BCS Classification

“Biopharmaceutics Classification of Drugs (BCS Classification) is a drug development tool, that is based on correlation of solubility and permeability with the bioavailability of drugs”.

This classification system was proposed by Amidon. BCS classification is a scientific approach for classification of drug substances and Active Pharmaceutical Ingredients (API’s), based on their aqueous solubility and intestinal permeability.

This classification is an important consideration for development of new dosage forms.

Any drug’s therapeutic effectiveness is based on its bioavailability. Further, bioavailability is based on drugs absorption and drugs permeability through biological membrane. Thus this classification has considered as important tool for development of optimized drug dosage form formulations.

Two major determinations are considered in BCS classification system.

Solubility

The solubility of a drug substance is the amount of that drug, that has passed or reached into solution until equilibrium is established and no further drug molecules reach to solution under any specific temperature and pH.

According to USFDA BCS guidelines: a drug substance is considered highly soluble when the highest dose of it is completely soluble in 250 ml. or less quantity of aqueous media over the pH range of 1-7.5.

the amount of water (250 ml.) is considered because this is approximate volume of water consumed with orally administered dosage form.

Whereas according to World Health Organization (WHO) the same parameters are considered over pH range of 1.2-7.5.

Permeability

The permeability is a parameter of drug absorption. Permeability is the measurement of the rate of mass transfer across biological membrane.

According to USFDA, a drug substance is considered highly permeable when the extant of drug absorption is determined to be 85% or more of an administered dose, based on mass balance or in comparison to reference intravenous dose.

Some Dimensionless Numbers Used in BCS

Absorption Number (A_n):

Absorption Number indicates how easily a drug can pass through the intestinal membrane and get absorbed into the blood stream.

It is a measure of drug permeability.

can be defined as ratio of mean residence time to the mean absorption time.

• If Aₙ is high, the drug has high permeability.
• If Aₙ is low, the drug has low permeability.
          A_n = Mean Residence time Mean Absorption Time
It can also be written as:

          A_n = P_eff × A R

Where:
P eff = Effective intestinal permeability of the drug
A = Surface area of the intestine available for absorption
Q = Volumetric flow rate of intestinal contents

Dissolution Number

It is mainly used in BCS classification to define that how fast a drug dissolves in gastrointestinal (GI) fluid before it reaches the absorption site.

It is a measure of drug solubility and dissolution rate.
A higher Dₙ means: Drug dissolves quickly.
A lower Dₙ means: Dissolution is slow
          D_n = Mean Residence time Mean DIssolution Time
It can also be written as:

          A_n = P_eff × A R

Dose Number (D_o):

Dose Number tells whether the entire highest dose of a drug can dissolve in 250 mL of water (the standard GI fluid volume).

It is a measure of drug solubility.
          D₀ = Highest single dose of the drug (M_o) Uptake Volume (250 ml.) X Drug Solubility (C_s)
• D_o ≤ 1 → High Solubility (Entire dose dissolves in 250 mL)

• D_o > 1 → Low Solubility (Dose does NOT fully dissolve in GI fluid)

  BCS Classification Table

  Class	Solubility	Permeability	Rate Limiting factor
  Class I	High	High	Drug dissolution, but if dissolution is very fast then gastric emptying time
  Class II	Low	High	Dissolution (because until the drug dissolves, absorption cannot become high)
  Class III	High	Low	Permeability (although solubility is high, but until the drug is absorbed, it cannot become bioavailable)
  Class IV	Low	Low	Case dependent, drug modifications, site conditions

  Some examples of drugs of various classes

  Class I	Class II	Class III	Class IV
  Chloroquine Diltiazem Metoprolol Paracetamol Theophylline Propranolol Verapamil	Carbamazepine Glibenclamide Ketoconazol Nifedipine Phenytoin Danazol	Acyclovir Atenolol Captopril Cimetidine Metformin Ranitidine Neomycin B	Coenzyme Q Furosemide Retonavir Taxol Cyclosporine A Ellagic acid

  Significance or Applications of BCS classification in Development of Drug delivery systems

  BCS system is based on drug solubility and permeability, and the basis of dosage form development is also the same to achieve optimized release profile, controlled release and sustain release.
  • Class I drugs are best suited for controlled release formulation because they have high solubility and high absorption rate.
  • Class II drugs are required for some dosage modifications through drug size reduction (Micronization), use of surfactants, development of microemulsion technique etc.
  • Class III drugs dosage forms are developed through high frequency capsules, by manipulating gastric retention time, permeability enhancers etc, because they have low permeability.
  • Class IV drugs are modified through all above-mentioned techniques because they are less soluble and less permeable.

  BCS Bio-waivers

  BCS classification is effective tool to reduce the time and cost of approval of drug products from FDA and WHO etc.

  Certain products are exempted or waived (are called Bio-waivers) from various in-vivo bioavailability and bioequivalence studies. For Bio-waivers substance in-vivo bioavailability and / or bioequivalence studies may be waived (not considered necessary for product approval).
  Instead of conducting expensive and time consuming in-vivo studies, the test products are considered same with reference product, if the test product show similar in-vitro dissolution and solubility profile.
  BSC based bio-waivers are suitable for development of immediate release solid dosage form. There are various fixed criteria for a drug to considered as bio-waiver.