What are the different types of granulation technologies III
Writer： admin Time：2020-03-30 14:43 Browse：℃
What will influence the wet granulation
1.Material properties
1)Fine powders are loose, dry and of poor viscosity. It hardly dissolve in water, so more adhesive of strong adhesion should be used.
2)Some raw materials are of strong viscosity and can dissolve in water easily. For them, moisturizer or adhesive of weaker adhesion should be added in small dosage.
3)For some materials which are sensitive to humidity and hydrolyzable, water cannot be the solvent for adhesive, but absolute ethanol or other organic solutions can.
4)Some materials are sensitive to heat and decomposed easily. Therefore, ethanol of certain concentration, instead of water, can be the solvent for adhesive to shorten drying time and decrease drying temperature.
5)If materials keep stable to humidity and heat, we can choose water, which cost less, to be the solvent for adhesive.
1)Moistening agents: It is a liquid which can moisturize materials and generate enough viscosity for granulation. Moisturizer itself obtains no viscosity or just weak viscosity, but it can wet materials and make they generate viscosity and aggregate ti mixture, which is then granulated. Some moisturizer examples are distilled water and ethanol.
2)Adhesives: It is solid powder or viscous liquid which can aggregate materials without viscosity or of poor viscosity to particles or the compressed., such as PVP, HPMC, CMC-Na, syrup, etc..
3)Types:
A.Distilled water: Water obtains no viscosity. But some material ingredients can generated viscosity when moisturized. Therefore, distilled water can be used for the purpose of viscosity generation. However, since materials used to absorb water quickly, non-uniform distribution of water might occur. Also, drying temperature is pretty high, which is not friendly to heat-unresistant, perishable or soluble medicines. It’s better to use some starch or ethanol of low concentration to overcome the above shortage.
B.Ethanol: Sometimes medicine obtains viscosity and will go bad or obtain strong viscosity after being wet, which will lead to troublesome granulation; non-uniform humidity will also trouble drying or harden granules and tablets made from them are not easy to disintegrate. At that time, ethanol of appropriate concentration should be used as moisturizer. Ethanol concentration depends on medicine properties and environment temperature. Generally, it should be 30-70% or even thicker. And as ethanol concentration increases, material viscosity become poorer and poorer after wetting. To some extent, ethanol functions as dispersant to weaken granule viscosity so that materials of strong viscosity can be granulated. Ethanol is often used in Chinese extract granulation. But it requires quick operation in case that ethanol volatilize.
C.PVP: It is white milky, powdery and non-toxic. It obtains high melting point and stable chemical properties and can keep stable in high temperature (It discolors in 150°C). Its solution in water or ethanol is viscous and jelly. All of these make it good adhesive.
a.PVP has different specifications. Among them, PVPK30 is always used as adhesive.
b.PVP solution in water or ethanol and PVP powder can all be applied.
c.Dry PVP powder can be directly used as dry adhesive during tablet pressing.
d.Ethanol containing 3%-15% PVP (3%-5% is more common) is usually used to granulate medicines which are sensitive to water. The granules produced are of good compressibility. Therefore, the solution can be used for medicines of poor compressibility. But it should be noted that the adhesive is of high viscosity. Tablets will be hard and slight excess will lead to overrun of tablet disintegrating capacity.
e.PVP is also good adhesive to chewing tablets.
f.PVPK30 is also the adhesive used in granulation of Azithromycin granules, with its concentration of 5%.
D.HPMC (hydroxypropylmethyl cellulose): It is white, powdery, odorless, tasteless and keeps stable to light, heat and humidity. It is the most common used film material, which can be dissolved in water or some organic solvents. It can dissolve and swell in cold water to produce viscous solution. HPMC cannot be dissolved in ethanol, ether, and chloroform, but ethanol with concentration of 10-80% or the mixing liquid of methanol and dichloromethane.
a.When preparing HPMC solution, HMPC is better to be added into hot water (80°C-90°C) with volume of 1/5-1/3 of the total volume. After it fully disperses, dissolves and cools down, it should be stirred and added with cold water to the total volume.
b.Common concentration of HPMC as adhesive is 2%-5%.
c.HPMC features quick disintegration and dissolution.
E.Syrup: Solution of sucrose is viscous and applicable for loose and flexible plant medicine. Its common concentration is 50-70% (g/g).
a.When sucrose concentration is high to 70%, it is over-saturated. Therefore, it should be used when being hot, otherwise it will separate out crystals.
b.Medicines of strong acid or alkaline will change nature of sucrose and cause hygroscopicity, which is not advantageous for tablet pressing. As a result, it is not applicable to granulate.
c.Sugar powder is dry adhesive.
d.Sucrose obtains certain hygroscopicity, which is relative with its purity. The less purity is, the stronger hygroscopicity will be.
e.Sometimes, sucrose is used with starch to strengthen adhesion, or mixed and wet with raw material to granulate.
