Application and improvement of wet granulation technology in granules

1 The mechanism of wet granulation is firstly that the liquid in the adhesive moistens the surface of the drug powder, which makes the adhesive force between the powder particles Then, under the action of liquid bridging and external mechanical force, the particles of certain shape and size are made After drying, Zui is finally consolidated in the form of solid bridge Wet granulation mainly includes the process of making soft materials, making wet particles, drying wet particles and the whole particles 2 The factors affecting wet granulation are related to the properties of the original auxiliary particles, the selection of the binder, the time of granulation and stirring, the screen, the drying equipment, etc 2.1 properties of raw and auxiliary materials 2.1.1 fine powder, loose texture, poor drying and viscosity, low solubility in water; select adhesive with strong viscosity, and the amount of adhesive should be more 2.1.2 high solubility in water, strong viscosity of raw and auxiliary materials; select wetting agent or adhesive with small viscosity, and the amount of adhesive is relatively small 2.1.3 it is sensitive to humidity and easy to hydrolyze; it is not allowed to select water as the solvent of the adhesive, but anhydrous ethanol or other organic solvent as the solvent of the adhesive 2.1.4 it is sensitive to heat and easy to decompose; try not to use water as the solvent of adhesive, and choose ethanol with constant solubility as the solvent of adhesive, so as to reduce the drying time and temperature of particles 2.1.5 it is stable to humidity and heat; water with lower cost is selected as the solvent of adhesive 2.2 wetting agents and binders The wetting agent itself has no viscosity or weak viscosity, but it can wet the material and induce the viscosity of the material itself, so that it can agglomerate into soft material and make particles Such as: distilled water, ethanol Where the drug itself has viscosity, but when it encounters water, it can cause deterioration or too strong viscosity after wetting, resulting in difficult granulation, uneven humidity, difficult drying or hard granulation after drying, ethanol of appropriate concentration can be selected as the wetting agent The concentration of ethanol depends on the nature of the drug and the ambient temperature, generally 30% - 70% or more To a certain extent, ethanol is a kind of dispersant, which can reduce the viscosity between particles and make the materials with too strong viscosity easy to form particles 2.2.2 adhesives: cohesive solid powder or viscous liquid that can make the cohesionless or less cohesive materials aggregate and stick into particles or compression molding For example, PVP, HPMC, CMC Na, syrup, etc 2.2.2.1 PVP: white or milky white powder, non-toxic, high melting point, 150 ℃ color change for heat stability, stable chemical properties, soluble in water and ethanol to become viscous colloidal liquid, good adhesive PVP has different specifications and models Pvpk30 is often used as binder, and its common concentration is 3% - 15% For example, PVPK30 is used as the binder in azithromycin granules, and its concentration is 5% 2.2.2.2 the aqueous solution of syrup sucrose, with strong viscosity, is suitable for the plant drugs with loose texture and strong elasticity and the chemical drugs with loose texture and easily lost crystal water The aqueous solution of 50% - 70% (g / g) is commonly used When the concentration of sucrose is up to 70% (g / g), it is supersaturated at room temperature and can only be used at heat, otherwise it is easy to precipitate and crystallize 2.2.2.3 CMC Na: common concentration is 1% - 2% The products with degree of substitution equal to 0.7 are mostly used in pharmaceuticals They are soluble in water, insoluble in organic solvents and soluble in 40% ethanol solution 2.2.3 selection of binders 2.2.3.1 selection of binders is related to the properties of raw and auxiliary materials, solvents of binders, mixing time and concentration of binders: for example, raw materials have fine powder, loose texture, small solubility in water, poor viscosity of raw materials, and more binder On the contrary, use less 2.2.3.2 when the amount of excipients in the prescription accounts for more than 80%, on the premise of not affecting the properties of the main drug, the characteristics of excipients should be considered to select adhesives If sucrose is used as the auxiliary material, when the dosage reaches more than 80%, the characteristics of "the viscosity of sucrose becomes too strong when it meets water" shall be taken into account Non-aqueous solvent shall be selected to dissolve the adhesive (only the adhesive soluble in water and not in organic solvent is not applicable), reduce the viscosity between particles, and relatively enhance the viscosity inside particles For example, the proportion of sucrose in the prescription of azithromycin granules is more than 80% The granulation performance of 5% pvpk30 prepared with 95% ethanol is better than that of 5% pvpk30 prepared with 20% ethanol The former can be granulating at one time up to 90%, while the latter can only be granulating at one time up to 50% This shows that the viscosity and granulation effect of the same binder are different when different solvents are selected 2.3 the granulation and cutting time should be controlled moderately when making soft materials Generally, it should be controlled by experience It can be lumped without sticking to the hand when being squeezed tightly by hand, and it can be split when being pressed lightly by fingers Stirring time is long, viscosity is too strong, granulation is difficult; stirring time is short, viscosity is not strong, granulation is not good 2.4 there are nylon wire, galvanized wire, stainless steel and plate screens commonly used The nylon screen is good for Zui, which is suitable for the soft material with "wet but not too sticky but good granulation" Other screens are easy to have metal chips (broken wire) or broken stainless steel wire into the particles, affecting product