Granulation purpose and granulation method
Most solid dosage forms undergo a "granulation" process. The granulation technology is not only applied to the preparation process of tablets, capsules, granules, etc., but also needs to be granulated in order to facilitate the processing of the powder, and the auxiliary materials for direct compression are also often required to be granulated to ensure The quality of the drug and the production went smoothly.
(1) The purpose of granulation
(1) The particles have good fluidity, and are easy to realize automation, continuous and quantitative in the transportation, packaging and filling of drugs;
(2) Preventing separation due to differences in particle size and density, and facilitating uniform mixing of various components;
(3) Prevent dust from flying during operation and adhesion on the wall to avoid environmental pollution and loss of raw materials;
(4) Adjust the bulk density to improve the solubility;
(5) Uniform pressure transmission during tableting;
(6) When the formula and operation are appropriate, the efficacy and stability of the drug can be improved;
(7) Easy to take, etc.
The granules may be intermediates, such as granulation during tablet production; it may also be a product such as granules. The purpose of granulation is different, and its requirements are different or focused. For example, the particles for tableting are mainly used for improving fluidity and compression formability; and the granulation process of granules and capsules has the main purpose of good fluidity, prevention of sticking and flying, improvement of mixing uniformity, and improvement of appearance. In recent years, with the development of the pharmaceutical industry, granulation technology has also been greatly improved.
(2) Classification of granulation methods
Granulation methods widely used in pharmaceutical production can be divided into two major categories. That is, wet granulation and dry granulation.
(1) Wet granulation: a method of preparing a granule by adding a binder solution to a raw material powder and agglomerating the powder together by bridging or bonding of the binder solution. Extrusion granulation, rotary granulation, fluidized bed granulation, agitation granulation, etc. are wet granulation.
(2) Dry granulation: no liquid is added to the raw material powder, and the compressive force acts to make the distance between the particles close to each other to produce a binding force, directly compress into a desired particle according to a certain size and shape, or first compress the powder into tablets. After the shape or the plate, it is re-pulverized into particles of the desired size.
(3) Bonding force between particles
Particles are formed by the incorporation of numerous particles (or crystalline particles) by some combination of binding forces. In order to distinguish between the raw particles of the raw material and the finished particles, the former is called *particle and the latter is called second particle or particle. In the granulation process, the binding force generated between the particles directly affects the various powder properties such as strength, particle size and density of the second particles. The binding force generated between the granules during granulation can be summarized as follows:
(1) solid bridge - solidification of local melt due to pressure or friction, formation of crystals precipitated after drying of the interparticle solution, and curing of the binder between particles;
(2) Adhesion and adhesion of non-flowing liquids - the binding force generated by the adsorption of viscous adhesives (such as sugars, glues, gums, etc.);
(3) Bridging effect of flowing liquid - the binding force generated by the capillary suction and surface tension of the liquid between the particles;
(4) The attraction between the powder particles - the intermolecular attraction (van der Waals force) generated mainly during the processing of the fine powder, electrostatic force, etc.;
(5) Mechanical toothing force - When agitating or compressing fibrous or massive particles, the particles are combined and joined together, and this combination is related to the structure of the particles.
In the bonding force between the particles discussed above, the bonding force of the solid bridge is strong, and the gravitation between the particles is weak.
Although the mechanical tooth force is large, it has little effect on the strength of the particles.
Granulation technology and experience
First, the concept of granulation technology
Granulation technology: A technique in which a material such as a powder, a melt, or an aqueous solution is processed into a pellet of a certain shape and size.
The purpose of granulation: 1 to improve fluidity, easy to pack and compress; 2 to prevent separation of various components due to particle size density; 3 to prevent dust flying and adhesion on the wall; 4 to adjust bulk density and improve solubility; 5 improve the uniformity of pressure transmission in tablet production; 6 easy to take, easy to carry, and enhance the value of the commodity.
