pharmaceutical binders

Pharmaceutical binders

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Pharmaceutical binders

Binders are materials that are added to impart cohesiveness to the drug and excipient combination during the formulation of an oral solid dosage form. Cohesiveness not only assists in the formation and flow of granules during the manufacturing process but also helps in maintaining the integrity of tablets upon compression from these granules. The nature of materials used as binders may be sugars such as sorbitol, sucrose, and glucose; or natural polymeric materials such as starch, pregelatinized starch, gelatin, acacia; or semi and synthetic polymers such as povidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose (MC), ethylcellulose (EC), and hydroxypropyl methylcellulose (HPMC) among others.

Several factors influence the choice and amount of a binder used in a formulation including physiochemical compatibility of the binder with the drug and other excipients, processability, cohesiveness, and the impact of the binder on functional properties of a dosage form including friability, disintegration, and dissolution. Among the range of polymers available today, synthetic polymers are preferred over natural sources to minimize lot-to-lot variability and also potential microbial contamination from natural materials.

Types of binders

Natural Polymers

Starch: Starch, a carbohydrate made up of linear amylose and branched amylopectin, had been a popular choice for a binder historically. Being insoluble in cold water, starch is prepared in the form of paste using hot water. Aqueous starch paste is used in the concentration range of 5–10% w/w. However, the use of starch as a binder has been less preferred in recent years.

Use of starch as a binder can lead to softer tablets with higher friability. Moreover, high viscosity of starch paste not only makes the distribution of binder difficult but also leads to uneven distribution in granules in addition to time-consuming process of preparing starch paste itself. Due to these reasons, it has been largely replaced by pregelatinized starch, which can be added as a dry powder as well.

Pregelatinized starch: It is a starch that has been chemically or mechanically modified to partially or completely rupture all of the starch granules. In contrast to starch, fully pregelatinized starch is soluble in cold water. Pregelatinized starch is used in the concentration range of 5–10% w/w for wet granulation purposes and up to 20 wt% as a binder for direct compression. In addition to being used as a paste, partial pregelatinization of starch also results in a freely flowable powder form, which can be used as a directly compressible material.

Synthetic Polymers

Povidone: Polyvinylpyrrolidone (PVP), a polymer of 1-vinyl pyrrolidone, is one of the most widely used binders. PVP is available in a range of average molecular weights, which gives them different viscosities in solution. Though different molecular weights are available, low to medium viscosity grades are used more often than high viscosity grades because of the potential for dissolution slowdown with high viscosity grades and also due to difficulty in handling high-viscosity solutions. As a binder, it is used in the concentration range of 0.5–5% w/w in a formulation.

A binder solution of PVP may be made using either water or a hydroalcoholic solution. If the PVP concentration in water is high (e.g., 50% w/w in water), the binder solution is heated to 50–60 ∘C and heated jacketed vessel and tubing systems are used to ensure delivery of the viscous binder solution. PVP may also be added as a dry powder, with water added during granulation to activate the binder.

However, higher amounts of dry powder PVP may be necessary to achieve the same level of binder functionality compared to PVP solution. One of the major drawbacks with the use of PVP is its hygroscopicity. Under high humidity storage conditions, PVP-containing formulations can take up water and eventually have an impact on tablet hardness, disintegration, and dissolution. In addition, solubilization effect of PVP can negatively impact the stability of dosage forms as reported for hydrolytic degradation of hydrochlorothiazide (HCTZ) tablets.

Methylcellulose (MC): MC is substituted cellulose where 27–32% of the hydroxyl groups are substituted by methyl ether. It is available in a variety of molecular weights resulting in solutions of different viscosities. As a binder, low and medium viscosity grades are used in the concentration range of 1–5% w/w. They may be used in the form of dry powder or as a binder solution.

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MC is practically insoluble in hot water and forms viscous colloidal dispersion in cold water. Therefore, to prepare a solution, MC is first mixed with a portion of water at 70–80 ∘C. To get a clear solution, cold water is added to the slurry to bring the temperature below 20 ∘C. One of the advantages of using MC is that it does not cause hardening of tablets on storage.

Hydroxypropyl cellulose (HPC): HPC is hydroxypropylated substituted ether of cellulose, which is used as a binder typically in the concentration range of 2–6% w/w. HPC is used in wet and dry granulation and in direct compression. Particle size of HPC can influence whether the binder is added in wet or dry form. For example, in the case of acetaminophen wet granulated tablets, fine particle grade of HPC (Klucel-EXF) added in the dry mix produced similar hardness versus compaction force profile compared to Klucel-EF distributed as solution. Aqueous solutions of HPC can undergo acid hydrolysis at low pH or base-catalyzed oxidation at high pH with best stability in the range of pH 6–8. Improved binding properties are observed with higher hydroxypropyl group substitution.

Ethylcellulose (EC): EC is an ethyl ether of cellulose. Similar to other polymeric materials, it is available in different viscosity grades. Low viscosity grades are used as binder while EC has other applications as a hydrophobic coating material and modified release polymer among others. As a tablet binder, it is used in the dry form or distributed from a solvent in the concentration range of 2–15% w/w. Due to its very low solubility in water, alcoholic solutions are used to disperse EC. Due to its low chemical reactivity in water, it is useful to formulate EC as an excipient for moisture-sensitive drugs. However, its hydrophobic nature can cause delayed penetration of water into the tablets with a potential to slow down dissolution. This slow dissolution could be an issue for an immediate release tablet but desirable for a sustained release formulation.

Hydroxypropyl methylcellulose (HPMC): HPMC or hypromellose is cellulose hydroxypropyl methyl ether. It is available in different grades that differ in viscosity and substitution. As a binder, it is used in the concentration range of 2–5% w/w in wet or dry granulation. Water or hydroalcoholic solvents are used to distribute or activate the binder. The binder efficacy is similar to MC. At higher concentrations, HPMC is routinely used as a drug release controlling polymer for modified release dosage forms.

Polyethylene glycol (PEG): The application of polyethylene glycol (PEG) as a binder is limited compared to its use for preparation of solid dispersions, hot melt granulation, and also as plasticizer in other oral solid dosage forms. They are available in different molecular weight grades with the lower-molecular-weight grades being liquids and higher molecular weights being semisolids and solids.

Sugars

Sugars such as glucose, sucrose, and sorbitol may be used as binders. Sucrose syrup is used at the concentration range of 50–67% w/w for wet granulation purposes. Sucrose at 2–20% w/w is used for dry granulation. Water or hydroalcoholic solvent is used as the granulating solvent. They are also used in combination with other binders such as starch. Liquid glucose at the concentration range of 5–10% w/w is used during wet granulation.

In general, sugar binders produce hard and brittle tablets especially at higher concentrations of the binder. Over time, there can be increase in hardness leading to slower disintegration. Reducing sugars have a tendency to react with amines. Due to its pleasant taste, these binders are used in chewable tablets and for bitter-tasting drugs.

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