The biopharmaceutics classification system

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The Biopharmaceutics Classification System (BCS) is a guidelines for classifying drugs based on their aqueous solubility and intestinal permeability.

There are four categories which are as follows;

  • Solubility HIGH, Permeability HIGH = Class I
  • Solubility LOW, Permeability HIGH = Class II
  • Solubility HIGH, Permeability LOW = Class III
  • Solubility LOW, Permeability LOW = Class IV

The solubility classification of a drug in the BCS is based on the highest dose strength in an immediate release product. A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media over the pH range of 1.0-7.5; otherwise, the drug substance is considered to be poorly soluble. The volume estimate of 250 mL is derived from typical bioequivalence study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water.

The permeability classification is based directly on the extent of intestinal absorption of a drug substance in humans or indirectly on the measurements of the rate of mass transfer

across the human intestinal membrane. Adrug substance is considered highly permeable when the extentof intestinal absorption is determined to be 90% orhigher. Otherwise, the drug substance is considered to bepoorly permeable.

DMU04A

This drug has a solubility of 7.8 mg / 100mL, therefore in 250 mL it has a solubility of 19.8 mg (250 X 7.8 /100 ). This shows that the highest dose which is 20 mg is NOT soluble in 250 mL, hence DMU04A is considered to have LOW solubility. With regards to permeability,

since it has a bioavailability of more than 90 %, then it is considered to have HIGH permeability.

To summarise DMU04A has low solubility and high permeability, thus according to BCS it belongs to class II.

DMU05B

This drug has a solubility of 2.2 mg / 100mL, therefore in 250 mL it has a solubility of 5.5 mg (250 X 2.2 /100 ). This shows that the highest dose which is 5 mg is soluble in 250 mL, hence DMU05B is considered to have HIGH solubility. With regards to permeability, since it has a bioavailability of 90 %, then it is considered to have HIGH permeability.

To summarise DMU05B has high solubility and high permeability, thus according to BCS it belongs to class I.

DMU06C

This drug has a solubility of 4.5 mg / 100mL, therefore in 250 mL it has a solubility of 11.25 mg (250 X 4.5 /100 ). This shows that the highest dose which is 10 mg is soluble in 250 mL, hence DMU06C is considered to have HIGH solubility. With regards to permeability, since it has a bioavailability of less than 90 %, then it is considered to have LOW permeability.

To summarise DMU06C has low solubility and high permeability, thus according to BCS it belongs to class III.

Solubility

Permeability

BCS Class

DMU04A

LOW

HIGH

II

DMU05B

HIGH

HIGH

I

DMU06C

HIGH

LOW

III

DMU04A has low solubility and belongs to BCS class II drugs, conventional dosage forms of these drugs usually lack consistency and show variable performance in preclinical and clinical evaluation leading to below optimum therapeutic concentration. Due to low solubility of these drugs the rate at which the drug dissolves in the gastrointestinal fluids may be the rate determining step governing the appearance of drug in the systemic circulation.

There are two kinds of modifications that can be done to improve the solubility, one is physical modification and the other one is chemical modification.

The physical modifications that can be made are particle size reduction, crystal form, complexation, drug dispersion in carriers, and the chemical modifications that can be made are salt formation and soluble prodrugs.

Size reduction can be achieved by jet milling, high energy ball milling, super critical fluid extraction, high supersaturation crystallisation, and spray drying. [3]

The reduction in particle size would increase the surface area of the drug

Noyes-Whitney states dm/dt = KA (Cs - C)/h, where

dm/dt = rate of dissolution

A = the surface area of the solid.

C = the concentration of the solid in the bulk dissolution medium.

Cs = the concentration of the solid in the diffusion layer surrounding the solid.

K = the diffusion coefficient.

h = the diffusion layer thickness.

It can be seen clearly that rate of dissolution is directly proportional to the surface area, in other words if the surface area is increased , the dissolution rate is increased.

Should the drug exist in more than one crystal form ( i.e. showing polymorphism) then the highly energetic form (the metastable polymorph) will be more soluble than the stable crystal form of the drug. This solubility is due to the fact that in the metastable form the packing arrangement of the molecules are not very cohesive. Therefore the solubility of the drug can be improved by choosing the metastable form of the drug.

Solubilisation of the drug in surfactant micelles also leads to increased solubility of the drug.

When micelles form in water, their tails form a core that can encapsulate the poorly soluble drug, and their (ionic/polar) heads form an outer shell that maintains favorable contact with water.

Cyclodextrins complexation can also be used to improve the physico-chemical properties of various drug molecules. Cyclodextrins are able to form both inclusion and non-inclusion complexes.

Cyclodextrins and their complexes form water soluble aggregates in aqueous solutions. These aggregates are able to solubilize lipophillic water-insoluble drugs through non-inclusion complexation or micelle-like structures. However, use of CDs in pharmaceutical dosage forms is limited by their relatively high cost and due to problems of formulation, all principally related to the large amount necessary to obtain the desired drug-solubilizing effects. Some cyclodextrins s are reported to have significant renal toxicity.

Another method to increase solubility is salt formation. It is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs.

In general salts of acidic and basic drugs have higher solubilities than their corresponding acid or base forms. For solid dosage forms, it has been demonstrated as early as in 1950s that dissolution rates of salt forms of several weakly acidic compounds under gastrointestinal pH conditions were much higher than those of their respective free acid forms. The higher dissolution rate of a salt was attributed to its higher solubility (relative to the free acid form) in the aqueous diffusion layer surrounding the solid. The interest in salt formation has grown greatly over the past half a century and, in recent years, it has become the most commonly applied technique of increasing solubility and dissolution rate in drug product development.

DMU05A has high solubility as well as high permeability and belongs to BCS class I drugs, therefore no special strategies are needed for its formulation.

DMU06A has low permeability and belongs to BCS class III drugs.

One method of modification that would improve the permeability of this drug would be the use of permeability enhancers.

One permeability enhancer is chitosan.

In recent years chitosan has attracted much attention as a potential absorption enhancer across mucosal epithelia, especially for peptide drugs. Chitosan is regarded as a biocompatible, biodegradable, natural origin polymer. Chitosan is known to improve peptide transport across the epithelial barrier, however, this polymer is only soluble in an acidic environment. N-Trimethyl chitosan chloride, a derivative of chitosan, is soluble in the entire pH range and has proven to be a potent absorption enhancer of peptide drugs by opening the tight junctions between epithelial cells, thereby facilitating the paracellular transport of hydrophilic compounds

Another method to improve permeability is the addition of bioadhesive polymers.

The addition of bioadhesive polymer has shown to increase permeability / bioavailability.

This enhancement of absorption can be attributed to the fact that the polymer can attach to the mucin covering of stomach together with the drug particles for extended period of time.

The increased permeability / absorption may also be due to the intimacy of the dissolved drug with the absorbing membrane.