F.CMC-Na (carboxymethycellulose sodium)
a.It is a carboxymethyl etherate of cellulose. It cannot dissolve in ethanol or chloroform. When it dissolve in water, particle surface puffs first and water penetrate into the internal slowly to yield transparent solution. But it cost too much time in this process. It’s better to heat to 60-70°C after primary puffing and dissolution to fasten this process.
b.Common concentration is 1-2%.
c.Products with degree of substitution of 0.7 is most used, which can dissolve in ethanol (60%).
G.Starch pulp: It is commonly known as starch paste, used as adhesive for medicines which keep stable in humidity and heat. Normal concentration is 5-30%. 10% is the most common. There are two methods of production: pulp brewing and pulp boiling.
a.Pulp brewing: Adding small amount cold water (1-1.5 times of starch volume), stirring, adding hot water to total volume, continuing stirring it to be semi-transparent. Such a method can be operated conveniently and suit mass production.
b.Pulp boiling: Adding required volume of cold water into starch slowly, stirring, heating and continue to stir it to become paste. In this process, starch cannot be heated by straight fire to avoid scorch, which influences appearance.
c.Starch pulp can wet materials uniformly and is of good adhesion, which makes it widely used adhesive.
d.At the temperature of 77°C, starch will be totally gelatinized, i.e., starch after being heated will form uniform mash .
H.Colloidal solution: It commonly consists of 10-20% gelatin solution and 10-25% Acacia senegal. It is used for medicines which are loose or cannot be granulated by starch.
I.Other cellulose derivative
a.MC: soluble in water to be viscous glue. Note: it will be separate out and precipitate when sucrose or electrolyte reach to certain concentration.
b.EC: soluble in ethanol. It is mainly used as the adhesive of sustained-release preparation. Common concentration of it is 2%-10%. Its solution can also be the adhesive for medicines which are sensitive to water. Note: EC is of high viscosity and does not dissolve in gastric and intestinal juice, which will block medicine disintegration and release. Currently, it is commonly used in sustained- and controlled-release preparation.
c.HPC: It is hydroxypropyl etherate of cellulose, including 53.4%-77.5% hydroxypropyl (if only 7%-19% is included, it is L-HPC, commonly used as disintegrant). it is white, powdery and soluble in cold water. When heated to 50°C, it can gelatinize or swell. Besides, it is also soluble in methanol, ethanol, isopropanal and propylene glycol. Therefore, HPC can be the adhesive both in wet granulation and in powder tableing.
4)Factors influencing selection of adhesive
A.Properties of materials: If powders are fine, loose, hardly soluble in water or viscous, adhesives should be used more; otherwise, it can be used less.
B.Adhesive and its solvent should be taken into consideration for medicines sensitive to humidity and heat. Its OK to use dry adhesive of low drying temperature and its solvent.
C.Mixing time: The longer time it cost to mix, the more viscous mixture will be and the harder granules will be.
D.Adhesive concentration: If other technical conditions keeps constant, the more concentrated the adhesive is, the harder granules will be.
E.If auxiliary materials take up more than 80% in formula, viscosity should be selected considering auxiliary material properties without influencing main materials. For example, if it is used as auxiliary materials and takes up more than 80%, its viscosity change in water should be considered. Therefore, non-water solvent can be used to dissolve adhesive (adhesives soluble in water but not in organic solvent cannot be dissolved so) to decline granule viscosity but to relatively increase internal viscosity of granules. Take Azithromycin Granules as example. In its formula, sucrose takes up more than 80%. Two methods can be used to prepare adhesive. One is with 95% ethanol with 5% PVPK30 and the other is with 20% ethanol and 5% PVPK30. It is shown that the former can bring better granulation, whose granulation rate can reach 90%, while that of the latter can be 50%.
F.The same adhesive, if dissolved in different solvent, its viscosity and granulation performance can be different.
G.Viscous materials can be first moisturized and dispersed by ethanol and then added with adhesive, which brings better granulation. This method is taken in granulation of Amoxicillin granules and Azithromycin granules.
H.According to material properties, two kinds of adhesives can be used. For example: for Amoxicillin granules, materials can be wet and dispersed by ethanol first, and added with CMC-Na and syrup for granulation.
3.Granulation mixing time
The mixing time should be controlled. Appropriate mixture can be crumpled but not stick to hand, also can be dispersed when pressed.
The longer mixing time is, the more viscous mixture will be and the harder granulation will be.
But if mixing time is short, mixture will be not enough viscous and granulating performance is not good.
