Overall, the tablet is a substance composed of two types, one is to play the role of drug therapy (ie primary drug), the other is not a number of physiologically active substances, and their role include: filling action, adhesion, lubrication and disintegration, sometimes, also play a role in coloring, flavoring and aesthetic effect of the role, in pharmaceutics, these materials are typically referred to as excipients (or excipients & Adjuvants). According to them the role of different, often the materials into four categories.
(A) a diluent (Diluents)
The main role of the diluent (or filler, Fil1ers) is used to fill the volume or weight of the tablet, thereby facilitating tabletting; commonly used fillers are starch, sugars, celluloses, and inorganic salts; determined by the tabletting process, preparation equipment and other factors, the tablet diameter generally not be less than 6mm, weighing more than 100mg or more, if the tablet is the main drug only a few milligrams or tens of milligrams, without the addition of a suitable filler , will not be made into tablets, therefore, diluents here played more important, to help increase the volume of its shaping role.
More commonly used corn starch, it is very stable, and most drugs do not work, the price is relatively cheap, moisture absorption, good appearance and color, in the actual production, often with better compressibility of powdered sugar, dextrin mixed use, because the starch compressibility is poor, if used alone, it will press out the tablet is too loose.
2, powdered sugar
Powdered sugar means crystalline sugar after low-temperature drying and crushing of a white powder, the advantage of strong adhesion, can be used to increase the hardness of the tablet, and the tablet surface is smooth and beautiful, the drawback is that hygroscopic long-term storage, make the tablet hardness is too large, difficult to disintegration or dissolution, except for buccal tablets or soluble tablets, it is generally not used alone, often with dextrin, starch used in conjunction.
Dextrin starch hydrolyzate is a generic term of intermediate products, and its chemical formula (C6H10O5) n • XH2O, which was about 80% soluble in cold water to dissolve slowly, easily soluble in water, soluble in ethanol. Traditionally known as a high paste (high viscosity dextrin), which has strong adhesion, improper use will make one-sided pitting, watermarks or cause slow tablet disintegration or dissolution; Similarly, the content of If the determination is not sufficiently pulverized extraction will affect the measurement accuracy and reproducibility of the results, so rarely used alone as a filler dextrin heavy use, often associated with powdered sugar, starch used in conjunction.
Lactose is an excellent tablet fillers from bovine whey is extracted in the system, is widely used in foreign countries, but more expensive, not much use in the country. Common crystalline lactose containing a molecule of water (ie α- lactose hydrous), non-hygroscopic, compressible good, stable, and most drugs can not afford chemical reaction, pressed into pills bright and clean; the spray-drying method were lactose amorphous lactose, flowability, good compressibility, powder for direct compression to use.
5, compressible starch
Also known as pre-gelatinized starch (Pregelatinized starch), is a new pharmaceutical excipients, Britain, the United States, Japan and China have switched Pharmacopoeia reproduces, the successful development of our country in 1988, a lot has been supplied to the market. Domestic compressible starch is partially pregelatinized products (whole pre-gelatinized starch, also known as α- starch), with foreign Colorcon’s Starch RX1500 fairly. This product is a multi-functional materials, can be used as a filler, has good flowability, compressibility, self-lubricating and dry adhesion and a better disintegration. If used for direct tableting powder, magnesium stearate amount should not exceed 0.5%, in order to avoid softening effect.
6, microcrystalline cellulose
Microcrystalline cellulose (Microcrystalline cellulose, MCC) is obtained by partial hydrolysis of cellulose and the degree of polymerization of smaller crystalline cellulose, has good pressure, there is a strong binding force, a more compressed into tablets great hardness, as a powder directly compressible “dry adhesive” use. Foreign products under the trade name Avicel, and according to the size of about a number of different specifications. Domestic microcrystalline cellulose has been widely used in China, but the quality needs to be improved, the product range also need to be rich. Further, when the tablets containing microcrystalline cellulose disintegrant is preferably 20%.
