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The Biopharmaceutics Classification

System (BCS)

BCS as a tool in drug product development


BCS can be used to flag drugs that should not be tested clinically
unless appropriate formulation strategies are employed

Drug dosage forms should be designed to


maximize bioavailability
As an example, a BCS Class II compound,
permeable but relatively insoluble, would
likely not be a good clinical candidate without
the use of enhanced formulation techniques
aimed at increasing solubility or rate of
dissolution

High solubility:
A drug substance is considered highly soluble
when the highest dose strength is soluble in
250 ml or less of aqueous media over the pH
range of 1-7.5. The pH solubility profile of the
drug substance is determined at 37 10C in
aqueous medium with pH in the range of 17.5. A sufficient number of pH conditions
should be evaluated to accurately define the
pH-solubility profile.

High permeability:
A drug substance is considered to be highly
permeable when the extent of absorption in
humans is determined to be 90% or more of
an administered dose based on a mass
balance determination or in comparison to an
intravenous reference dose. (e.g., when the
absolute bioavailability is 90% or more, or
when 90% or more of the administered drug is
recovered in urine).

The methods used for determination of


permeability include:
a. Mass balance studies, Absolute
bioavailability studies and Intestinal
perfusion methods in human
b. In vivo or in situ intestinal perfusion in a
suitable animal model
c. In vitro permeability methods using excised
intestinal tissues
d. Monolayers of suitable epithelial cells e.g.
Caco-2 cells or TC-7 cells

Class I drugs exhibit a high dissolution and absorption. The rate


limiting step is drug dissolution and if dissolution is very rapid
then gastric emptying rate becomes the rate determining step.
Class 2 drugs have a high absorption but a low dissolution
therefore absorption is limited primarily by drug dissolution in the
gastrointestinal tract. In vivo drug dissolution is then a rate
limiting step for absorption except at a very high dose.
Class 3 drugs, have high dissolution, low absorption. In vivo
permeability is rate limiting step for drug absorption. These drugs
exhibit a high variation in the rate and extent of drug absorption..
Class 4 drugs exhibit a lot of problems for effective oral
administration. The route of choice for administering is parenteral
with the formulation containing solubility enhancers.

Factors Influencing Bioavailability


A. Pharmaceutical factors
1. Physicochemical attributes of Drug substances
Drug solubility and dissolution rate
Particle size and effective surface area
Bulk and tapped density, Powder flow characterization
Polymorphism, amorphism and hygroscopicity
Pseudopolymorphism (hydrates/solvates)
Salt form of the drug
Lipophilicity
pKa of the drug and pH
Drug stability (% volatile, LOD, moisture content)

2. Dosage Form Characteristics and Pharmaceutical


Ingredients
Disintegration time (tablets/capsules)
Dissolution time
Manufacturing variables (method of granulation,
compression force, intensity of packing of capsule
contents)
Pharmaceutical ingredient (excipients/adjuvants)
Nature and type of dosage form
Product age and storage condition

B. Barrier functions of the organism:


Age
Gastric emptying time & Intestinal transit time
Gastrointestinal pH
Diseases states
Blood flow through the GIT
Gastrointestinal contents:
Other drugs, Food, Fluids, Other normal GI
contents
Presystemic metabolism by:
Lumenal enzymes, Gut wall enzymes, Bacterial
enzymes, Hepatic enzymes.

A drug with poor bioavailability is the one with


Poor aqueous solubility and/or slow
dissolution rate in the biologic fluids.
Inadequate partition coefficient and thus poor
permeation through the biomembrane
Poor stability of the dissolved drug at the
physiologic pH
Extensive presystemic metabolism

Over 90% of the marketed drugs qualify under Class II and


Class IV low solubility
Over 60% of new chemical entities that are poorly soluble
qualify either as BCS Class II or Class IV and they provide
challenges as well as opportunities to scientists working in
formulation development.
The conventional solubilization approaches such as physical
modifications of drug crystals (surface alteration of API,
micronization or micro-milling) usually lead to a
limited dissolution and solubility enhancement, but when
developing a medium or high dosed formulation, the nonconventional formulation approaches are often required
particularly when dealing with almost water-insoluble
compounds usually characterized by a high melting point
and/or very high lipophilicity.

The solubility in water defined by activity


coefficient and the crystal terms of a drug
molecule and can be represented by
Log Sw = 0.8 log Kow - 0.01 (MP 25)
where,
Sw is the aqueous solubility of drug expressed in
mol/L,
Kow is the octanol/water partition coefficient,
MP is the melting point in oC.

