the biopharmaceutics classification system (bcs)

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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 techniquesaimed at increasing solubility or rate of

dissolution

High solubility:

• A drug substance is considered highly solublewhen 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 thedrug substance is determined at 37 ± 10°C in

aqueous medium with pH in the range of 1-

7.5. 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 highlypermeable 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 isrecovered in urine).

The methods used for determination ofpermeability include:

a. Mass balance studies, Absolutebioavailability studies and Intestinalperfusion methods in human

b. In vivo or in situ intestinal perfusion in asuitable animal model

c. In vitro permeability methods using excisedintestinal 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 dissolutiontherefore 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 vivopermeability 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 parenteralwith 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 GIcontents

• Presystemic metabolism by:Lumenal enzymes, Gut wall enzymes, Bacterialenzymes, Hepatic enzymes.

A drug with poor bioavailability is the one with

Poor aqueous solubility and/or slowdissolution 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 andClass IV low solubility

• Over 60% of new chemical entities that are poorly solublequalify either as BCS Class II or Class IV and they providechallenges as well as opportunities to scientists working informulation development.

• The conventional solubilization approaches such as physicalmodifications of drug crystals (surface alteration of API,micronization or micro-milling) usually lead to alimited dissolution and solubility enhancement, but whendeveloping a medium or high dosed formulation, the non-conventional formulation approaches are often required

particularly when dealing with almost water-insolublecompounds usually characterized by a high melting pointand/or very high lipophilicity.

• The solubility in water defined by activity

coefficient and the crystal terms of a drugmolecule and can be represented by

Log Sw = 0.8 – log Kow - 0.01 (MP – 25)

• where,

– Sw is the aqueous solubility of drug expressed inmol/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 indevelopment of poorly soluble lipophilic

molecules with 2 < logP > 4.

• SEDDS and SMEDDS provide an easy scale up formanufacturing of these dosages in oral solutions,liquid/semi-solid for soft gel, and/or pellets forhard gel capsules or tablets, and are amenable tothose requiring highest achievable doses

• The excipients for LBDS are comprised of a widerange of molecular structures, compositions and

functionalities.• These include but are not limited to solubilizers/

surfactants with polar and non-polar entities thatare able to form self-assembled aggregates in

aqueous solutions, and are able to maintain thedesired concentrations in gastrointestinal (GI)fluids.

• Most importantly, these surface active excipients

(natural or synthetic) are characterized by theircritical micelle concentration (CMC) and/orhydrophilic lipophilic balance (HLB) values

• The surfactant molecules with higher molecularweight tend to possess the lower CMC values and

vice versa. In contrast, those with higherhydrophilicity, possess the higher HLB values.

• For instance, KolliphorTM P 188 or Poloxamer188 (MW 8000) and KolliphorTM P 407 orPoloxamer 407 (MW 12000), possessrespectively, the CMC values of 1.4 x 10-3 M and8.0 x 10-4 M.

In addition, these surfactants/solubilizers meetthe sound safety and regulatory standards, andare 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; Neobee®M-5

• Long Chain Triglycerides of LCT (C14-C18)

Corn oil, soybean oil, saffl ower oil, olive oilMono- 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®

PG-8), 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 biologicallyinert matrix. Drug in soluble hydrophilic carrierimproves the dissolution rate by reducing particlesize, higher porosity, drug is in amorphous state,

improving wettability and hence possiblybioavailability for poorly water soluble drugs

• The solid dispersions are fully exploited for highlycrystalline, high melting lipophilic drugs, wherein,

the drugs are converted to a high energyamorphous powder to increase the solubility andbioavailability

• Enablers are the excipients that play a crucial

role for a robust formulation. The structure-function hallmarks of excipients, interaction

with drugs, and their consequences on long-

term stability and formulation performance,are considered for compatibility and

predicting the stability of amorphous

dispersions

The commonly used excipients for soliddispersions are:

• Neutral cellulose derivativesHydroxypropyl methylcellulose (Hypromellose):HPMC

Hydroxypropyl cellulose: HPCCellulose acetate butyrate: CAB

• Acidic cellulose derivativesHPMC acetate succinate: HPMC-AS

HPMC phthalate: HPMC-P

• Cellulose acetate phthalate: CAP

• Neutral (non-cellulosics)PVP: Polyvinylpyrrolidone (K12, K17, K25, K-30, K-

90)Copovidone: Vinylpyrrolidone - vinyl acetatecopolymerSoluplus®: 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 Approaches to

overcome the hurdle

Poor Solubility

Liberation

Chemical degradation

Class II

Class IV

Formulation approaches

Chemical modifications

All Classes

Formulation approaches

Enzymatic degradation

Poor Permeability

All Classes Enzyme inhibitors

Class III

Class IV

Sorption

promoters

metabolism

All Classes Alternative route

Prodrug approach

Absorption

Distribution

Metabolism

Excretion

the biopharmaceutics classification system (bcs)

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