Granulation method: wet granulation, dry granulation (also known as one-step granulation), where wet granulation application is more zui, (most domestic and foreign pharmaceutical, food, chemical companies are switching to dry granulation).
Application of granulation technology: The use of zui in solid preparations, especially in granules and tablets, is extensive.
Second, the granulation method
(1) Wet granulation (most domestic and foreign pharmaceutical, food, and chemical companies are switching to dry granulation)
Wet granulation: adding a binder or a wetting agent to a drug powder to form a soft material, sieving to form wet granules, and drying the wet granules and then granulating them. The wet-made granules have the advantages of better surface modification, beautiful appearance, strong wear resistance and good compression formability, and are widely used in the pharmaceutical industry.
Wet granulation mechanism: First, the liquid in the binder wets the surface of the drug powder, causing adhesion between the particles, and then forming particles of a certain shape and size under the action of liquid bridging and external mechanical force. After drying, the zui is finally consolidated in the form of a solid bridge.
Wet granulation mainly includes processes such as making soft materials, making wet granules, drying wet granules and granules.
1. Making soft materials: Mix the raw materials and fine powders weighed according to the prescription, and add appropriate amount of wetting agent or adhesive to mix them into soft materials.
Pay attention to the problem of making soft materials
(1) The type and amount of binder should be determined according to the nature of the material;
(2) The concentration of the added binder and the stirring time should be flexibly controlled by different varieties;
(3) Quality of soft materials. Due to the difference of raw and auxiliary materials, it is difficult to set a unified standard. Generally, it is mastered by experience. It can be clumped by hand, and the fingers can be broken and opened.
(4) The length of the wet agitation time has a great relationship with the soft material of the granule. The longer the wet mixing time, the greater the viscosity and the harder the granules are.
2. Wet granules: make the soft materials pass through the sieve to form granules. When the granules fall from the sieve holes, such as a long strip, it indicates that the soft material is too wet, and the wet mixture or the wetting agent is excessive. On the contrary, if the soft material passes through the sieve hole and is powdery, it indicates that the soft material is too dry and should be properly adjusted.
Common equipment: rocking granulator, rotary granulator
Screen: There are four kinds of screens: nylon wire, galvanized iron wire, stainless steel and plate.
3. Drying of wet granules: The wet granules obtained by sieving should be dried immediately to avoid agglomeration or deformation under pressure. (The stainless steel disc can be used to spread the prepared wet granules and occasionally flip to solve the problem of wet granule storage and deformation. problem).
Drying temperature: from the nature of the raw materials, generally 50-60 ° C; some wet, heat stable drugs, drying temperature can be appropriately increased to 80-100 ° C.
Dryness: Control by measuring water content. Granules require that the water content of the granules should not exceed 2%; the granules of the tablets retain appropriate moisture, usually around 3%, depending on each specific species.
Drying equipment: commonly used in the box type (such as drying room, oven) drying, boiling drying, microwave drying or far infrared drying and other heating and drying equipment.
4. Whole granules: After the wet granules are dried, they are sieved to granulate the granules to break up the granules to meet the particle size requirements of the granules or the tableting requirements of the tablets.
(1) Granules: The sieves which are smaller than the sieve mesh used for the wet granules and which are within 10 mesh (screen No. 1) can be suitably pulverized by the sieve which cannot pass through the sieve holes, and then according to the particle size requirements, The lower limit of the particle size specification, over 60 mesh or 80 mesh (No. 5 sieve), is classified, and the particles are between 10-80 mesh;
(2) Tablets: The granules may have a mesh size larger than that of the sieve used for the wet granules.
(2) Dry granulation
Dry granulation: a method in which a drug powder (if necessary, a diluent, etc.) is mixed, and then directly pressed into a block by a suitable apparatus, and then broken into particles of a desired size. This method relies on the action of compressive forces to create a bond between the particles. Can be divided into heavy pressure method and rolling method.