Liquid Dispersions
The lipid-based delivery systems (LBDS) have
been identified as true liquid dispersions for self
(micro) emulsification drug delivery systems
(S(M)EDDS) and applied successfully in
development of poorly soluble lipophilic
molecules with 2 < logP > 4.
SEDDS and SMEDDS provide an easy scale up for
manufacturing of these dosages in oral solutions,
liquid/semi-solid for soft gel, and/or pellets for
hard gel capsules or tablets, and are amenable to
those requiring highest achievable doses

The excipients for LBDS are comprised of a wide


range of molecular structures, compositions and
functionalities.
These include but are not limited to solubilizers/
surfactants with polar and non-polar entities that
are able to form self-assembled aggregates in
aqueous solutions, and are able to maintain the
desired concentrations in gastrointestinal (GI)
fluids.
Most importantly, these surface active excipients
(natural or synthetic) are characterized by their
critical micelle concentration (CMC) and/or
hydrophilic lipophilic balance (HLB) values

The surfactant molecules with higher molecular


weight tend to possess the lower CMC values and
vice versa. In contrast, those with higher
hydrophilicity, possess the higher HLB values.
For instance, KolliphorTM P 188 or Poloxamer
188 (MW 8000) and KolliphorTM P 407 or
Poloxamer 407 (MW 12000), possess
respectively, the CMC values of 1.4 x 10-3 M and
8.0 x 10-4 M.
In addition, these surfactants/solubilizers meet
the sound safety and regulatory standards, and
are compatible with most of the drugs.

The typical components of SEDDS include:


Surfactants (HLB >12) and co-surfactants
(HLB<12)
Examples: Polyoxyl 35 castor oil (Kolliphor EL),
Polyoxyl hydrogenated 40 castor oil (Kolliphor
RH 40), Polyoxyl 15 hydroxystearate (Kolliphor
HS15), Polysorbate 80, vitamin E-TPGS
(Kolliphor TPGS) , Transcutol P, Labrafi l
1944 C, Kolliphor P 188 (Poloxamer 188),
Kolliphor P407 (Poloxamer 407), and Kolliphor
P 124 (Poloxamer 124) among others.

Triglycerides (Oils)
Medium chain triglycerides or MCT (C6-C12):
Glyceryl tricaprylate/caprate: Captex 300;
Miglyol 810; Miglyol 812; NeobeeM-5
Long Chain Triglycerides of LCT (C14-C18)
Corn oil, soybean oil, saffl ower oil, olive oil
Mono- and Di-glycerides
Glyceryl caprylate/caprate (Capmul MCM,
Imwitor 742), Glycerol Monocaprylate
(Imwitor 308, Glycerol monooleate(Capmul
GMO))

Propylene glycol esters


Propylene glycol monocaprylate (Capmul PG8), Propylene glycol monolaurate (Capmul
PG-12, Lauroglycol)
Co-solvents/fatty acids
Propylene glycol, ethanol, polyethylene glycols
(PEG 300, 400, 600), oleic acid, palmitic acid,
stearic acid, linoleic acid, linolenic acid.

Solid Dispersions
Solid dispersion is drug dispersed in a biologically
inert matrix. Drug in soluble hydrophilic carrier
improves the dissolution rate by reducing particle
size, higher porosity, drug is in amorphous state,
improving wettability and hence possibly
bioavailability for poorly water soluble drugs
The solid dispersions are fully exploited for highly
crystalline, high melting lipophilic drugs, wherein,
the drugs are converted to a high energy
amorphous powder to increase the solubility and
bioavailability

Enablers are the excipients that play a crucial


role for a robust formulation. The structurefunction hallmarks of excipients, interaction
with drugs, and their consequences on longterm stability and formulation performance,
are considered for compatibility and
predicting the stability of amorphous
dispersions

The commonly used excipients for solid


dispersions are:
Neutral cellulose derivatives
Hydroxypropyl methylcellulose (Hypromellose):
HPMC
Hydroxypropyl cellulose: HPC
Cellulose acetate butyrate: CAB
Acidic cellulose derivatives
HPMC acetate succinate: HPMC-AS
HPMC phthalate: HPMC-P
Cellulose acetate phthalate: CAP

Neutral (non-cellulosics)
PVP: Polyvinylpyrrolidone (K12, K17, K25, K-30, K90)
Copovidone: Vinylpyrrolidone - vinyl acetate
copolymer
Soluplus: PEG-co-PVAc-co-PVCap
Kollicoat IR: PEG-co-PVA
Polyethylene oxide: PEO (MW > 20K) or PEG (MW
< 20K), PEG/PPG
Ionic (non-cellulosic)
Methacrylic or acrylic copolymers: Kollicoat
MAE 100 P, Eudragit EPO, L100-55, RS, RL.

LADMER system, biopharmaceutics hurdles in drug development,


approaches to overcome them

LADMER

Biopharmaceutic hurdle

Biopharmaceutic class

Drug
Poor Solubility

Class II
Class IV

Liberation
Chemical degradation

Approaches to
overcome the hurdle

Formulation approaches
Chemical modifications
Formulation approaches

All Classes

Chemical modifications

Enzymatic degradation

All Classes

Enzyme inhibitors
Chemical modifications

Poor Permeability

Class III
Class IV

Sorption

Absorption

promoters
Chemical
modifications

First
Distribution
Metabolism
Excretion
Response

pass
metabolism

All Classes

Alternative route
Prodrug approach