7, inorganic salts
Mainly because some inorganic calcium salts such as calcium sulfate, calcium carbonate, calcium hydrogen phosphate and pharmaceutically acceptable (by the legal settlement was also called precipitated calcium carbonate) and the like. Wherein the calcium sulfate is more commonly used, the nature of its stable, odorless and tasteless, water-soluble, and can be compatible with a variety of drugs, tablets made of smooth appearance, hardness, disintegration are good, no adsorption of the drug. Use of calcium sulfate dihydrate in the tablet excipients often. It should be noted calcium sulphate on some major drugs (tetracyclines) absorption interference, this time should not be used.
Mannitol in granular or powder form, dissolved in the mouth absorbs heat, so there is a sense of cool, while both a certain sweetness in the mouth no gravel sense, it is more suitable for the preparation of a chewable tablet, but the price is a little expensive, often associated with sucrose With the use of.
(B) an adhesive (Adhesives)
Certain drugs powder itself has a sticky, just add the appropriate liquid can be inherent viscosity inducing out, then the added liquid called wetting agent (moistening agents); certain drugs powder itself is not sticky or tacky small, need to add starch and other viscous material, in order to bond them together, then added a viscous substance called a binder. Because they play a major role in virtually all of the drug powder together, so the above may be referred to as wetting agents and adhesive binders.
1, distilled water
Distilled water is a humectant. When applied, since the material tends to absorb water faster. Therefore more prone to the phenomenon of uneven wetting, preferably starch or ethanol instead of low concentration to overcome these shortcomings.
Ethanol is a humectant. Can be used for water decomposition of the drug can also be used with water too viscous drugs. With increasing concentration of ethanol, after wet sticky generated reduced, so that the alcohol concentration depends on the nature of raw materials, generally 30% -70%. Chinese medicine extract tablets commonly used ethanol as a wetting agent, it should be noted operation quickly to avoid ethanol evaporation caused by strong sticky clumps.
3, starch paste
Starch is the most commonly used tablet binders, commonly 8% to 15% concentration, and 10% starch slurry is most commonly used; if less compressible material, can be an appropriate increase in starch concentration to 20% Instead, it may be appropriate to reduce the concentration of starch slurry, i.e. such as aluminum sheets with 5% starch as a binder. There are boiled pulp and red pulp of two ways starch slurry system of law, are able to use a starch pasting properties. The so-called gelatinization (Gelatinization) refers to the phenomenon of the formation of starch heated evenly paste (fully gelatinized maize starch temperature is 77 ℃). Gelatinized, starch viscosity increases sharply, which can be used as a tablet binder. Specifically, the pulp is washed starch was suspended in a small amount (1 to 1.5 times) of water, depending on the concentration and amount of the requirements into the boiling water, stirring continuously pasting together; mashing starch is suspended in the full amount of water and heated in a sandwich container and stirring constantly (should not use direct fire heating, to avoid coking) until pasting. Because starch readily available and inexpensive, and good adhesion, so that those using the starch slurry can be granulated and meet the case of tableting requirements, the choice of the majority of this starch adhesive.
4, sodium carboxymethyl cellulose
Sodium carboxymethyl cellulose (carboxymethylcellulose sodium, CMC-Na) is a cellulose carboxymethyl ether compounds, insoluble in ethanol, chloroform and other organic solvents coal; when dissolved in water, the initial particle surface puffing, and then soaked in water slowly to the inside of a transparent solution, but it requires long time, preferably heated to 60 ℃ ~ 70 ℃ after the initial puffing and swelling, can greatly speed up the dissolution process. Concentration used as the binder is generally 1% -2%, its strong adhesive, commonly used in poorly compressible drug, but should pay attention to whether the tablet hardness is too large or cause disintegration overrun.
5, hydroxypropyl cellulose
Hydroxypropyl cellulose (hydroxypropylcellulose, HPC) is hydroxypropyl cellulose ether, containing hydroxypropyl 53.4% ~ 77.5% (which is just hydroxypropyl content of 7% to 19% of the low-substituted called low-substituted hydroxypropyl cellulose, namely L-HPC, see disintegrating agent), its characters as a white powder, soluble in cold water, heated to 50 ℃ gelling or swelling phenomenon; soluble in methanol, ethanol, isopropanol and propylene glycol in. This product can be wet granulation binders can also be used as a powder for direct compression binder.