Heavy pressing method: also known as the large-scale method, the solid powder is first pressed into a 20-25 mm diameter piece on a heavy-duty tablet press, and then broken into particles of a desired size.
Rolling method: The powder of the medicine is rolled into a sheet by a roller press, and is broken into particles of a certain size by a pelletizer.
Dry granulation characteristics: It is often used in heat-sensitive materials, water-stable unstable drugs and compression-formable drugs. The method is simple, labor-saving and time-saving. However, attention should be paid to the crystal transformation and activity reduction that may be caused by compression.
(3) Chinese medicine granules
Chinese medicine granules: generally used rotary granulation
1. Fine powder granulation: When the dosage of the formula is not large, the medicinal material can be ground into a fine powder of 100 mesh or more, added with a suitable wetting agent or a soft material made of a binder, and sieved and granulated.
2. Mixing of medicinal materials and medicinal materials with fine powder: granules are made into a thick extract, and the other part is ground into a fine powder. The two are mixed into a soft material, sieved and granulated and dried. This method can replace the binder with a thick paste of medicinal materials, which is beneficial to reduce the volume of the film and is used more. Other adhesives may be added if the adhesive strength is insufficient when only a thick paste is used as the adhesive.
3. Dry extract granulation: The medicinal materials in the formula (except the medicinal materials containing volatile components) are extracted and made into a dry extract. The dry extract is ground into granules; or the dry extract is ground into a fine powder, and then a suitable wetting agent (such as an appropriate concentration of alcohol alcohol) is added to make a soft material, and then granulated.
Third, factors affecting wet granulation
1, the nature of raw materials
(1) The powder is fine, the texture is loose, the drying and the viscosity are poor, and the solubility in water is small; the adhesive with stronger viscosity is used, and the amount of the binder is more.
(2) The solubility in water is large, and the raw materials are inherently viscous; the wetting agent or the less viscous binder is used, and the amount of the binder is relatively small.
(3) It is sensitive to moisture and easy to be hydrolyzed; water cannot be used as a solvent for the binder, and anhydrous alcohol alcohol or other organic solvent is used as a solvent for the binder.
(4) It is sensitive to heat and easy to decompose; try not to use water as a solvent for the binder, and use a certain solubility of alcohol as a solvent for the binder to reduce the drying time of the particles and reduce the drying temperature.
(5) It is stable to moisture and heat; water with lower cost is used as a solvent for the binder.
2, wetting agent and adhesive
Moistening agents: Wetting the material to produce a viscosity of sufficient strength to facilitate the formation of a liquid of the particles. The wetting agent itself is non-tacky or not very viscous, but it wets the material and induces the viscosity of the material itself, allowing it to coalesce into a soft material and form a granule. Such as: distilled water, alcohol.
Adhesives: A non-tacky or less viscous material that can be aggregated into granules or compression-formed viscous solid powders or viscous liquids. Such as povidone (PVP), hypromellose (HPMC), sodium carboxymethylcellulose (CMC-Na), syrup and the like.
(1) Category
1 distilled water: water itself is not sticky, when the material contains water-visible components, it can be induced to be viscous by diluting with distilled water to make suitable particles. However, when water is used as a wetting agent, since the material tends to absorb water faster, it is more prone to wet unevenness, and the drying temperature is higher, so it is not suitable for drugs that are not heat-resistant, easily deteriorated by water, or are easily soluble in water. use. Zui is better to use low concentrations of starch or alcohol to replace the above shortcomings.
