selectappropriate lubricant
In addition to the liquidity of the drug powder and compressibility, the type and amount of lubricant also has an important role for the tabletting process. The lubricant can reduce the friction of the surface metal of the tablet and the punch, and its lubricating ability is closely related to the difficulty of the release of the tablet from the upper and lower punch. The selection of the suitable lubricant can make the whole pressing process more smooth. Magnesium stearate is the most widely used lubricant at present. It has many advantages, such as strong lubricity, good viscosity resistance, light weight, large specific volume, uniform distribution after mixing with powder, good adhesion and hard separation. The particle size and specific surface area of magnesium stearate powder are the two main factors affecting the lubrication performance. The study found that the hardness, disintegration time and solubility of the 3 batches of the tablets prepared by the 3 batch of magnesium stearate with different morphology, specific surface area, volume density and particle size were all different by the same process and prescription. There are many kinds of lubricants to choose suitable lubricants, in different situations. Preparation of vitamin B tablets is superior to lubricant talc magnesium stearate, talcum powder is the adsorption of vitamin B on intestinal interference of vitamin B. The absorption of. Hu was [1 study found that magnesium stearate was added to reduce the angle of repose of the powder and the collapse angle, but with magnesium stearate with increasing quantity of fine powder increases, lead powder flow between the friction increases, the effect is gradually weakened, so the excess lubricant will lead to the fluidity of the powder worse, the negative effect.
2.2 tableting equipment improvement and optimization
(1) increase the feeding powder and preloading device: in order to make the powder uniformly flow into the mold of the press machine, the oscillating feeding powder or the forced feeding device can be added to the press machine. Before compression, the compression time was prolonged and the problem of adhesion was observed under the action of long time pressure. If the sticky impact occurs, the pressure and speed of the press should be adjusted to achieve good results. (2) increase the sealing and dust removal device to prevent the powder leakage phenomenon, so that the tablets fill more stable tablet machine should have automatically sealed feeding device and a dust removal device is better, and the ash scraper and the turntable should be tight joint. (3) optimize impeller parameters: in forced filling process, impeller diameter, speed, shape, blade and impeller number will have great influence on the fluidity of powder, and the good liquidity of powder can reduce the problem of sticking and punching. The higher the rotational speed of the turntable is, the larger the volume of the impeller is required, and the speed of the impeller is also high. When the turntable's speed is low, and the volume of the impeller is low, the speed of the impeller can be reduced. In order to minimize the impact on the material, the impeller speed should be lower to meet the requirements of the output. (4) the choice of punch and die and the adjustment of pressure and speed of the press: for the raw materials with large stickiness, the punch with no pattern or handwriting should be used. If the punch and die surface is not smooth and unclean, it can be cleaned with organic solvents such as liquid paraffin and corn oil, etc., to replace different sizes of dies, or to smear tiny liquid paraffin wax on the surface of the lettering punch to lubricate the punch surface. The degree of difficulty of the researchers usually in tablets from the die surface detachment as a quantitative indicator of sticking, but Saniocki u believes the index and sticking quantitative relationship does not exist strictly, he believes should be cohesion and adhesion of the punch surface tablet and tablet itself as a quantitative indicator of red clay. It is found that the adhesion force on the surface of the tablet and die increases with the increase of the speed of the press and the content of the adhesive on the Kakimi. Therefore, in the case of no impact on production, the velocity of the sheet can be slowed down properly so as to avoid the occurrence of sticky punching. Mollereau and so on using the image analysis method to determine the situation of the production of sticky flushing.
2.3 control of temperature and humidity
System tablet containing low melting point component, should choose a low indoor temperature environment. The high ambient temperature will increase the viscosity of raw materials, especially those with lower melting point, resulting in sticky and punching. Therefore, the ambient temperature of pressing operation should be controlled within a suitable range. Humidity control is also very important. Indoor relative humidity is too high or moisture on the surface of the punch can increase the moisture content of the powder, and it is easy to occur sticky and punching. Kottala and other studies found that temperature and humidity were the important reasons for the hardness of tablets. The hardness of bilayers decreased because the humidity was too high, leading to the wetting of particles on the surface of the tablets and the adhesion force of powder particles. Some absorbents should be added properly when the humidity is too high.