6, methyl cellulose, ethyl cellulose, and
Methyl cellulose and ethyl cellulose (Methylcellulose, MC; Ethylcellulose, EC) are methyl or ethyl cellulose ether compound, a methoxyl group or 26.0% – 33.0% – 51.0% 44.0% ethoxy. Among them, methyl cellulose has a good solubility in water, forming a viscous colloidal solution as a binder, it should be noted: When the sugar or electrolyte up to a certain concentration of this product will be precipitated. Ethyl cellulose is insoluble in water, ethanol and other organic solvents in the greater solubility, and stickiness of different intensities depending on the concentration of ethanol which can be used as a water-sensitive adhesive drug, it should be noted that the present viscous product stronger and does not dissolve in the gastrointestinal fluids, release tablet will disintegrate and produce drugs blocking effect. Currently, ethylcellulose is often the use of this feature, which will be used for slow, controlled release preparation (controlled release film or matrix type).
Hydroxypropyl methyl cellulose (Hydroxypropylmethyl cellulose, HPMC) is one of the most popular film-coated material, because of its soluble in cold water to become a viscous solution, hence its usual 2% to 5% was used as a binder. Preparing an aqueous solution of HPMC, the best first HPMC was added to the total volume of hot water 1/5 ~ l / 3 of (80 ℃ ~ 90 ℃), the fully dispersed and hydrated, and then under cooling, stirring constantly, add cold water to a total volume. This product is not soluble in alcohol, ether and chloroform, but soluble in ethanol or a mixture of 10% to 80% methanol and methylene chloride.
8, other binders
5% to 20% gelatin solution, 50% ~ 70% sucrose solution, 3% to 5% of polyvinyl pyrrolidone (PVP) aqueous or alcoholic solution, to be used in poorly compressible drug, it should be noted: these very sticky adhesive, tablets made of hard, slightly in excess will cause disintegration of the tablet overrun.
(C) disintegrant (Disintegrants)
The tablet is disintegrating agent in gastrointestinal fluids quickly crack broken into small particles of matter, in addition to the tablet slow (controlled) release tablets as well as some special purpose, the general tablet disintegrating agents should be added. Because of their strong swelling property can be disintegrated binding tablets, the tablet from a whole sheet crack broken into many small particles to achieve disintegration of the tablet, it is very beneficial to the tablet the main drug dissolution and absorption.
1, dry starch
Dry starch is one of the most classic disintegrating agents, moisture content below 8%, highly absorbent and have a certain degree of expansion, is more suitable for water-insoluble or sparingly soluble drug tablets, but soluble drugs collapse lipolysis poor, because the dissolution of water soluble drug concentration difference, the tablet through the outside water can not readily penetrate into the level of the solution inside the tablet, the tablet interior hindered swelling starch. In production, the general use of external, internal addition or “internal and external addition” to achieve the desired effect of disintegration. The so-called plus method, the starch is placed at 100 ℃ ~ 105 ℃ dried lh, was added to the dry granules before tableting, so that disintegration of tablets will occur between the particles; within adder is during granulation adding a certain amount of starch, therefore, disintegration of tablets inside the particles will occur. Obviously, part of the increase in the starch and then applied a portion of the starch “internal and external addition”, can occur in both the disintegration of tablets inside the particles took place between the particles, so as to achieve a good disintegrating effect, usually plus disintegrating dosage 25% – 50% of the total amount of disintegrating agent, the disintegrating dosage add 75% – 50% of the total amount of disintegrating agent (total weight of the tablet disintegrant is generally 5% to 20%).
2, sodium carboxymethyl starch
Sodium carboxymethyl starch (Carboxymethyl starch sodium, CMS-Na) is a white amorphous powder, water swelling effect is very significant, after absorbing water can be expanded to 300 times its original volume (sometimes a slight adhesive effect), is one kind of excellent performance disintegrants and prices are low, generally in an amount of 1% to 6% (foreign products under the trade name “Primojel”).
