Antioxidants Use n Pharmaceutical Suspension

Antioxidants are included in pharmaceutical solutions or suspensions to enhance the stability of therapeutic agents that are susceptible to chemical degradation by oxidation. Typically antioxidants are molecules that are redox systems that exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition.

Typically in aqueous solution antioxidants are oxidised (and hence degraded) in preference to the therapeutic agent, thereby protecting the drug from decomposition. Both water-soluble and
water-insoluble antioxidants are commercially available, the choice of these being performed according to the nature of the formulation.

Pre Formulation for Suspensions : Introduction and Requirement

Suspension is a preparation containing the solid ingredients in the form of subtle and not soluble, dispersed in a liquid carrier. The main aim in the preparation of suspension is to keep the suspended particles dispersed and for this number of components which belongs to the vehicle itself.

Structured Vehicle

For the need of a stable suspension, the term Structured vehicle is most important for formulation view and stability criteria. The main disadvantage of suspension dosage form that limits its use in the routine practice is its stability during storage for a long time. The structured vehicle is the vehicle in which viscosity of the preparation under the static condition of very low shear on storage approaches infinity. The vehicle behaves like a ‘false body’, which is able to maintain the particles suspended which is more or less stable.

Structured vehicle concept is applicable only to deflocculated suspensions, where hard solid cake forms due to settling of solid particles and they must be redispersed easily and uniformly at the time of administration. Flocculated suspension settled floccules get easily redispersed on shaking that is why structured vehicle concept is not applicable.

Sweeteners in Pharmaceutical Suspensions

Sweetening agents are employed in liquid formulations designed for oral administration specifically to increase the palatability of the therapeutic agent. The main sweetening agents employed in oral preparations are sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium and aspartame. The use of artificial sweetening agents in formulations is increasing and, in many formulations, saccharin sodium is used either as the sole sweetening agent or in combination with sugars or sorbitol to reduce the sugar concentration in the formulation. The use of sugars in oral formulations for children and patients with diabetes mellitus is to be avoided.

Following is the list of sweetening agents.

Bulk sweeteners Artificial sweetening agents
Sugars : xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose Sodium cyclamate
Hydrogenated glucose syrup Na saccharin
Sugar alcohols : sorbitol, xylitol, mannitol, glycerin Aspartame
Partially hydrolysed star Ammonium glycyrrhizinate
Corn syrup solids Mixture of thereof


Pharmaceutical Excipients For Tablet Formulation

Pharmaceutical excipient means any component other than the pharmacologically active drug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form.

While selecting excipients for any formulation following things should be considered wherever possible: keep the excipients to a minimum in number minimize the quantity of each excipients and multifunctional excipients may be given preference over unifunctional excipients.

Fewer ingredients in the formulation are better for the following reasons:
  • Excipients are not completely inert. Even commonly used excipients that are deemed to be pharmaceutically inactive and nontoxic may cause adverse reactions;
  • Less ingredient variability to influence process and product consistency;
  • Better economic efficiency in product manufacturing;
  • Less probability of chemical or physical interaction between API and excipients and among excipients.
Excipients play a crucial role in design of the delivery system, determining its quality and performance. Excipients though usually regarded as nontoxic there are examples of known excipient induced toxicities which include renal failure and death from diethylene glycol, osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from lanolin and cardiotoxicity induced by propylene glycol.

Factors Affecting Granulation Process

Wet granulation is the process by which powders are converted to granules with the desired properties to ensure good tablet production.

Important consideration are :
  1. Type and quantity of Binder
  2. Compatibility
  3. Characteristics of drugs and other excipients
  4. Spreading of Binder
  5. Temperature and Viscosity
  6. Method of Addition of Binder
  7. Mixing Time
  8. Material of Construction of Granulator
  9. Type of Granulator
  10. Process Variables
  11. Apparatus Variables
  12. Impeller Movement

Type and quantity of Binder 
Criteria Performance Impact
High cold water dispersibility and solubility Fast solution preparation when binder is added to solution
Low viscosity solutions Ease of handling and pumping of solution
High binding efficiency Lower use levels. Tablets have higher breaking force and/or require lower compaction force
High water solubility No impact on drug dissolution at high use levels



The uniformity of the particle size, hardness, disintegration and compressibility of the granulation depends on type and quantity of binder added to formulation.

As for example hard granulations results due to stronger binder or a highly concentrated binder solution which require excessive compression force during tableting. On the other hand, fragile granulations results due to insufficient quantity of binder which segregates easily. Larger quantities of granulating liquid produce a narrower particle size range and coarser and hard granules i.e. The proportion of fine granulates particle decreases. Therefore the optimum quantity of liquid needed to get a given particle size should be known in order to keep a batch to batch variations to a minimum.