2 Alcohol alcohol: Where the drug itself is sticky, but the water can cause deterioration or wetness, the viscosity is too strong, so that the granulation is difficult, the humidity is uneven, the drying is difficult or the finished granules are hardened after drying, and the pressed tablets are pressed. The agent is not easy to disintegrate, etc., and an alcohol alcohol of a suitable concentration may be used as a wetting agent. The alcohol alcohol concentration depends on the nature of the drug and the ambient temperature, and is generally 30% to 70% or more. And as the concentration of alcohol alcohol increases, the viscosity generated after wetting decreases. To a certain extent, alcohol alcohol is a dispersing agent, which reduces the viscosity between the particles, and makes the viscous material easy to granulate. Traditional Chinese medicine extract tablets are commonly used as humectants for alcohol alcohols, but care should be taken to avoid rapid reaction of alcohol alcohols to produce strong viscous masses.
3 povidone (PVP): white or milky white powder, non-toxic, high melting point, stable to heat (150 ° C discoloration), chemically stable, soluble in water and alcohol to become a viscous gelatinous liquid, good Adhesive.
PVP has different specifications and models, commonly used PVPK30 as adhesive.
? PVP aqueous solution, alcohol solution or solid powder can be applied.
• PVP dry powder can also be used as a dry binder for direct compression.
PVP 3%-15% (usually 3~5%) alcohol alcohol solution is often used for granulation of water-sensitive drugs, and the prepared granules have good compressibility. It can be used for drugs with poor compressibility, but it should be noted that these adhesives are very viscous and the tablets are made to be hard. A slight excess will cause the tablet to disintegrate.
PVP is also an excellent binder for chewable tablets.
PVPK30 is used as a binder for granulation in azithromycin granules at a concentration of 5%.
Hydroxypropylmethyl cellulose (HPMC)
It is a white powder, odorless and tasteless, and has considerable stability to light, heat and humidity. It is a commonly used film coating material. It is soluble in water and partially polar organic solvents. It can swell in cold water to form a viscosity. Solution. It is insoluble in alcohol alcohol, alcohol ether and chloroform, but soluble in 10%~80% alcohol alcohol solution or a mixture of methanol and dichloromethane.
When preparing HPMC aqueous solution, Zui first adds HPMC to the total volume of 1/5~1/3 of hot water (80 °C ~ 90 °C), fully disperses and hydrates, and then continuously stirs under cooling conditions. Cold water to total volume.
HPMC is used as a binder and is usually used at a concentration of 2% to 5%.
HPMC as a binder is characterized by rapid disintegration and fast dissolution rate.
5 syrup: sucrose aqueous solution, its viscosity is strong, suitable for loose texture, strong plant chemicals and loose chemical and crystallization water, commonly used 50%-70% (g / g) aqueous solution .
When the sucrose concentration is as high as 70% (g/g), it is a supersaturated solution at room temperature and can only be used when it is hot, otherwise it will precipitate crystals.
Strong acid or strong alkaline drugs can cause the conversion of sucrose to produce hygroscopicity, which is not conducive to tableting, so it is not suitable for granules.
? Powdered sugar is a dry binder.
Sucrose has a certain hygroscopicity, its hygroscopicity is related to purity, and the hygienic property of poor purity is stronger.
Sometimes combined with starch slurry to enhance adhesion, sometimes mixed with sucrose powder and raw materials and then wetted with water.
6 carboxymethy cellulose sodium CMC-Na
? is a carboxymethyl etherate of cellulose, insoluble in organic solvents such as alcohol alcohol, chloroform; when dissolved in water, the surface of the initial particles of zui is puffed, and then the water slowly penetrates into the interior to become a transparent solution, but the time required Longer, Zui is better heated to 60 °C ~ 70 °C after initial expansion and swelling, which can greatly accelerate the dissolution process.
The usual concentration is 1%-2%.
The application of zui in the medicament is a product with a degree of substitution equal to 0.7, which is soluble in 60% alcohol alcohol solution.
7 starch slurry: commonly known as starch paste, suitable as a binder for moist heat stable drugs, the general concentration is 5%-30%, 10% is commonly used for zui. There are two kinds of methods: the pulping method and the boiling method.
?Pulping method: the starch is first added with a small amount (1-1.5 times) of cold water, stirred, and then flushed into the full amount of boiling water, and continuously stirred into a translucent paste. This method is easy to operate and suitable for mass production.