quality In addition, when using the swing type particle mechanism wet particles, the degree of tightness of the screen installation has a greater impact on the particle quality: if the screen installation is relatively loose during granulation, when the drum is rotated and stirred repeatedly, the viscosity of the soft material can be increased, and the wet particles produced are thick and tight On the contrary, the particles are fine and loose Therefore, the tightness of the screen installed in the production should be moderate 2.5 drying and drying equipment 2.5.1 drying is the process of removing moisture from wet materials by gasification In the process of drying, it should be noted that the wet particles should be dried as soon as possible, the drying speed of particles should be strictly controlled, and the temperature should gradually rise during the drying process 2.5.2 drying equipment has van drier, spray dryer, fluidized bed dryer (also known as boiling dryer) Fluidized bed dryer is commonly used in large-scale production, which is characterized by simple structure, convenient operation, intense movement of particles and hot gas flow, large contact area, fast drying speed, and suitable for heat sensitive materials The horizontal fluidized bed dryer is suitable for drying granules with good effect 3 The application and improvement of wet granulation technology in the production of Granules Combined with the technical problems encountered when amoxicillin dry syrup was changed into granules and the improvement methods to illustrate the application and improvement of wet granulation technology in granules 3.1 in amoxicillin dry syrup production process, raw materials and crushed auxiliary materials (mainly sucrose) are mixed for 5 minutes, 1% CMC Na pulp is added, and granulation is carried out for 180 seconds Particles under 14 mesh are taken through 14 mesh stainless steel screen by yk-160 swing granulator and dried 3.2 problems encountered in changing from dry syrup to granules 3.2.1 according to the production process of dry syrup, the qualified rate of one-time granulation is less than 30%, and the unqualified particles should be re granulating every time, so that a batch of production can reach the above standard after repeated granulation, which wastes working hours, energy and increases production cost; It also affects the stability of the product 3.2.2 it is easy to block the screen (stainless steel) when the soft material is prepared by wet granulation and mixed with swing type granules It used to make soft material and then dry it by boiling dryer for 2 minutes, and then use swing granule to make granules As a result, agglomeration, high hardness, easy to crush and break the screen A large number of stainless steel screens shall be replaced in each batch of production 3.2.3 the prepared particles are loose, the hardness is not enough, and there are more fine powders after boiling drying 3.2.4 due to the large viscosity of soft materials, the use of stainless steel screen is prone to fracture, resulting in broken stainless steel wire mixed in the particles Every time it occurs, it is necessary to stop for selection, which not only wastes working hours, but also has serious consequences caused by unclean selection It is imperative to use other screens 3.3 the improvement of wet granulation technology shall be carried out on the premise that the original prescription remains unchanged 3.3.1 improvement of binder 3.3.1.1 In this prescription, 1% CMC Na is used as the binder, because it can only dissolve in the ethanol solution with high concentration of Zui of 43%, the method of increasing the ethanol concentration of the solvent is not feasible 3.3.1.2 first add 1% CMC Na, and then add some ethanol to granulation, the effect is not good 3.3.1.3 adding 1% CMC Na first, and then adding syrup for granulation, the effect is not good 3.3.1.4 because the amount of sucrose in this prescription is large, and the viscosity is too strong after being wetted with water, the method of "first adding ethanol to wet and disperse, then adding adhesive" can be used for granulation That is to say, "first add ethanol to wet and disperse, then add CMC Na adhesive, Zui and then add syrup" to granulation, the effect is good 3.3.2 use nylon screen because nylon screen is suitable for "wet but not too sticky but well granulated" soft materials Use "first add ethanol to wet and disperse, then add CMC Na adhesive, Zui and then add syrup" to granulate, which is very suitable for nylon screen It solves the problem of using stainless steel mesh to mix broken stainless steel wire in particles This method can be basically used for the materials which are difficult to be granulated due to too much viscosity after nylon screen is used, that is to say, the method of "first adding ethanol for wetting and dispersing, then adding adhesive" is used to solve the problem 3.3.3 control the mixing time when making soft material, and find out the mixing time after adding wetting agent and adhesive successively through experiments 3.4 amoxicillin granules production process through the improvement of wet granulation technology and production verification, has summed up the mature process of amoxicillin granules production 3.4.1 in the improved process, the raw materials and crushed auxiliary materials (mainly sucrose) are mixed for 5 minutes, the mixing is stopped, 95% ethanol is added, the stirring is cut for 120 seconds, 1% CMC Na slurry is added to the prescription amount, the stirring is cut for 60 seconds, syrup is added, the stirring is cut for 120 seconds, the granules are made through 14 mesh nylon screen with yk-160 swing granulator, dried, and the granules are taken from 12-60 mesh screen 3.4.2 the particle size qualification rate of the improved particle production process is more than 90%, which solves the problem of difficult granulation, greatly improves the production efficiency, and the particles produced are more uniform, with appropriate hardness and good results 3.4.3 after accelerated test and sample observation, the quality is stable and all indexes meet the quality standard.