Binders ( Adhesives and Granulating agent) Used in Tablet

Binder is one of an important excipient to be added in tablet formulation. In simpler words, binders or adhesives are the substances that promotes cohesiveness. It is utilized for converting powder into granules through a process known as Granulation. Granulation is the unit operation by which small powdery particles are agglomerated into larger entities called granules.

Types of Binders 

Classification of Binders

SugarasNatural BindersSynthetic/Semisybthetic Polymer
Sucrose Acacia Methyl Cellulose
Liquid glucose Tragacanth Ethyl Cellulose

Gelatin Hydroxy Propyl Methyl Cellulose ( HPMC)

Starch Paste Hydroxy Propyl Cellulose

Pregelatinized Starch Sodium Carboxy Methyl Cellulose

Alginic Acid Polyvinyl Pyrrolidone (PVP)

Cellulose Polyethylene Glycol (PEG)


Polyvinyl Alcohols


Polymethacrylates

Types and List of Tablet Disintegrants

Starch (Amylum)
The mechanism of action of starch is wicking and restoration of deformed starch particles on contact with aqueous fluid and in doing so release of certain amount of stress which is responsible for disruption of hydrogen bonding formed during compression.

The conditions best suited for rapid tablet disintegration are sufficient number of starch agglomerates, low compressive pressure and the presence of water. The concentration of starch used is also very crucial part. If it is below the optimum concentration then there are insufficient channels for capillary action and if it is above optimum concentration then it will be difficult to compress the tablet.

Pregelatinized starch (Starch 1500)
Pregelatinized starch is produced by the hydrolyzing and rupturing of the starch grain. It is a directly compressible disintegrants and its optimum concentration is 5-10%. The main mechanism of action of Pregelatinized starch is through swelling.

Modified starch - Sodium starch glycolate (primogel, explotab)
To have a high swelling properties and faster disintegration, starch is modified by carboxy methylation followed by cross linking. Mechanism of action of this modified starches are rapid and extensive swelling with minimum gelling. Optimum concentration is 4-6 %. If it goes beyond its limit, then it produces viscous and gelatinous mass which increases the disintegration time by resisting the breakup of tablet. They are highly efficient at low concentration because of their greater swelling capacity.

Cellulose and its derivatives
Sodium carboxy methylcellulose (NaCMC and carmellose sodium) has highly hydrophilic
structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original volume when it comes in contact with water.

Microcrystalline cellulose (MCC)
MCC is insoluble and act by wicking action. The moisture breaks the hydrogen bonding between adjacent bundles of MCC. It also serves as an excellent binder and has a tendency to develop static charges in the presence of excessive moisture content. Therefore, sometimes it causes separation in granulation. This can be partially overcome by drying the cellulose to remove the moisture.

Alginates (alginic acid and Na-alginate)
Alginates are hydrophilic colloidal substances which has high sorption capacity. Alginic acid is insoluble in water, slightly acidic in reaction.It should be used in only acidic or neutral granulation. Alginates do not retard flow and can be successfully used with ascorbic acid, multivitamin formulations and acid salts of organic bases.

Ion-exchange resin
Ion exchange resin (Ambrelite IPR-88) has highest water uptake capacity than other disintegrating. It has tendency to adsorb certain drugs.

Miscellaneous
This miscellaneous category includes disintegrants like surfactants, gas producing disintegrants and hydrous aluminium silicate. Gas producing disintegrating agents is used in soluble tablet, dispersible tablet and effervescent tablet.

Polyplasdone XL and Polyplasdone XL10 act by wicking, swelling and possibly some deformation recovery. Polyplasdone®XL do not reduce tablet hardness, provide rapid disintegration and improved dissolution. Polyplasdone® as disintegrating agent has small particle size distribution that impart a smooth mouth feel to dissolve quickly.


List of Disintegrants

DISINTEGRANTS CONCENTRATION
IN GRANULES
(%W/W)
SPECIAL COMMENTS
Starch 5-20 Higher amount is required, poorly compressible
Starch 15005-15-
Avicel®(PH 101, PH 102)10-20 Lubricant properties and directly compressible
Solka floc® 5-15 Purified wood cellulose
Alginic acid1-5 Acts by swelling
Na alginate2.5-10Acts by swelling
Explotab®2-8 Sodium Starch Glycolate, superdisintegrant.
Polyplasdone®(XL)0.5-5 Crosslinked PVP
Amberlite® (IPR 88)0.5-5 Ion exchange resin
Methyl cellulose, Na CMC,
HPMC
5-10

-
AC-Di-Sol®1-3
2-4
Direct compression
 Wet granulation
Carbon dioxide- Created insitu in effervescent tablet

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