? Boiler method: slowly add the whole amount of cold water to the starch, stir it, heat it and stir it continuously until it is a paste. This method should not be heated by direct fire, so as to avoid the appearance of the bottom coking mixed with black spots. This method has been used sparingly in production.
The starch slurry can uniformly wet the material, is not prone to local over-wetting, and has good adhesion. It is a widely used adhesive.
The temperature at which corn starch is completely "gelatinized" (gelatinization refers to the phenomenon of a uniform paste formed when the starch is heated) is 77 °C.
8 glue: commonly used 10%-20% gelatin solution and 10%-25% gum arabic solution. It is suitable for drugs that are easy to loose and cannot be granulated with starch syrup.
9 other cellulose derivatives
? Methyl cellulose (MC): soluble in water, becoming a thick and viscous glue. However, it should be noted that when the sucrose or electrolyte reaches a certain concentration, the product will precipitate.
Alcohol-based cellulose (EC): It is mainly used as a binder for sustained-release preparations. It is commonly used at a concentration of 2%-10%. Alcoholic alcohol solution can be used as a binder for water-sensitive drugs, but it should be noted that the viscosity of the product is strong and does not dissolve in the gastrointestinal fluid, which may hinder the disintegration of the tablet and the release of the drug. Currently, it is commonly used in slow and controlled release preparations (skeletal or membrane controlled release).
Hydroxypropyl cellulose (HPC)
It is a hydroxypropyl etherified cellulose containing 53.4% ​​to 77.5% of hydroxypropyl group (containing 7% to 19% of low-substituted hydroxypropyl cellulose L-HPC, which is often used as a disintegrating agent). White powder, soluble in cold water, gelled or swollen when heated to 50 °C;
Soluble in methanol, alcohol, isopropanol and propylene glycol.
This product can be used as a binder for wet granulation and dry granulation, or as a binder for direct compression of powder.
(2) The choice of adhesive is related to which factors
1 is related to the nature of the raw materials: if the raw material powder is fine, the texture is loose, the solubility in water is small, the viscosity of the raw material itself is poor, and the amount of the binder is more. On the contrary, the amount is less.
2 For drugs that are unstable to heat and humidity, consider the binder and binder solvent. An anhydrous, low drying temperature binder and its solvent are used.
3 is related to the mixing time: the mixing time is long when the soft material is made, the viscosity of the soft material is large, and the produced particles are hard.
4 is related to the binder concentration: the larger the binder concentration, the harder the pellets produced are produced under other process conditions.
5 When the amount of excipients in the prescription accounts for more than 80%, the binder should be selected with special emphasis on the characteristics of the excipients without affecting the nature of the main drug. For example, when sucrose is used as an auxiliary material, when the amount is more than 80%, the characteristics of "sucrose viscous water becomes stronger" should be considered, and a non-aqueous solvent is used to dissolve the binder (only soluble in water and insoluble in organic solvent) The mixture is not suitable), reducing the viscosity between the particles and relatively enhancing the viscosity of the inside of the particles. For example: azithromycin granules: the proportion of sucrose in the prescription is more than 80%, the granulation property when 5% PVPK30 is prepared by using 95% alcohol alcohol as granulation, and 5% PVPK30 is prepared by using 20% ​​alcohol alcohol as binder. The effect of the granules is good, the former can achieve granulation up to 90%, and the latter granulation is only 50%.
6 The same adhesive, the viscosity and granulation effect are different when different solvents are used.
7 For materials with too much viscous material, the method of “wetting and dispersing with alcohol alcohol and adding binder†can be used to make the granulation effect better during granulation. For example, this method is used in the re-granulation granules and azithromycin granules, and the effect is good.