3, low-substituted hydroxypropylcellulose
Low-substituted hydroxypropyl cellulose (L-HPC) applications in recent years, this is the more of a disintegrating agent. Because of a large surface area and porosity, so it has good water absorption rate and water absorption, water absorption expansion rate of 500% – 700% (substituent representing 10% to 15%), after the disintegration of the particles also finer, and therefore it is beneficial to dissolution of the drug. Usually an amount of 2% to 5%.
4, cross-linked polyethylene pyrrolidone
Crosslinked polyvinyl pyrrolidone (Cross-linked polyvinyl pyrrolidone, also known as cross-linked PVP) is white, good fluidity powder; not dissolved in water, an organic solvent and acid and alkali solution, but rapidly swelling in water but does not appear high viscosity gel layer, so its performance is excellent disintegration, Britain and other countries has been collected contained pharmacopoeia, domestic products have been developed.
5, cross-linked sodium carboxymethyl cellulose
Cross-linked sodium carboxymethylcellulose (Croscarmellose sodium, CCNa is cross-linked carboxymethyl cellulose ether (about 70% of a sodium salt type carboxyl), due to the presence of crosslinks, it is insoluble in water, but It can absorb several times its own weight in water and swell, and therefore have a better disintegration; when combined with sodium carboxymethyl starch, disintegrating better, but when combined with the disintegration of dry starch will be reduced.
(D) a lubricant (Lubricants)
In pharmaceutics, the lubricant is a broad concept, glidants, anti-adherents and (narrow) lubricants in general, where: ① glidant (Glidants) is to reduce the friction between the particles so as to improve the flow of powder of substance; ② anti-adherents (Antiadherent) is to prevent the raw materials adhered to the surface of the punch material; ③ (narrow) lubricant is to reduce friction between the tablet and the die hole wall substance, which is a real sense of lubrication agent. Therefore, an ideal lubricant should both above glidants, anti-sticking and lubrication three roles, but in the lubricants currently available, there is no such ideal lubricant, they are often in one or two a aspect has good performance, but other effects are relatively poor. Classification of materials according to custom, the general will have any effect described above are collectively referred to as lubricant.
l, magnesium stearate
Magnesium stearate is a hydrophobic lubricant, easy and particle blending, tableting after one-sided glossy appearance, the most widely used. The amount is generally 0.1% to 1%, while excessive use, due to their hydrophobicity, can cause disintegration of the tablet (or dissolution) slow. In addition, the product should not be used acetic acid, certain antibiotics and tablets most organic alkali salts of the drug.
2, silica powder
Silica powder (Aerosil) is an excellent tablet glidant can be used as a powder for direct compression glidant. Its properties are as light anhydrous white powder, odorless and tasteless, large surface area, the usual dose is 0.1 to 0.3%, but because of higher prices, in domestic applications still not broad enough.
Mainly as a glidant talc use, it can be recessed at the surface of particles fill up flat to reduce the roughness of the surface of the particles, the former to reduce the friction between the particles, to improve the flow of particles to the object (it should be noted: Because tabletting process, mechanical shock, causing it to separate from the particles), the usual dose is generally 0.1% to 3%, at most not more than 5%.
4, hydrogenated vegetable oil
This product was spray-drying method is a good lubrication performance lubricant. The application, which was dissolved in hexane or light liquid paraffin, and then the solution was sprayed on the dry granules, in order to facilitate uniform distribution (terms of hexane solvent, after spray method using hexane was removed under reduced pressure) .
5, polyethylene glycols and the moon hung over magnesium alcohol
Both are all typical of the water-soluble lubricant. The former is mainly used polyethylene glycol 4000 and 6000 (Jieke dissolved in water), the resulting tablet disintegration and dissolution is not affected to give a clear solution; the latter is the new water-based lubricant currently under development.
In addition to these four materials, the tablet also add some coloring agents, flavoring agents and other excipients to improve taste and appearance, but no matter what kind of added materials should meet the medicinal requirements are not react with the primary drug, shall not prevent the main drug dissolution and absorption. Currently known lactose can reduce pentobarbital, spironolactone absorption of starch can delay the absorption of sodium salicylate, calcium can affect the absorption of tetracycline drugs. It should therefore be based on the physicochemical and biological properties of the main drug, combined with the specific production process, through the in vivo experiments, choose the appropriate accessories.