8 According to the nature of the raw materials, two kinds of binders can be used for granulation. For example, granulation is carried out in "Relin granules" by first adding "alcoholic alcohol to wet dispersion, adding CMC-Na binder, and adding syrup after Zui".
3, granulation and cutting time:
When making soft materials, the mixing time should be moderately controlled. Generally, it is mastered by experience. It can be clumped by hand without sticking to the hands, and the fingers can be broken and opened.
Long mixing time, too strong viscosity, difficult granulation;
The mixing time is short, the viscosity is not strong, and the granulation property is not good.
4, the screen
(1) Nylon wire screen: It does not affect the stability and elasticity of the drug. It is suitable for soft material pellets that are “wet but not sticky but good in granulationâ€. When the soft material is relatively sticky, the sieving is slow, and the soft material is repeatedly kneaded and mixed, the hardness of the prepared granule is large, and the nylon mesh is easy to break.
(2) galvanized iron wire screen: It can be used for viscous soft material granules, but it is easy to have metal chips (broken wire) to bring into the granules, and may also affect the stability of some drugs. The magnet wire that is adsorbed by the magnet can be added at the key position of the device, and the effect is good.
(3) Stainless steel screen: The pure stainless steel screen with good quality has better granulation effect, but the broken stainless steel ribbon is easy to break into the particles and cannot be adsorbed by magnet.
(4) Slab screen: It can solve the problem of metal chips being brought into the particles, but the price is expensive and the production speed is slow.
What is the effect of the tightness of the screen installation on the quality of the pellets when using a swaying particle mechanism to wet the granules?
If the screen is loosely installed during granulation, the drum can be reciprocally rotated and stirred to increase the viscosity of the soft material, and the obtained wet granules are thick and tight. On the contrary, the obtained granules are fine and loose. Therefore, the tightness of the screen installed in production should be moderate.
5, drying and drying equipment
Drying is the process of removing moisture from a wet material by gasification.
(1) Drying process of wet granules means that moisture is diffused from the inside of the wet material to reach the surface, so that the surface of the material is heated and vaporized. After the surface moisture evaporates, the internal moisture diffuses to the surface through the humidity difference inside the particles, and continues to evaporate on the surface to achieve the purpose of drying.
(2) Problems that should be paid attention to during the drying process of wet particles
A, wet particles should be dried as soon as possible, otherwise, it will easily cause deformation, agglomeration or deterioration of wet particles.
B. Drugs that are granulated with dilute alcohol and easily hydrolyzed should be dried as soon as possible. The alcohol is evaporated and the water is increased correspondingly after the release, so that the hydrolysis of the drug is accelerated.
C. Strictly control the drying speed of the particles. The drying speed depends on the external conditions and the difficulty of diffusing the liquid inside the particles to the surface. The external conditions are the humidity, temperature, flow and dispersion of the air.
D. The temperature should be gradually increased during the drying process, otherwise the surface of the particles will form a hard film after drying, which will affect the evaporation of internal moisture.
E. If the granules contain icing sugar and starch, a sudden increase in temperature may cause the sugar to melt and the starch gelatinization to affect the disintegration of the tablet.
Fourth, the application of granulation technology in pharmaceutical production
1. Application of granulation technology in granules
Granules refers to dry granular preparations of the drug and suitable excipients.
Particle Size The 2005 edition of the Chinese Pharmacopoeia has a clear definition of the particle size of the granules: the weight of the granules and powder which cannot pass through the No. 1 sieve and the No. 5 sieve shall not exceed 15% of the total weight (the general internal control standard is 10%).
All granules should be granulated, and the qualification rate of one-time granulation is high. It is necessary to comprehensively consider various factors and determine the granulation prescription through experiments.
Common granules: azithromycin granules, amoxicillin granules, and the like.
2. Application of granulation technology in tablets
Usually, the preparation of the tablet includes two methods of direct tableting and granulation tableting, and the wet granulation tableting method is widely used.
Wet granulation tablet for drugs that are stable to damp heat.
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